JPH0247700B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an apparatus for continuously and automatically monitoring the concentration of specific components in blood.

More specifically, when blood is continuously sampled from a patient using an intravascular indwelling catheter and the concentration of a specific component is automatically measured over a long period of time, the flow rate fluctuation of the tube pump that forms the measurement flow path is The present invention relates to providing a measurement device that is immune to effects and detector drift.

In the following, explanation will be given particularly regarding glucose in blood, that is, blood sugar, but it goes without saying that the explanation is not limited to blood sugar.

In recent years, blood glucose levels have been measured by continuously collecting small amounts of blood over long periods of time, for measuring blood glucose fluctuation patterns in various stress tests, for bedside monitoring of patients with severe diabetes, and for monitoring blood glucose levels during and after surgery for diabetic patients. Development of a device to continuously measure .

In this type of device, a double-tube catheter having an anticoagulant injection port is placed in a blood vessel, and blood collected from a living body while being diluted with an anticoagulant is sent to a sensor by an appropriate pump means. When calibrating the sensor, the double-tube catheter is removed from the cannula, calibrated using a solution of known concentration, and then connected to the cannula again to continue measurement. However, this method not only requires complicated operation, but also has the disadvantage that blood tends to coagulate in the cannula during sensor calibration.

In order to avoid such drawbacks, Japanese Patent Laid-Open No. 52-
In 135795, a flow path switching device is installed in the flow path (using a tube pump) leading to the sensor.
However, it is said that pumps other than tube pumps can be used in the device of this invention, but in the case of a syringe pump other than a tube pump, for example, it is difficult to precisely align the phases of each minute flow due to large pulsations. Since the dead volume is large, it is not suitable for continuously delivering a small amount of liquid at a stable flow rate. Therefore, when handling such a small amount of liquid, a tube pump is usually used. Aside from that, the flow path switching device has a continuously flowing sample source and a reference liquid source used during calibration connected in series, and normally the sample is flowed to the sensor section for continuous measurement. On the other hand, when calibrating the sensor, the flow path from the reference liquid is opened, the reference liquid is allowed to flow through the sensor, and the flow of the sample is diverted and flows to the drain section without passing through the sensor section. In this way, even during sensor calibration, there is no need to remove the catheter, and the sample remains in a flowing state, thereby avoiding the disadvantage of easy coagulation.

In addition, the reference liquid is used to calibrate the sensor so that it shows the correct concentration value when the dilution rate of the sample is constant, but in reality, due to the subtle deformation of the flow path (tube pump), the dilution rate is If the deviation is more or less than the value, it tends to cause errors in measurement, so this prior art adopts the following method. That is, in order to detect the actual dilution rate of the sample inhaled from the cannula with buffer solution, etc.
Collect a liquid that can be considered to be the same or equivalent to the sample,
Create a calibration sample by diluting it at a certain dilution rate,
The actual dilution rate can be determined by reading the measured value by flowing the sample directly from the flow path (tube pump) during calibration to the sensor and comparing it with the measured value when the sample was flowed from the cannula.

However, this prior art (Japanese Patent Application Laid-Open No. 52-135795)
However, it also has the following drawbacks that need to be resolved.
This is due to the fact that the sample source and the reference liquid source are comprised of separate channels.

In other words, when one tube pump is actually used continuously for a long time, the degree of change in flow conditions such as flow rate is large enough that it cannot be ignored.
It is not uncommon for the flow rate to change by more than 10% when used continuously for hours. The causes of this change in flow state are changes in the tube itself over time (due to tube pump roller pressure), and contamination due to adhesion of blood cells, proteins, and other impurities in the liquid to the inner wall of the tube. it is conceivable that. In the former case, the changes over time of each tube are different due to differences in tube wall thickness, material, and even subtle differences in the structure of the tube pump, so if separate flow path systems are used, It can be said that it is impossible to equalize the degree of change on both sides. Regarding the latter factor, when separate flow path systems are used, the quality of flowing liquid is different between each flow path system, that is, the sample source and the reference liquid source, so differences are more likely to occur.

Therefore, due to the difference in the way the flow conditions change between the sample source flow path and the reference liquid source flow path during continuous measurements, the dilution ratio of the sample and buffer solution will gradually change during measurement. , the calibrated conditions established by measuring the actual dilution rate at the beginning of the measurement gradually become disturbed. However, changes in the flow conditions over time in the sample source flow path and the reference liquid source flow path are completely independent and cannot compensate for each other. In addition, only the sensitivity of the sensor can be calibrated at any time using the reference liquid, and the difference due to fluctuations in the flow paths between the sample source and the reference liquid source, for example, the mixing ratio of the sample liquid and the buffer solution, that is, the dilution rate, has changed. However, it is not compensated for and the measured value in that case will contain an error.

Furthermore, a dilution rate compensation method using a calibration sample that is considered to be the same or equivalent to the sample described above is effective if the glucose concentration in the sample can be assumed not to fluctuate during the time being calibrated. In reality, the glucose concentration usually shows economical changes during measurement, and it may change in any way, so it is necessary to prepare a calibration sample equivalent to the sample being measured. It is difficult to use in practice. Furthermore, even if a calibration sample is prepared and used during measurement as described above, the preparation itself is a time-consuming operation, and the fluctuations in the glucose concentration of the sample during the time required for calibration will result in measurement errors. It becomes apparent.

That is, since there is a concern that the flow rate of the tube pump may change over time for each tube, it is necessary to compensate for this change sequentially for measurement accuracy, but the calibration sample in the prior art described above It is not suitable for being created and used sequentially during measurements, and sequential compensation is not possible.

The present invention has been made to eliminate the drawbacks of the prior art including these prior art, and by sharing a flow path (tube pump) with the sample liquid and other calibration liquid, and by sequentially calibrating the device. The present invention provides a device that accurately monitors blood sugar levels continuously over a long period of time.

Hereinafter, the present invention will be explained in detail based on the drawings. FIG. 1 is a block diagram showing an example of the configuration of an automatic continuous measuring device for blood components according to the present invention. 4, a measurement section 5, an operation section 6, a measurement/control circuit section 7, etc.

First, the blood collection section 1 includes a disposable double tube catheter 11, an anticoagulant 12, a tube pump P ₁ for feeding anticoagulant, a tube pump P ₂ for blood sampling, a tube 13 for feeding anticoagulant, and blood sampling. It is composed of a tube 14. Blood from a subject (not shown) is continuously collected at the distal end of the catheter 11 while being diluted with an anticoagulant 12 and subjected to anticoagulation treatment, and is sent to a sample liquid cup 15. still,
The anticoagulant 12 is heparin or the like dissolved in physiological saline. When the amount of liquid in the sample liquid cup 15 exceeds a certain level, the excess amount overflows and is drained, so that a certain amount of fresh sample liquid 16 is always retained. Also tube pump
P ₁ and P ₂ are driven coaxially. As mentioned above, the tubes 13 and 14 and the tube pumps P ₁ and P ₂
It is very difficult to perfectly match the characteristics of anticoagulants, and in order to determine the exact ratio between the amount of anticoagulant pumped by pumps _P1 and _P2 and the amount of blood drawn, as well as the dilution rate, we need to use standards with known concentrations. standard 2 liquids 1 liquid
7 is used. How to determine the dilution rate will be described later. Furthermore, in order to obtain a dilution rate of a constant value that is not dependent on the shapes of both tubes 13 and 14 in the blood sampling section, the concentration of the anticoagulant 12 is increased and the amount is decreased to bring the dilution rate close to 1. You can expect it to some extent. Furthermore, in this embodiment, tubes 13, 14
Although a disposable double-tube catheter is used in order to have the same characteristics, it goes without saying that a single-tube catheter may also be used. Coating with an anticoagulant or fibrinolytic enzyme (mainly urokinase) can also solve the problem of dilution at the blood collection site.

The calibration liquid feeding unit 2 supplies standard liquid 21 and base liquid 22, which are standard liquids necessary for sequential calibration, to standard liquid cups 23 using tube pumps P ₃ and P ₄ , respectively.
and the base liquid cup 24 is continuously fed. The standard liquid cup 23 and the base 24, like the sample liquid cup 15, are always filled with fresh constant amounts of each liquid, and excess liquid overflows and is drained as described below. In this embodiment, a buffer solution 41, which will be described later, is used as the base solution 22, so the solution is delivered from the buffer solution reservoir 42, but it is also possible to provide another base solution reservoir and send the solution from there. Of course, it is good to do so. The standard 1 liquid 21 is fed from the standard 1 liquid reservoir 21. Further, in the figure, 25 is a tube for feeding the standard liquid, and 26 is a tube for feeding the base liquid.

The sampling mechanism 3 includes a sampling nozzle 3
1 is a tube pump P ₁₁ which pumps sample liquid cup 15, standard liquid cup 23 and base liquid cup 2 in the order predetermined by measurement/control circuit 7.
It is designed to suck the liquid from 4 and send it to the manifold M ₂ of the measuring section 5 through the knob tube 32. Its detailed operation will be described later. In addition, another cleaning tank may be provided, in which case the nozzle 3
1 are also set to be immersed in a cleaning tank in a predetermined order.

In the buffer solution feeding section 4, the buffer solution 41 is passed through a heat exchanger 43 in advance to constant temperature, and then transferred to the manifold _M1.
One part is sent to the base liquid cup 24 as the base liquid 22, and the other part is continuously sent to the manifold _M2 for mixing with the sample liquid (or standard 1 liquid, base liquid). . In the figure, P ₅ is a tube pump that sends the buffer solution 41 to the heat exchanger 43 through the tube 44, and P ₆ is a tube pump that sends air to the manifold M ₂ through the tube ₄₅ .
P ₆ is driven coaxially with the tube pumps P ₃ and P ₄ of the calibration liquid feeding section 2 described above and the drain tube pump P ₇ described later.

Next, the measuring section 5 is equipped with a manifold _M2 as described above.
A constant temperature buffer solution 41 is sent through the manifold M ₁ of the buffer solution delivery section 4 . Air is also sent into the manifold _M2 to divide the flow of the buffer solution 41, and the sample solution 16 (or standard 1 solution,
The base liquid) is injected and flows as the measurement liquid. The purpose of the air segment is to prevent the measurement liquid from spreading and provide a mixing effect, and can also be expected to have a cleaning effect on the tube wall. The measuring liquid is mixed in the mixing coil 51.
After being inverted and mixed by passing through, for example, it is sent to an immobilized enzyme membrane electrode 52 for measuring glucose concentration, which is a combination of a GOD immobilized membrane and a hydrogen peroxide electrode, and the glucose concentration is measured. In this case, an air layer and a measurement liquid layer flow alternately through the electrode 52 without defoaming, and measurement can be continued while the air segment cleanses the entire measurement system including the electrode 52. Mutual contamination of each measurement liquid is minimized. The liquid and air bubbles that have been measured are discharged via the drain cup 53 to the drain bolt 54 by the drain tube pump _P7 . The drain cup 53 also contains the liquids that have overflowed the cups 15, 23, and 24 described above from the sample liquid overflow tube 1.
8. Same tube pump P ₈ , standard 1 liquid overflow tube 27, same tube pump
P ₉ , base liquid overflow tube 28,
The liquid is sent by the same tube pump R ₁₀ and drained to the drain bolt 54 as well. The tube pumps P ₈ , P ₉ , P ₁₀ and the sampling tube pump P ₁₁ are coaxially driven.

The operation unit 6 controls all operations of the device,
The device is operated using an operation switch 61 and a keyboard 62.

Finally, the measurement/control circuit section 7 includes an IV converter 7
1. Consists of an A-D converter 72, a microcomputer 73, and a display 74, which processes the output signal from the glucose electrode 52 and sequentially displays the blood glucose level after sequential calibration on the display 74. The operation of the robot is controlled.

Next, the present invention will be explained according to the operating procedure.

First, after preparing each calibration solution, etc.,
Turn on the power switch SW, operate all tube pumps P ₁ to _{P 11} , and enter the date, number, etc. into the microcomputer 73 using the keyboard 62. When the predetermined warm-up is completed, the standard switch 612 of the operation switch 61 lights up, the pump switch 611 goes out, and each pump stops. Next, when the CALB switch 613 is pressed, each pump starts operating again, and the sampling mechanism 3 also starts operating. Insert the catheter 11 into the standard 2 liquid 17, measure the delay time required from inhaling the liquid 17 until it flows into the sample liquid cup 15 using a stopwatch, etc., and input this time from the keyboard 62 for later measurements. use Once measured, the lag time can be assumed to be essentially constant unless the catheter specifications change (unless the type and tube length change).
When replacing the catheter thereafter, only that value needs to be input. Subsequently, standard 2 liquid 17 of known concentration was measured instead of the sample liquid,
Determining the dilution rate of the blood and anticoagulant 12 in the blood collection section 1 and storing it in the microcomputer 73,
Used for subsequent measurements. The measurement of the dilution rate in blood collection 1 can also be omitted by using a single-tube catheter whose inner wall is coated with an anticoagulant.

When the catheter 11 is set in the patient, the blood is diluted at the above-mentioned dilution rate, anticoagulated, and continuously fed into the sample liquid cup 15. When the amount of sample liquid 16 in cup 15 exceeds a certain level, the excess liquid overflows and is discharged to drain bolt 54, so that a certain amount of fresh sample liquid 16 is always retained in cup 15. It's summery. Therefore, although the nozzle 31, the sample liquid 16, the standard 1 liquid 31, and the base liquid 22 are repeatedly sucked in sequence, mutual contamination is avoided.

Next, when the check switch 614 is pressed, the patient's blood sugar level is continuously measured.

First, the sampling nozzle 31 sucks a certain amount of standard 1 liquid 21 from the standard liquid cup 23 in a predetermined manner. For example, as shown in Figure 2, inhale for 20 seconds with the air divided into two parts. Next, the nozzle 31 moves to the base liquid cup 24 and sucks in the base liquid 22 for 40 seconds in a predetermined state, for example, in a state in which the air is divided into eight air segments as shown in FIG. Next, the nozzle 31 enters the sample liquid cup 15 and performs standard 1 liquid 2 in a predetermined manner, for example, as shown in FIG.
As in case 1, the sample liquid 16 is inhaled for 20 seconds while being divided into two by the air segment. Furthermore, nozzle 3
1 enters the base liquid cup 24 and sucks it into the base liquid 22 for 40 seconds using the same action as described above. Thereafter, the knob 31 enters the standard solution cup 23 again and repeats the above operating circle. In Figure 2, AIR is the air segment, and STD, BASE, and SAM are the standard 1 liquid 21 and base liquid 2, which are separated by the above air segment.
2. The bubbles of the sample liquid 16 are shown, and air segments of an appropriate size can be created at arbitrary intervals and in any number by moving the nozzle 31 in and out of each liquid.

This movement of the nozzle 31 is performed by a sampling mechanism 3 as shown in FIGS. 3a and 3b, for example.
First, the nozzle 31 is fitted and fixed into a vertical through hole 331 of the nozzle arm tip 33a, and a nozzle tube 32 connected to the sampling tube pump _P11 is fitted into the upper part of the nozzle 31. On the other hand, the nozzle arm 33 is supported by a support shaft 333 fitted laterally into a long hole 332 provided on the side of the rear end 33b, and a disk 335 that supports a pin 334 protruding from the side of the tip of the nozzle arm. Ru. This pin 334 is loosely fitted into a through hole 336 at the peripheral edge of a disc 335 (the left end in the figure), and as the disc 335 is rotated by a certain angle, for example, 180 degrees, by a motor 337, the pin 334 is connected to the pin 334. The nozzle arm tip 33a is moved back and forth in an arc as shown in FIG. 3a. That is, due to the rotation of this disk 335, the nozzle 31 and the nozzle arm 33 reciprocate between the solid line position and the broken line position, and the nozzle 31 is applied to the base liquid cup 24 when it is in the solid line position, and to the standard liquid cup 24 when it is in the broken line position. They are inserted into the liquid cup 23 and the sample liquid cup 15, respectively.
The standard liquid cup 23 and measuring device cup 15 are placed on a slide base 34, and the slide base 34 is moved back and forth by an eccentric cam 341 and a spring 342 rotated by a motor 343 or by a rack and pinion (not shown). , both cups 2
3 and 15 are sequentially brought to the suction position. The movements of these arms 33 and slide base 34 are controlled by a microcomputer 73. In addition to the above-described method, the nozzle arm 33 may be driven by electrical or mechanical means such as a combination of a photomicro sensor and a stepping motor, which rotates the disk 335.

Next, in this example, as can be seen from FIG. 2, one measurement cycle requires two minutes. That is, although the present invention does not measure the sample liquid continuously in a strict sense, the blood sugar level in the sample liquid changes fairly smoothly as shown in FIG. There is no sudden change in the time interval of 2 minutes, and measurement at 2 minute intervals is sufficient to carry out measurements equivalent to continuous measurement. Furthermore, the present invention is not characterized by the fact that the measurement cycle is at 2-minute intervals; it goes without saying that this cycle may be shorter or longer.

For example, the flows of standard 1 liquid 21, base liquid 22 _, and sample liquid 16 shown in FIG. Here, each solution is similarly diluted with a constant-temperature buffer solution 41, decomposed by an air layer, and mixed into a measurement solution for the standard solution, a measurement solution for the base solution, and a measurement solution for the sample solution. It is sent to the coil 51. Each measurement liquid mixed and homogenized by the mixing coil 51 sequentially flows into the glucose electrode 52 while being divided by an air layer, and each measurement liquid is measured.

The signal from the electrode 52 then reaches a microcomputer 73 via an IV converter 71 and an AD converter 72. These signals represent the measured value of the standard 1 liquid 21, that is, the standard value, the measured value of the base liquid 22, that is, the base value, and the value of the sample liquid 16, that is, the test value, respectively. These three measured values are obtained in all measurement channels after the nozzle 31.
Each liquid 21, 22, 16 passes through the same flow path,
It should be noted that the values were similarly diluted and measured. That is, as mentioned above, in a flow path using a tube pump, it is common for the flow state to change over time, but in this case, three liquids, two
Since the flow paths 1, 31, and 16 are exactly the same, changes in the flow conditions of the flow paths (ie, nozzle tube 32) can cancel each other out and compensate for their effects. As mentioned above, if the flow paths for the sample liquid and the calibration liquid are separated, changes in flow conditions cannot be compensated for.

Here, a method for calculating the blood sugar level using the output signal from the electrode 52 will be explained using FIG.

The horizontal axis is time, and the vertical axis is the output from the electrode 52 (more specifically, the moving average count number of the output). In Figure 5, S1 is the maximum value when measuring the standard 1 solution, SB is the maximum value when measuring the sample solution, and B is the minimum value when measuring the base solution immediately after the standard 1 solution. ing. The dilution rate D in the blood collection section ₁ mentioned above is explained based on _FIG . The maximum values, C ₁ and C ₂ , are the concentrations of standard solution 1 and solution 2, respectively, and are both known.

The sample liquid blood sugar level B/G is expressed using the value of S1 and the value of B just before this, and the net test value
SB-B is determined based on the percentage of the previous net standard value S1-B. That is, B.G=1/D×SB−B/S1−B× _C1 .

The values of S1 and B used in the measurement may be calculated using another method, for example, using the B value immediately before the test value and the S1 value immediately after the test value in FIG.
However, when using a tube pump, it is normal for the flow condition to change over time, so
It is necessary to calibrate the span of measurement, i.e. S1-B,
The S1 value and B value used are the signals to be measured.
It is clear that it is advantageous to use a location close to the SB.

In the present invention, since the calibration is performed sequentially as described above, it is less affected by changes in the flow state of the channel, and the sequential calibration is also performed using two types of standard liquid and base liquid. This method is extremely effective because it uses the same calibration solution and the calibration solution and sample solution flow in exactly the same flow path.

In this way, the blood glucose level of the sample liquid measured sequentially, for example every two minutes, is displayed on the display 74 in the form of a bar graph as shown in FIG. 6, for example (START mode).
Here, the vertical axis is time, and the horizontal axis is blood sugar charge (BLOOD
GLUCOSE (mg/d1)).

Note that the operation switch 61 is also provided with a start switch 615, and is suitable for use in various load tests. For example, in the case of OGTT (oral glucose tolerance test) measurement, if the start switch 615 is turned on at the beginning of glucose tolerance, the time will start from this time.
Measurement proceeds in the same manner as with the check switch 614, and measured values are obtained over time.
In addition, if you specify the measurement result display in OGTT mode using the keyboard 62, the blood sugar level 30 minutes after glucose loading, the blood sugar level 60 minutes later, the blood sugar level 90 minutes later, 120
Of course, the blood sugar level per minute, which is the blood sugar level per actual time,
The blood sugar level every 2 minutes, the total blood sugar amount for 2 hours, the highest concentration value within 22 hours and its appearance time are displayed after 2 hours of measurement. Figure 4 is an example (before the separate examination from Figure 6). In addition, Figure 7 is a representation of the graph in Figure 4 with the time axis shortened, and although the peaks are easier to see than in Figure 4, it is possible to replace the graph in Figure 7 with the graph in Figure 4. , or can be displayed in parallel.

The liquid and bubbles that have been measured by the electrodes are drained to the drain bolt 54 via the drain cup 53. Each cup 15, 2 is attached to the drain bolt 54.
As described above, the liquids that overflowed through 3 and 24 are also drained.

When the series of measurements is completed, the stop switch 61
Pressing 6 stops the operation of the device.

As described above, the automatic continuous blood glucose measuring device that embodies the present invention repeatedly samples the sample solution, standard solution, and base solution in sequence while the sample solution is continuously flowing, and samples them in exactly the same flow path. Since the blood glucose level and its fluctuation pattern are measured while sequentially calibrating by flowing the fluid, it is possible to automatically, continuously, and accurately measure blood glucose levels and their fluctuation patterns without being affected by the changes in flow conditions that are characteristic of tube pumps. This makes it possible. Furthermore, each liquid is separated by an air layer and flows, so there is no cross-contamination, and since an immobilized enzyme membrane electrode is used, no defoaming device is required, simplifying the equipment, making it easy and reliable to measure and set the dilution rate of the sample liquid. It is extremely effective in the field of continuous blood glucose measurement, as it allows easy measurement in various modes. Furthermore, it goes without saying that the present invention is not limited to the above embodiments, and can be applied to various other applications such as measurement of blood components other than blood sugar.

[Brief explanation of drawings]

Fig. 1 is a block diagram showing an example of the device according to the present invention, Fig. 2 is a schematic diagram of the liquid feeding state in the sampling mechanism, and Fig. 3 is a schematic diagram of the sampling mechanism, with a side view and b a plan view. , Figure 4 is
Graph chart showing the results of OGTT mode measurements,
Fig. 7 is a graph chart showing a modification of Fig. 4;
FIG. 5 is a graph showing temporal changes in electrode output, and FIG. 6 is a graph showing blood sugar level measurement results in START mode showing another measurement example. DESCRIPTION OF SYMBOLS 1...Blood collection part, 2...Calibration liquid feeding part, 3...Sampling mechanism, 4...Buffer liquid feeding part, 5...Measurement part, 6...Operation part, 7...Measurement/control circuit, 11...Catheter,
15...Sample solution cup, 16...Sample solution, 21...Standard 1 liquid, 22...Base solution, 23...Standard solution cup, 24...Base solution cup, 31...Sampling nozzle, 32...Nozzle tube, 41...Buffer solution, 52 ...electrode, 61...operation switch, 62...keyboard, 73...microcomputer, P ₁
~P ₁₁ ...tube pump.

Claims (1)

[Claims] 1. In a device that automatically and continuously measures specific components in blood that is continuously collected from a subject using a catheter, overflow is used to introduce a sample solution and a standard solution and base solution as calibration solutions, respectively. a cup, a nozzle that repeatedly suctions each liquid from the overflow cup in sequence, and a manifold configured to mix each liquid with a buffer solution in the same proportion through the same flow path and segment the mixed liquid with air. , into which the liquid sent from the manifold is introduced, and has an immobilized enzyme membrane electrode that continuously and automatically measures the concentration of a specific component in the blood, and a display that displays the measurement results. Automatic continuous measurement device for components.