JPH0323866A - Extracorporeal circulation circuit - Google Patents

Abstract

PURPOSE:To prevent the generation of the rising of the internal pressure of a circuit and to eliminate trouble such as the damage of the circuit accompanied by the rising of internal pressure, hemolysis, the extension of the restriction time of a patient or the like by mounting an apparatus capable of controlling a water removing amount to a control means and mounting an apparatus capable of equalizing the flow rate of plasma separated by a plasma separation means and that of the plasma controlled by the control means to a reflux means. CONSTITUTION:A reflux means 6 consists of pumps 61, 62, 63... and tubes 71, 72, 73, 74... and a blood pump 61 is controlled to 0.5-100ml/min, desirably, 10-30ml/min in its flow rate. A plasma pump 62 is controlled to 0.1-100ml/min, disirably 1-50ml/min in its flow rate. A controlled plasma pump 63 is controlled so that the flow rate thereof becomes equal to that of the plasma pump 62. Pref., as the plasma pump 62 and the controlled plasma pump 63, the same pump, for example, a two-throw peristaltic pump is used. In this case, when the same tubes are used as both tubes, the flow rates of both of them can be made equal.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an extracorporeal circulation circuit used for the treatment of static tumors such as A=.

(Prior technology) ``Double filtration plasma separation and exchange method'' (Agishi Tetsutsumugi Collection, Igakushoin , 1984)
Or is it being offered?

In this method, one blood sample is continuously drawn from the patient, separated into plasma and blood cells using a separation membrane, and the large molecular weight fraction is removed from the obtained plasma using another separation device.
(Plasma fluorescence such as albumin fraction is left behind), and the patient's blood is returned along with the blood cell components. blood a (including 1)
The above-mentioned large molecular weight fraction to be used is, for example,
It is believed that this is a divine specific and non-specific immunosuppressant substance. Immunosuppressive substances belonging to such large molecular fractions, for example, bind to antibodies produced by the surface of malignant tumor cells, which act as specific antigens, through various chemical forces such as antigens, antibodies, and complement. It is thought to be an immune complex in the form of a large matrix. In patients with malignant tumors, these immunosuppressive substances act as a nuisance, weakening the immune system, and as a result of a complex interplay of these substances and other factors, tumor cells become more active than normal. It is said that it deviates from the state's immune surveillance mechanism and proliferates and metastasizes. Therefore, malignant tumors can be improved by selectively removing large molecular weight fractions as in the above method. However, such methods of removing immunosuppressants do not have the effect of actively attacking malignant tumor cells and causing necrosis. Furthermore, when removing a large molecular weight fraction using a separation membrane, there is a risk that a portion of plasma proteins necessary for living organisms may also be removed.

In addition, as an example of the improvement of malignant tumors by blood treatment, there is an article in this other paper, ``Cornerous tumor necrosis obtained by intravenous administration of serum from tumor-bearing rabbits treated with hypertonic food'' (Takashi Yamamoto,
Clinical Immunology, June 1986 issue, pages 544-547). According to this report, serum obtained from tumor-bearing rabbits was mixed with a concentrated aqueous sodium chloride solution, the concentration of sodium chloride was lowered by dilution or dialysis, and the treated serum was then returned by intravenous injection. 'C is there. It has been confirmed that cancer shrinkage is caused by such treatment.

In addition, the treatment method for this malignant tumor is disclosed in Japanese Patent Application Laid-Open No. 6391330.
No. f is also disclosed. That is, "(1) contacting plasma or serum obtained from a living body with a malignant tumor with a hypertonic salt solution, and (2) contacting the plasma or serum obtained in step (1) above with the same or ``A method for treating malignant tumors that includes the step of in vivo administration of a tumor.''The mechanism of action is that the immune complex is denatured or cleaved and the activity of the anti-malignant tumor antibody is increased. Furthermore, this inventor developed a device for use in this treatment in Japanese Patent Application Laid-Open No. 10276/1983.
It is disclosed in Publication No. 3.

In addition, as a treatment method for such stomach ulcers, Japanese Patent Application Laid-open No. 6
No. 3-93730 discloses that it is effective to treat plasma not only with a C1 hypertonic salt but also with an acidic solution. JP-A-63-200768 discloses an extracorporeal circulation circuit for this treatment.

These routes, which are used to treat malignant tumors, include a plasma separation means for separating plasma from blood collected from a living body, and a method that separates the separated plasma with an inorganic salt solution, an organic salt solution, and an acidic solution. at least 1' selected from the group of plasma processing solutions
a plasma processing means for processing the plasma by contacting it with the VM; a conditioning means for adjusting the treated plasma to the in-vivo environment; and a plasma separated from the conditioned plasma by the plasma separation means. It consists of a 11J1 path that is equipped with a mixing means for mixing blood cell components and a reflux means that can continuously or intermittently reflux the mixed blood into the living body.
As shown in the figure.

In circuit C of FIG. 2, blood collected from a living body or the like is supplied from the introduction means 51 to the plasma separation means 1 through the reflux means 6 consisting of a pump 61 and a tube 71, and a part of the plasma is separated. .

The remaining plasma and blood cell components are sent to the mixing means 4 through the tube 72. On the other hand, the separated plasma is supplied to the plasma processing means 2 (the part surrounded by the dotted line) by a reflux means 61 consisting of a pump 62 and a tube 73, and is brought into contact with a plasma processing liquid such as an inorganic salt solution. The plasma processing means 2 includes:
A plasma processing liquid storage tank 21, a tube 22, a pump 23, a plasma processing reaction tank 24, and a cock 25 if necessary.
Consisted of. The plasma processing liquid in the plasma processing liquid storage 6-1 and 21 is supplied to the reaction 4fI 241 by the bomb 23 and through the tube 22.

The treated plasma is adjusted in a preparation means 3 for adjusting the plasma to the in-vivo environment. The adjusted plasma is supplied to the mixing means 4I by the reflux means 6 consisting of a tube 74, and the plasma is mixed with the remaining plasma fraction and blood cell components as described above (means 1). Therefore, the deriving means 54f continuously or intermittently injects f into the living body.
2. In such a circuit, the internal pressure within the reflux means may rise during operation, which may cause damage to the circuit or hemolysis. Therefore, if the internal pressure rises, the circulation in the circuit may be After temporarily stopping and taking treatment to restore the internal pressure to normal value,
Since the process has to be restarted, efficiency decreases as the patient is restrained for a long time, and safety is compromised. Therefore, there is a need for an extracorporeal guide that does not cause an increase in internal pressure.

(Problems to be Solved by the Invention) The present invention is intended to solve the above-mentioned conventional drawbacks, and its purpose is to eliminate the 1-rubble caused by the increase in internal pressure during operation of the extracorporeal circulation circuit. In addition, this is a system that can effectively treat malignant tumors without removing active biological components. To provide the above-mentioned system that can treat solitary disorders.

(Top Means for Solving the Problems) The extracorporeal circulation circuit of the present invention includes a plasma separation means for separating plasma from blood collected from a living body, and a plasma separating means for separating plasma from blood collected from a living body. a plasma processing means for processing the plasma by contacting it with at least one extraction selected from the group of plasma processing solutions consisting of salt solutions and acidic solutions; a regulating means for regulating the in-vivo environment of the treated plasma; Comprising a mixing means for mixing the adjusted plasma and the plasma separation means (separated blood cell components), and a reflux means capable of continuously or intermittently refluxing the mixed blood into the living body. The adjusting means is equipped with a device capable of controlling the amount of water removed, and the reflux means controls the flow rate of the plasma separated by the plasma separating means and the plasma adjusted by the adjusting means. The circuit of the present invention is equipped with a device that can equalize the flow rate of blood collected from a living body, etc., and the above object is achieved by this circuit.As shown in FIG. Means 51, plasma separation means 1, plasma processing means 2 (area 2 surrounded by dotted lines), adjustment means 3 equipped with a device capable of controlling the amount of water removed (area 3 surrounded by dotted lines), adjusted plasma and blood cells It has a mixing means 4 with the components, a deriving means 54 for returning the mixed substance to the living body, a reflux means 6 consisting of pumps 61, 62, 63, etc., and tubes 7172, 73, 74, etc. , the reflux means 6 is equipped with a device that can equalize the flow rate of plasma separated by the plasma separation means 1 and the flow rate of plasma adjusted by the adjustment means 9-3 (dotted line including pump 62 and pump 63). ).

The method of using the circuit of FIG. 1 is generally similar to that described in the description of FIG. 2 in the prior art section.

Also, the same reference numerals as in FIG. 1 and FIG. 2 represent the same devices (means) as in FIG. 2.

As the blood introduction means 51 and blood extraction means 54, a special needle or the like is used as appropriate.

As the plasma separation means 1, for example, a hollow fiber type plasma separator or a centrifugal type plasma separator can be used, but preferably a hollow fiber type plasma separator is used.

Further, the plasma processing means 2 includes a plasma processing liquid reservoir 21, a tube 22, a pump 23, a plasma processing reaction tank 24, and a tank 25 as required. The processing liquid reservoir 21
One chamber houses the plasma processing solution. There are no particular limitations on the shape of the reaction vessel 24. In order to effectively contact the plasma processing solution with the plasma in the bag-shaped reaction tank, for example, a spiral-shaped reactor, a coil-shaped reaction vessel, etc. reactors, loop reactors may also be used. However, for the former two cases, it is desirable to attach a pot 25 to the blood treatment means 2. It is preferable to close the cock until the reaction chamber is filled with plasma and plasma processing solution, and then open it.
It is also recommended to set the reaction tank in an inverted rocker platform type mixer, or to install it in a container (equipped with a stirrer).

As the plasma treatment liquid, at least one of an inorganic salt solution, an organic salt solution, and an acidic solution is used. The six inorganic salts used are sodium chloride, potassium chloride, magnesium chloride, magnesium sulfate, sodium phosphate,
These include potassium phosphate, ammonium phosphate, ammonium sulfate, sodium borate, and potassium borate.

Self-salts include, for example, sodium citrate, potassium citrate, sodium acetate, potassium acetate, sodium pyrophosphate, potassium pyrophosphate, sodium phthalate,
Potassium phthalate, sodium fumarate, potassium fumarate, sodium tartrate, potassium tartrate, sodium cono citrate, potassium succinate, sodium formate, potassium formate, sodium lactate, and potassium lactate. Furthermore, PIF, which is known as a component of “GOOd buffer”
ES-sodium, PIPES monopotassium, MOPS-
Sodium, MOPS-potassium, HEPES-sodium, HEPES-potassium, TrlS monohydrochloride, glycine-hydrochloride, Tri ine hydrochloride, TAC PS-sodium, TAPS monopotassium, CAps-sodium, CAPS-potassium, TBS-tthorium,
These include T E S Ichiriki IJ Um, Bic+ne hydrochloride, etc. The above-mentioned inorganic salts and organic salts can be used to adjust the pH to 6.0.
Provide a buffering effect in the range of pH 6.0 to 8.0, or use an appropriate buffer solution to adjust the pH to 6.0 to 8.0. Of rubbing is preferred.

These inorganic or organic salts are 0. Make an aqueous solution (hypertonic salt) of 5 M or more, preferably about 1 to 4 M, and add 1
-0.1~toome, preferably 0.5~30 per
ml! used at a rate of

As the acidic solution, common aqueous inorganic or organic acids such as hydrochloric acid, phosphoric acid, acetic acid, and citric acid can be used, and various acidic buffers are preferably used. Examples of acidic buffers include glycine-hydrochloric acid buffer, citrate buffer, acetate buffer, phosphate buffer, borate buffer, and potassium phthalate-hydrochloric acid buffer. The pH of the acidic aqueous solution is adjusted to be 5.0 or less, preferably 3.5 or less (usually 10 -8 mol or more) when mixed with plasma.

The adjusting means 3 is, for example, a desalting device or a diluting device, and has a function of adapting the plasma, which has been processed in the plasma processing means 2 and has a high salinity or low pH, to the original in-vivo environment. has. As the desalting device, a dialysis device, an ion exchanger, a Kel filtration device, etc. are used. these are,
Removal 13 - This device is equipped with a device that can control the amount of water, and by the function of this device, an amount of water approximately equivalent to the amount of plasma processing solution supplied from the pump 23 is removed. The eleventh numeral 32 is its control device. Adjustment means 3
As a specific example, a combination of a hollow fiber type dialyzer 31 and a dialysis control device 32 that removes water using a negative pressure method is desirable. As an example of a dialysis control device 32 that removes water using a negative pressure method, 'C
Examples include NCD-11, a personal dialysis device with an automatic water removal amount control mechanism manufactured by Nipro Corporation. In addition, Ponop 2 of plasma processing solution
3 is flow io. 1 ~ 100ml? /tin, preferably 1 to 50 ml/win. In addition, NaCl is removed using an ion exchange resin (here, N
The cation exchange resin columns except for "a" and the anion exchange resin columns except for CI- are arranged in sequence, and the volume of the plasma treatment solution is subtracted from the total volume of the mixed solution of the treated plasma and plasma treatment solution by water removal. The Kell filtration device must be able to remove out of the circuit salts that are eluted later than plasma, and must also be able to remove water.

The mixing means 4 may be of any type as long as it can mix the adjusted plasma and blood cell components. It is not essential to provide a special stirring means, and a simple container may be sufficient. A preferred example of C is an air chamber used in a normal blood circuit. Also, as the mixer 4, it is possible to avoid using one with a special shape.
It is also sufficient to simply connect the flow path for blood cell components and the flow path for ordered plasma components.

The reflux means 6 includes the pumps 61, 62 . 6
3... and tubes 71, 72, 7374, etc. Six blood pumps have a flow rate of 0.5 to 10
0 m. e/old, preferably 10-30 me
/ Controlled by au+. In addition, the plasma pump 62 has a flow rate of 0. 1 to 100 me/m, preferably 1 to 50 rrd! /in. The conditioned plasma pump 63 is controlled such that its flow rate is equal to the flow rate of the plasma pump 62. Preferably, the plasma pump 62 and the conditioned plasma pump 63 are the same pump, for example, a periscuit pump that can be used in duplicate. In this case, if the same tube is used for both tubes, the flow rates for both can be made equal.

Further, in FIG. 1, C152 is a blood coagulation inhibitor supply device, and examples of the coagulation inhibitor include heparin sodium 1-lium and citrate sodium 1-lium. 53 is a neutralizing agent supply device for a coagulation inhibitor, and for example, protamine is used, but this is not always necessary.

In addition, a pressure sensor 8182. 83
．． 84 etc. are provided, and examples of these include a billows type pressure detector and the like.

(Function) Flow rate of plasma bomb 62 and adjusted blood! By making the Iu flow rates of the pumps 63 equal, the plasma that has entered the plasma processing means 2 and the adjustment stage 3 in the pump 62 flows through the pump 63.
'C is sent out of the regulating means at an equal flow rate.

Further, the flow rate of the plasma processing liquid flowing into the plasma processing means 2f by the plasma processing liquid pump 23 is equal to the flow rate flowing into the plasma processing means 1 through the dialysis control device t32 which can remove water from the plasma processing means 3. Since water is removed by the flow rate, the inside of the reflux means f
No increase in internal pressure occurs.

(Example) Hereinafter, examples of the present invention will be given and further explained.

Example 1 A dog was used, and blood was circulated extracorporeally using the extracorporeal circulation circuit shown in FIG. The manufacturing equipment (materials) used for the circuit is as follows.

Plasma separation means 1: Plasma flow AP-03H (hollow fiber type) (Asahi Medical Co., Ltd.) Plasma processing liquid storage tank 21: Blood bathog. Terumo Separation Bag Teruflex 3 0 0
me (Terumo Corporation).

Pump 23: Terfufusion infusion pump STC-50
3 (Terumo Corporation) Plasma processing reaction tank 24: Terufujo/Constant 17 volume infusion set 1. Ring part. Approximately 100 me (Terumo Corporation) Dialyzer 31: AM-03 (hollow fiber type) (Asahi Medical Corporation) Dialysis control device 32: Personal dialysis device [NCD11 (Nipro Corporation) Mixing means 4: Air chamber pump 61: 4 @ Bomb MP150 (Nipro Co., Ltd.) for liquid sleeve liquid Pump 62 63: Infusion fluid replacement pump MPI50 (Nipro Co., Ltd.) was used as two sets (that is, bombs 62 and 63 are common).

Tubes 22, 71, 72, 73, 74: Vinyl chloride tubes Dogs were anesthetized with Nembutal (Ahotl Co., Ltd.) I and fixed in supine position C. Catheter 51 for removing the major artery
(introducing means) was collected, blood was introduced into the circuit f, and heparin sodium (Novo) was introduced from the blood coagulation inhibitor supply device 52. The pump 61 for blood 18 was operated at 20 me/mf.

3 me with plasma pump 62 (2 series) from plasma separator 1
/m of plasma was obtained and introduced into the plasma processing reaction tank 24. At this time, the pot 25 was kept closed.

On the other hand, the plasma processing liquid storage tank 21 contains steam-sterilized 3MNa.
Add CI aqueous solution and pump 3 me/WJ at Bump 23.
n into reaction 8l24 for plasma processing.

After about 18 minutes, the pot 25 was opened to allow the treated plasma to flow out and introduced into the dialyzer 31. In the dialysis controller l&t32, the amount of water removed is set to 3 me / 3 tn, and the dialysate (AF
-3, Fuso Pharmaceutical Co., Ltd.) was refluxed at 500 me/cm. Dialyzed and water-removed plasma is pumped into the pump 6, which is common to the plasma pump.
2 (double series) I was introduced into the mixer 4 at a flow rate of 3 mel, and the blood mixed with blood cell components was returned to the major vein through the derivation means 54. During this time, no increase in internal pressure within the circuit was observed.

Example 2 An extracorporeal circulation circuit consisting of the same equipment (materials) as in Example 1 was prepared, except that the plasma processing means shown in FIG. 3C was used instead of the plasma processing means in Example 1.

In the plasma processing means in FIG. 3, the same numbers (21, 22, 23) as in Example 1 represent the same devices (materials) as in Example 1, and the plasma processing reaction m26 is
Two JMS blood warming coils (capacity jl55me, JMS Co., Ltd.) are connected in series (total capacity: approximately 110me).
).

A dog was used, and blood was circulated using this extracorporeal circulation circuit. In the same manner as in Example 1, blood was introduced into the circuit, plasma was separated, and 3 tne/tube of plasma was added to the reaction tank 26.
On the other hand, the plasma treated solution was introduced into 3.
A similar flow rate (3
me/urn) into the reaction chamber 26.

After about 18 minutes, the treated plasma flowed out from the outlet of the reaction tank 26 and was introduced into the dialyzer 31. In the dialysis control device 32, the amount of water removed was set to 3 me/my, and the dialysate (AF-3, Fuso Pharmaceutical Co., Ltd.) was refluxed at 500 me/my.

Dialyzed and water-removed plasma is introduced into the mixer 4 at a flow rate of 3 me/cm using a pump 62 (double set) I trowel, which is common to the plasma pump, and the mixture with blood cell components is transferred to the deriving means 54. Blood was returned to the greater integumentary vein. During this time, no increase in internal pressure within the circuit was observed.

Comparative Example 1 The same circuit as in Example 1 was used except that the plasma-treated liquid pump 63 was removed from the circuit shown in FIG. 14 used in Example 1 (the equipment and materials for this circuit were also changed) (Same as Example 1). This circuit is shown in Figure 4.

A dog was used to circulate blood using this circuit. Blood was introduced into the circuit in the same manner as in Example 1, and plasma was
Me/ytn were each introduced into the plasma processing reaction chamber 24.

On the other hand, as the plasma treatment solution, a 3M NaCt aqueous solution was used as in Example 1, and the same flow rate M(3me/i++
+) into the reaction chamber 24. At this time, Kotoku 25
I kept it closed.

After about 18 minutes, the pot 25 was opened, and the treated plasma flowed out and was introduced into the dialyzer 31.

The dialysis control device Kasumi 32 has a water removal depth of 3 m. The dialysate was refluxed at 500 me/man. Dialyzed and water-removed plasma is mixed with blood cell components in the mixer 4, and the liquid level rises, creating a risk of backflow, so the plasma pump 6
2. In order to stop the plasma processing liquid pump 23 and lower the internal pressure, it was necessary to take measures such as gradually opening a part of the circuit to the atmosphere. Since these procedures C took more time, the time required to complete the entire process was approximately 15 minutes compared to Example 11.
It was about a minute longer.

Comparison 2 A circuit similar to that of Example 2 was prepared, except that the plasma-treated liquid pump 63 was removed from the circuit used in Example 2. (The equipment and components of this circuit are the same as in Example 2.) This circuit is shown in FIG.

22 dogs were used to circulate blood using this circuit. In the same way as in Example 2, blood was introduced in C and plasma was injected in C.
me/ was introduced into the plasma processing reaction tank 26.

On the other hand, as the plasma treatment solution, 3MNac+aqueous solution was used as in Practical Example 2, and the anti-Rl'.
It was introduced into plants 2 and 6.

After about 18 minutes, the treated plasma flowed out from the outlet of the reaction tank 26 and was introduced into the dialyzer 31.

In the dialysis control device 532, the water removal tank was set at 3 me/m, and the dialysate was refluxed at 500 me/m. dialysis,
The dehydrated plasma was mixed with blood cell components using a mixer 4I, and was returned to the major vein through the derivation means 54. At this time, the internal pressure of the blood circuit increases and the liquid level in the mixer 4 rises, creating a risk of backflow, so the plasma pump 62 and plasma processing liquid pump 23 are stopped to lower the internal pressure.
This required measures such as gradually opening part of the circuit to the atmosphere. These steps 1 ( } took a long time, so the time to complete the entire process was about 15 minutes longer than in Example 2.

Example 3 A dog with a milk effect (naturally occurring) measuring approximately 3 cm x 3 . Circuit {The device (material) used is a practical example l
It is similar to

The same treatment procedure as in Example 1 was carried out once every two weeks, and this dog survived for 146 days, counting from the day when the sores were approximately 3 × 3 × 3 × 3 × 3 × 3 × 3 × 3.

Comparative Example 3 When a male dog with a natural growth of about 36 m x 3 am was observed without treatment using the extracorporeal circulation circuit C in the 1st iml, a seed wound of about 3 mm was observed. ■×3 It only survived for 53 days counting from the day it was steel.

(Effects of the Invention) As described above, when the circuit of the present invention is used, an increase in internal pressure does not occur within the circuit, which eliminates problems such as circuit damage, hemolysis, and prolonged patient restraint time due to increase in internal pressure. It is possible to treat malignant tumors more safely and effectively.

The basic operation method is to process the patient's blood and return it, so it does not put a burden on the patient's body like a surgical operation, and there is almost no loss of plasma proteins during the process. ,
Since the circuit is isolated from the external environment, it is safe and free from contamination by germs.

Using this circuit, patients who are difficult to undergo surgery or patients with malignant tumors for whom anticancer drug administration is inappropriate can be continuously and effectively treated.

[Brief explanation of the drawing]

The first diagram is an explanatory diagram showing a first version of the circuit of the present invention, FIG. 2 is an explanatory diagram showing an example of a conventional circuit, FIG. 3 is an explanatory diagram showing another example of the present invention, and the fourth diagram is FIG. 5 and FIG. 5 are explanatory diagrams showing a circuit of a comparative example. 1... Plasma separation means, 2. Plasma processing means, 3. Adjustment means, 4. Mixing means, 6. Reflux means, 21. Plasma processing liquid storage tank, 24. 26. Plasma processing reaction tank, 25.・Cook, 31...Dylyzer, 32...Performance 25 Analysis control device, 51 Introduction means, 54 Output means, 23,
61,62.63 Pump, 22 7172,73.
74.-Tube.

Claims (1)

[Scope of Claims] 1. A plasma separation means for separating plasma from blood collected from a living body, and the separated plasma is selected from the group of plasma processing solutions consisting of inorganic salt solutions, organic salt solutions, and acidic solutions. plasma processing means for processing the plasma by contacting it with at least one type of blood plasma, a conditioning means for adjusting the treated plasma to the in-vivo environment, and a plasma separated by the plasma separation means. A device comprising a circuit comprising a mixing means for mixing blood cell components and a reflux means capable of continuously or intermittently refluxing the mixed blood into the living body, and the adjusting means can control the amount of water removed. and the reflux means is equipped with a device that can equalize the flow rate of plasma separated by the plasma separation means and the flow rate of plasma adjusted by the adjustment means. extracorporeal circulation circuit.