JPH0478295B2 - - Google Patents

Description

Detailed Description of the Invention [Industrial Application Field] The present invention intermittently draws blood into a flow cell connected to a catheter placed in a blood vessel, and uses a chemical component sensor installed in the flow cell. The present invention relates to a device that stably measures the concentration or partial pressure of a specific chemical component in blood over a long period of time without discarding the blood.

[Conventional technology] Gas components such as oxygen and carbon dioxide in blood, hydrogen,
Continuous or intermittent measurement of important chemical components in the blood, such as ions such as sodium, potassium, calcium, and chloride, and compounds such as glucose, urea, uric acid, and creatinine, is useful in determining the patient's pathological condition. monitoring, anesthesia management during surgery,
It is also becoming an important medical technology indispensable for purposes such as observing therapeutic effects. Methods for continuously measuring chemical components in blood can be broadly divided into: (i) placing the chemical component sensor itself inside the blood vessel;
There is an in vivo method, and (ii) an ex vivo method in which a chemical component sensor is installed outside the body and blood is guided there.

Among these methods, the in vivo method is useful for measuring the concentration of chemical components at a specific site, but since it is placed in the blood vessel, it is limited in size, making it difficult to use multiple Although it is prone to drift due to protein adsorption, it has not yet been widely used in the clinical field for several reasons, including the difficulty of calibrating it after it has been placed in the body. . On the other hand, in the ex vivo method, the sensor is installed outside the body, so there are fewer restrictions on size and easier multiplication, and automatic calibration and periodic cleaning of the sensor are possible, so it can be used for a longer period of time. Due to the fact that stable measurements are possible, great developments are expected in the future.

This ex vivo type blood component measuring device is further divided into a blood disposal type and a blood return type. Blood disposal method is a method of discarding blood after measurement.
This method has the advantage that the sensor and calibration fluid do not need to be sterilized, and the disadvantage that valuable blood is discarded. The blood return method is a method in which the blood is returned to the blood vessel after measurement, and the sensor is sterilized, and the calibration solution is also sent into the blood at the same time as the blood, so it is harmless to living organisms. However, the biggest advantage is that the patient's precious blood does not have to be thrown away.

An example of a blood chemical component measuring device using the blood waste method is the one published by JSClark et al. in 1971.
PH, PCO ₂ , PO ₂ monitor (JSClark et al.;
Computers and Biomedical Research 4262
(1971)) and potassium, sodium, calcium, and hydrogen ion monitors published by A.Sibbald et al. in 1985 (A.Sibbald et al.;
Medical and Biological Engineering &
Computing 23329 (1985)). In these monitors, a multi-sensor that measures chemical components is installed in a thermostatic cell outside the body that is connected to a catheter placed in a blood vessel via a tube, and the blood flows through the tube into the thermostatic cell. and discarded after measurement. The biggest drawback of this type of device is, of course, the waste of blood. Except for patients undergoing surgery while receiving blood transfusions, it is generally unacceptable to discard more than a few tens of ml of blood per day from ordinary seriously ill patients just for the purpose of measuring blood components. I can say it.

An example of an ex vivo blood component measuring device using a blood return method is the so-called infusion method blood component measuring device (Japanese Patent Publication No. 17448/1983) submitted by the present applicant. This device attaches a blood component sensor to a catheter placed in a blood vessel as an infusion line that sends infusion fluid for sensor calibration to the sensor, and aspirates blood to the sensor part at any time during the infusion. After measuring the chemical components,
This method returns blood into the blood vessel along with the transfusion fluid. Since then, various improvements have been made to this infusion type blood component measuring device, which is still in use today (Japanese Patent Application Laid-open Nos. 155240-1982 and 116382-1982).

[Problems to be Solved by the Invention] While conducting repeated experiments with the aim of putting the above-mentioned infusion-type blood component measuring device into practical use, the present inventors discovered that, like the above-mentioned infusion-type blood measuring device, blood was intermittently aspirated. Even in the case of a method that performs measurements using a chemical sensor, the chemical component sensor is still exposed to proteins, blood cells,
Adsorption of fibrinogen, etc. occurs, and the response of the sensor becomes slow. In order to prevent blood components from adhering to such sensors, an attempt was made to add a small amount of heparin to the infusion so as not to affect the human body (Japanese Patent Application No. 78881/1982). The heparin addition method described above had excellent effects in short-term measurements, but because the amount of heparin added is limited, if the amount added is small enough to not have a negative effect on the human body, blood components may be affected during long-term continuous use. It was found that highly accurate measurement was difficult due to the influence of adhesion of
In addition, the response slowdown due to the adhesion of blood components to the sensor surface can be avoided by changing the measurement cycle from 10 minutes to 5 minutes, for example.
It becomes even more noticeable when shortened to minutes. However, clinically, shortening the measurement period is extremely important for prompt medical treatment.

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a blood component measuring device that can prevent the response of the sensor from slowing down even if the measurement cycle is shortened.

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have made extensive studies and found that in an infusion type blood component measuring device, the surface of the detection part of the chemical sensor, the inner wall of the flow cell, or the catheter The present inventors have discovered that an infusion-type blood component measuring device can be used stably for a long period of time by coating at least a portion of each blood-contacting portion of the inner wall with an antithrombotic agent, and have thus arrived at the present invention.

The configuration of this device will be explained with reference to FIG. The device of the present invention includes a flow cell 3 that can be directly connected to a catheter 2 inserted into a blood vessel 1 and placed therein, an infusion reservoir 4,
An infusion device 7 is provided by a conduit 5 that connects both 3 and 4, and an infusion pump 6 installed in the middle of the conduit 5.
is configured. Further, a detecting section 11 is constituted by one or more types of chemical component sensors 10 installed in the flow cell 3. Furthermore, an infusion pump drive circuit 12 that controls the operation of the infusion pump 6, a sensor operation circuit 13 that operates the chemical component sensor 10, and a sensor operation circuit 13 that simultaneously controls the infusion pump drive circuit 12 and the sensor operation circuit 13 to control the sensor output. a processing device 14 for reading and converting it into a measured value, and an output device 1 for displaying the measured value
It is equipped with 5.

Further, the processing device 14 includes the pump control means 1
7 and a calibration means 21, the pump control means 17 controls the direction in which the infusion is injected from the flow cell 3 into the blood vessel 1 in the forward direction, and the direction in which blood is sucked from the blood vessel 1 into the flow cell 3 in the reverse direction. When defined as the direction, the above infusion pump drive circuit 1
2, the infusion pump 6 is operated alternately in forward and reverse directions according to a predetermined operation program.

The feature of the present invention is that the part that comes into contact with blood, that is, the chemical component sensor 10 or the inner wall of the flow cell 3,
Alternatively, at least one inner wall of the catheter 2 may be coated with an antithrombotic agent.

Antithrombotic agents to be coated on areas that come into contact with blood include blood coagulation inhibitors that suppress the production of fibrin by inhibiting the activity of blood coagulation system enzymes, and thrombolytic agents that activate the fibrinolytic system and degrade fibrin. Agents can be used. Examples of the former include heparin, protein C, protein S, thrombomodulin, etc.; examples of the latter include plasmin, urokinase, streptokinase, tissue plasminogen activator, etc. It is also possible to use precursors and derivatives of these. Furthermore, a mixture of two or more of these substances may be used. Among them, heparin has excellent thermal stability, can withstand autoclave sterilization, and is excellent in safety and economical efficiency, so it is most suitable as the antithrombotic agent for the device of the present invention.

The following method is exemplified as a method for coating with an antithrombotic agent.

(1) For example, ion-sensitive field effect transistor type
A silane coupling agent having an amino group (e.g. 3-aminopropyltriethoxysilane) is bonded to a part covered with a metal oxide, such as the detection part of a PH sensor, and then excess dialdehyde (e.g. glutaraldehyde ) to introduce aldehyde groups onto the surface, then add an antithrombotic agent, and use the amino groups present to covalently bond the antithrombotic agent.

Further, in the case of heparin, the following method can be further used.

(2) A method in which a silane coupling agent containing quaternary ammonium (for example, dimethyloctadecyl-3-trimethoxysilylpropylammonium) is used, the same is bonded to the same detection part as above, and then heparin is ionically bonded.

(3) A method in which quaternary ammonium, which has a long-chain alkyl group, is ionically bonded to heparin, and the complex is bonded to a part that comes into contact with blood, such as a detection part, using a hydrophobic bond.

Methods (1) and (2) are suitable for treating metal oxide surfaces because they use a silane coupling agent, but
It is not suitable for surface treatment of polymeric materials that do not have functional groups on the surface. On the other hand, method (3) is particularly advantageous because it is suitable for coating hydrophobic surfaces and can be applied not only to metal oxide surfaces but also to flow cells and catheters made of polymeric substances that do not have functional groups.

Method (3) will be described in detail below. First, how
Let us now discuss the quaternary ammonium salt used in (3). It is thought that heparin, which is a type of polyanion, and quaternary ammonium, which is a cation, are bonded by ionic bonds, and quaternary ammonium and the substance to be coated are bonded by hydrophobic bonds. In order to form a good hydrophobic bond with the substance to be coated, it is necessary for the quaternary ammonium to have strong hydrophobicity, and for this purpose, quaternary ammonium having 10 or more carbon atoms is usually used. Particularly preferred are those having 20 to 50 carbon atoms. For example, tridodecylmethylammonium and methyltricaprylammonium are easily available and can be dissolved in low-boiling organic solvents, making them easy to handle and therefore particularly suitable.

Next, a method of coating heparin using these quaternary ammoniums will be described. All of these methods are well known, but one is to dissolve the above quaternary ammonium in an organic solvent such as toluene, immerse the substance to be coated therein to bind the quaternary ammonium, and then dissolve the quaternary ammonium in an aqueous heparin solution. The other method is to prepare a solution in which heparin and quaternary ammonium are ionically bonded, and then immerse the material to be coated in the solution to bond the heparin. be. Although either method can provide a good coating, the latter method is better because it can be processed in a shorter time.

Furthermore, the above-mentioned method of binding heparin using quaternary ammonium is resistant to autoclave sterilization and ethylene oxide gas sterilization, so it is particularly useful for medical devices that require sterilization, such as the present device. When sterilizing in an autoclave, it is necessary to fill the detection part and the inside of the cell with a preservation solution.
By adding heparin to the solution, it is possible to prevent heparin from being removed during sterilization and storage. The heparin concentration used at that time is preferably 10 to 10,000 units per ml of preservation solution. Furthermore, in order to prevent withdrawal of heparin during measurement, it is best to add heparin to the infusion, and the concentration at this time is preferably 100 to 20,000 units per infusion.

[Operation] According to the present invention, since the blood contact part is coated with an antithrombotic agent, there is almost no adhesion of blood components such as blood cells and fibrin to the detection part of the chemical component sensor, and high accuracy can be achieved over a long period of time. This makes it possible to measure or monitor chemical components in blood.

[Example] The configuration of the device of the present invention will be described in detail using an infusion type blood PH, PCO ₂ and PO ₂ measuring device as an example.

FIG. 2 illustrates the chemical sensor 10 of FIG. 1 and the flow cell 3 housing it. In FIG. 2, 10A, 10B and 10C are respectively
PH sensor based on ISFET (Ion Sensitive Field Effect Transistor), based on ISFET
PCO ₂ sensor, and Clark type PO ₂ sensor. In other words, the chemical sensor 10 consists of three sensors 10.
It is a multi-sensor equipped with A, 10B, and 10C. The temperature sensor 9 is also built into the PH sensor 10A, and the temperature of the detection section 11 can be measured.

Next, a block diagram of the electric circuit of the infusion type blood PH, PCO ₂ and PO ₂ measuring device is shown in FIG. Third
In the figure, 41 is an ISFET for the PH sensor, 42
is the reference electrode for the PH sensor, 43 is the PH-ISFET4
This is a temperature sensor diode integrated with 1. 44 is for PCO ₂ sensor - ISFET, 44 is
A reference electrode 46 for the PH-ISFET 44 for the PCO ₂ sensor is a gas permeable membrane for the PCO ₂ sensor.
47 is an anode for the PO ₂ sensor, 48 is also a cathode, and 49 is a gas permeable membrane for the PO 2 sensor.

50 and 51 are for PH sensor and PCO ₂ respectively
This is a constant current circuit for operating the sensor PH-ISFETs 41 and 44, and has a function of flowing a constant drain current to each PH-ISFET 41 and 44. Also,
52-1, 52-2 are these two PH-ISFETs
This is a DC constant voltage source for supplying drain voltage to 41 and 44. 52 is a constant current circuit, each PH-
If ISFET41 and 44 are shorted due to an accident,
It also has the function of preventing overcurrent exceeding a predetermined value from flowing through each ISFET 41, 44. 53 is a DC constant voltage source for supplying a constant voltage between the anode and cathode of the PO ₂ sensor. 54 and 55 respectively
This is an amplifier for reading the source potential and diode potential of the PH-ISFET 41 for the PH sensor. 56
is an amplifier for reading the source potential of the PH-ISFET 44 for the PCO ₂ sensor. 57 is a current-voltage converter for reading the reduction current of the PO ₂ sensor.

58 is a multiplexer, which includes amplifiers 54, 55,
56, the output of each sensor sent from the current-voltage converter 57 is selected and the isolation amplifier 59
send to 60 is an analog/digital converter, 14
is a central processing unit composed of, for example, a microcomputer. Multiplexer 58 is operated by signals from central processing unit 14 through photocoupler 62. 63 is a DC stabilized power supply, and 64 is a DC/DC converter using magnetic coupling. By the isolation amplifier 59, photocoupler 62 and DC/DC converter 64,
Within the sensor operation circuit 13, the power source 63 and the central processing unit 14 side, and the detection unit 1 connected to the living body.
1 to achieve electrical isolation between the two. Reference numeral 12 denotes a drive circuit for controlling the operation of the infusion pump 6, which is operated by signals from the central processing unit 14. Reference numeral 15 denotes an output device, which includes a display device that displays measurement results in numerical values and graphs.

As described above, this device includes an infusion pump 6, an infusion device including an infusion reservoir, a conduit, a flow cell, etc. (not shown in FIG. 3), a detection section 11, an infusion pump control circuit 12, a sensor actuation circuit 13, and a central The system consists of six parts: an arithmetic processing unit 14 and an output device 15. Furthermore, since this device is a medical device, the sensor operating circuit 13 is an isolation part as described above.
It is designed to extremely reduce leakage current from the detection unit 11 to the living body to be measured.

Next, FIG. 4 shows an operating program of this device during one pumping cycle. If time zero is the time when the rotation of the infusion pump changes from the forward direction F to the reverse direction R, then from time zero to t _R , the pump rotates in the reverse direction R, and from time t _R to t _T , it rotates in the forward direction. Rotate to F. Therefore, if t _F = t _T − t _R , then
The forward rotation time of the pump is t _F , the reverse rotation time is t _R , and the time required for one cycle is t _T . On the other hand, the flow rate of the pump is V ₁ from time zero to t _R and from t _R to t _T
V2 is set.

There are several possible time schedules for reading the output of each sensor, but in this device, the time t _F from time t _R to t _T is divided into n equal parts (each divided time is represented by i), t Time starting from _R
For every t _F /n, the four sensors 9, 10A, 1 of Fig. 3
I read the output of 0B and 10C. The pump reversal period 0 to t _R in FIG. 3 was used to calculate the concentration and partial pressure of each chemical component from the read sensor output.

Examples 1 to 3 and Comparative Example 1 Operating conditions of the device The operating program of the above PH, PCO ₂ and PO ₂ measuring device was set as follows.

t _R = 1 min t _F = 4 min t _T = 5 min V ₁ = 0.5 ml/min V ₂ = 0.75 ml/min The forward flow volume/reverse flow volume calculated from this is 6.

n=20 The following equation was used as the calibration formula.

PH=a・MS1+b PCO ₂ =MC1・10 ^(C

Claims (1)

[Claims] 1 A chemical component sensor housed in a flow cell connected to a catheter placed in a blood vessel measures the components of the blood drawn into the flow cell, and the blood drawn into the flow cell is infused into the blood vessel. A blood component measuring device that returns blood components to the body, characterized in that at least one of the detection part surface of the chemical component sensor, the inner wall of the flow cell, or the inner wall of the catheter is coated with an antithrombotic agent. .