CHAMBER FOR EXTRACORPOREAL CIRCUIT
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to a chamber or reservoir used when an extracorporeal circuit is formed in which a bodily fluid such as blood is circulated. More specifically, the present invention relates to an open-type blood reservoir with anticoagulant, the reservoir having a high removing ability of air bubbles to effectively prevent thrombus formation. Description of the Related Art
Extracorporeal circulation of a bodily fluid such as blood is generally applied to patients suffering from lowered renal functions and patients requiring heart surgeries. Extracoφoreal circulation introduces the patient's blood outside his/her body, treats the blood in an artificial dialysis device or an artificial heart and lung system extracoφoreally arranged, and returns the treated blood inside the patient's body. Extracoφoreal circulation is generally performed using a extracoφoreal circuit including, for example, a chamber (or blood reservoir), a filter and a tube.
A problem in extracoφoreal blood circulation is thrombus formation. Air mixed in the extracoφoreal circuit activates a blood coagulative system and promotes the thrombus formation. Accordingly, the extracoφoreal circuit generally includes means for removing air bubbles mixed therein. The air bubbles mixed in the extracoφoreal circuit are generally removed in the above-described chamber. An open-type chamber is in a wide use due to its easy operation and a high removing ability of air bubbles. An open-type chamber has an air layer therein so
as to have a sufficiently large contact area between blood and air. Thus, the open- type chamber promotes the air mixed in the extracoφoreal circuit to move the air layer with certainty, thus removing the air from the extracoφoreal circuit.
A thrombus can be also formed by the contact between the blood and a foreign object such as plastic which forms the extracoφoreal circuit.
Generally, thrombus formation can be prevented by systematically administering an anticoagulant such as heparin. However, an anticoagulant which is systematically administered generally has a long intracoφoreal metabolic time and remains in the patient's body even after the extracoφoreal circulation is completed. As a result, problems such as bleeding is not stopped at the site of the surgery even after the surgery is completed occur. Moreover, in the case of patients having diathesis for bleeding, the dose of the anticoagulant needs to be reduced or the use of the anticoagulant needs to be avoided for extracoφoreal circulation. In order to solve these problems, extracoφoreal circuits having heparin, which is one type of anticoagulant, immobilized on all the faces to be in contact with blood have been developed and marketed. However, an extracoφoreal circuit using an open-type chamber cannot immobilize an anticoagulant at the interface between air and blood, and accordingly, thrombus formation caused by the contact of the air and blood in the chamber cannot be prevented. As a result, the dose of heparin which is systematically administered cannot be reduced as expected.
As an alternative attempt to prevent thrombus formation, physiological saline is supeφosed on the blood in the open-type chamber so that direct contact between air and blood is prevented. According to this method, however, since the layer of the physiological saline and the layer of blood are mixed together, longtime prevention of direct contact between the air and blood cannot be realized.
Japanese Publication for Opposition No. 7-96031 describes a method for preventing direct contact between air and blood by superimposing aliphatic ester on the blood in the open-type chamber. This method involves the danger that the aliphatic ester is mixed in the blood.
Closed-type chambers accommodating no air therein have been developed and marketed. In the case where a closed-typed chamber is used, air needs to be completely removed from the circuit before extracoφoreal circulation. Since such an operation is troublesome and time-consuming, extracoφoreal circulation using the closed-type chamber has not been widely used.
SUMMARY OF THE INVENTION
To overcome the above-described problems and to improve a conventional chamber for use in an extracoφoreal circuit, the objective of the present invention is to provide an easy-to operate chamber for extracoφoreal circulation having a high removing ability of air bubbles to effectively prevent thrombus formation. To achieve the above-described objective, an open-type chamber according to the present invention includes air blocking means with anticoagulative properties. Preferably, the air blocking means is disposed at an interface at which blood and air contact each other. The air blocking means includes a carrier with the anticoagulant. Preferably, the anticoagulant is immobilized on the carrier. The carrier preferably has a specific gravity of 1 or less, and is, for example, a plastic mold accommodating air therein.
Brief Description of the Drawings
Figure 1 is a schematic view of a chamber for extracoφoreal circulation according to the present invention.
Figure 2 is a schematic view of an extracoφoreal circuit used in one embodiment of the present invention.
Figure 3 is an exemplary carrier used in one embodiment of the present invention. (A) shows a perspective view of the carrier, (B) is a plan view of the carrier, and (C) and (D) are side views of the carrier.
Detailed Description of The Invention As used herein, the term "anticoagulant" refers to any anticoagulant usually used clinically, which includes but is not limited to various heparin compounds including heparin and low molecular weight heparin; urokinase; nafamstat mesilate; gabexate mesilate; prostaglandin b; prostaglandin D2; prostaglandin Ei; sodium citrate, calcium chelating agent such as EDTA; and mixtures thereof. Heparin is currently the preferable anticoagulant.
As used herein, the term "carrier" refers to any type or form of material which can disperse and/or retain the anticoagulant. Preferably, the carrier can float in the blood and has a specific gravity of 1 or less so as to float on a blood surface in the chamber and form air blocking means for preventing contact of air and blood. As used herein, the term "specific gravity" refers to an apparent specific gravity unless otherwise specified. Since the carrier moves freely in the vicinity of the blood surface, the air bubbles mixed in the extracoφoreal circuit can be removed with certainty as in the conventional open-type chamber. The form of the carrier is not specifically limited, therefore, a liquid or solid of any shape can be used. A solid carrier can be, for example, a membrane such as a porous membrane, a plastic mold accommodating air inside a particle, or a
particle having, for example, a large surface area. An exemplary carrier in the form of a particle may float at the interface between the blood and air in the chamber. A carrier in a form of a plurality of particles can fill the whole interface between the blood and air in a closely packed manner and thus form effective air blocking means.
The size, shape or form of the carrier is not specifically limited as long as the carrier forms the air blocking means in the chamber. The carrier usually has a diameter in a range of 100 mm to 5 mm, preferably in a range of 70 mm to 10 mm, and more preferably in a range of 50 mm to 15 mm. The material of the carrier can be any material available to those skilled in the art. Usable materials include, for example, synthetic and natural organic and inorganic materials, and can be plastic materials such as polypropylene and polyethylene, natural high molecular weight materials such as cellulose, active carbon, diatomaceous earth, and silica. Preferably, a plastic mold accommodating air therein can be used as the carrier. Such a plastic mold easily floats in the blood collected in the blood reservoir for the extracoφoreal circuit.
Preferably, the plastic mold may have a three-dimensional shape which is polygonal when seen in a plan view and substantially elliptical when seen in a side view, so that the interface between the blood and air is easily filled with a plurality of carriers in a closely packed structure to form effective air blocking means. Usually, the three-dimensional shape has dome-like portions on a front face and a rear face thereof. Plastic molds of such shapes are easily available from usual manufacturers. The carrier may be coated with a solution containing an anticoagulant or an anticoagulant may be incoφorated in the material of the carrier in any other appropriate manner. Preferably, the anticoagulant is immobilized on the carrier. Immobilization is performed using a known method depending on the
anticoagulant used and the properties ofthe carrier. For example, an anticoagulant can be immobilized on the carrier utilizing physical adsoφtion of the anticoagulant to the carrier, chemical binding between the anticoagulant and the carrier, and an intermediate such as a binder. Usable as the binder are, for example, polyethyleneimine and quaternary ammonium such as benzalkonium chloride. Polyethyleneimine may be covalently bonded with an anticoagulant through glutaraldehyde or the like to facilitate immobilization ofthe anticoagulant to the carrier. Quaternary ammonium may be bonded with an anticoagulant by ionic bond to facilitate immobilization ofthe anticoagulant to the carrier. In one preferred embodiment, shown in Figure 1 , an open-type chamber 3 includes a blood inlet 5, a blood outlet 6, a defoaming body 4, and a carrier 2 including an anticoagulant 1. The anticoagulant 1 is immobilized on a surface of the carrier 2. The carrier floats at the interface between the blood and air.
Blood which has been introduced outside the patient's body and put into an extracoφoreal circuit is guided to the defoaming body 4 through the blood inlet 5. The defoaming body 4, which is formed of polyester nonwoven cloth and polyurethane sponge removes air bubbles mixed in the extracoφoreal circuit. The blood which has been put into the open-type chamber is retained in the chamber for a prescribed residence time period, so that the air bubbles in the blood are removed with certainty. The level ofthe blood 7 is maintained substantially constant in the chamber, and the carrier 2 retaining the immobilized anticoagulant 1 floats on the contact face between the blood and air layers, so as to prevent the contact ofthe blood and air layers. The blood 7 in the chamber is discharged through the blood outlet 6 and returned to the extracoφoreal blood circuit. The present invention will be described more specifically with reference to the following examples.
Example 1: Immobilization of an anticoagulant
Four hundred milliliters of aqueous solution of 15% (w/v) stearylkonium chloride (Tokyo Kasei) was dropped to 200 mL of aqueous solution on 12% (w/v) heparin-sodium (Wako Chemical Industries, Ltd.) to obtain a precipitate of stearylkonium-heparin composite. The precipitate was filtered, recovered, and then dried to obtain a powder ofthe steanylkonium-heparin composite. The resultant powder is dissolved in a mixture solvent of 1,1, 2-trifluoro- 1,2,2- trichloroethane and ethanol so that the content ofthe resultant powder was 0.2% (w/v). The resultant solution was used for coating a carrier. An examplary spherically shaped polypropylene carrier (with a diameter of about 20 mm) accommodating air therein was dipped in the above-obtained coating solution (dipping) and dried, and heparin was immobilized on a surface of the polypropylene sphere.
Example 2: Evaluation test for anti-thrombogenic properties
The heparin-immobilized polypropylene sphere obtained as above- described in Example 1 was set in a venous blood reservoir (HSR-4000G; Baxter) and was used for the experiment.
An extracoφoreal circuit including a venous blood reservoir in which the heparin-immobilized sphere was set was attached to an adult beagle which had been operated on so that a shunt between arterial femoralis and femoral vein was formed (A-N shunt method), and extracoφoreal circulation was performed.
As seen in exemplary embodiment of Fig. 2, the blood drained by gravitation from the arteria femoralis 12 ofthe beagle 10 was introduced into a reservoir 23 through a tube 18 formed of polyvinyl chloride (PNC) and a connector 22. After being kept in the reservoir 23 for a prescribed residence time period, the blood was transported by a centrifugal pump 24 to pass through the PVC tube 18 in the direction of arrow "a" shown in Figure 2. The blood was
passed through the connector 22 and the PVC tube 18 and returned to the femoral vein 14. In Figure 2, letters "A" and "V" respectively refer to artery and vein. Ringer's solution was optionally supplemented to the extracoφoreal circuit. The Ringer's solution was supplemented from a supplementing bottle 20 containing the Ringer's solution through the PVC tube 18 connected to a vein.
The conditions ofthe extracoφoreal circulation of Example 2 were as follows:
Wweight ofthe beagle: 15 to 20 kg; Anesthesia: Continuous injection of ketamine Blood flow rate: 300 to 600 mL/min.
ACT (activated clotting time): 150 seconds or less After extracoφoreal circulation was performed using the above extracoφoreal circuit for 6 hours or more, no thrombus formation was found.
Example 3: Evaluation test for anti-thrombogenic properties
A polyethylene carrier (with a longer axis size of about 30 mm) accommodating air therein and having, for example, the three-dimensional shape shown in Figure 3 was obtained from a manufacturer. The carrier has a three- dimensional shape which is hexagonal when seen in a plan view as shown in exemplary embodiment of Figure 3 (B) and substantially elliptical when seen in a side view as shown in Figures 3 (C) and 3 (D). As shown in Figure 3 (D), the carrier has longer axis "b" and shorter axis "c." In one example shown in Figs. 3 A-D, the carrier has 6 elliptical external faces "d" and dome-like portions "e" and "f," respectively, on a front face and a rear face. Heparin was immobilized on a surface ofthe carrier in the same manner as in Example 1. More than 10 but less than 20 heparin-immobilized carriers thus obtained were set in a venous blood reservoir (HSR-4000G; Baxter), and extracoφoreal circulation was performed in the same manner as in Example 2.
After extracoφoreal circulation was performed using the extracoφoreal circuit for 6 hours or more, no thrombus formation was found.
For purposes of comparison, an adult beagle was attached to an extracoφoreal circuit with a venous blood reservoir (HSR-4000G; Baxter) that had no air-blocking means with an anticoagulant ofthe present invention (such as exemplary heparm-immobilized sphere). The beagle had been operated on so that a shunt between arteria femoralis and femoral vein was formed (A-V shunt method) and extracoφoreal circulation was performed as in Example 2. Observation after about 6 hours later found thrombus formation in the reservoir.