DEVICE AND PROCESS OF TREATMENT OF BLOOD WITH SELECTIVE EXTRACTION OF AQUEOUS SOLUTIONS

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Ν0253 PCM

The present invention relates to a device and a method for treating blood with selective extraction of solutes.

The object of the invention is the filtration of blood in order to selectively separate and extract molecules size via extracorporeal systems for separating substances.

Such systems are used for the treatment of different blood, using a. urea solutes of molecular weight

Such substances are example 1

molecular weight of 60 daltons, phosphate (96-97 daltons), creatinine (daltons 113), vitamin B₁₂ (1355 daltons), inulin (5200 daltons), beta 2- midroglobuline (12000 daltons), albumin (daltons 58000).

Herein is the result of small molecules

molecules having a molecular weight lower

2000 daltons, the average mass molecules mol

the molecular weight is between 2,0 0,0|

|

daltons molecules of large mass and the molecules having a molecular weight of greater than 50000 daltons (e.g. proteins).

the e size to about 50000 êcules , and

Such systems are often systems

ià extracorporeal membrane for the separation of solutes¹¹ a lower mass than albumin

renal failure.

applied

of

treatments

The progress has always been searched improves the clearance, for decreasing the duration of-j.; and treatment to render such systems simpler and less expensive.

The biases that the clearance of a solute is the rate of solute in blood cleaned for a given volume.

In the field of dialysis, the first ^ membranes used were highly permeable to small solutes having a size up to 200 Daltons. The clearance^! small solutes depends on the permeability and the diffusion capacity the membrane used.

The lack of permeability of the first membranes for some solutes average molecular size in the range of vitamins B₁₂ (1355 daltons) has been held responsible for the occurrence of multiple uremic neuropathies.

For improving the average clearance molecules, a first solution was at ajoutër diffusive flow through the membrane a convective flow in

using high flux membranes with point I_i

cut ("cut off" English) of molecular size of 40000 dalton. The biases that the point of cut ;; off of a membrane is defined by the molecular size (which only has 10% solutes pass through the merribrane.

But the problems encountered during the processing of this solution are difficult to control to the ultrafiltration rate obtained by the convective flow, and the high loss of components useful plasma such as hormones, vitamins, and amino acids.

A second solution for improving the average clearance was then 1 molecules' hemofiltration, i.e. a purely convective method of removal of solutes by the membrane. Extract But such a method requires much liquid and compensàtion a dilution of sterile liquid as a pre-dilution and/or post-dilution and use of a membrane highly ' permeable to solutes of molecular size reaching 40,000 Daltons.

Only, convective board clearance depends on the dilution mode (pre or post-dilution), the rate of blood flow and 1' infusât. With a conventional hemofiltration, the clearance of small molecules is lower than that obtained by haemodialysis mode. Clearance hemofiltration The mode could achieve that of 1 'hemodialysis by increasing the flow rate of 1' infusât , blood flow and the membrane surface. But all is not practical, increases the cost of treatment and causes loss of amino acids and hormones. Furthermore, the blood flow rate is limited, in particular for patients having low blood access.

For the clearance of small molecules, when it has been determined the clearance hemofiltration mode was limited, the two phenomena hemofiltration and hemodialysis have been combined. The technique for both same membrane is referred to as the hemodiafiltration. Determined But problems are the difficulty of precise control of the flow of hemofiltration, the high loss of hormones and amino acid, the complexity of the system, large amounts of sterile liquid and dialysate required and thus the cost of such treatment.

Therefore, the use of a single filter working in different operating modes does not always has been for example, such as a loss of molecules of a certain size and cost of the treatment.

Then A proposal has been made by the doctors, J.C. Kingswood and F.D. Thompson. It had concerns a continuous hemofiltration free liquid re-injection: the treatment of 1' ultrafiltrate was provided by a second membrane operative further spontaneous ultrafiltration. Figure 1 represents the dialysis device from this proposal.

It is processing a first ultrafiltrate from a first hollow fiber membrane by passage through a second hollow fiber membrane ultrafiltration mode. A first ultrafiltration is carried out through a first high flux membrane and non-permeable to molecules of molecular weight greater than 10000 dalton. The size of the openings through the second membrane is smaller than that of the first.

As shown in Figure 1, output from the first membrane, the unfiltered liquid mainly containing molecules of large mass is brought into re-injection to the patient. The first ultrafiltrate containing molecules of small and average mass is filtered through the second membrane. Unfiltered liquid by the second membrane mainly containing molecules average mass is collected in a waste pocket. The second ultrafiltrate mainly containing small molecules mass is reinjected as post-dilution on the venous line of the patient.

This allows as not to consume much sterile liquid as a post-injection, and return to the patient a liquid containing few particles of average size.

But a high loss of nutrients, amino acid, glucose and vitamins was noted; and the clearance of small ions such as potassium is not good.

Also, another device has been accomplished by dialysis. It has been considered that the removing uremic molecules had a molecular weight of less than 200 daltons and a molecular weight of between 10000 daltons and 40000.

This assumption was to the origin of the producing a device comprising three filters, represented in Figure 2.

A first filter has a cut off point about 40000 daltons. Blood passes through the first filter and outputs a first filtrate containing small and medium molecules, i.e., molecules with a molecular mass of less than 40000 daltons. The solutes with a mass of between 10000 and 40000 daltons are then removed by ultrafiltration through the filter 2 having a cut off point less than 10000 daltons. The second filtrate is treated Then hemofiltration with a membrane with a cut-off point of about 200 daltons. Therefore, the purified filtrate containing the solutes between 200 and 10000 daltons is returned in post infusion to the patient who is also receiving the molecules of mass greater than 40000 daltons.

But the clearance of all solutes depends on the ultrafiltration rate in the filter 1, which may be no greater than 30% of the blood flow, which is a low value compared to 1' conventional hemodialysis. Also the cost is high.

Finally, patent US6,193,681 provides an apparatus for treating sepsis in blood represented in Figure 3. Blood passes through a irradiation device and then through a UVR haemoconcentrator before being re-injected into the patient. A secondary circuit is connected to a second output of 1 'haemoconcentrator exiting fluid passes through a filter, and a membrane module and a diluent source before being injected upstream of 1' haemoconcentrator.

There are also a problem equivalent for plasmapheresis. The exchange plasmapheresis therapeutic is administered to the patient, whose plasma contains one or more noxious or toxic materials.

The removal of solutes from the plasma is carried out on the same principle as the removal of solutes from the blood, a difference being the largest molecular weight solutes to retrieve from the plasma.

Therefore, recurring problems have been encountered during the construction of devices for the prior art:

The high consumption of the infusion liquid,

The high loss of nutrients, amino acid, glucose and vitamins,

Solutes The low clearance,

The cost of the device with multiple filters and pumps.

The problem with the request is selectively remove molecules range (s) by molecular weight with good clearance and consume very little sterile liquid.

For example, for patients in sepsis state, it is desired to eliminate many molecules of average size while maintaining a correct removal of molecules of small mass. The biases as sepsis is characterized by repeated discharges and important pathogens formed from a furnace pitch.

Auxiliary A problem would be optimal fitting of such a system to a long-term therapy made intensive care without risk of filters. The adaptation occurs by the selection of the operating modes of the different filters, use and expedient placement of flow rate adjusting means, controlled rates of, the architecture and hydraulic lines.

To achieve the problem is provided, according to the invention, a device for extracorporeal blood treatment, comprising at least one exchanger 1 comprising at least a first input 2 for the blood to be treated, a first output 4 of fluid and a second outlet fluid 5, an input line 10 of the blood to be treated connected to the first inlet 2 of the exchanger l, an output line (or venous line) 11 blood connected to the first outlet 4 of the exchanger 1, at least one processing unit 21 comprising at least a first input 22 of fluid and at least a first output fluid 24, the second outlet 5 of the exchanger 1 being in fluid communication with the first inlet 22 of the processing unit 21, characterized in that the first outlet 24 of the processing unit 21 is in fluid communication with the input line 10.

The invention also relates to a method for extracorporeal blood treatment for the implemented on a device for extracorporeal blood treatment comprising an exchanger 1 on which are connected an input line 10 of the blood and a blood output line 11, and a processing unit 21, the method comprising the steps of:

send the blood on the input line 10 connected to 1' exchanger 1, performing a first filtering the blood via the exchanger 1 by producing a first filtrate, performing at least a second filtering the first filtrate via the processing unit 21 by producing a second filtrate, return the second filtrate on the input line 10 to effect a pre-dilution of the blood to be treated, send the blood leaving the exchanger 1 to the output line 11.

Other advantages and features of the invention shall become apparent from the description that follows.

See to the accompanying drawings on which:

figure 1 represents the state of the art in respect to the use of two filters with different cut and re-injection with a post-dilution;

figure 2 represents the state of the art in respect to the use of filters with three points with a different cut and re-injection by post-dilution;

figure 3 represents the state of the art Patent US6,193,681;

figures 4 to 10 are schematic representations of the liquid treatment device according to the physiological invention, as well as alternative embodiments;

figures 11 and 12 represent the estimated results in terms of clearance based on molecular size for two solutes device configurations according to 1' invention.

Figure 4 represents, schematized the principle of the invention: the passage of blood through an input line, its input in an exchanger and its outlet of the exchanger to an output line, and treating the first filtrate by a processing unit and the injection of the liquid at the output of the processing unit in pre-dilution on the venous line.

Figure 5 shows the device extracorporeal blood treatment of the invention comprising a exchanger (1) having a first input 2 for the blood to be treated, a first output 4 of fluid and a second outlet fluid 5, an input line 10 of the blood to be treated or arterial line connected to the first inlet 2 of the exchanger 1, an output line of the blood or venous line 11 connected to the first outlet 4 of the exchanger 1. A processing unit 21 has a first input 22 of fluid and a first outlet 24 fluid, the second outlet 25 of the exchanger 1 is in fluid communication with the first inlet 22 of the processing unit 21, and the first outlet 24 of the processing unit 21 is in fluid communication with the input line 10.

The exchanger 1 may include a semi-permeable membrane 6 dividing it into a first chamber 7 and a second

1' exchanger.

The input line 10 blood said "arterial line" connected to the first inlet 2 of the exchanger 1, the output line 11 blood said "venous line" connected to the first outlet 4 of the exchanger and the first compartment 7 of the exchanger are part of an extracorporeal blood treatment circuit.

In one embodiment shown in fig. 6, the exchanger 1 may include a second input 3 in fluid communication with the second chamber 8 and in fluid communication with a first source of dialysis fluid 9. In this mode of operation, blood and dialysis liquid flow in opposite directions in each of the two chambers.

Figure 5 represents the processing unit 21 with a semipermeable membrane 26 dividing it into a first chamber 27 and a second chamber 28.

Advantageously, the processing unit 21 may include a second fluid outlet 25.

Also, the first outlet 24 of the processing unit 21 is in fluid communication with the first chamber 27 of the processing unit 21 and the second outlet 25 of the processing unit 21 is in fluid communication with the second chamber 28 of the processing unit 21.

Alternatively, the first input 22 of the processing unit 21 may be in fluid communication with either the second chamber 28 of the processing unit 21 is with the first chamber 27 of the processing unit 21.

The second output 25 of the processing unit 21 is in fluid communication with a first discharge line 30 waste liquid, said first discharge line 30 being able to connect the second outlet 25 of the treatment unit 21 to a drain or a first waste liquid tank 31.

The processing unit 21 may also include a second input 23, the second input 23 being in fluid communication with the second chamber 28 and with a second source of dialysis fluid 29. In this mode of operation of the processing unit shown in fig. 7, the dialysis fluid is circulated in the opposite direction relative to the physiological liquid arriving through the first inlet 22.

The exchanger 1 and the processing unit 21 have different characteristics. Indeed, the membrane 6 of the exchanger 1 can be a high flux membrane and the membrane 26 of the processing unit 21 may be a low-flux membrane.

Also, the permeability to molecules of the membrane 6 of the exchanger 1 is higher than the permeability to molecules of the membrane 2,6 of the processing unit 21 at least above a certain molecular weight.

More particularly, the cut-off point difference between the first membrane and the second membrane is of 20000 daltons and 30000. It is contemplated that the cut-off point of the first membrane is less than or equal to 4000,0 daltons, that the cut-off point of the second membrane is less than or equal to 10000 daltons. In one embodiment used the cut-off point of the first membrane is approximately equal to 4,0 000 daltons and the cut-off point of the second membrane is approximately equal to 10,000 daltons.

To re-infusing water to the treated subject, may be connected on the output line 11 a post-dilution line 50 is connected to a first source of sterile liquid 51 and/or on the input line 10 a pre-dilution line 60 connected to a second sterile liquid source 61.

A conduit 40 fluidly communicates the first outlet 24 of the processing unit 21 and the first input 2 of 1' exchanger 1.

The pre-dilution line 60 may be directly plugged into said pipe 40 or directly on the input line 10.

The different sources of sterile liquid 51, 61 may be pockets sterile liquid and/or can be obtained by an online preparation of sterile liquid from the water network.

In the application of the present invention in the particular case of plasmapheresis, represented in Figures 9 and 10, the exchanger is a plasma filter. The plasma-filter has a cut-off point between one million and five million daltons.

Also, the processing unit 21 comprises a unit capable of binding at least one given substance. It can be a cartridge adsorption, a reactor, for example a cell électrophérèse.

The processing unit may include a semi-permeable membrane 26 dividing it into a first chamber 27 having a first outlet 24 and a second chamber 28 having a first input 22 and a second outlet 25. The second output is connected to a discharge line. The processing unit may have a cut-off point lower than or equal to 250000 daltons.

Figure 10 represents a reaction device comprising means on at least certain molecules 70. These means are connected to the pipe 12 between the second output 5 of the exchanger 1 to the first input 22 of the processing unit 21. These means for reacting to at least certain molecules 70 can be a reactor, a radiation device, such as a électrophérèse , enzyme reaction, radiation, ultraviolet ray irradiation. the plasma filter can then have pores of one micron. The processing unit may have failure less than or equal to 90000 daltons passing the proteins to the patient's blood.

Another aspect of the invention is added a third filtering means for performing further remove molecular weight range, represented in Figure 8. The device may include at least one auxiliary exchanger 81 having a membrane 86 separating it into a first chamber 87 in fluid communication with a first input and a first output 84 82 and a second chamber 88 in fluid communication with at least a second output 85. The cutoff point such a heat exchanger would be smaller than the auxiliary cut-off points of the other two membranes (6, 26).

The first input 82 of the auxiliary exchanger 81 is in fluid communication with the second outlet 24 of the processing unit 21 and one of the two outputs 84, 85 of the auxiliary exchanger 81 is in fluid communication with the first inlet 2 of the exchanger 1.

A second discharge line 90 connects the other waste liquid output 84, 85 of the auxiliary exchanger 81 to a sewer, the sewer, which may be a second waste liquid tank 91.

Figure 8 represents the auxiliary exchanger dialysis mode: the auxiliary exchanger 81 comprises a second inlet 83 in fluid communication with the second chamber 88 of the auxiliary exchanger 81 and in fluid communication with a third dialysis liquid source 89, the first output 84 of the auxiliary exchanger 81 being in fluid communication with the first inlet 82 of the exchanger 1, the second outlet 85 of the auxiliary exchanger 81 being in fluid communication with a sewer 91 by a second discharge line for used liquid 90.

The choice of three membranes will be performed very precisely as the patient and the treatment to assume about the mass of molecules desired to remove or keep. The first membrane 6 allows people to work on the molecules of high molecular weight (preferably hemofiltration mode), the second membrane 26 for a work on average molecular weight molecules (preferably hemofiltration mode), and the third membrane 86 for a work on the small molecular weight molecules thus preferably dialysis mode. This does not prevent the auxiliary exchanger 81 operate in ultrafiltration mode also. The selection of the operation to customize the treatment and access to an optimal function of the membranes without too sealing.

For the setting of the different fluid flow rates, there are provided first rate adjusting means 101 active liquid on the input line 10 connected to the first input 2 of the exchanger 1.

Alternatively, the first flow rate adjusting means (101) can be exactly between the first inlet 2 of the exchanger 1 and the branch point 110 connecting the inlet line to the pipe or upstream from the coupling point 110 connecting the inlet line 10 to the pipe 40.

In the first alternative, the depression of the pipe 40 requires a lower positive pressure on the pipe 12 to reach the transmembrane pressure (TMP) of the membrane 26 desired.

Also, in the first alternative, there is no need for a pump on the pipe 40:a single pump 101 is sufficient to the pipe 40 and the arterial line 11.

In the second alternative, second means flow control 102 active liquid are on the pipe 40 connecting the first outlet 24 of the processing unit 21 to the first input 2 of the exchanger 1.

There is also provided a third rate adjusting means 103 liquid acting upon the conduit 12 connecting the second outlet 5 of the exchanger 1 to one of the inputs 22, 23 of the processing unit 21.

Also fourth means flow control 104 active liquid can be connected to the post-dilution line 50.

The fifth liquid flow rate adjusting means 105 active can be connected to the discharge line 30 waste liquid connecting the second outlet 25 of the treatment unit 21 to a drain 31.

In the configuration having at least three rate adjusting means on the input line 101, 102 on the pipe 40 and 105 on the discharge line 30, it will take to the different rate kept imposed and compatible.

The sixth liquid flow rate adjusting means 106 active can be connected to the pre-dilution line 60.

These rate adjusting means 101, 102, 103, 104 and 105 can be pumps and/or valves. In particular the flow rate adjusting means on the discharge line 30, or on the post-dilution line 50 or the pre-dilution line 60 will be valves.

In a particular embodiment, the first source 51 sterile liquid for the post-dilution is a sterile liquid bag, and the first reservoir 31 waste liquid connected to the discharge line at the output of the processing unit is a used liquid bag. The Device comprises a first set of scales 120 for measuring the weight of the sterile liquid bag 51 and a second set of scales 121 for measuring; the weight of the used liquid bag 31. Alternatively, one set of scales 120, 121 can measure the total weight of the sterile liquid bag 51 and of the used liquid bag 31.

Therefore, a computing and control unit 130 receives the signals from at least one scale 120, 121 and control the liquid flow rate adjusting means 101, 102, 103, 104, 105.

The computing and control unit periodically calculates the actual flow rate or a parameter dependent upon the actual flow rate for example from the weight and the time interval between each two measurements. It will compare the actual flow rate measured at the desired rate and will be able to control one or more liquid flow rate adjusting means (101, 102, 103, 104, 105).

Therefore, the amounts of sterile liquid and waste liquid, or their difference can be known and controlled during processing. Knowing said weights, the command and control unit will be able to obtain a desired amount of sterile liquid solution and waste liquid.

The device described above is applicable to plasmapheresis.

The invention also relates to a method for extracorporeal blood treatment for the implemented on a device for extracorporeal blood treatment comprising an exchanger 1 on which are connected an input line 10 of the blood and a blood output line 11, and a processing unit 21, the method comprising the steps of:

send the blood on the input line 10 connected to 1' exchanger 1,

performing a first filtering the blood via the exchanger 1 by producing a first filtrate,

performing at least a second filtering the first filtrate via the processing unit 21 by producing a second filtrate,

return the second filtrate on the input line 10 to effect a pre-dilution of the blood to be treated,

send the blood leaving the exchanger to the output line 11.

Specifically, the method will have a second filtration performed through a semi-permeable membrane 26 in a processing unit 21 divided into a first chamber 27 and a second chamber 28 outputting the second filtrate on the other hand and sending output the unfiltered liquid to a sewer line 30.

Another feature of the method is that the first filtration is carried out through a semi-permeable membrane 6 dividing the exchanger 1 into a first chamber 7 and a second chamber 8.

Another feature of the method is that the membrane 26 of the processing unit filters molecules of molecular weight below the molecular weight of the molecules filtered from the; membrane 16 of the exchanger.

According to another feature of the invention, the method comprising the step of infusing a sterile liquid in the output line 11 of blood from the exchanger.

According to another feature of the invention, the method includes the step of infusing a sterile liquid in the input line 10 of blood from the exchanger.

According to another feature of the invention, the method employs a membrane 16 of the exchanger with a cut-off point daltons less than 40000.

According to another feature of the invention, the method employs a membrane 16 of the processing unit with a cut-off point less than 10000 daltons.

According to another feature of the invention, the processing performed is plasmaphoresis and the processing unit at least some fixed given substance.

According to another feature of the invention, the membrane 16 of the exchanger operates with a cut point between one million and five million daltons.

According to another feature of the invention, the membrane 16 of the processing unit operates with a cut point less than 250000 daltons.

Simulations have been made on the different cut-point. Figures 11 and 12 represent the estimated results in terms of clearance as a function of the molecular weight of the solutes for two configurations of the device of the invention. Figure 11 represents a first configuration having a cutoff exchanger equal to 40000 daltons, and a processing unit having a cutoff exchanger equal to 10000 daltons. The clearance (curve 1) for molecules around 11000 daltons is very good, while the clearance of small molecules is kept constant relative to an operating device having a single filter (curve 2).

Figure 12 represents a second configuration for plasmapheresis exchanger having a cutoff equal to 1,000 000 daltons, and a processing unit having a cutoff exchanger equal to 250,0 00 daltons. The clearance (curve 1 ') for molecules around 300,000 daltons is very good, while the clearance averages molecules is kept constant relative to an operating device having a single filter (curve 2').

The invention provides many advantages: it makes it possible to:

multiplying by three or four, to treatment standard long time, the purification of average molecules (or large for plasmapheresis) without increasing the amount of exchange liquid and without changing the standard purification small molecules (small and medium for plasmapheresis),

-consuming much least sterile liquid, have lower cost,

of sufficiently removing molecules of average size, keep the trace elements and nutrients that are fed back to the patient,

filtering high volume.

Specifically, in the configuration shown in Figure 5, numerous other advantages are present. A minimum number of flow rate adjusting means is required: a peristaltic pump 101 on the arterial line and a pump 103 on the pipe 40 enable operation of the device.

Also, the position of the flow rate adjusting means is intelligently interest: it is not necessarily require pump 40 on the pipe, even if this is possible, and the flow adjustment means 103 need not be very powerful. This enables the long-term operation for intensive care by avoiding a high pore plugging of each membrane.

Finally, it has been believed to apply this scheme of operation to an alternative mode of extracorporeal blood treatment: the^: plasmapheresis. Operation plasmapheresis reaches its optimum when the membranes are selected and used carefully.