APPARATUS FOR SEPARATING FROM A BIOLOGICAL LIQUID, IN PARTICULAR BLOOD, A FRACTION HAVING MOLECULAR WEIGHT BETWEEN AN UPPER AND LOWER LIMITING VALUE

Abstract: An apparatus for separating from a biological liquid, in particular blood, a fraction having molecular weight between an upper and a lower limiting value, comprises a liquid container (B1) for the separated fraction and included in a closed circulation circuit (I2) between a first and a second molecule filter (F1, F2) each with a flow driving pump (P1, P2). A control system is provided for controlling the liquid volume V in the container in accordance with the equation: dV/dt = Qa + Qb, in which V is the regulated liquid volume, the desired value of which is stored as predetermined time function V(t) in the memory (H) of the control system, and Qa and Qb are the total liquid flows into and out of the closed circulation circuit, respectively. Blood from a patient under treatment is supplied to the first molecule filter (F1), and the liquid filtrate which is discharged from the output side of the second molecule filter (F2), is fed back to the blood flow system (M) of the patient. The predetermined time function V(t) is defined in such a way that the separated liquid volume is automatically adjusted in agreement with prior experience and adapted to the particular patient under treatment. A third filter (F3) may be disposed in the feed back conduit to the patient in order to extract liquid from the returned filtrate and thus increase the protein concentration in this filtrate, the extracted liquid being returned to the container (B1) in the closed circulation circuit. In cooperation with a protein detector (PD) the filter (F3) may then serve as a controller of the protein concentration in the fed back filtrate.

Description: Apparatus for separating from a biological liquid, in particular blood, a fraction having molecular weight between an upper and a lower limiting value. The present invention is related to an apparatus for separating from a biological liquid, in particular blood, a fraction having molecular weight between an upper and a lower limiting value. Such apparatus is included as an essential part of the outfit described in Norwegian Patent Specification No. 144.411 and is particularly useful for cleansing the.^blood of patients having kidney deficiency. This outfit comprises essentially an apparatus for grading of biological liquid, in particular blood, according to molecular weight, the apparatus being provided with at least two filter units, each comprising a molecule filter adapted to filter out molecules of molecular weight essentially below a predeter¬ mined limiting value, as well as an inlet conduit for cir¬ culating liquid along one side of the filter and an outlet . conduit for conducting liquid filtrate essentially con¬ sisting of molecules of molecular weight below said limiting value away from the other side of the filter, a selected unit among said filter units being adapted for connection with a source of said biological .liquid to be graded, e.g. the blood circuit of a patient, in closed circuit with the inlet con¬ duit of said selected unit. Said filter units, starting with said selected unit, are sequ¬ entially interconnected to form a filter unit array in such a way that the outlet conduit of each unit, apart from the last unit in the array, communicates with a liquid container in¬ cluded in closed circuit in the inlet conduit of the subsequ¬ ent filter unit, the outlet conduit of the last unit of the array being adapted for connection with said source of the biological liquid to be graded, the predetermined limiting value of the various molecule filters essentially decreasing along the array from the first to the last filter unit of the array. By means of such outfit substances within a desired molecular weight range may be eliminated without losing vitally essential matters. In conjunction with blood cleansing such system would to a great extent simulate the processes actually going on in the kidneys. Thus, in these organs first a filtering takes place through a filter having a limiting value at a molecular weight of about 60.000 daltons, whereupon water and some vitally essential sub¬ stances are reabsorbed with increased concentration of certain toxin molecules, which then are eliminated with the urine. Usually it is sufficient and suitable to the purpose to use only two filter units, the outlet conduit of the last filter unit being connected through a dialyser to the inlet circuit of the first filter unit. The liquid in this conduit will then be fed back to the source of the biological liquid together with the circulating liquid in the inlet circuit of the first filter unit. Thus, each such pair of filter units constitutes an apparatus for separating from a biological liquid, in particular blood, a fraction having molecular weight between an upper and a lower limiting value, the apparatus comprising a first molecule filter operatively adapted for filtering out mole¬ cules of molecular weight essentially below the upper limiting value, and provided with an inlet conduit for circulating liquid along the input side of the filter; an outlet conduit with a flow driving pump being disposed for conducting liquid filtrate of molecular weight essentially below said upper limiting value away from the output side of the filter and into a liquid container, which together with a circul¬ ation pump is included in a closed circulation circuit disposed to conduct liquid from the container along the input side of a second molecule filter operatively adapted for filtering out molecules of molecular weight essentially OMPI below said lower limiting value, an outlet conduit with a second flow driving pump being disposed for conducting liquid filtrate essentially consisting of molecules of molecular weight below said limiting value away from the output side of the filter, by which the liquid fraction having molecular weight between said upper and lower limi¬ ting values being progressively concentrated in the liquid container. With practical use of such apparatus, in particular for treatment of patients with kidney deficiency, it has been found that the liquid volume in said container, which actu¬ ally functions much as an artificial urine bladder, must be carefully controlled to gain optimum effect from the treat¬ ment. This requires, however, constant supervision by skilled ward personnel over extended time periods, which is a significant obstacle to more comprehensive use of apparatus of this kind. Thus, it is an object of the present invention to provide an apparatus of the type specified above and which overcomes the indicated disadvantage. For this purpose attempts have been made to drive the liquid flow on the inlet side of the liquid container and the outlet side of the second molecular filter, respectively, by means of identical peristaltic pumps on the same driving shaft in order to secure the same liquid flow into and out of the container circuit. However, this has not given satisfactory operation in practice. Neither by controlled adjustment of the same pressure across the two molecular filters has the intended result been obtained. The desired controlling effect is, however, achieved accor¬ ding to the invention by applying a control system for con¬ trolling the liquid volume in the container in accordance with the equation dV/dt = Qa - Qb, in which V is the 'BUREA OMPI controlled liquid volume, which is stored as a desired predetermined time function V(t) in a memory of the control system, and Qa and Q-b are the total flows of liquid filt¬ rate, respectively, into and out of the circulation circuit; the control system comprising means for sensing the liquid volume in the container, comparing the sensed value with and determining its deviation from the predetermined stored time function V(t), sensing the pumped liquid flows in all the inlet and outlet conduits of the circulation circuit except one, and adjusting the pumped liquid flow in the remaining inlet or outlet conduit in accordance with the total sensed flow value and in such a way that the time derivate dV/dt of the liquid volume assumes such value according to the control equation that said deviation is cancelled. Regulation of molecule filter systems in order to obtain an intended optimum operational function is known in principle from the published European Patent Application No. 81.3016136 (Publication Number 0038203). The control process according to the present invention is, however, of a different and more comprehensivenature, as it is performed with a liquid container in a closed circulation circuit as main component. A corresponding container is not included in the filter system described and illustrated in the above European patent application. This container is a very important part of the present apparatus when used for plasmapheresis treatment. In the container substances which are more or less blocked by the second molecule filter, are gaining increased concentration. A certain substance (A) of this kind may then be concentra¬ ted in the container to such extent that it would pass said filter in such amount that the concentration of this sub¬ stance (A) on the output side of the filter would be the same as in blood. Another such substance (B) having approximately the same molecule size as (A) , but somewhat lower sieving-coefficient than (A) in the filter, would require more increased concentration than .(A) in order that (B) may pass the mole¬ cule filter to the same extent as (A) . Thus, (B) would achieve a higher concentration than:-- (A) in the container, as a greater portion of (A) than of (B) would pass the filter. However, the increased concentration would not be so strong that (B) would pass the filter nearly to the same extent as (A) . If the concentrations of (A) and (B) are maintained at levels which result in 'a concentration of (A) downstream of the filter approximately equal to the concentration of (A) in blood, whereas the concentration of (B) is much less than the natural concentration of (B) in blood, a far better separation of (A) and (B) have been obtained by means of the filters in the present case than by the ordinary cascade connection of the filters, as shown in the above European patent application. With a plasmapheresis treatment in which it may be desired e.g. to remove immuglobin G (IgG) and return albumin to the patient, this effect is utilized. A good molecule filter has a sieving-coefficient of approximately 0.5 for albumin (A) and approximately 0.1 for IgG (B) . One method for controlling the concentrations in the con¬ tainer is to regulate the liquid volume contained as a function of time. On the basis of acquired knowledge about the molecule filter and the patient in question an empiric time function for the liquid volume, which optimizes this effect according to the invention, is then programmed into the memory of the control system. By automatically controlling an important parameter as the accumulated liquid volume in the container in accordance with gained experience and adapted to the patient in question, optimum results of the treatment may be achieved without unnecessarily occupying skilled ward personnel during a rather extensive treat'tien process. The container also gives option for suitable feed-back of liquid extracted in a possible third filter disposed in the outlet conduit from the second molecule filter, in order to thereby also controlling e.g. the protein concentration in the liquid returned to the patient to a prefixed favourable value, under the superior control process according to the equation indicated above. The invention will now be explained in more detail with reference to the accompanying drawings, on which: Figure 1 shows flow circuits and components in an apparatus according to the invention, Figure 2a illustrates in principle the basic or superior control process according to the invention, and Figure 2b shows a block diagram of the complete control system according to the invention with both superior and subordinate - controlling processes. In Figure 1 it is shown an apparatus of the type described in Norwegian Patent Specification No. 144.422 and which also in principle is illustrated in German "Offenlegungsschrift" No. 2.017.473. Such apparatus comprises at least two molecule filters Fl, F2 operatively adapted to filter out molecules having molecular weight essentially below a predetermined limiting value, and each provided with an inlet conduit II, 12 for passing liquid along one side of the molecular filter, as well, as an outlet conduit for conducting liquid filtrate essentially consisting of molecules of molecular weight below said limiting value away from the other side of the filter. In the figure it is indicated that one of the filters Fl with its inlet conduit II is connected in closed circulation circuit with the blood circulation system M of a patient. An outlet conduit Ul from this filter opens into a liquid container B, which is included in a closed circulation circuit 12 on the input side of the second filter. The outlet conduit U2 from the second filter F2 is in turn fed back, possibly through a third filter F3, to a mixing chamber L in the inlet conduit II on the down¬ stream side of the molecule filter Fl in connection with the blood circulation system M of the patient. A peristaltic pump PI is disposed in the inlet conduit II to the filter Fl, and a further peristaltic pump PS is included in said circulation circuit on the input side of the filter F2. Further pumps PI and P2 are disposed in the respective outlet conduits Ul, U2 of the two filters. As shown, the circulation circuit through the container B is also provided with a throttle valve R. The molecular filter Fl may e.g. have a limiting value corre¬ sponding to a molecule weight of 50.000 daltons, and all sub¬ stances having lower molecular weight than this limiting value in the blood passed in closed circulation through the inlet conduit II along one side of the molecular filter Fl by means of the pump PI, will then gradually be extracted from the blood and discharged through the outlet conduit Ul to the liquid container B, driven by the peristaltic pump PI. Liquid from the container B is by means of the peristaltic pump PS circulated in closed circuit past one side of the molecule filter F2 and through the open valve R back to the container. This molecule filter may have e.g. a limiting value of 10.000 daltons, and with repeated circulation of liquid from the con¬ tainer in closed circuit along the input side of the filter, substances with molecular weight below this value are gradually removed from the liquid, whereas substances with molecular weight between 50.000 and 10.000 are concentrated in the con¬ tainer B. On the other side of the molecular filter F2 liquid filtrate consisting of molecules of molecular weight essentially below the limiting value of 10.000 daltons is extracted, and this filtrate is pumped by means of the peristaltic pump P2 through the outlet conduit U2 and possibly through the filter F3, back to the inlet circuit II of the first filter and the mixing chamber L, after heating by means of heater elements HE. By means of the valve R in the circulation circuit 12 of the second filter the liquid flow of this circuit may be so ad¬ justed that optimum liquid pressure across the filter is achieved and suitable concentration of uremia toxins of high molecular weight is obtained in the liquid container B, which thus has an- operative function corresponding to an urine bladder. The apparatus shown in Fig. 1 may be used for uremia treatment as well as for plasmapheresis treatment of blood. In both cases an automatic control of the liquid volume V in the con¬ tainer B according to the invention is an essential part of the treatment. In Fig. 2 it is schematically shown how this control is per¬ formed. The desires liquid volume is adjusted in accordance with a predetermined time function V(t) , which is stored in advance in the memory H of the control system. This function is selected on the basis of well tested experience and suit¬ ably adapted to the patient in question. The liquid volume V in the container B is gauged, e.g. by means of an electronic scale E, and the sensed value expressed in volume is compared in the control system with the momentary value of the stored time function by means of a comparator K. The detected devia¬ tion is transferred to a controller S, v/hich senses and adjusts the total liquid filtrate flows respectively into and out of the circulation circuit in order to cancel said deviation in accordance with the fundamental control equation: dV/dt = Qa - Qb (1) in which V is the liquid volume present in the container B at any time and dV/dt is the time derivate of this function. Qa is the total liquid flow into the circulation circuit. Qb is the total liquid flow out of the circulation circuit. If the filter F3 is not included in the apparatus shown in Fig. 1, the liquid flow Ql in the outlet conduit Ul repre sents the total flow Qa into the circulation circuit, where¬ as the liquid flow Q2 in the outlet conduit U2 (broken line) represents the total liquid flow Qb out of the circuit. The control equation (1) is then expressed by: dV/dt = Qa - Qb = Ql - Q2 In practical operation the control system may then be arranged and operatively adapted for sensing the speed of the flow driving pumpe P2 in the outlet conduit U2 of the second filter F2 as a calibrated indication of the liquid flow Q2 in this conduit, and for adjusting the speed of the first flow driving pump Pl in the outlet conduit Ul of the first filter Fl, bearing calibrated relation to the liquid flow in this outlet conduit, in such accordance with the sensed pump speed that a possible sensed deviation from the stored time function in the memory H is cancelled at any time. In this operation the pump PS in the circulation circuit is suitably operated with a surplus of pumping power, a throttle valve R in the closed circulation circuit main¬ taining the input side of the second molecule filter F2 approximately at maximum allowable superpressure, whereas the output side of the filter assumes approximate atmos¬ pheric pressure. Also, the control system is arranged and adapted for monitoring the pressure across the molecule filters Fl, F2 and for adjusting the filter pressure to a lower value, in case a prefixed maximum pressure is exceeded, the control process according to the control equation (1) or (2) being, however, maintained at all times as superior control. ith uremia treatment the filter F3 shown in Fig. 1 is preferably used as dialyser, the pressure across this filter being balanced approximately to zero. The dialyser then operates essentially independently of the volume and flow control indicated above, as described in the Norwegi¬ an Patent Specification No. 144.411 mentioned above. With plasmapheresis treatment a filter F3 may be used for extracting liquid, but not protein, from the outlet conduit U2 prior to the feeding of the filtrate in this conduit back to the inlet circuit II of the first filter and the blood flow system of the patient. In this way the protein concentration is icnreased in the filtrate which is fed back to the blood, whereas the liquid ex¬ tracted inthe filter F3 preferably is returned to the con¬ tainer B and the circulation circuit by means of a flow conduit U3 having a flow driving pump P3 and a liquid flow Q3. In the control equation the total liquid flow Qa into the circulation circuit is then the sum of the respective liquid flows in the flow conduits Ul and Q3, and the equa¬ tion may assume the form: dV/dt = Qa + Qb = (Ql+Q3)-Q2 (3) In this case the pumps PS, Pl and P2 may advantageously be set in such a way that the filters ' Fl and 'F2 are optimized, the pump F3 being so adjusted in accordance with the set and subsequently senses pump values that dV/dt assumes such value that a possible deviation of the gauged liquid volume V in the container B from the pre¬ fixed stored time function V(t) is cancelled. With a further control process the filter F3 may be utili¬ zed as a controller of the protein concentration in the filtrate fed back to the blood of the patient, the control system sensing by means of a protein detector PD the protein content of the filtrate in the outlet conduit U2 on the downstream side of the filter F3. In accordance " BURE4 __O PI ~ " with the sensed value of the protein concentration the control system then adjusts the flow Q3 of extracted liquid from the output side of the filter F3 in such a way that the protein concentration in the fed back filtrate is main¬ tained at a prefixed value. In order to maintain the above superior volume control according to the control equation during this protein con¬ centration adjustment, the liquid flows Ql and Q2 may be sensed and adjusted as previously indicated. The protein concentration in the fed back filtrate may, however, also be maintained by adjustment of a flow Q4 of protein solu¬ tion driven by a pump P4 through a branch conduit U4 from a container B2 for such solution. This branch conduit opens into the outlet conduit U2 on the downstream side of the protein detector PD and possibly the input portion of a filter F3, which, however, is not required for controlling the protein content in the outlet filtrate in this case. Instead the protein concentration is regulated by operating the pump P4 in the branch conduit in accordance with the protein value sensed by the protein detector PD, in such a way that the prefixed concentration value is maintained. In order to bring the protein concentration control in agreement with the superior volume control,, the protein so¬ lution container B2 is made a part of the container B and is weighed together with this, the remaining part Bl of the container being included in the closed circulation circuit. The control equation then assumes the form: dV/dt = d(Vl+V2) =- Qa+Qb = Qa-(Qa+Q4) Here VI is the liquid volume in the container part Bl which is included in the closed circulation, whereas V2 is the liquid volume in the container part B2 which con¬ tains protein solution. In Fig. 2b all the superior and subordinate control alternatives are schematically illustrated, the control IJUREΛ∑ O PI WΪPO connections being indicated by full lines and certain liquid flow connections by broken lines. It should be understood, however, that usually not all the indicated alternatives are operative at the same time. OMPI

Claims: Claims . 1. Apparatus for separating from a biological liquid, in particular blood, a fraction having molecular weight between an upper and a lowerlimiting value, the apparatus comprising a first molecule filter (Fl) operatively adapted for filtering out molecules of molecular weight essentially below the upper limiting value, and provided with an inlet conduit (II) for circulating liquid along the input side of the filter; an outlet conduit (Ul) with a flow driving pump (P1) being disposed for conducting liquid filtrate of molecular weight essentially below said upper limiting value away from the output side of the filter and into a liquid container (B) , which together with a circu¬ lation pump (PS) is included in a closed circulation circuit disposed to conduct liquid from the container (B) along the input side of a second molecule filter (F2) opera¬ tively adapted for filtering out molecules of molecular weight essentially below said lower limiting value, an outlet conduit (U2) with a second flow driving pump (P3) being disposed for conducting liquid filtrate essentially consisting of molecules of molecular weight below said limiting value away from the output side of the filter, by which the liquid fraction having molecular weight between said upper and lower limiting values being progressively concentrated in the liquid container, c h a r a c t e r i z e d i n that a control system is disposed for controlling the liquid volume in the container (B) in accordance with the equation dV/dt = Qa - Qb, in which V is the controlled liquid volume, which is stored as a desired predetermined time function V(t) in a memory (H) of the control system, and Qa and Qb are the total flows of liquid filtrate, respectively, into and out of the circulation circuit; the control system comprising means for sensing the liquid volume in the container (B) , com¬ paring the sensed value with and determining its deviation from the predetermined stored time function V(t) , sensing the pumped liquid flows (Q1,Q2,Q3) in all the inlet and OMPI outlet conduits (U1,U2, U3) of the circulation circuit except one, and adjusting the pumped liquid flow in the remaining inlet or outlet conduit in accordance with the total sensed flow value and in such a way that the time derivate dV/dt of the liquid volume assumes such value according to the control equation that said devia¬ tion is cancelled. 2. Apparatus as claimed in claim 1, c h a r a c t e r i z e d i n that the container (B) is disposed to be weighed by an electronic weighing device (Ξ) , the indicated weight value of which is sensed by the control system as an indication of the volume V of the liquid in the container. 3. Apparatus as claimed in claim 1, c h a r a c t e r i z e d i n that the circulation pump (PS) has a surplus of pumping power, a throttle valve (R) in the closed circulation circuit maintaining the input side of the second molecule filter (F2) at maximum allowed superpressure, whereas the output side of the filter assumes approximate atmospheric pressure; the control system being arranged and operatively adapted for sensing the speed of the second flow driving pump (P2) as a calibrated indication of the liquid flow (Q2) in the outlet conduit (U2) of the second filter and thus the total flow (Qb) out of the circulation circuit, and for adjusting the speed of the first flow driving pump (Pl) , bearing a calebrated relation to the liquid flow (Ql) in the outlet conduit (Ul) of the first filter and thus the total flow (Qa) into the circulation circuit, to a value in such accordance with the sensed pump speed that said time derivate assumes such value according to the control equation that a possible deviation from the stored time function is cancelled. 4. Apparatus as claimed in claims 1-3, c h a r a c t e r i z e d i n that the control system is further operatively adapted for monitoring the pressure across at least one of the molecule filters (F1,F2), and to lower the filter pressure if a prefixed maximum pressure is exceeded, the control process in accordance with the equation dV/dt = Qa - Qb being maintained at all times as a superior control. 5. Apparatus as claimed in claim 1, in which a third molecular -filter (F3) is disposed with its input side in the outlet conduit (U2) from the second -filter and operatively adapted to extract liquid, but not proteins, from said outlet conduit of the second filter (F2) and to pass such extracted liquid to its output side, c h a r a c t e r i z e d i n that said output side of the third molecule filter is connected with the closed circulation circuit through an outlet conduit, (U3) with a flow driving pump (P3) for returning the extracted filtrate liquid as a pumped liquid flow (Q3) to said circulation circuit, the control system comprising means for sensing the pumped liquid flows (Ql,Q2,Q3) in two of the three outlet conduits (ϋl,U2,U3) and for adjusting the pumped liquid flow in the remaining output conduit in accordance with the sensed liquid flows in such a way that the time derivate dV/dt of the liquid volume in the container (B) assumes such value according to the control equation that the determined deviation between the sensed liquid volume (V) and the stored time function V(t) is cancelled. 6. Apparatus as claimed in claim 5, c h a r a c t e r i z e d i n that the control system further comprises means (PD) for sensing the concentration of protein in the liquid flow in the outlet conduit (U2) from the second molecule filter (F2) downstream of the input side of the third filter (F3) , and are operatively adapted for adjusting on this basis the liquid flow (Q3) in the "BU EAU OMPI A WIP <> outlet conduit (U3) from said third filter in such a way that a predetermined protein concentration is maintained under the superior control performed in accordance with the equation dV/dt = Qa - Qb = (Ql + Q3) - Qb 7. Apparatus as claimed in claims 1-5, c h a r a c t e r i z e d i n that the container (B) is subdivided into two parts, of which only a first part (Bl) with liquid volume VI is included in the closed circulation circuit, a second part (B2) containing protein solution of a liquid volume V2 and being connected through a branch conduit (U4) and a flow driving pump (P4) with the outlet conduit (TJ2) of the second molecule filter (F2) down¬ stream of its passage through a possible third filter (F3) ; the control system comprising means (PD) for sensing the concentration of protein in said outlet conduit (U2) upstream of its conjunction with said branch conduit (U4) , and being operatively adapted to control the flow driving pump (P4) of the branch conduit to produce such-liquid flow (Q4) that a predetermined protein concentration is maintained within the superior control process in accord¬ ance with the equation: dV/dt = d(Vl - V2)/dt = Qa - Qb = Qa - (Q2 + Q4)

Inventors: JOERSTAD STOERKER, SMEBY LEIF, JOERSTAD, STOERKER, SMEBY, LEIF
Applicants: NOR TRON AS, NOR-TRON A/S
Application year: 1983
Main classification: A61M1
IPC codes: A61M1