FR2530146A1 - Process and device for the purification of blood - Google Patents

Abstract

Invention relating to the purification of blood. Process and device for the purification of blood on the basis of combining haemodialysis with haemofiltration. The filtrate extracted from the "haemofilter" is brought to an adsorption system, is regenerated therein and is returned in cyclic circulation to the haemofilter, so that in this device the blood is "dialysed" with respect to its own regenerated filtrate. Application to the making of artificial kidneys.

Description

The invention relates to blood purification, more specifically relates to a method for the purification of blood by extracorporeal removal of particularly ureogenic substances by diffusion (hemodialysis) and their convective transport (hemofiltration) through a semi-permeable membrane, the arterial blood passing along one side (blood side) of the membrane and the dialysis fluid, maintaining a transmembrane pressure, along the other side (filtrate side) of the membrane, against the current or in the same direction, and the thread
Trat formed thereby being extracted by the membrane and re @@.

It is known to treat the symptoms of renal insufficiency in case of failure of acute or chronic functioning of the queens with extracorporeal hemodialysis. In this process dedialyse the products of re
@@@@ @@@ ines are eliminated by the process
fusion. They diffuse out of the blood through a semipermeable membrane into the dialysis fluid. The
diffusion rate depends on the ratio of the size of delamembrane p @@ s and the molecular size of the sub
stance to be eliminated as well as the concentration gradient
mg / dialysis liquid. Plus the concentration gradient
is small and the larger the molecular weight of a substance, the more slowly it is removed by dialysis.

 The method of hemodialysis has the disadvantage that to maintain a high concentration gradient it is necessary to prepare large amounts of dialysis fluid. For the implementation of the method, therefore, there are important installations which impose limits on the mobility of the system relative to use as a portable artificial kidney. Another important disadvantage of hemodialysis lies in the fact that substances with relatively small molecules (molecular weight <5000 Dalton) can not be eliminated, since the removal of substances from the blood is carried out by a process pure diffusion.

In contrast to the dialysis process, the metabolic products are separated in the natural kidneys by a filtration process, ie using a convection transport. In the years 1967-69 we developed a method modeled on the mode of action of the natural kidneys, in which the elimination of the urogenous substances is carried out exclusively by convection transport in the course of an ultrafiltration through a permeable membrane of superior quality. In this process, referred to as "haemofiltration", the ultrafiltrate is removed from the patient using a hydrostatic pressure, this ultrafiltrate being replaced by a drip solution. An advantage of the method over the dialysis method lies in the does that inside a domain
limited by the pore diameter of the membrane and the flow of the filtrate, all the substances, whatever the molecular weight and the size of the molecules, are eliminated at the same rate. Thus with this process it is also possible to eliminate substances with a higher molecular weight (up to 100,000 daltons and more) and in particular large quantities of water. The disadvantage with this method is that, in order to compensate for the liquid sample in the blood, it is necessary to inject a relatively expensive substitution solution again and that the process for the removal of low molecular weight substances is not necessary. particularly effective because the elimination is carried out exclusively by a convection transport.

 In order to improve the removal of low molecular weight substances in a haemofiltration process, combined methods have already been proposed which make use of both hemodialysis and haemofiltration (AW Leber, V. Wiezeman). and F. Techert, Art Organs, 4 (4), 1980, 108). These methods correspond to the kind of treatment mentioned in the introduction. For this, the filtrate side of the semipermeable membrane is passed through the dialysis liquid. In the membrane there is a convective transport as well as a diffusion phenomenon, so that by this process it is possible to extract substances having a low or a medium or even a large molecular weight. The filtrate separated by the membrane is then completely discarded. The process has the disadvantage that an exact control of the filtration rate encounters difficulties and that in this case also large quantities of dialysis liquid and solution of solution are required. substitution. Therefore, this method also has a limited "mobility" and seems difficult to use in the form of an artificial portable kidney.

 It is an object of the invention to provide a method for the purification of blood, whereby substances having a low molecular weight or a medium or large molecular weight can be removed without the need for this purpose. to use large quantities. dialysis fluid and replacement fluid. In addition the method should be able to be realized in the form of a device simply constructed and portable, for example a portable artificial kidney.

 According to the invention, in a process of the kind described in the introduction, the desired result is achieved by the fact that only a part of the filtrate extracted by the membrane is rejected, while the remainder of the filtrate is continuously fed into a system with adsorption, while the filtrate is regenerated by removal of at least a portion of the substances captured in the blood, the regenerated filtrate being brought into closed circuit to the filtrate side of the membrane and again used as a dialysis liquid.

 In the method according to the invention, the blood is, as it were, dialyzed in the ultrafilter (semipermeable membrane) with respect to its own regenerated filtrate. As a result of the negative pressure (or depression) maintained on the filtrate side of the membrane, the filtration rate as well as the flow rate of the filtrate are controlled. As the depression increases on the wire side, the filtration rate increases. The process is preferably carried out so that only as much filtrate is discarded as is necessary for a constant flow of liquid to be maintained.

In order to start the process of the invention at the beginning, a relatively small amount of dialysis liquid (about 3 to 5 l) is needed, which is much less than that of dialysis fluid which must be put into play in a conventional hemodialysis. Depression on the filtrate side of the membrane is produced using a filtrate pump. When the pressure takes on the filtrate side a positive value, this means that through the filter more liquid is introduced into the filtrate circuit than it is removed. The extraction rate must then be increased to establish again on the filtrate side of the membrane a negative pressure or depression and to maintain a constant circulation of liquid.

This can be done by opening a valve.

 The main advantages of the process of the invention are that large amounts of dialysis liquid and substitute liquid are not required, while a relatively small proportion of the filtrate is also discarded. can be fixed by the attending physician and is necessary for dehydration of the patient. This means that for the implementation of the method according to the invention there is also no need for bulky device for storing the dialysis liquid and / or the rejected filtrate. Therefore the process can be implemented in a simple and inexpensive way, which provides a very high "mobility".

 With regard to the removal of substances, those having a low molecular weight, in a manner substantially comparable to conventional hemodialysis, as well as substances of medium or large molecular weight can be extracted in a comparable way. hemofiltration. The process according to the invention thus combines the advantages of the two known processes, without however needing for this purpose large quantities of dialysis liquid and replacement liquid.

 When the process according to the invention is to act in the manner of an artificial kidney, the adsorption system for the regeneration of the filtrate is adjusted so as to mainly remove urea, creatinine and uric acid from the filtrate. But the method of the invention is not limited to this field of application. Other toxic blood substances can also be removed by means of it, so that the process can be carried out, for example, also with patients contaminated with drugs or poisons and generally with immunotherapy.

 Thus, the method is essentially applicable in many ways more than the known methods of hemodialysis and haemofiltration or combinations thereof, because the adsorption system can be adjusted for each particular application case, that is, that is to say that one can make use of an adsorption system that acts on the corresponding substances to eliminate blood. As has been mentioned, it may be, when used as an artificial kidney, a system mainly binding urea, creatinine, and uric acid. In other cases, an adsorption system can be used which acts on the corresponding substance to be removed.

 In known methods there is no such possibility of extracting very particular substances from the blood. With hemodialysis and haemofiltration, only the molecular size for the substances to be extracted plays a role, that is to say that all the substances having a molecular weight less than a certain amount are extracted from the blood, that they possess or not toxic properties. On the other hand, with the invention it is possible to selectively extract a very particular substance by simply employing an adsorption system adapted to said substance.

 To complete the state of the art, it will be further indicated that it is already known to combine a hemo perfusion with an ultrafiltration (TMS Chang, E. Chirito, P. Barre, C. Cole, C. Lister and E. , Resurrection, Lo, G. Clinical C. Cole, C. Lister and E. Resurreccion, Long Term Clinical Assessment Combined ACAC Hemoperfusion Urrafiltration in Uremia, Artificial Organs 3 (2), 1979, 127). In this case the blood is directly passed through a column of activated charcoal and then subjected to ultrafiltration by means of a semipermeable membrane, the extracted filtrate being completely rejected. Although this method is relatively simple to implement, it has the disadvantage that in this case the blood is directly in contact with the activated carbon filter, so that blood cells can be destroyed. A very particular kind of activated carbon which is enclosed in microcapsules of cellulose nitrate must also be used. The method of the invention does not have these disadvantages, since here only the filtrate separated from the blood is passed through an adsorption system (activated carbon filter), that is to say that in this case the adsorption system does not occur. not find in direct contact with the blood.

 For the reasons already given above, it is also possible, with the method according to the invention, to work with relatively large blood currents (greater than 150 cm 3 / min.), Which is not possible with the method of hemoperfusion. because of possible damage to blood corpuscles and the risk of hemolabies. Furthermore, with the method of the invention the adsorption system does not need to be sterilized either, because bacteria and viruses do not pass through the ultrafilter.

 As already mentioned above, the method according to the invention can also be used for the detoxification of drug addicts and the elimination of poisons. It can be used for the treatment of elimination of antigen-antibody complexes and other proteins For this purpose, instead of an ultrafilter, a membrane filter with a pore size of 0.1 to 0.5 Adsorption in the system.

 The filtrate guided in the cyclic circulation is advantageously maintained substantially at body temperature. This is obtained optionally by heating the circulating filtrate, which preferably passes through a heat exchanger.

 Blood circulation on the blood side of the membrane is achieved as much as possible without a blood pump by using the pressure gradient specific to the body.

This pressure gradient of the body is about 50 to 80 mmHg, and this pressure is largely sufficient to pass 200 to 250 cm3 of blood per minute through a conventional ultrafilter. In the process according to the invention, it is preferable to operate with a filtration rate (filtration - spleen) of between 10 and 50 cm 3 / min, which is much less than with a corresponding haemofiltration process. When the process is applied to a patient to whom large amounts of liquid are injected, it works with a filtration rate higher than 50 cm / min. Of course one can also use a blood pump.

 When the process must assume the function of an artificial kidney, it works usefully with a membrane whose cutoff limit (cutroff) is between 5000 and 100,000 Dalton. By using such a membrane the previously mentioned filtration rate of 10 to 50 cm3 / min with a relatively low transmembrane pressure can be achieved. Preferably one operates with a transmembrane pressure Qpm less than 200 mm Hg, or in particular 80 mm Hg. As this value is relatively very small, the risk of tearing of the membrane and a corresponding passage of blood in the filtrate circuit are also minimal.

 In many cases of application, particularly as an artificial kidney, activated carbon is used in the adsorption system for the process of the invention.

In this way a large part of the uremic substances can be removed from the filtrate. Although the binding power of activated carbon to urea is relatively poor, no better material has been heretofore provided for this use. For example, it has been found that in order to remove 40 grams of urea per treatment, about 3 kg of activated charcoal and 3 liters of withdrawn liquid are sufficient.

 It is clear that the filtrate can not be recirculated until the filtrate circuit is completely filled with liquid. According to an alternative of the process according to the invention it is possible to start by filling the circuit of the filtrate initially with a fresh dialysis liquid. But when it is not desirable to have a dialysate filling, the treatment can begin, another alternative of the process, by a fast and pure ultrafiltration until the filtrate circuit is filled. Subsequently the filtrate serves as a dialysis liquid in the cyclic circulation of the filtrate. As a result, there is no need for a foreign dialysate.

 According to the invention it is possible to use an adsorption system divided into three or more small systems, which are used either in parallel or one after the other in time. With the last variant for example, a saturated adsorption cartridge is replaced by a fresh adsorption cartridge in a simple manner. This variant makes it possible to implement the method by means of a device that can be attached to the body allowing movements. If, for example, several adsorption cartridges are placed in parallel with each other, care must be taken that each cartridge causes the same pressure drop, so that the same flow conditions prevail everywhere.

 Thus, the method of the present patent application is very flexible as regards the realization of the adsorption system, because the number of cartridges placed can be adapted to existing needs. The used cartridges can be regenerated very quickly. For example, a column of activated carbon can be regenerated with steam and reused for the same patient, so that the treatment is less expensive than with other systems. This is advantageous in cases where fresh cartridges are not available. also because of this one can give up to store fresh cartridges.

 The invention furthermore relates to a device for implementing the method previously described, comprising a first system of conduits for the establishment and maintenance of an extracorporeal blood stream from an artery to a vein, a hemofilter plugged into the first duct system with a semipermeable membrane, along one side of which blood passes, and a second duct system to guide the dialysis fluid by maintaining a transmembrane pressure along the other side of the diaphragm against the current or in the same direction relative to the blood stream, so that hemodialysis with haemofiltration occurs, and the evacuation and rejection of the filtrate extracted by the membrane.

 According to the invention, this device is particularly distinguished by the fact that the second duct system has a bifurcation point downstream of the hemofilter, from which a duct for establishing and maintaining a cyclic circulation of the filtrate to the hemofilter, while another conduit serves for evacuation of the filtrate, in that a filtrate pump is arranged in the filtrate circuit between the hemofilter and the bifurcation point, and a system adsorption downstream of the bifurcation point, and in that there exists, in the conduit for discharging the filtrate, a closing or dosing valve, in particular for manually controlling the amount of filtrate in circulation.

 The device according to the invention is distinguished by a simple construction and easy maneuverability and a high mobility. This makes it particularly suitable for use as a portable artificial kidney on the body. In this case, by adjusting the closing or dosing valve, which is arranged in the conduit for the removal of the filtrate, it is possible to adjust in a simple way, particularly by hand, the amount of filtrate in circulation or the The adsorption system has a number of possible modifications which, in particular, also allow for the rapid exchange and replacement of spent adsorption elements, which can be regenerated rapidly to be used again.

 Different aspects of the device according to the invention will also emerge from the following.

 The device will now be described based on an embodiment with reference to the drawing, this non-limiting. The drawing represents the schematic construction of a device according to the invention, constituted in the form of an artificial kidney (single figure).

The device includes a first conduit system 1 for establishing and maintaining an extracorporeal blood stream from an artery to a vein. In this duct system is a hemofilter 2 which may be of a known model, for example an Amicon diafilter, an Asahi hemofilter or a hemofilter RP-6. The cutoff limit of the semipermeable membrane of the filter can reach, in the embodiment shown here for an artificial kidney, up to a molecular weight of 100,000.
Dalton. For other application cases, even higher cut-off limits are possible. Before, as well as after the hemofilter 2, a manometer 4, 21 has been arranged. In the duct system 1 there is also a bubble trap 3. The system described here does not normally require a blood pump. in the duct system 1, because the pressure drop in the hemofilters mentioned above is small. They must also operate with a relatively low transmembrane pressure and less than 200 mm Hg, and preferably close to 8 mm Hg. As a result, the system is further simplified and there is no risk of damage to the filter.

 The device further comprises a second duct system 5 which, in connection with a duct 11, serves to establish and maintain a cyclic circulation of the filtrate. Using this flow of filtrate 5, 11, the filtrate extracted from the blood through the semipermeable membrane is circulated by diffusion and convective transport, that is to say by hemodialysis and hemofiltration, being regenerated by passage The blood is thus 'dialyzed' in hemofilter 2 with respect to its own filtrate-regenerate. To circulate the filtrate, there is a filtrate pump 13 which determines both the filtration rate and the circulation rate. The preferably miniaturized pump draws the filtrate through the semipermeable membrane and delivers it through the adsorption system. 15. To adjust the pressure drop in the filtrate circuit, between the adsorption system 15 and the hemofilter-2, a closure or dosing valve 20 is provided. (The filtrate pump could be of a roller type).

 Naturally, the filtrate pump 13 is disposed downstream of the haemofilter 2 and is upstream of a bifurcation point 6 in the duct system, where the duct II diverts to form the filtrate circuit and a duct 7 for the ductwork. evacuation or rejection of the filtrate extracted from the membrane. In the duct 7 there is provided another closure or dosing valve 9 through which the amount of filtrate circulating or discharged can be adjusted, particularly by hand. The amount of filtrate discharged can be brought for example into a container 10, in which it is stored and later discarded. In line 7 a flowmeter 8 is preferably arranged.

 The filtrate circuit 5, 11 further contains, in the embodiment shown here, a heat exchanger 18, serving to maintain the circulating filtrate substantially at body temperature, a bubble trap 19 for deaeration and a flowmeter 17. In the circuit are further arranged manometers 12, 14, 16.

 The device described above operates so that the filtrate circuit 5, 11 is first filled with a conventional dialysis liquid. In this case naturally the valve 9 is closed and the valve 20 open. When the filtrate circuit is filled by the dialysis liquid, the filtrate pump 13 is actuated, so that the dialysis liquid and the filtrate are circulated. By the valves 9 and 20 can then adjust the flow so that there is just as much filtrate discharged into the container 10 for a substantially constant circulation of liquid is maintained.In other words, when the pressure in the filtrate circuit reaches a positive value on the filtrate side of the diaphragm, this means that the liquid transport through the membrane in the filtrate circuit is greater than the extraction of liquid in the container 10. By adjusting the valve 9 the equilibrium can be restored simply and vice versa. This can be done by the patient himself after the corresponding instruction by the doctor.

 In the embodiment described here, for the removal of about 40 g of urea by treatment requires about 3 kg of activated carbon in the adsorption system and 3 liters of filtrate subtracted. In this case the whole device weighs no more than 8 kg, including the dialysis liquid, the filtrate pump, the valves, etc. Thus the device is significantly lighter than known systems and can be taken away attached to the patient's body.

 For the regeneration of the filtrate in the case described here of application as an artificial kidney is preferably used activated carbon. This can be done in the form of cartridges, so that the used cartridges can be changed quickly and replaced with new ones. It is also possible to place several cartridges in parallel with each other or put them into service one after the other. Instead of the activated charcoal Redy cartridges can also be used which, however, have the drawback of requiring a larger quantity of dialysis liquid.

 In case it would not be desirable to have an initial filling of the filtrate circuit with dialysis liquid, the treatment can also start with pure ultrafiltration fast until the filtrate circuit is filled. Then the hemodialysis can begin relative to the regenerated filtrate.

The operating mode of the device described above is confirmed by the test below:
an Amicon Hlx50 hollow fiber filter (930 cm 2 surface area) was used as a hemofilter and 120 g of extruded activated charcoal, carefully washed, was used for the regeneration of the filtrate. In this test was used as "blood" a solution of urea and uric acid (1500 cm3). This solution was circulated through the filter at a rate of 200 cc / min so that a filtration rate of 10 cc / min was obtained, which was maintained together with the 200 cc circulation rate. / min. At regular intervals, samples were taken from the "blood" in a container and the filtrate leaving the activated carbon column to determine the urea and uric acid contents.

 This test has shown that after a duration. By 60 minutes the concentration of uric acid in the "blood container" was brought to zero. The amount of urea removed was 1 g.

Claims (21)

 1. Method for purifying blood by extracorporeal removal of blood particularly ureogenic substances by diffusion (hemodialysis) and their convective transport (haemofiltration) through a semipermeable membrane, the arterial blood passing along one side (blood side) of the membrane and the dialysis liquid, maintaining a transmembrane pressure along the other side (filtrate side) of the membrane, countercurrently or in the same direction, and the filtrate formed thereby being extracted by the membrane and discharged, said process being characterized in that only a part of the filtrate extracted by the membrane is rejected, while the remainder of the filtrate is continuously fed into an adsorption system, while the filtrate is regenerated by removal of at least a portion of the substances captured in the blood, the regenerated filtrate being returned to the filtrate side of the membrane in a closed circuit and again used as a dialysis liquid.  2. Method according to claim 1, characterized in that it rejects just enough filtrate to maintain a substantially constant liquid flow.  3. Method according to claim 1 or 2, characterized in that the filtrate introduced in closed circuit is maintained, optionally by heating, substantially at body temperature.  4. Method according to one of the preceding claims, characterized in that operates with a filtration rate (filtration rate) of between 10 and 50 cm3 / min.  5. Method according to one of claims 1 to 3, characterized in that operates with a filtration rate greater than -50 cm3 / min, if the method is applied to a patient who receives large amounts of liquid.  6. Method according to one of the preceding claims, characterized in that a membrane is used whose cut-off limit corresponds to a molecular weight between 5000 and 100,000 Dalton.  7. Method according to one of the preceding claims, characterized in that it operates with a transmembrane pressure S-Pm <200 mm Hg, or in particular 80 mm Hg.  8. Method according to one of the preceding claims, characterized in that the flow of blood on the blood side of the membrane is effected, without the use of a blood pump, by exploiting the pressure gradient of the body  9. Method according to one of the preceding claims, characterized in that it begins with a filling of the filter circuit with fresh dialysis liquid.  10. Method according to one of claims 1 to 8, characterized in that it starts with pure ultrafiltration fast until the filtrate circuit is filled, after which the hemodialysis begins relative to the regenerated filtrate.  11. Method according to one of the preceding claims, characterized in that an adsorption system is used divided into at least three small systems, which are involved in parallel or one after the other.  12. Apparatus for carrying out the method according to one of claims 1 to 11, comprising a first conduit system for the establishment and maintenance of an extra-c orporal blood stream from an artery to a vein, a hemofilter plugged into the first duct system with a semipermeable membrane, along one side of which the blood passes, and a second duct system for guiding the dialysis fluid by maintaining a transmembrane pressure along the on the other side of the diaphragm against the current or in the same direction relative to the blood stream, so that hemodialysis with haemofiltration takes place, and the evacuation and discharge of the filtrate extracted by the membrane, characterized in that the second conduit system (5) has, downstream of the hemofilter (2), a bifurcation point (6) from which a conduit (11) for establishing and maintaining a cyclic circulation of the filtrate (5); , 11) returns to haemofilter (2), while another duct (7) serves to evacuate the filtrate, in that a filtrate pump (13) is arranged in the filtrate circuit (5, 11) between the hemofilter (2) and the dewatering point (6), as well as an adsorption system (15) downstream of the bifurcation point (6), and in that it exists in the exhaust duct (7) of the filtrate, a closing or dosing valve (9), in particular for manual regulation of the amount of filtrate in circulation.  13. Device according to claim 12, characterized in that it comprises for the adjustment, in particular manual, of the pressure drop, a valve (20) for closing or dosing arranged after the adsorption system (15), in the filtrate circuit (5, 11).  14. Device according to claim 12 or 13, caarratcit S lseh in that it is established in the form of a kidney / portable on the body.  15. Device according to one of claims 12 to 14, characterized in that the adsorption system (15) comprises at least one column or cartridge activated carbon.  16. Device according to claim 15, characterized in that several columns or activated carbon cartridges are arranged parallel or in series with respect to each other.  17. Device according to claim 14, characterized in that the haemofilter (2) has a cutoff limit corresponding to a molecular weight between 5000 and 100,000 Dalton.  18. Device according to one of claims 12 to 17, characterized in that a heat exchanger (18) is disposed in the filtrate circuit (5,11).  19. Device according to one of claims 12 to 18, characterized in that the filtrate pump (13) is miniaturized.  20. Device according to claim 19, characterized in that the miniaturized pump is roller or membrane.  21. Device according to one of the preceding claims, characterized in that the adsorption system is constructed based on several different adsorbers each having a specific action.