CA2247031A1 - Selective membrane/sorption techniques for salvaging blood - Google Patents
Selective membrane/sorption techniques for salvaging blood Download PDFInfo
- Publication number
- CA2247031A1 CA2247031A1 CA002247031A CA2247031A CA2247031A1 CA 2247031 A1 CA2247031 A1 CA 2247031A1 CA 002247031 A CA002247031 A CA 002247031A CA 2247031 A CA2247031 A CA 2247031A CA 2247031 A1 CA2247031 A1 CA 2247031A1
- Authority
- CA
- Canada
- Prior art keywords
- plasma
- blood
- solute
- plasma chamber
- targeted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/145—Ultrafiltration
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- A61M1/342—Adding solutions to the blood, e.g. substitution solutions
- A61M1/3424—Substitution fluid path
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- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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- A61M1/3482—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate by filtrating the filtrate using another cross-flow filter, e.g. a membrane filter
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- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
- A61M1/3493—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate using treatment agents in suspension
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3601—Extra-corporeal circuits in which the blood fluid passes more than once through the treatment unit
- A61M1/3603—Extra-corporeal circuits in which the blood fluid passes more than once through the treatment unit in the same direction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3621—Extra-corporeal blood circuits
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/145—Ultrafiltration
- B01D61/146—Ultrafiltration comprising multiple ultrafiltration steps
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/24—Dialysis ; Membrane extraction
- B01D61/243—Dialysis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/04—Hollow fibre modules comprising multiple hollow fibre assemblies
- B01D63/046—Hollow fibre modules comprising multiple hollow fibre assemblies in separate housings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3672—Means preventing coagulation
- A61M1/3675—Deactivation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2313/00—Details relating to membrane modules or apparatus
- B01D2313/40—Adsorbents within the flow path
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2315/00—Details relating to the membrane module operation
- B01D2315/06—Submerged-type; Immersion type
Abstract
Methods and apparatuses for salvaging blood from a patient are disclosed. A blood salvaging circuit (140) coupled to a cardiopulmonary bypass circuit (144) includes a hemoconcentrator (152) and a sorbent-containing plasma separator. A combination device (142) for salvaging blood includes a closed plasma chamber (172) containing a plasma chamber solution (176), a hollow fiber plasma-separating membrane (156) for receiving blood and permitting plasma to be transported therethrough into the plasma chamber solution (176) and for refiltering the treated plasma back into the blood salvaging circuit (140), a selective sorbent (180) for contacting the selected solute in the plasma and binding the selected solute and an ultrafiltration membrane (184) for removing water, fluids and low molecular weight components from the plasma.
Description
WCl 97~32653 PCT/US97104126 SELE~C11VE hlEMBRANElSORPl~ON TECHNIQUES FOR SA~VAGING BLOOD
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
60/013,135, filed March 8, 1996.
BACKGROUND OF THE INVENTION
This invention relates to a system and method for salvaging or recovering blood to reduce net blood loss during surgery or other m~
procedure and selectively removing solutes from plasma. More particularly, the invention relates to a system and method for removing excess water and/or fluid from whole blood or plasma and selectively removing solutes, such as drugs (e.g. heparin), ~lltoantibodies~ toxins, ~ntigPn~, plasma components, and lipids (e.g. cholesterol) from plasma such that the treated blood can be ~tlminict~red ~ile-;~ly to the patient or saved for later ~ .alion.
A patient undergoing major cardiac surgery with cardiopulm-)n~ry bypass (CPB) can lose a ~ignifir~nt amount of blood. If the blood loss is profuse, the patient may require the ~lmini~tration of homologous blood 2 0 products. Homologous blood products can somt~-tim~s be in short supply and may carry blood-borne pathogens.
To reduce the amount of blood loss during surgery and thus the need for ~lmini~tration of homologous blood products, several methods of intraoperative blood salvage or autol,~l~ru~ion have been tried. These methods include ~lminictration of drugs (e.g. aprotinin, ~-amino caproic acid), hemoconcentration, modified ultrafiltration, cell washing, autologous predonation of blood for perioperative reinfusion, and aulu~ rusion of processed shed blood. J. Boldt et al., Blood Conservation in Cardiac Operations -- Cell Separation Versus Hemofiltration, 97 J. Thorac. Cardiovasc.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
60/013,135, filed March 8, 1996.
BACKGROUND OF THE INVENTION
This invention relates to a system and method for salvaging or recovering blood to reduce net blood loss during surgery or other m~
procedure and selectively removing solutes from plasma. More particularly, the invention relates to a system and method for removing excess water and/or fluid from whole blood or plasma and selectively removing solutes, such as drugs (e.g. heparin), ~lltoantibodies~ toxins, ~ntigPn~, plasma components, and lipids (e.g. cholesterol) from plasma such that the treated blood can be ~tlminict~red ~ile-;~ly to the patient or saved for later ~ .alion.
A patient undergoing major cardiac surgery with cardiopulm-)n~ry bypass (CPB) can lose a ~ignifir~nt amount of blood. If the blood loss is profuse, the patient may require the ~lmini~tration of homologous blood 2 0 products. Homologous blood products can somt~-tim~s be in short supply and may carry blood-borne pathogens.
To reduce the amount of blood loss during surgery and thus the need for ~lmini~tration of homologous blood products, several methods of intraoperative blood salvage or autol,~l~ru~ion have been tried. These methods include ~lminictration of drugs (e.g. aprotinin, ~-amino caproic acid), hemoconcentration, modified ultrafiltration, cell washing, autologous predonation of blood for perioperative reinfusion, and aulu~ rusion of processed shed blood. J. Boldt et al., Blood Conservation in Cardiac Operations -- Cell Separation Versus Hemofiltration, 97 J. Thorac. Cardiovasc.
3 0 Surg. 832 (1989); Y. N~k~mllra et al., Cv~ a,~Live Study of Cell Saver and Ultrafiltration No,-l-~f~rusion in Cardiac Surgery, 49 Ann. Thorac. Surg. 973 (1990); J. Boldt et al., Six Dirr~-enl Hemofiltration Devices for Blood Conservation in Cardiac Surgery, 51 Ann. Thorac. Surg. 747 (1991); D. Tixier et al., Blood Saving in Cardiac Surgery: Simple Approach and Tendencies, 6 Perfusion 265 (1991); Y. Iu et al., ~xi...i~ Blood Conservation in Cardiac Surgery, Perfusion Life 14 (July 1994); R. Breyer et al., A Comparison of Cell Saver Versus Ultrafilter During Coronary Artery Bypass Operations, 90 J.
Thorac. Cardiovasc. Surg. 736 (1985); P. Page, Ultrafiltration Versus Cell Washing for Blood Concentration, 22 J. Extra-Corp. Tech. 142 (1990); H.
Johnson et al., Conl~alalive Analysis of Recovery of Cardiop-llmon~ry Bypass si(i--~l Blood: Cell Saver vs. Hemoconcentrator, 26 J. Extra-Corp. Tech. 194 (1994); J. Morris & Y. Tan, Autotransfusion: Is There a Benefit in a Current Practice of Ag~l~ssive Blood Conservation?, 58 Ann. Thorac. Surg. 502 (1994). Of these ter'nniq 1es, hemoconcentration and cell washing are among the most cnmm~ rlly encoullLc.c~l Hemoconcentration or ultrafiltration extracts water and low molecular weight solutes from the plasma fraction of whole blood. Plàsma proteins, including prolt;i,ls involved in the coagulation c~cc~-le, remain relatively intact.
HemoconcellLlatols are generally small, c~.mract, cost-er~(;Live, and can be added to an exi~tin~ CPB circuit without major mt-Aific~tir.n.~. A disadvantage of hemocollc~lllldLion is that debris cannot be removed, thus shed blood collected during surgery cannot be processed through a hemoconcentrator 2 0 unless it has first been filtered, i.e. through a cardiotomy reservoir. Moreover, hemoconcc;llll~lion does not remove heparin from the blood, thus even though water has been removed, the blood remains fully h~a~ ed. Another disadvantage is that plasma-free hemoglobin, which results from hemolysis and is known to be toxic to the kidneys, is not erÇecLively removed by 2 5 hemoconcentration filters.
Cell washing is a method of blood concentration wherein whole blood is subjected to cenL.irugation while being rinsed with a saline solution. Cell washing removes debris, plasma-free hemoglobin, and heparin, thus the method can be used on shed blood as well as blood re.~ in the CPB circuit and 3 0 cardiotomy reservoir. A major disadvantage of cell washing is that all of the plasma proteins, incl~Aing coagulation proteins, are discarded. Platelets are lost as well. Further, cell washing recluires that a separate system, including a WO g7~32653 PCT/US97/04126 centrifuge, be dedicated for such a procedure. Therefore, the process of cell washing is more e~ellsive than hemocollce,~ Lion~ Moreover, since coagulation proteins are removed in the process, it is sometimes n~ces~ry to mini~ter replacement factors after cell washing.
Shettig~r et al., U.S. Patent No. 5,211,850, describes a plasma membrane sorbent system for removal of solutes from blood. The system comprises a bundle of U-shaped hollow fibers i~ n~lscd in an electrolyte solution with a sorbent cont~in~d in a closed plasma chamber. As blood flows through the entry arm, plasma filtration into the plasma chamber occurs.
o Solutes in the plasma are selectively depleted in the plasma chamber through binding to the sorbents. The purified plasma then reenters the membrane by reverse filtration.
S. Ash et al., U.S. Patent No. 4,071,444, discloses a portable "flat plate" reactor for use as an artificial kidney. The device comprises a sealed outer casing that is divided int~ ly by a series of flexible men~,dl-es into chambers ~ ptP l to receive blood and other chambers adapted to receive a solution co"~;.i"i..~ water, activated charcoal, zirconium phosphate, ~ilcolliumoxide and urease or other sorbents for absorbing the urea and c~ "i,.~ drawn through the membrane from the blood.
2 0 S. Ash, U.S. Patent No. 4,348,283, describes a dialyzer for use as an artificial kidney or extracorporeal mass l.~ir~r device. The device comprises a plurality of dialyzer units, each unit comprising a pair of semipermeable membranes spaced apart by a gasket such that a blood ch~lll)el is formed between the membranes. Spacers are used to separate the dialyzer units and 2 5 support the membranes. The spaces between the dialyzer units form dialysis chambers, which contain a suspension of sorbents, such as activated charcoal, calcium-sodium loaded zeolites, and/or urease.
S. Ash, U.S. Patent No. 4,581,141, teaches a dialysis material and method for removing uremic substances, wherein the dialysis material 3 0 comprises an a~ueous slurry Cont~inin~ charcoal, a highly calcium-loaded zeolite cation exchanger, a purified urease, a suspending agent such as methylcellulose, and an aliphatic carboxylic acid resin in the acid form.
S. Ash, U.S. Patent No. 4,661,246, discloses a dialysis illsL~ lent with a pump on the dialysate side of the in~ L for moving blood through the il~Ll unlent~ The instrument contains a sorbent column for purification of the dialysate, the sorbent column co~ activated charcoal, immobilized urease, zirconium phosphate cation exch~n~Pr, and zirconium oxide anion exchanger.
S. Ash, U.S. Patent No. 5,277,820, describes a device and method for extracorporeal tre~tm~nt of blood for the removal of toxins. A sorbent ~u~nsion is used for removing such toxins wh~ ;ll the sorbent comprises a powdered surface adsorptive agent such as activated charcoal, physiological eleckolytes, a cation exch~nger for removing ammonium ions and the like, and macromolecular flow inducing agents such as polyoxyalkylene derivatives of propylene glycol or polyvinylpyrrolidone. Cisplatin and metho~ could be removed from the blood by this method.
These appa,~uses and methods all lack the ability to be used for both hemoconr~ntr~ti~n and removal of selected solutes from the blood.
In view of the foregoing, it will be appreciated that development of a system and process that removes excess water and/or fluid from whole blood or plasma, conserves plasma proteins including coagulation ploL~;hls, reduces 2 o and/or removes plasma-free hemoglobin and heparin and other targeted molecules, is cost effective, and is easily used and incorporated into an t?Xi~tin~
CPB circuit or in parallel with a CPB circuit, in contrast to the prior art where expensive, stand-alone devices are used and perhaps require additional personnel to operative them, would be a signifi~nt adv~nr~m~nt in the art.
W~ 97/3~653 PCT/US97/04126 BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide a system and method for conserving blood during cardiac surgery or other m~flic~l procedure where blood loss can be copious.
It is also an object of the invention to provide a system and method for removing excess water and/or fluid from whole blood or plasma, wherein plasma proteins, including co~ tion proteins, can be conserved.
It is another object of the invention to provide a system and method for conserving blood during cardiac surgery or other medical procedure where blood loss can be copious wherein sel~cte~ solutes, such as heparin, plasma freehemoglobin, and selected proteins or hormones that have been activated, are reduced or removed.
It is still another object of the invention to provide a system and method for conserving blood during cardiac surgery wherein such system and method are cost erf~clive, easy to use, and can be incorporated into an existing CPB
circuit.
These and other objects can be accomplished by providing a system for salvaging blood from a patient for the selective removal of a targeted solute inthe blood and the removal of water, fluids, and low molec~ r weight solutes 2 0 c~ il,g:
(a) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for lc;L~ g components selected from the group con~i~ting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a 2 5 molecular weight less than the cut-off to be removed from blood or plasma; and (b) a first solute removal device for selectively removing the targeted solute from blood by means of convective and diffilsive transport of plasma from the blood across a hollow fiber plasma-s~al~lil,g membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted 3 0 solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-s~l~Lillg membrane back into ~e blood, comprising (i) a closed plasma charnber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in the plasma chamber solution under relatively u~iru pressure;
(ii) the hollow fiber plasma-s~a,ali~g membrane, wherein the plasma-s~alillg membrane has an inlet arm and an outlet arm and is configured for being immersed in the plasma chamber solution in the closed plasma chamber;
(iii) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is cont~in~d in the closed plasma chamber;
(iv) means for securing the inlet arm and outlet arm of the plasma-s~L)dldling membrane in the plasma ch~llbeL and closing the chamber to ~ l relatively ul~iÇullll plasma chamber solution ples~iule; and (v) means for circ~ tinp: the blood into the inlet arm, through the plasma-st;L,d,~lillg ,llell~ld,le, and out through the outlet arm; and (c) means for coupling the hemoconcelJIld~or to the first solute removal device to permit liquid cnl~ ic~tion therebetween and for coupling 2 0 the hemoncentrator and the first solute removal device to the patient to permit blood to be received from and ret lrn~l to the patient.
Preferably, the porous ultrafiltration lll~nll)l~e of the hemoconcentrator comprises a plurality of hollow fibers having a molecular weight cut-off in the range of about 10,000 to 100,000. Preferred materials include 2 5 polyacT~lonitrile, polysulfone, polynethylm.oth~crylate, cellulose acetate, cellulose di~et~te, and cellulose triacetate.
Preferably, the hollow fiber plasma-separating n~llll)l~u,e coll~L)lises a bundle of parallel hollow fibers constructed of a blood-comp~tible material having a suitable pore size to allow passage of plasma into the plasma chamber 3 0 solution while ret~inin~ blood cells and platelets from the blood within the hollow fibers. It is pl~fellcd that pore sizes in the plasma-s~a~dLillg membranerange between about 0.01 ,um to l.O ,um and the plasma-s~alalillg membrane is made from a material selected from the group consisting of poly~Lo~ylene, cellulose ~ et~te~ polycarbonate, polyvinylchloride, polyvinylalcohol, polymethylmPth~rrylate, polyethylene, polysulfone, and polyethylenevinylalcohol .
The sorbent should be of a size and configuration such that said sorbent is not permeable to the plasma-sepa~ g membrane. The sorbent colll~lises a ligand immobilized on a substrate wherein the ligand is preferably a member selected from the group con~i~ting of enzymes, living tissue, fr~ nt.c of tissue, cells, antibodies, peptides"llacrolllolecules, nucleic acids, lectins, carbohydl~tes, and c~Pl~tin~ agents. In ~l~relled embo(limPnt~, the sorbent has affinity for heparin and the substrate is agarose. In an especially ~leÇ~..ed embo-lim~nt, the sorbent is poly-~lysine-coupled agarose.
The hemoc~ ce~ dtol- and solute removal device can be configured for simllt~n~ous hemoconcentration and removal of the targeted solute or for sequential hemoconcentration and removal of the targeted solute. The system can also be configured such that hemoconcentration, i.e. removal of water, fluids, and low molecular weight solutes, is carried out in the blood or in the plasma. To remove water, fluids, and low molecular weight solutes from the plasma, the porous ultrafiltration membrane can be placed in the plasma 2 0 chamber of the solute removal device or a second solute removal device can be added to the system, wherein the hemoconcentrator is placed to interconnect the two plasma chambers.
Thus, an a~-lalus for selectively removing a targeted solute from blood by binding the targeted solute to an affinity sorbent and removing water, fluids, and low molecular weight solutes by ultrafiltration comprises:
(a) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in the plasma chamber solution under relatively ullirullll ~res~ule;
(b~ a hollow fiber plasma-s~alalhlg membrane having an inlet arm 3 0 and an outlet arm and configured for being immersed in the plasma chamber solution in the closed plasma chamber;
(c) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is cl-nt~int~cl in the closed plasma chamber;
(d) means for securing the inlet arm and outlet arm of the plasma-s~al~lhlg membrane in the plasma chamber and closing the chamber to m~int~in relatively uniform plasma chamber solution ~rc:S~ulc; and (e) a porous ultrafiltration ln~ e disposed in the closed plasma chamber and configured for being immersed in the plasma chamber solution, the ultrafiltration melllbl~lle having a selected molecular weight cut-off for allowing water, fluids, and solutes with a molecular weight lower than the cut-off to pass th~;lc; ln~ ugh and for ret~ining solutes with a molecular weight greater than the cut-off and means for withdrawing the water, fluids, and solutes that pass through the ultrafiltration membrane; and (f) means for circ~ ting the blood into the inlet arm such that plasma, including water, fluids, and low molecular weight solutes therein, is transported from the blood across the plasma-se~ala~illg mf~ A~-~ by convective and diffusive transport into the plasma chamber solution where the selective removal of the targeted solute from non-~lgeLed solutes using the affinity sorbent is accomplished followed by the subseq~lent transport of the non-targeted solutes across the mellll)ldlle back into the blood and out through2 0 the outlet arm.
Moreover, a system for salvaging blood from a patient for the selective removal of a targeted solute in the blood and the removal of water, fluids, and low molecular weight solutes cc,~ ises:
(a) a hemoconcentrator comprising an inlet port, an outlet port, and a porous ultrafiltration Lu~lllbl~le having a selected molecular weight cut-off for rt;~ i.,g components selected from the group con~i.ct;ng of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids,and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and 3 0 (b) first and second solute rPmoval devices for selectively removing the targeted solute from blood by means of convective and diffusive transport ofplasma from the blood across a hollow fiber plasma-s~aldtillg membrane into a WO 971326~i3 PCT/US97/04126 plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accnmrli~h.s(l followed by the subsequent transport of the non-targeted solutes across the plasma-s~aldlhlg men31"~le back into the blood, each first and second solute removal device comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulatet equilibrate, and interact plasma in the plasma chamber solution under relatively ul~irO
pressure;
(ii) the hollow fiber plasma-se~ Lh~g membrane, wherein the plasma-sel,a,alillg membrane has an inlet arm and an outlet arm and is configured for being immersed in the plasma ch~mher solution in the closed plasma chamber;
(iii) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is contained in the closed plasma 1 5 chamber;
(iv) means for securing the inlet arm and outlet arm of the plasma-se~ld~ing membrane in the plasma challlbe. and closing the chamber to ~ i-- relatively ul~iÇ~ ll plasma chamber solution pressure; and 2 0 (v) means for circnl~tin~ the blood into the inlet arm, through the plasma-separating lllenll)l~e, and out through the outlet arm;
(c) means for coupling the plasma chamber of the first solute removal device to the inlet port of the hemoconc~llLlalol and means for couplingthe outlet port of the hemoconcentrator to the plasma chamber of the second 2 5 solute removal device such that plasma can flow from the f rst solute removal device through the hemoeollcellll~lor to the second solute removal device such that water, fluids, and low molecular weight solutes can be removed from the plasma by ultrafiltration, and means for coupling the outlet arm of the first solute removal device to the inlet arm of the second solute removal device such 3 0 that blood can flow therebetween; and (d) means for coupling the first and second solute removal devices to the patient to permit blood to be received from and returned to the patient.
1~
A m~tho~l of select}vely removing a targeted solute and water, fluids, and low molecular weight solutes from blood comprises:
(a) providing a system comprising:
(1) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for rel~;.,i-,g components selected from the group con~i~ting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (2) a first solute removal device for selectively removing ~e targeted solute from blood by means of convective and dirrusiv~
transport of plasma from the blood across a hollow fiber plasma-se~aldLillg membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subse~uent transport of the non-targeted solutes across the plasma-sepa~dlillg membrane back into the blood, comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, 2 0 equilibrate, and interact plasma in the plasma rh~mher solution under relatively ul~irullll pressure;
(ii) the hollow fiber plasma-s~alalil~g ,l. ,n~l~le, wherein the plasma-s~ g membrane has an inlet arm and an outlet arm and is configured for being immersed in the plasma 2 5 chamber solution in the closed plasma chamber;
(iii) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is contained in the closed plasma chamber;
(iv) means for securing the inlet arm and outlet arm of the 3 0 plasma-s~al~ g membrane in the plasma chamber and closing the chamber to m~int~;n relatively unif~ plasma chamber solution pressure; and WO 97/32653 PCT/U~97/~4I26 (v) means for circulating the blood into the inlet arm, through the plasma-sepa~dti,lg membrane, and out through the outlet arm; and (3) means for coupling the hemoconcellL.~lol to the first solute removal device to permit liquid ccl.-ll..ll-it~.~ti-)n therebetween and for coupling the hemoncellllalof and the ffrst solute removal device to the patient to permit blood to be received from and retllrnP-~i to the patient;
(b) directing the blood from a source into the inlet arm by the means for circlll~ting the blood, through the plasma-se~alalillg membrane and out the outlet arm at a volume and a velocity that permits convective and ~lir~u~ive transport of plasma from the blood across the plasma-se~alalh~g membrane along the inlet arm of the plasma-s~ldling ll~lllI"~le into the plasma chamber SOllltifm;
(C) c~ ing the plasma m the plasma ch~mher solution to come into contact with the sorbent such that the targeted solute is selectively bound to the sorbent;
(d) c~n~ing the non-targeted solutes to pass by diffusive and convective transport from the plasma chamber solution across the plasma-2 0 s~a.ilLiulg membrane into the blood retained by the plasma-s~aldlhlg membrane and out of the device;
(e) c~n~in~ the blood or plasma to pass through the hemoconcentrator such that water, fluids, and solutes with a molecular weight less than the cut-off pass through the porous ultrafiltration membrane and are 2 5 withdrawn from the blood or plasma, and the ultraffltration membrane retains cells and solutes with a molecular weight greater than the cut-off in the blood or plasma.
CA 0224703l l998-08-l8 WO 97l32653 PCT/US97/04126 BRIEF DESCRIPTION OE~ THF SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 shows a srhpm~tic diagram of a CPB circuit according to the prior art.
FIG. 2 shows a sçhPm~t~ agram of an illustrative embodiment of a blood salvage circuit according to the present invention comprising a hemocon;enlldlol and a solute removal device.
FIG. 3 shows a srllPm~tic diagram of a solute removal device according to the present invention.
FIG. 4 shows a sch~qm~tir diagram of another illustrative embodiment of lQ a blood salvage circuit according to the present invention.
FIG. S shows a scht-m~tic diagram of still another illustrative embodiment of a blood salvage circuit according to the present invention.
FIG. 6 shows a scltem~tiC~ diagram of a combined device according to the present invention coll~ishlg a plasma se~al~lol with sorbent for removing selecte~l solutes and an ultrafiltration membrane for hemocollcellLl~Lion.
DETAIL~D DESCRIPTION
Before the present system and mPtho(l for salvaging or recovering autologous blood are disclosed and described, it is to be understood that this 2 0 invention is not limited to the particular emborlim~nt~, process steps, and materials disclosed herein as such embollim~ont~, process steps, and m~t~ri~l~
may vary somewhat. It is also to be understood that the t~rminology employed herein is used for the purpose of describing particular embo~lim~nts only and isnot intended to be limiting since the scope of the present invention will be 2 5 limited only by the appended claims and equivalents thereof.
It must be noted that, as used in ~is specification and the appended claims, the singular forms "a," "an," and "the" include plural rer~ Ls unless the context clearly ~lirt~tes otherwise. For example, reference to "a solute"
inrln~les reference to two or more of such solutes, and reference to a device 3 0 co~ isillg "a sorbent" includes reference to a device CO~l~)liS~l1g one or more or such sorbents.
In describing and cl~imin~ the present invention, the following terminology will be used in accordance with the de~mitions set out below.
As used herein, "patient" refers to a human or a warm-blooded animal.
As used herein, "patient blood" refers to blood taken directly from a patient, such as blood collected by predonation for storage and eventual lmini~tration to the patient.
As used herein, "circuit blood" refers to blood that is circulated through the CPB circuit. Circuit blood is typically given back to the patient before theend of surgery or shortly thereafter.
As used herem, "shed blood" refers to blood that is lost during surgery.
Shed blood is aspildled from the body and stored in a cardiotomy reservoir.
As used herein, "peptide" means peptides of any length and includes proteins.
Blood consists of cellular and non-cellular fractions, or, alternatively, of formed and non-formed elements. As used herein, "plasma" means the non-cellular fraction or non-formed el~mP-rltc of blood. In other words, plasma means the portion of blood exclusive of the cellular fraction or formed elem~.ntc thereof.
As used herein, "sorbent" means a ligand coupled to a ~ul~ le.
2 0 Sorbents can be in any usable form of sufficient size that the sorbent is not permeable to the plasma-s~l~ling membrane of the solute removal device, i.e.
does not enter the blood. For e~ample, sorbents can be in particulate form, such as beads, spheres, or the like. ~orbents can also be present as fil~mPnt~, strands, sheets, or films. The form is not important as long as there is a(leqll~te 2 5 OppOl~Ulli~y for the circulation of plasma and contact between the sorbent and the plasma. Suitable substrates include biocolll~atible polymers, such as agarose, polyacrylamide, nylon, nitrocellulose, poly~lylelR, and the like. The substrate should have functional groups to which the ligand can be att~h~d according to principles and materials well known in the art. Suitable ligands 3 0 include antibodies, peptides, enzymes, nucleic acids, lectins, carbohy~ s, chelating agents, macromolecular ligands, and the like.
As used herein, "plasma chamber solution" means the solution contained in the plasma chamber. ~t the beginning of a separation procedure, the initial solution will typically comprise water or an electrolyte, i.e. saline, solution co~ g sorbents and other selected materials. As the various plasma components enter the plasma chamber by convection or ~liffilsion from the hollow fiber plasma-se~ Lillg m~lllbl~le, equilibration will take place such that, except for the targeted components bound to the sorbent in the plasma chamber, the concentration of plasma components in the blood inside the lumens of the hollow fibers will be the same as the concentration of the plasma components in the plasma chamber. Hence, the m~keup of the plasma chamber solution can vary during the removal process, but functionally the action composition is not critical.
Referring to FIG. 1, there is shown a scllPm~tir repres~t~tion of a CPB
circuit 4. Venous blood is removed from the patient 6 and con-!ucted by gravity flow to a venous or CPB circuit blood rest~ ~/oh 8. Blood is pumped out of the CPB reservoir 8 by a pump 12. This blood optionally can be circulated through a hemoconce~ tol~ 16 for removing water, fluids, and low molecular weight molecules. Blood that has passed through the hemoconc~ LoI is 2 0 returned to the venous reservoir 8. Blood can also be pumped through an oxygenator 20 for supplying oxygen to the blood. The oxygenator 20 is coupled to a source of oxygen 24 through an oxygen line 28. The oxygenator 20 is coupled to an arterial filter 32 for filtering the ~ ygenaLed blood before it is recirculated into the CPB circuit reservoir 8 or returned to the patient 6.
2 5 Shed blood is removed from the patient 6 by means of a pump 36 and stored in a cardiotomy reservoir 40, where the shed blood is filtered. The cardiotomy reservoir 40 is coupled to the CPB circuit reservoir 8 such that filtered shed blood can selectively be mixed with CPB circuit blood.
FIG. 2 shows an embodiment of the present invention CUlll~JLi~iillg a CPB
3 0 circuit blood reservoir or cardiotomy reservoir or patient 48 coupled to a blood salvage circuit 56. The blood salvage circuit comprises a pump 60 for ~u~ ing the blood out of the reservoir 48 and moving it through the blood salvage ~ CA 02247031 1998-08-18 circuit. The blood salvage circuit further comprises a hemoco.lcen~laLur 88 for removing water and low molecular weight solutes from the blood and a solute removal device 64 for separating plasma from the blood and cont~ ting the separated plasma with a specific sorbent for removing a selected solute. Such a device is described in U.S. Patent No. 5,211,850, which is hereby incorporated by ler~ ce, and is shown in FIC;. 3. Line 50 couples the blood reservoir 48 to the hemoconcentrator 88, line 52 couples the hemoconcentrator to the solute removal device, and line 54 couples the solute removal device to the blood reservoir 48.
Referring now to FIG. 3, the solute removal device 64 comprises a bundle of hollow fibers that make up a hollow fiber plasma-s~al~lulg membrane 66. Each hollow fiber has a central lumen through which the whole blood passes from the inlet arm 68 to the outlet arm 72 of the sorbent removal device. Each hollow fiber m~ml~,~e has a series of pores or openings through which plasma and plasma coll~ullclll~, toxins, drugs, or other solutes having 1e~:j smaller than the pores can pass into a ~ulloullding plasma ch~mher solution 76 ct)~t~ining a sorbent 80. The hollow fiber plasma-separating membrane 66, plasma chamber solution 76, and sorbent 80 are cont~inP~ in a housing 84. The housing is closed by f~ed potting material 85 and 86. The 2 o inlet arm of the plasma-sepal~lillg membrane is coupled to an inlet line 87, and the outlet arm is coupled to an outlet line 89. Optionally, a plasma port 82 in the housing permits access to the plasma chamber for removing plasma thc.erl~lll, for making pressure measurements, adding sorbent or plasma chamber solution, or the like. The plasma may contain various sugars, plo~ills, hormones, antibodies, fats, bile salts, toxins, electrolytes, and the like, as well as other substances that may have been ~-lmini~tered for various purposes. Heparin, for example, is added to the patient for its ~ntiro~gulation opellies, but is desirably removed or inactivated at the end of CPB. When heparin and other small solutes exit the membranes through the pores by 3 0 convection (pl~s~ule gradients) or diffusion, they enter into the plasma chamber solu~ion 76 co~ sorbent particles 80 that have a specificity for binding heparin or other selected solutes.
CA 0224703l l998-08-l8 The hollow fiber plasma-sc~al~lillg membrane can be made of any blood compatible material having suitable pore size to allow passage of selecte~l solute materials into the plasma chamber, even those of high molecular weight, and yet retain the blood cells and platelets in the lumen of the hollow fiber. Pore sizes in the lllclllblane are relatively large, with sizes ranging between about0.01 ,um to l.0 ,um being suitable, with pore sizes of about 0.1 ,um to 0.8 ,um being preferred and pore sizes of about 0.4 to 0.75 ,um most l,refe.lcd.
Fxemrl~ry of suitable fiber materials are poly~ro~ylene, cellulose diacetate, polycarbonate, polyvinylchloride, polyvinylalcohol, polymethylmPth~rylate, polyethylene, polyethylenevinylalcohol, polysulfone, and the like.
The hollow fiber plasma-s~a.dLillg membrane ~1impn~cic)rls (hollow fiber lumen (1i~m~ter~ length of each hollow fiber, and the number of fibers) and the blood flow rate through the fiber have to be ~3plimi~ed based on the art of membrane plasma sel,al~lion. It is well known in the art of membrane plasma separation that the plasma s~aldLion rate is directly pl~olLional to the blood shear rate and the tr~n~mt~mhrane pres~ulc. Damage to the blood cells, however, may occur if the tr~n~m~mhrane ~lesbu.e is increased beyond a particular limit. Also, blood cells are susceptible to high shear rate. For a given blood flow rate and total membrane surface area, tr~ncmPmhrane plCSsulc 2 0 increases with the hlc-ease in hollow fiber length and with the decrease in lumen size. Shear rate also increases with the decrease in lumen size. The above-mentioned factors may be considered in arriving at the o~Lilllum size of the hollow fiber membrane. The removal rates of solutes from the blood depend on the plasma separation rate, the amount (surface area, etc.), affinity of 2 5 sorbents, and the extent of plasma-sorbent interaction. Hollow fibers of the plasma-sep~ g m~mb-alle having inside ~ m~ters of between about 150 ~um and 500 ,um and wall thicknesses of between about 50 ,um to 400 ,um are typical. The internal surface area of a typical plasma-s~al~Ling membrane can be between about 0.1 and 5.0 m2, and the volume of the plasma chamber can be 3 o between about 50 and lO00 ml. The length of the plasma-sepaldLillg membrane from the inlet port to ~e exit port should be between about 10 and lO0 cm, CA 0224703l l998-08-l8 WO 97~326~i3 PCT~US97/04126 with lengths of about 20 to 25 cm being prel;lled. Flow rates of blood through the plasma-separating membrane can vary from about 50 to 3000 ml/min.
The plasma chamber should be sized to hold an ~çqn~te amount of sorbent materials to adsorb the unwanted solutes, such as heparin. This may vary depending on the medical procedure for which the blood salvage system is being used and the amount of heparin or other rnaterial to be removed and the nature of the sorbent material.
An illustrative commercial device according to FIG. 3 is a heparin removal device (HRD, Research Medical Inc., Midvale, UT). This unit is a disposable hollow fiber membrane-type plasma sel~a.dl~r cQ~eieting of a microporous polypropylene hollow fiber bundle mounted in polyurethane exit ports and a polystyrene plastic housing. Blood enters the fiber bundle through the blood inlet port, passes through the hollow fiber lumens in which a positivetr~n.em~..l.l~le ~l~S~ul~, allows plasma to pass through the porous hollow fibermembrane along its entire length into the plastic housing where it contacts the sorbent. Solutes in the plasma with an affinitv for the sorbent bind to the sorbent and are immobilized. The plasma with a reduced co-.ce~ ion of the selected solute can then be removed from the plasma chamber through the plasma port or can reenter the hollow fiber m~l,-l,-~.e by refiltration for 2 0 transport out the device through the outlet port.
Prior to use, the plasma ch~mhPr is prefilled with plasma chamber solution cl)..l;.i.-;i-g sufficient sorbent particles to bind the plasma component to be s~-dled. The sorbent can be placed in the plasma chamber prior to, simlllt~neously with, or after filling the plasma chamber with the plasma 2 5 chamber solution. Such unit is suitable for use as a .cimnlt~n~ous plasma pl~rmlc~tion and reinfusion system having the above-described advantages.
The removal of heparin from an extracorporeal circuit is a primary objective of the invention. The binding of heparin to a solid substrate by affinity adsorption techniques is docnm~--nt~ in the art. E.g., Moh~mm~fl et 3 0 al., Ql~ e Removal of Heparin from Plasma and Other Aqueous Solutions by Affinity Adsorption on Poly(L)lysine Sepharose 4B, 20 wo 97/32653 PCT/USg7/04126 Thrombosis Res. 599-609 (1980). Poly(L)lysine-coupled agarose beads are one form of plcÇ~lled sorbent.
The plasma separator device is applicable to any plasma sorbent system where separation, interaction, and recolll'Lhlalion takes place. Typical m~-lir~l procedures where the blood is hcp~lini~ed include cardiop--lmnn~ry bypass, hemodialysis, angioplastic procedures, pl~m~rh~resis, ~uloll~rusion, and hemocollcellLr~lion. Exemplary of other potential applications of the system areremoval of ~-~lo~ ihodies using sorbents such as immobilized protein A;
removal of circul~ting toxins and tumor antigens using sorbents such as immobilized monoclonal antibodies and specific immobilized ligands; removal of protein-bound toxins and drugs (e.g., in the case of a drug overdose);
procedures using live cells in the plasma ~h~llbel in the place of sorbents suchas islet cells or liver tissue fr~rnent~ for the tre~tm~n~ of diabetes, hepatocytes for the tre~tmPnt of liver failure and the like; selective removal of plasma components using immobilized enzymes as sorbents; and removal of cholesterol (low density lipuploteills, LDL) using sorbents specific to LDL.
While not shown in FIG. 2, the hemoconcellLldtor 88 can be placed in circuit 56 either uy~Lle~ll or downstream of the solute removal device 64. The hemoconcellLl~Lol 88 is pl~;rel~bly of a type already known in the art for 2 0 removing water, fluids, and low molecular weight molecules from blood by ultrafiltration. A plcr~llcd hemoconcentrator (FIG. 2) col~ ises a bundle of hollow fiber ultrafiltration ll,tlnl)l~es 100 in a housing 104 that defines a chamber in which the hollow fibers are disposed. Inlet 108 and outlet 112 ports are coupled to the bundle of hollow fibers for con~ ctin~ blood, plasma, or water into and out of the hemoc~"lcellLl~tor. One or more ports 116 and 120 can also be present in the wall of the housing for con~luctin~ blood, plasma, orwater into or out of the chamber. A vacuum line 124 is also preferably coupled to the hemoconcellLl~or for removing water ~eLerl~,m. The vacuum line in FIG. 2 is coupled to a port 120 in ~e wall of the housing. A collection vessel 3 0 128 and vacuum pump 132 are also coupled to the vacuum line. For experimPn~l purposes, plcs.,ulc ports can be placed at various points in the system ~or m~ rin~ pressure. In FIG. 2, ~ s~ule ports 134, 135, 136, 137, W<:l 97r32653 PCT/US97/04126 and 138 are for m~e~lring, respectively, hemoconcentrator inlet ~les~ulc, hemoconce~ dtor outlet pressure and solute removal device inlet plcs~urc, solute removal device plasma pressure, solute removal device outlet ~c~u,e, and hemoconrentr~tQr vacuum prcs~ulc. A shunt line 139 from line ~2 to line 54 permits the solute removal device 64 to be bypassed. For example, clamping lines 52 and 54 at sites 58 and 60 proximal to the solute removal device permits blood to flow through the shunt line directly from the hemoconcelllldtor to the blood reservoir. In this configuration, multiple cyclesof hemoconcentration can be ~clÇulllled without passing through the solute removal device. Opening such clarnps at sites 58 and 60, and clamping the shunt line at site 62 causes the blood to flow through the solute removal device.
Thus, the system shown in FIG. 2 permits operation in selected operational modes, such as (1) allowing the blood to flow through the solute removal device each time the blood flows through the hemoconcen~ld~or (.~imnlt~nPous mode), or (2) allowing the blood to flow through the hemo~;ollcc;~ d~ur for several cycles and then to flow through the solute removal device (seqllenti~l mode).
A ~lcfcllcd hemoconcclllld~or for use in the present invention is a BIOFIL~ER 140 ~Research Medical, Inc., Midvale, Utah) co..l;.i..il~g a porous hollow fiber, cçllnlose (li~et~t~ clllbl~e. Other suitable ll~-lll,l~e materials2 0 include polyacrylonitrile, polysulfone, polymethylmethacrylate, cellulose acetate, cellulose tri~et~t~, and the like. Preferably, the hemocollce.l~ldtor is ul~s~leam of the solute removal device 64 so that blood passing through the hemocollcellLI~lol is hel)alil.i~ed and has less likelihood of foll~ g clots than if the hemoconcentrator were placed dowl~LI~dlll of the solute removal device, 2 5 particularly where such solute removal device is a heparin removal device.
Placing the hemocollcclllldlor dowllsllcdlll of the heparin removal device increases the likelihood of clots collecting in the hemoconcentrator. Moreover, concell~d~illg the blood also concell~la~es the targeted solute, e.g. heparin, which makes the solute removal device operate more efficiently.
3 0 Although the present invention is shown in ler~ ce to a CPB circuit, the invention can also be used by conn~octing the blood salvage circuit to the cardiotomy circuit or by connecting the blood salvage circuit directly to the patient for processing of patient blood.
Another illustrative embodiment of the present invention is shown in FIG. 4. This system 200 comprises a hemoconcclllr~tor 204 and a pair of selected solute removal devices 208 and 212 coupled to a blood reservoir 216.
The blood reservoir could be a cardiotomy reservoir, a CPB circuit, a patient, or the like. The blood rcs~lvoil is coupled to device 208 by line 220. A roller pump 224 is disposed on line 220 for pumping the blood through the system.
One end of line 220 is coupled to the imet port ~8 of device 208, and the other 1 0 end of the line 220 is coupled to the blood reservoir. ~nother line 232 is coupled at one end to the outlet port 236 of device 208 and at the other end to the inlet port 240 of device 212. Line 244 is coupled at one end to the outlet port 248 of device 212 and at the other end to the blood reservoir. The plasma port 252 of device 208 is coupled by line 256 to the inlet port 260 of the hemoeollcel,lla~or 204, and the outlet port 264 of the hemoconce~lLlalol is coupled to the plasma port 268 of device 212 by line 272. The vacuum port 276 of the hemoconcentrator 204 is coupled to a vacuum line 280, which is coupled to a collection vessel 284 and a vacuum pump 288. For experimental purposes, ple~,~ule ports 290, 292, 294, 296, 298, and 300 are placed in the 2 0 system as shown for taking pressure measurements. The pressure measurements taken at ports 290, 292, 294, 296, 298, and 300 represent, respecti~ely, ~LeS~Ule at the imet port 228 of device 208, pressure at the outlet port 236 of device 208 and at the inlet port 240 of device 212,1,lcs~,ule at theplasma cha-nbt;l 304 of device 208 and ~lcs~ulc of inlet port 260 of the hemoconcentrator 204, pressure at the plasma chamber 308 of device 212, plcssulc at the outlet port 248 of device 212, and vacuum plcs~ule at the vacuum port 276 of the hemoconcenll~lor 204. A flow probe 312 in line 256 measures the plasma filtration rate of device 208.
In this configuration, blood is pumped through the first solute removal 3 0 device 208, and the plasma that is separated from the blood cells is con~ ete(l to the hemoconc~ r. In the hemocc,llcen~lator, water and low molecular weight solutes are removed from the plasma and con~ t~l to a collection vessel. The concentrated plasma that exits the hemoconce"~ld~or is then conducted into the plasma chamber of the second solute removal device, where the plasma is combined with blood cells again after refiltration. The blood thatexits the second device has thus been subjected to both hemoconcentration and affinity removal of a selected solute.
Not all of tne plasma separated from tae blood in the first solute removal device 208 passes through the hemoconc~llL,~lol. A portion of the plasma lc~nl~l~. the hollow fiber m~n,l,l~lle by refiltration for ,~...;x;..~ with the blood cells, exits the device at outlet port 236, and is transported tnrough line 232 to the second solute removal device 212. In the second solute removal device 212, the plasma can again pass through the pores in the hollow fiber membranes into the plasma ch~mh~r 308. In the plasma chamber 308 there can be mixing of plasma with concentrated plasma from the hemoconcentrator and additional affinity removal of selected solutes. The plasma can then return to the hollow fiber mell,b,~,e by refiltration, where it is mixed with the blood cells, and eventual retllrn~od to the blood lt:StlVOil. Preferably, a fine mesh screen is placed at port 252 of device 208 and at port 268 of device 212 to retain sorbentin the plasrna chambers.
A variant of the embodiment shown in FIG. 4 is illustrated in FIG. S, 2 0 where like reference numbers are used to indicate similar parts. The dirrt;,~.lces between FIG. 4 and FIG. S are in how the plasma and the water removed thele~lolll pass through the hemoco"c~"Ll~lor. In FIG. 4, the plasma enters the h~ml-con~P..~.alor into the chamber that ~wl~ullds the hollow fibers,and the water and low molecular weight solutes pass from the chamber through 2 5 the pores in the hollow fiber ultrafiltration membrane into the lumens of the hollow fibers and then into the vacuum line for collection in the collection vessel. In contrast, in the system 316 shown in FIG. 5, the plasma enters the - hemoconcentrator into the lumens of the hollow fibers, and the water and low molecular weight solutes pass from the lumens of the hollow fibers through the 3 0 pores in the hollow fibers into the chamber and then into the vacuum line for collection in the collection vessel.
In FIG. 6 there is shown a coll~bilLalion device 142 for carrying out the processes of hemoconc~l-L-~tion and selective removal of a targeted solute. The co~ h aLion device 142 is placed in a blood salvage circuit 140 coupled to a CPB circuit 144, as in FIG. 1. The blood salvage circuit comprises a pump 148 for pumping blood from the CPB circuit 144 through the co~ ion device 142 and optionally through a separate hemocollc~ k)r 152. The colllbi~lion device comprises a hollow ~lber plasma-sepal~tillg lllellll,l~e 156 coupled to an inlet port 160 and an outlet port 164. The hollow fiber plasma-sepal~illg m~lllbla-le 156 is enclosed in a housing 168 that encomr~ses a plasma chamber 172 Cont~;nin~ a plasma chamber solution 176 and a selective sorbent 180. The hollow ffbers have pore sizes in the range of about 0.01 ,~m to 1.0 ,um, as described above. Also contained within the plasma chamber 172 is an ultrafiltration membrane 184 having an outlet port 188. This ultrafiltration membrane is also made of hollow fibers having a molecular weight cut-off in the range of about 10,000 to 10Q,000, as described above in conn~ction with the hemoconce,lllalol. Not only can vacuum be applied to enh~nre hemoconcentration, but the system also accommodates countervalent or dialysis solutions.
Blood is pumped into the c~lllbill~Lion device 142 such that the blood 2 o enters at the inlet arm 160. The blood passes through the lumens of the hollow fiber membranes, and the plasma and solutes pass through the pores of the .le,l.l,.~e into the plasma chamber solution co..~ g a selective sorbent.
When selected solutes contact the sorbent, the selected solutes bind to the sorbent, thus depleting the concentration of the select~(l solute in the plasma. If the outlet port 188 of the ultrafiltration mem~l~e is closed, then the selected-solute-depleted plasma passes through the pores of the hollow fiber plasma-st;l)a~ g ~ e 156 by refiltration and passes out of the device 142 into the blood salvage circuit 14û. The solute-depleted blood can optionally be passed through a separate hemoconcentrator 152, where water, fluids, and low 3 0 molecular weight solutes are removed by ultrafiltration, or can pass directly into the CPB circuit 144. In this configuration, the blood can be subjected to ,simlllt~n~ous or sequential hemoconcentration and solute depletion.
-CA 0224703l l998-08-l8 By opening the outlet port 188 of the ultrafiltration membrane 184, solute-depleted plasma can be subjected to hemoconcentration in the con~ ion device. Preferably, the outlet port 188 is coupled to a vacuum line, similar to what is shown in FIGS. 2, 4, and 5. Water, fluids, and low molecular weight molecules pass through the ultra~filtration membrane 184 and are drawn out of the device 142 through the outlet port 188 for coTl~octiQn The pore size of the ultrafiltration ~n~ l)ldl~e 184 can be selected such that the size of the low molecular weight mfllec~lles removed is select~ble. Typically, the molecular weight cut-off is in the range of about 10,000 to about 100,000. The concentrated plasma in the plasma chamber let;~ the hollow fiber plasma-s~alaLillg membrane 156 by refiltration, mixes with blood cells in the lumens of the hollow fibers, and passes out of the device through the outlet arm 164.
As with the blood salvage circuit of FIGS. 2, 4, and 5, the collll,hl~ion device can be used by c.-nn~ction to the CPB circuit, the cardiotomy circuit, orby connection ~lilc;-;~ly with the patient for processing of patient blood.
The co"~ alion device possesses a number of advantages that are not otherwise obtained. For example, the Collll)ilk-lion device permits blood salvage and targeted solute removal in a single, low cost device. Also, higher pressures can be used for ultrafiltration than are otherwise possible because the 2 0 ultrafiltration is done in the plasma phase rather than the whole blood phase.
Such higher pressures are not possible in the whole blood phase because of the res-lltin~ lysis of blood cells. Further, the colllbillation device provides for a quick and easy means for responding to the systemic infl~mm~tory response that accc ,ll~allies cardiopulmonary bypass in a significant proportion of patients. This systemic jnfl~,l""~loly response is believed to result from the rapid release of certain cytokines into the blood. These cytokines can be removed by using selected sorbents, such as immobilized immnn(>globulins, - receptors, and/or whole cells, for specific binding of the cytokines. Removal of the cytokines from the blood of a patient undergoing systemic infl~ y 3 0 response is believed to alleviate such response.
, Further advantages of the present invention derive from the lack of high tr~n~m~,mhrane pressure in the plasma separating and sorbent-co~ g device.
This relatively low tr~n~m~--mhrane pressure results in improved rheology as compared to other devices known in the art such ~at the present system can be operated at higher flow throughputs. This higher rate of flow results in less tirne being needed to process the blood, and con~eqll~ntly less time is needed to treat a patient.
Example 1 In this e~mrle, ~,1~s~ul~ and flow data were d~;le, .. ~ for a plasma separation and sorbent-co~ device similar to the plasma sorbent system described in U.S. Patent No. 5,211,850 to Shetti~r & McRea and illu~lla~;d in PIG. 3.
In this exarnple, a plasma sorbent system col.~ .;..g a heparin-speci~lc sorbent (HRD, Research Medical Inc., Midvale, UT) was tested to deterrnine inlet pressure (P;n)~ outlet ~res~ul~ (PoU~~ plasma ~ s~ule (Pp,asma), arld tran~m~,lnhrane ~l.,ssule (TMP). Pressure mea~ulelllell~ were taken at the inletline 87, outlet line 89, and plasma port 82. TMP was calculated as the average of inlet and plasma pressures less plasma l~leS~U'e [(Pin + Pplasma)/2 - PplasmJ2 0 Table 1 shows the results of such an experiment using porcine whole blood as the m~-1inm Blood was pumped through the HRD using a SARNS 5000 blood pump.
Table 1 25Flow (ml/min) Pin P0ut Pplasma TMP
(mm Hg) (mm Hg) (mm Hg) (mm Hg) sOo 380 95 210 100 , WO 97J3~653 PCT/US97~04126 These data show that the inlet blood pressure (Pjn) increases with the increase in blood flow rate through the hollow fiber lumen. The plCS'.Ule in the~ plasma ~h~mher (Pplasma) also increases proportionately, while the outlet blood pressure (Pout) increases at a much slower rate. The tr~nem~mhrane pressure (TMP) is a direct measure of the driving force for the filtration rate of fluid from the blood in the inlet arm of the plasma-sepaLa~ g m~lllbld,le into the plasma ch~mher. This driving force is seen to be increasing with the increase in the blood flow rate. This test demonstrates that as the Pplasma increases with the increase in Pin, two di~r~relll regions of mass transfer are created. In theinlet arm of the plasma-separating membrane where Pin > Pp,asma, there is a positive convection of mass L,~.rt;r across the m~m~ ule through its pores into the plasma chamber solution. However, in the outlet arrn of the plasma-sepal~lhlg membrane where Pout < Pp,asma, this causes a negative or reverse convective mass L,~u~.r~ across the membrane through its pores frorn the plasma chamber solution into the lumen.
Example 2 In this ~x~mple, a hemoconc~ or (BIOFILTER 140, Research 2 0 Medical Inc., Midvale, UT) was tested to ~lelr~ vacuum ples .ur~ (PVacuum), inlet pressure (Pin), outlet pressure (Pout)~ tr~n.~m~...l.l~le prc~s~ c (TMP), and ultrafiltration rate (UFR~ at three ~liLr :renl flow rates using human blood in human clinical trials. TMP was det~rmin~d as the average of inlet and outlet pressures less va~uum pressure [(Pin + PoUt)/2 - PVacuum]. Blood was pumped 2 5 with a roller pump from a cardiotomy reservoir or cardioplllmnn~ry bypass circuit into the hemoconcentrator through the inlet port. Water and solutes having a molecular weight lower than that of the molecular weight cut-off of theultrafiltration ~ nll),~le passed from the lumens of the hollow fibers through the pores of the membrane into the chamber defined by the housing. A ~a~;uum 3 o line was coupled to a port in the housing and to a collection flask and a vacuum pump for applying reduce pressure to the chamber. Concentrated whole blood passed through the outlet port for return to the cardiotomy reservoir or CPB
eircuit. Tables 2-4 show the results of such t~ climents at hemoconcentrator flow rates of 200 ml/min, 300 mlfmin, and 400 ml/min, respectively.
Table 2 HemocollcellLI~tor Flow Rate = 200 ml/min Pvacuum Pin Pout TMP ~JFR
(mmHg~ (mmHg) (mm Hg) (mm Hg)(ml/min) Table 3 ~T~moconcentrator Flow Rate = 300 ml/min Pvacuum Pin Pout TMP UFR
(mm Hg) (mm Hg) (mm Hg) (mm Hg)(ml/min) _ Table 4 Hemoconcenll~lol Flow Rate = 400 ml/min Pvacuum Pin Pout TMP UFR
(mm Hg~ (mm Hg) (mm Hg~ (mm Hg)(ml/min) These results show ultr~filtr~ n rates can be manipulated by varying flow rates and vacuum pr~s~ures. At a given flow rate, the ultrafiltration rate can generally be increased by increasing the vacuum ~)lc;S~
Example 3 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 2, wherein hemocon~entr~tion and heparin removal were carried out simlllt~n~.ously. The hemocollcell~l~lor was a BIOFILTER 140 and the solute removal device was an HRD for removing 2 0 heparin. The shunt line was clamped such that blood passed through the hemoconcentrator and the solute removal device in each passage through the circuit.
In this ex~mple, bovine whole blood was recirculated through the system at a flow rate of 500 ml/min for 60 ll~illul~s. The pn,~u,e, ultrafiltration rate, 2 5 and heparin removal data from this experiment are shown in Table 5.
Table 5 Example 3 Exa!nple 4Example Hemo Pjn (mmHg) 538 238 NA
5Hemo PoUt/HRD Pin (mm Hg) 348 42 314 HRD Pout (mm Hg) 2 NA 290 HRD Pplasma (rnm Hg) 131 NA -34 Pvacuum (mm Hg) NA -172 -300 Hemo TMP (mm Hg) 477 312 NA
10HRD TMP (mm Hg) 118 118 162 UFR (ml/min) 122 95 15 % HeparinRemoved/Pass 15 16 17 Example 4 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 2 and according to the procedure of Example 3 except that at the begh~ lg of the expwi ~ l the shunt was used to bypass the heparin removal device until a selected volume was removed, and 2 0 then the blood was caused to circulate through the heparin removal device.
Thus, this example shows that hemoconct;nlldlioll and heparin removal can be carried out seqll~nti~lly. It is ~le~lled to perform the hemoconrentration priorto heparin removal, because pelrull,lillg heparin removal prior to hemoconcentration leads to a greater likelihood of clot formation.
2 5 In this ex~mp1e, bovine whole blood was recirculated through the system at a flow rate of S00 rnl/min for 60 millules. The pressure, ultrafiltration rate, and heparin removal data from this experiment are shown in Table S.
Example 5 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 6, wherein hemoconcentration and selected solute removal were carried out in a single device combining a hemoconcell~ralol- and a solute removal device. Pressure measurements were taken so that inlet pressure (P;~), plasma chamber pressure (Pp,~ma), outlet pressure (Pout), and vacuum pressure (PVaCuum) were determined In this example, bovine whole blood was recirculated through the system at a flow rate of 500 ml/min for 60 m;mlt~s. The ~lCS;iUle, ultrafiltration rate, and heparin removal data from this experiment are shown in Table 5.
Example 6 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 4. Pl~s~,ule measu~ Ls were taken at ports 290, 292, 294, 296, 298, and 300, which ~ senl, respectively, pressure at the inlet port of device 208, ~)lCS~7Ule at the outlet port of device 208 and at the inlet port of device 212, pressure at the plasma chamber of device 208, ;7'57Ule at the plasma chamber of device 212, pl~S~,Ule at the outlet port of 2 0 device 212, and vacuum ~ S'7ule at the vacuum port of the hemoconc~llll~Lc l .
A flow probe 312 in line 256 measured the plasma filtration rate of device 208.
In this example, 3 liters of bovine whole blood at 30~C and a hematocrit of 0.26 was used in the system. The roller pump was a Masterflex Model 7524-00, and the vacuum pump was a GAST Model DOA-P104-AA. The selected solute removal devices were heparin removal devices (HRD, Research Medical Inc.), and the hemoconcelllraLor was a Biofilter 140 (Research Medical Inc.). Tygon tubing (S-50-HL Class VI, 6.35 mm x 1.59 mrn and 4.77 mm x 1.59 mm). The flow probe was a Transonic flow probe No. H6X117 used with a Transonic HT109R flowmeter and 6.35 mm x 1.59 mm tubing. Pressure 3 0 measurements were taken with a Deltran Disposable Ple,,~ulc; Tr~nedllcer (Utah Medical, Midvale, Utah). Data collection was with an HP 75000 system.
The results of these f;~elilllents are shown in Tables 6 and 7.
WO 97/326S3 PCTtUS97/04126 C
Illot~ w Wntcr lI ~w 1112 r3i l r-l rs r6 ~ v Vnc Cluscll 2(NI IJ0 ~N 47 45 3J 4 1 (J
l)l)cn lu ~lir 21111 191 98 3) 3X 35 3 4 13 -11111 nllllll8 2(11\ 1171().1~f):1-1 .111 4 95 4R
-2()t) D111lll8 2(N) 202I(IR11 35 12 4 -201 67 _3()l) IllllllIU 2()(1 216115-23 4~ -18 4 .30~ ~JS
Thorac. Cardiovasc. Surg. 736 (1985); P. Page, Ultrafiltration Versus Cell Washing for Blood Concentration, 22 J. Extra-Corp. Tech. 142 (1990); H.
Johnson et al., Conl~alalive Analysis of Recovery of Cardiop-llmon~ry Bypass si(i--~l Blood: Cell Saver vs. Hemoconcentrator, 26 J. Extra-Corp. Tech. 194 (1994); J. Morris & Y. Tan, Autotransfusion: Is There a Benefit in a Current Practice of Ag~l~ssive Blood Conservation?, 58 Ann. Thorac. Surg. 502 (1994). Of these ter'nniq 1es, hemoconcentration and cell washing are among the most cnmm~ rlly encoullLc.c~l Hemoconcentration or ultrafiltration extracts water and low molecular weight solutes from the plasma fraction of whole blood. Plàsma proteins, including prolt;i,ls involved in the coagulation c~cc~-le, remain relatively intact.
HemoconcellLlatols are generally small, c~.mract, cost-er~(;Live, and can be added to an exi~tin~ CPB circuit without major mt-Aific~tir.n.~. A disadvantage of hemocollc~lllldLion is that debris cannot be removed, thus shed blood collected during surgery cannot be processed through a hemoconcentrator 2 0 unless it has first been filtered, i.e. through a cardiotomy reservoir. Moreover, hemoconcc;llll~lion does not remove heparin from the blood, thus even though water has been removed, the blood remains fully h~a~ ed. Another disadvantage is that plasma-free hemoglobin, which results from hemolysis and is known to be toxic to the kidneys, is not erÇecLively removed by 2 5 hemoconcentration filters.
Cell washing is a method of blood concentration wherein whole blood is subjected to cenL.irugation while being rinsed with a saline solution. Cell washing removes debris, plasma-free hemoglobin, and heparin, thus the method can be used on shed blood as well as blood re.~ in the CPB circuit and 3 0 cardiotomy reservoir. A major disadvantage of cell washing is that all of the plasma proteins, incl~Aing coagulation proteins, are discarded. Platelets are lost as well. Further, cell washing recluires that a separate system, including a WO g7~32653 PCT/US97/04126 centrifuge, be dedicated for such a procedure. Therefore, the process of cell washing is more e~ellsive than hemocollce,~ Lion~ Moreover, since coagulation proteins are removed in the process, it is sometimes n~ces~ry to mini~ter replacement factors after cell washing.
Shettig~r et al., U.S. Patent No. 5,211,850, describes a plasma membrane sorbent system for removal of solutes from blood. The system comprises a bundle of U-shaped hollow fibers i~ n~lscd in an electrolyte solution with a sorbent cont~in~d in a closed plasma chamber. As blood flows through the entry arm, plasma filtration into the plasma chamber occurs.
o Solutes in the plasma are selectively depleted in the plasma chamber through binding to the sorbents. The purified plasma then reenters the membrane by reverse filtration.
S. Ash et al., U.S. Patent No. 4,071,444, discloses a portable "flat plate" reactor for use as an artificial kidney. The device comprises a sealed outer casing that is divided int~ ly by a series of flexible men~,dl-es into chambers ~ ptP l to receive blood and other chambers adapted to receive a solution co"~;.i"i..~ water, activated charcoal, zirconium phosphate, ~ilcolliumoxide and urease or other sorbents for absorbing the urea and c~ "i,.~ drawn through the membrane from the blood.
2 0 S. Ash, U.S. Patent No. 4,348,283, describes a dialyzer for use as an artificial kidney or extracorporeal mass l.~ir~r device. The device comprises a plurality of dialyzer units, each unit comprising a pair of semipermeable membranes spaced apart by a gasket such that a blood ch~lll)el is formed between the membranes. Spacers are used to separate the dialyzer units and 2 5 support the membranes. The spaces between the dialyzer units form dialysis chambers, which contain a suspension of sorbents, such as activated charcoal, calcium-sodium loaded zeolites, and/or urease.
S. Ash, U.S. Patent No. 4,581,141, teaches a dialysis material and method for removing uremic substances, wherein the dialysis material 3 0 comprises an a~ueous slurry Cont~inin~ charcoal, a highly calcium-loaded zeolite cation exchanger, a purified urease, a suspending agent such as methylcellulose, and an aliphatic carboxylic acid resin in the acid form.
S. Ash, U.S. Patent No. 4,661,246, discloses a dialysis illsL~ lent with a pump on the dialysate side of the in~ L for moving blood through the il~Ll unlent~ The instrument contains a sorbent column for purification of the dialysate, the sorbent column co~ activated charcoal, immobilized urease, zirconium phosphate cation exch~n~Pr, and zirconium oxide anion exchanger.
S. Ash, U.S. Patent No. 5,277,820, describes a device and method for extracorporeal tre~tm~nt of blood for the removal of toxins. A sorbent ~u~nsion is used for removing such toxins wh~ ;ll the sorbent comprises a powdered surface adsorptive agent such as activated charcoal, physiological eleckolytes, a cation exch~nger for removing ammonium ions and the like, and macromolecular flow inducing agents such as polyoxyalkylene derivatives of propylene glycol or polyvinylpyrrolidone. Cisplatin and metho~ could be removed from the blood by this method.
These appa,~uses and methods all lack the ability to be used for both hemoconr~ntr~ti~n and removal of selected solutes from the blood.
In view of the foregoing, it will be appreciated that development of a system and process that removes excess water and/or fluid from whole blood or plasma, conserves plasma proteins including coagulation ploL~;hls, reduces 2 o and/or removes plasma-free hemoglobin and heparin and other targeted molecules, is cost effective, and is easily used and incorporated into an t?Xi~tin~
CPB circuit or in parallel with a CPB circuit, in contrast to the prior art where expensive, stand-alone devices are used and perhaps require additional personnel to operative them, would be a signifi~nt adv~nr~m~nt in the art.
W~ 97/3~653 PCT/US97/04126 BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide a system and method for conserving blood during cardiac surgery or other m~flic~l procedure where blood loss can be copious.
It is also an object of the invention to provide a system and method for removing excess water and/or fluid from whole blood or plasma, wherein plasma proteins, including co~ tion proteins, can be conserved.
It is another object of the invention to provide a system and method for conserving blood during cardiac surgery or other medical procedure where blood loss can be copious wherein sel~cte~ solutes, such as heparin, plasma freehemoglobin, and selected proteins or hormones that have been activated, are reduced or removed.
It is still another object of the invention to provide a system and method for conserving blood during cardiac surgery wherein such system and method are cost erf~clive, easy to use, and can be incorporated into an existing CPB
circuit.
These and other objects can be accomplished by providing a system for salvaging blood from a patient for the selective removal of a targeted solute inthe blood and the removal of water, fluids, and low molec~ r weight solutes 2 0 c~ il,g:
(a) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for lc;L~ g components selected from the group con~i~ting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a 2 5 molecular weight less than the cut-off to be removed from blood or plasma; and (b) a first solute removal device for selectively removing the targeted solute from blood by means of convective and diffilsive transport of plasma from the blood across a hollow fiber plasma-s~al~lil,g membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted 3 0 solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-s~l~Lillg membrane back into ~e blood, comprising (i) a closed plasma charnber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in the plasma chamber solution under relatively u~iru pressure;
(ii) the hollow fiber plasma-s~a,ali~g membrane, wherein the plasma-s~alillg membrane has an inlet arm and an outlet arm and is configured for being immersed in the plasma chamber solution in the closed plasma chamber;
(iii) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is cont~in~d in the closed plasma chamber;
(iv) means for securing the inlet arm and outlet arm of the plasma-s~L)dldling membrane in the plasma ch~llbeL and closing the chamber to ~ l relatively ul~iÇullll plasma chamber solution ples~iule; and (v) means for circ~ tinp: the blood into the inlet arm, through the plasma-st;L,d,~lillg ,llell~ld,le, and out through the outlet arm; and (c) means for coupling the hemoconcelJIld~or to the first solute removal device to permit liquid cnl~ ic~tion therebetween and for coupling 2 0 the hemoncentrator and the first solute removal device to the patient to permit blood to be received from and ret lrn~l to the patient.
Preferably, the porous ultrafiltration lll~nll)l~e of the hemoconcentrator comprises a plurality of hollow fibers having a molecular weight cut-off in the range of about 10,000 to 100,000. Preferred materials include 2 5 polyacT~lonitrile, polysulfone, polynethylm.oth~crylate, cellulose acetate, cellulose di~et~te, and cellulose triacetate.
Preferably, the hollow fiber plasma-separating n~llll)l~u,e coll~L)lises a bundle of parallel hollow fibers constructed of a blood-comp~tible material having a suitable pore size to allow passage of plasma into the plasma chamber 3 0 solution while ret~inin~ blood cells and platelets from the blood within the hollow fibers. It is pl~fellcd that pore sizes in the plasma-s~a~dLillg membranerange between about 0.01 ,um to l.O ,um and the plasma-s~alalillg membrane is made from a material selected from the group consisting of poly~Lo~ylene, cellulose ~ et~te~ polycarbonate, polyvinylchloride, polyvinylalcohol, polymethylmPth~rrylate, polyethylene, polysulfone, and polyethylenevinylalcohol .
The sorbent should be of a size and configuration such that said sorbent is not permeable to the plasma-sepa~ g membrane. The sorbent colll~lises a ligand immobilized on a substrate wherein the ligand is preferably a member selected from the group con~i~ting of enzymes, living tissue, fr~ nt.c of tissue, cells, antibodies, peptides"llacrolllolecules, nucleic acids, lectins, carbohydl~tes, and c~Pl~tin~ agents. In ~l~relled embo(limPnt~, the sorbent has affinity for heparin and the substrate is agarose. In an especially ~leÇ~..ed embo-lim~nt, the sorbent is poly-~lysine-coupled agarose.
The hemoc~ ce~ dtol- and solute removal device can be configured for simllt~n~ous hemoconcentration and removal of the targeted solute or for sequential hemoconcentration and removal of the targeted solute. The system can also be configured such that hemoconcentration, i.e. removal of water, fluids, and low molecular weight solutes, is carried out in the blood or in the plasma. To remove water, fluids, and low molecular weight solutes from the plasma, the porous ultrafiltration membrane can be placed in the plasma 2 0 chamber of the solute removal device or a second solute removal device can be added to the system, wherein the hemoconcentrator is placed to interconnect the two plasma chambers.
Thus, an a~-lalus for selectively removing a targeted solute from blood by binding the targeted solute to an affinity sorbent and removing water, fluids, and low molecular weight solutes by ultrafiltration comprises:
(a) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in the plasma chamber solution under relatively ullirullll ~res~ule;
(b~ a hollow fiber plasma-s~alalhlg membrane having an inlet arm 3 0 and an outlet arm and configured for being immersed in the plasma chamber solution in the closed plasma chamber;
(c) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is cl-nt~int~cl in the closed plasma chamber;
(d) means for securing the inlet arm and outlet arm of the plasma-s~al~lhlg membrane in the plasma chamber and closing the chamber to m~int~in relatively uniform plasma chamber solution ~rc:S~ulc; and (e) a porous ultrafiltration ln~ e disposed in the closed plasma chamber and configured for being immersed in the plasma chamber solution, the ultrafiltration melllbl~lle having a selected molecular weight cut-off for allowing water, fluids, and solutes with a molecular weight lower than the cut-off to pass th~;lc; ln~ ugh and for ret~ining solutes with a molecular weight greater than the cut-off and means for withdrawing the water, fluids, and solutes that pass through the ultrafiltration membrane; and (f) means for circ~ ting the blood into the inlet arm such that plasma, including water, fluids, and low molecular weight solutes therein, is transported from the blood across the plasma-se~ala~illg mf~ A~-~ by convective and diffusive transport into the plasma chamber solution where the selective removal of the targeted solute from non-~lgeLed solutes using the affinity sorbent is accomplished followed by the subseq~lent transport of the non-targeted solutes across the mellll)ldlle back into the blood and out through2 0 the outlet arm.
Moreover, a system for salvaging blood from a patient for the selective removal of a targeted solute in the blood and the removal of water, fluids, and low molecular weight solutes cc,~ ises:
(a) a hemoconcentrator comprising an inlet port, an outlet port, and a porous ultrafiltration Lu~lllbl~le having a selected molecular weight cut-off for rt;~ i.,g components selected from the group con~i.ct;ng of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids,and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and 3 0 (b) first and second solute rPmoval devices for selectively removing the targeted solute from blood by means of convective and diffusive transport ofplasma from the blood across a hollow fiber plasma-s~aldtillg membrane into a WO 971326~i3 PCT/US97/04126 plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accnmrli~h.s(l followed by the subsequent transport of the non-targeted solutes across the plasma-s~aldlhlg men31"~le back into the blood, each first and second solute removal device comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulatet equilibrate, and interact plasma in the plasma chamber solution under relatively ul~irO
pressure;
(ii) the hollow fiber plasma-se~ Lh~g membrane, wherein the plasma-sel,a,alillg membrane has an inlet arm and an outlet arm and is configured for being immersed in the plasma ch~mher solution in the closed plasma chamber;
(iii) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is contained in the closed plasma 1 5 chamber;
(iv) means for securing the inlet arm and outlet arm of the plasma-se~ld~ing membrane in the plasma challlbe. and closing the chamber to ~ i-- relatively ul~iÇ~ ll plasma chamber solution pressure; and 2 0 (v) means for circnl~tin~ the blood into the inlet arm, through the plasma-separating lllenll)l~e, and out through the outlet arm;
(c) means for coupling the plasma chamber of the first solute removal device to the inlet port of the hemoconc~llLlalol and means for couplingthe outlet port of the hemoconcentrator to the plasma chamber of the second 2 5 solute removal device such that plasma can flow from the f rst solute removal device through the hemoeollcellll~lor to the second solute removal device such that water, fluids, and low molecular weight solutes can be removed from the plasma by ultrafiltration, and means for coupling the outlet arm of the first solute removal device to the inlet arm of the second solute removal device such 3 0 that blood can flow therebetween; and (d) means for coupling the first and second solute removal devices to the patient to permit blood to be received from and returned to the patient.
1~
A m~tho~l of select}vely removing a targeted solute and water, fluids, and low molecular weight solutes from blood comprises:
(a) providing a system comprising:
(1) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for rel~;.,i-,g components selected from the group con~i~ting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (2) a first solute removal device for selectively removing ~e targeted solute from blood by means of convective and dirrusiv~
transport of plasma from the blood across a hollow fiber plasma-se~aldLillg membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subse~uent transport of the non-targeted solutes across the plasma-sepa~dlillg membrane back into the blood, comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, 2 0 equilibrate, and interact plasma in the plasma rh~mher solution under relatively ul~irullll pressure;
(ii) the hollow fiber plasma-s~alalil~g ,l. ,n~l~le, wherein the plasma-s~ g membrane has an inlet arm and an outlet arm and is configured for being immersed in the plasma 2 5 chamber solution in the closed plasma chamber;
(iii) at least one sorbent having an affinity for binding the targeted solute, wherein the sorbent is contained in the closed plasma chamber;
(iv) means for securing the inlet arm and outlet arm of the 3 0 plasma-s~al~ g membrane in the plasma chamber and closing the chamber to m~int~;n relatively unif~ plasma chamber solution pressure; and WO 97/32653 PCT/U~97/~4I26 (v) means for circulating the blood into the inlet arm, through the plasma-sepa~dti,lg membrane, and out through the outlet arm; and (3) means for coupling the hemoconcellL.~lol to the first solute removal device to permit liquid ccl.-ll..ll-it~.~ti-)n therebetween and for coupling the hemoncellllalof and the ffrst solute removal device to the patient to permit blood to be received from and retllrnP-~i to the patient;
(b) directing the blood from a source into the inlet arm by the means for circlll~ting the blood, through the plasma-se~alalillg membrane and out the outlet arm at a volume and a velocity that permits convective and ~lir~u~ive transport of plasma from the blood across the plasma-se~alalh~g membrane along the inlet arm of the plasma-s~ldling ll~lllI"~le into the plasma chamber SOllltifm;
(C) c~ ing the plasma m the plasma ch~mher solution to come into contact with the sorbent such that the targeted solute is selectively bound to the sorbent;
(d) c~n~ing the non-targeted solutes to pass by diffusive and convective transport from the plasma chamber solution across the plasma-2 0 s~a.ilLiulg membrane into the blood retained by the plasma-s~aldlhlg membrane and out of the device;
(e) c~n~in~ the blood or plasma to pass through the hemoconcentrator such that water, fluids, and solutes with a molecular weight less than the cut-off pass through the porous ultrafiltration membrane and are 2 5 withdrawn from the blood or plasma, and the ultraffltration membrane retains cells and solutes with a molecular weight greater than the cut-off in the blood or plasma.
CA 0224703l l998-08-l8 WO 97l32653 PCT/US97/04126 BRIEF DESCRIPTION OE~ THF SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 shows a srhpm~tic diagram of a CPB circuit according to the prior art.
FIG. 2 shows a sçhPm~t~ agram of an illustrative embodiment of a blood salvage circuit according to the present invention comprising a hemocon;enlldlol and a solute removal device.
FIG. 3 shows a srllPm~tic diagram of a solute removal device according to the present invention.
FIG. 4 shows a sch~qm~tir diagram of another illustrative embodiment of lQ a blood salvage circuit according to the present invention.
FIG. S shows a scht-m~tic diagram of still another illustrative embodiment of a blood salvage circuit according to the present invention.
FIG. 6 shows a scltem~tiC~ diagram of a combined device according to the present invention coll~ishlg a plasma se~al~lol with sorbent for removing selecte~l solutes and an ultrafiltration membrane for hemocollcellLl~Lion.
DETAIL~D DESCRIPTION
Before the present system and mPtho(l for salvaging or recovering autologous blood are disclosed and described, it is to be understood that this 2 0 invention is not limited to the particular emborlim~nt~, process steps, and materials disclosed herein as such embollim~ont~, process steps, and m~t~ri~l~
may vary somewhat. It is also to be understood that the t~rminology employed herein is used for the purpose of describing particular embo~lim~nts only and isnot intended to be limiting since the scope of the present invention will be 2 5 limited only by the appended claims and equivalents thereof.
It must be noted that, as used in ~is specification and the appended claims, the singular forms "a," "an," and "the" include plural rer~ Ls unless the context clearly ~lirt~tes otherwise. For example, reference to "a solute"
inrln~les reference to two or more of such solutes, and reference to a device 3 0 co~ isillg "a sorbent" includes reference to a device CO~l~)liS~l1g one or more or such sorbents.
In describing and cl~imin~ the present invention, the following terminology will be used in accordance with the de~mitions set out below.
As used herein, "patient" refers to a human or a warm-blooded animal.
As used herein, "patient blood" refers to blood taken directly from a patient, such as blood collected by predonation for storage and eventual lmini~tration to the patient.
As used herein, "circuit blood" refers to blood that is circulated through the CPB circuit. Circuit blood is typically given back to the patient before theend of surgery or shortly thereafter.
As used herem, "shed blood" refers to blood that is lost during surgery.
Shed blood is aspildled from the body and stored in a cardiotomy reservoir.
As used herein, "peptide" means peptides of any length and includes proteins.
Blood consists of cellular and non-cellular fractions, or, alternatively, of formed and non-formed elements. As used herein, "plasma" means the non-cellular fraction or non-formed el~mP-rltc of blood. In other words, plasma means the portion of blood exclusive of the cellular fraction or formed elem~.ntc thereof.
As used herein, "sorbent" means a ligand coupled to a ~ul~ le.
2 0 Sorbents can be in any usable form of sufficient size that the sorbent is not permeable to the plasma-s~l~ling membrane of the solute removal device, i.e.
does not enter the blood. For e~ample, sorbents can be in particulate form, such as beads, spheres, or the like. ~orbents can also be present as fil~mPnt~, strands, sheets, or films. The form is not important as long as there is a(leqll~te 2 5 OppOl~Ulli~y for the circulation of plasma and contact between the sorbent and the plasma. Suitable substrates include biocolll~atible polymers, such as agarose, polyacrylamide, nylon, nitrocellulose, poly~lylelR, and the like. The substrate should have functional groups to which the ligand can be att~h~d according to principles and materials well known in the art. Suitable ligands 3 0 include antibodies, peptides, enzymes, nucleic acids, lectins, carbohy~ s, chelating agents, macromolecular ligands, and the like.
As used herein, "plasma chamber solution" means the solution contained in the plasma chamber. ~t the beginning of a separation procedure, the initial solution will typically comprise water or an electrolyte, i.e. saline, solution co~ g sorbents and other selected materials. As the various plasma components enter the plasma chamber by convection or ~liffilsion from the hollow fiber plasma-se~ Lillg m~lllbl~le, equilibration will take place such that, except for the targeted components bound to the sorbent in the plasma chamber, the concentration of plasma components in the blood inside the lumens of the hollow fibers will be the same as the concentration of the plasma components in the plasma chamber. Hence, the m~keup of the plasma chamber solution can vary during the removal process, but functionally the action composition is not critical.
Referring to FIG. 1, there is shown a scllPm~tir repres~t~tion of a CPB
circuit 4. Venous blood is removed from the patient 6 and con-!ucted by gravity flow to a venous or CPB circuit blood rest~ ~/oh 8. Blood is pumped out of the CPB reservoir 8 by a pump 12. This blood optionally can be circulated through a hemoconce~ tol~ 16 for removing water, fluids, and low molecular weight molecules. Blood that has passed through the hemoconc~ LoI is 2 0 returned to the venous reservoir 8. Blood can also be pumped through an oxygenator 20 for supplying oxygen to the blood. The oxygenator 20 is coupled to a source of oxygen 24 through an oxygen line 28. The oxygenator 20 is coupled to an arterial filter 32 for filtering the ~ ygenaLed blood before it is recirculated into the CPB circuit reservoir 8 or returned to the patient 6.
2 5 Shed blood is removed from the patient 6 by means of a pump 36 and stored in a cardiotomy reservoir 40, where the shed blood is filtered. The cardiotomy reservoir 40 is coupled to the CPB circuit reservoir 8 such that filtered shed blood can selectively be mixed with CPB circuit blood.
FIG. 2 shows an embodiment of the present invention CUlll~JLi~iillg a CPB
3 0 circuit blood reservoir or cardiotomy reservoir or patient 48 coupled to a blood salvage circuit 56. The blood salvage circuit comprises a pump 60 for ~u~ ing the blood out of the reservoir 48 and moving it through the blood salvage ~ CA 02247031 1998-08-18 circuit. The blood salvage circuit further comprises a hemoco.lcen~laLur 88 for removing water and low molecular weight solutes from the blood and a solute removal device 64 for separating plasma from the blood and cont~ ting the separated plasma with a specific sorbent for removing a selected solute. Such a device is described in U.S. Patent No. 5,211,850, which is hereby incorporated by ler~ ce, and is shown in FIC;. 3. Line 50 couples the blood reservoir 48 to the hemoconcentrator 88, line 52 couples the hemoconcentrator to the solute removal device, and line 54 couples the solute removal device to the blood reservoir 48.
Referring now to FIG. 3, the solute removal device 64 comprises a bundle of hollow fibers that make up a hollow fiber plasma-s~al~lulg membrane 66. Each hollow fiber has a central lumen through which the whole blood passes from the inlet arm 68 to the outlet arm 72 of the sorbent removal device. Each hollow fiber m~ml~,~e has a series of pores or openings through which plasma and plasma coll~ullclll~, toxins, drugs, or other solutes having 1e~:j smaller than the pores can pass into a ~ulloullding plasma ch~mher solution 76 ct)~t~ining a sorbent 80. The hollow fiber plasma-separating membrane 66, plasma chamber solution 76, and sorbent 80 are cont~inP~ in a housing 84. The housing is closed by f~ed potting material 85 and 86. The 2 o inlet arm of the plasma-sepal~lillg membrane is coupled to an inlet line 87, and the outlet arm is coupled to an outlet line 89. Optionally, a plasma port 82 in the housing permits access to the plasma chamber for removing plasma thc.erl~lll, for making pressure measurements, adding sorbent or plasma chamber solution, or the like. The plasma may contain various sugars, plo~ills, hormones, antibodies, fats, bile salts, toxins, electrolytes, and the like, as well as other substances that may have been ~-lmini~tered for various purposes. Heparin, for example, is added to the patient for its ~ntiro~gulation opellies, but is desirably removed or inactivated at the end of CPB. When heparin and other small solutes exit the membranes through the pores by 3 0 convection (pl~s~ule gradients) or diffusion, they enter into the plasma chamber solu~ion 76 co~ sorbent particles 80 that have a specificity for binding heparin or other selected solutes.
CA 0224703l l998-08-l8 The hollow fiber plasma-sc~al~lillg membrane can be made of any blood compatible material having suitable pore size to allow passage of selecte~l solute materials into the plasma chamber, even those of high molecular weight, and yet retain the blood cells and platelets in the lumen of the hollow fiber. Pore sizes in the lllclllblane are relatively large, with sizes ranging between about0.01 ,um to l.0 ,um being suitable, with pore sizes of about 0.1 ,um to 0.8 ,um being preferred and pore sizes of about 0.4 to 0.75 ,um most l,refe.lcd.
Fxemrl~ry of suitable fiber materials are poly~ro~ylene, cellulose diacetate, polycarbonate, polyvinylchloride, polyvinylalcohol, polymethylmPth~rylate, polyethylene, polyethylenevinylalcohol, polysulfone, and the like.
The hollow fiber plasma-s~a.dLillg membrane ~1impn~cic)rls (hollow fiber lumen (1i~m~ter~ length of each hollow fiber, and the number of fibers) and the blood flow rate through the fiber have to be ~3plimi~ed based on the art of membrane plasma sel,al~lion. It is well known in the art of membrane plasma separation that the plasma s~aldLion rate is directly pl~olLional to the blood shear rate and the tr~n~mt~mhrane pres~ulc. Damage to the blood cells, however, may occur if the tr~n~m~mhrane ~lesbu.e is increased beyond a particular limit. Also, blood cells are susceptible to high shear rate. For a given blood flow rate and total membrane surface area, tr~ncmPmhrane plCSsulc 2 0 increases with the hlc-ease in hollow fiber length and with the decrease in lumen size. Shear rate also increases with the decrease in lumen size. The above-mentioned factors may be considered in arriving at the o~Lilllum size of the hollow fiber membrane. The removal rates of solutes from the blood depend on the plasma separation rate, the amount (surface area, etc.), affinity of 2 5 sorbents, and the extent of plasma-sorbent interaction. Hollow fibers of the plasma-sep~ g m~mb-alle having inside ~ m~ters of between about 150 ~um and 500 ,um and wall thicknesses of between about 50 ,um to 400 ,um are typical. The internal surface area of a typical plasma-s~al~Ling membrane can be between about 0.1 and 5.0 m2, and the volume of the plasma chamber can be 3 o between about 50 and lO00 ml. The length of the plasma-sepaldLillg membrane from the inlet port to ~e exit port should be between about 10 and lO0 cm, CA 0224703l l998-08-l8 WO 97~326~i3 PCT~US97/04126 with lengths of about 20 to 25 cm being prel;lled. Flow rates of blood through the plasma-separating membrane can vary from about 50 to 3000 ml/min.
The plasma chamber should be sized to hold an ~çqn~te amount of sorbent materials to adsorb the unwanted solutes, such as heparin. This may vary depending on the medical procedure for which the blood salvage system is being used and the amount of heparin or other rnaterial to be removed and the nature of the sorbent material.
An illustrative commercial device according to FIG. 3 is a heparin removal device (HRD, Research Medical Inc., Midvale, UT). This unit is a disposable hollow fiber membrane-type plasma sel~a.dl~r cQ~eieting of a microporous polypropylene hollow fiber bundle mounted in polyurethane exit ports and a polystyrene plastic housing. Blood enters the fiber bundle through the blood inlet port, passes through the hollow fiber lumens in which a positivetr~n.em~..l.l~le ~l~S~ul~, allows plasma to pass through the porous hollow fibermembrane along its entire length into the plastic housing where it contacts the sorbent. Solutes in the plasma with an affinitv for the sorbent bind to the sorbent and are immobilized. The plasma with a reduced co-.ce~ ion of the selected solute can then be removed from the plasma chamber through the plasma port or can reenter the hollow fiber m~l,-l,-~.e by refiltration for 2 0 transport out the device through the outlet port.
Prior to use, the plasma ch~mhPr is prefilled with plasma chamber solution cl)..l;.i.-;i-g sufficient sorbent particles to bind the plasma component to be s~-dled. The sorbent can be placed in the plasma chamber prior to, simlllt~neously with, or after filling the plasma chamber with the plasma 2 5 chamber solution. Such unit is suitable for use as a .cimnlt~n~ous plasma pl~rmlc~tion and reinfusion system having the above-described advantages.
The removal of heparin from an extracorporeal circuit is a primary objective of the invention. The binding of heparin to a solid substrate by affinity adsorption techniques is docnm~--nt~ in the art. E.g., Moh~mm~fl et 3 0 al., Ql~ e Removal of Heparin from Plasma and Other Aqueous Solutions by Affinity Adsorption on Poly(L)lysine Sepharose 4B, 20 wo 97/32653 PCT/USg7/04126 Thrombosis Res. 599-609 (1980). Poly(L)lysine-coupled agarose beads are one form of plcÇ~lled sorbent.
The plasma separator device is applicable to any plasma sorbent system where separation, interaction, and recolll'Lhlalion takes place. Typical m~-lir~l procedures where the blood is hcp~lini~ed include cardiop--lmnn~ry bypass, hemodialysis, angioplastic procedures, pl~m~rh~resis, ~uloll~rusion, and hemocollcellLr~lion. Exemplary of other potential applications of the system areremoval of ~-~lo~ ihodies using sorbents such as immobilized protein A;
removal of circul~ting toxins and tumor antigens using sorbents such as immobilized monoclonal antibodies and specific immobilized ligands; removal of protein-bound toxins and drugs (e.g., in the case of a drug overdose);
procedures using live cells in the plasma ~h~llbel in the place of sorbents suchas islet cells or liver tissue fr~rnent~ for the tre~tm~n~ of diabetes, hepatocytes for the tre~tmPnt of liver failure and the like; selective removal of plasma components using immobilized enzymes as sorbents; and removal of cholesterol (low density lipuploteills, LDL) using sorbents specific to LDL.
While not shown in FIG. 2, the hemoconcellLldtor 88 can be placed in circuit 56 either uy~Lle~ll or downstream of the solute removal device 64. The hemoconcellLl~Lol 88 is pl~;rel~bly of a type already known in the art for 2 0 removing water, fluids, and low molecular weight molecules from blood by ultrafiltration. A plcr~llcd hemoconcentrator (FIG. 2) col~ ises a bundle of hollow fiber ultrafiltration ll,tlnl)l~es 100 in a housing 104 that defines a chamber in which the hollow fibers are disposed. Inlet 108 and outlet 112 ports are coupled to the bundle of hollow fibers for con~ ctin~ blood, plasma, or water into and out of the hemoc~"lcellLl~tor. One or more ports 116 and 120 can also be present in the wall of the housing for con~luctin~ blood, plasma, orwater into or out of the chamber. A vacuum line 124 is also preferably coupled to the hemoconcellLl~or for removing water ~eLerl~,m. The vacuum line in FIG. 2 is coupled to a port 120 in ~e wall of the housing. A collection vessel 3 0 128 and vacuum pump 132 are also coupled to the vacuum line. For experimPn~l purposes, plcs.,ulc ports can be placed at various points in the system ~or m~ rin~ pressure. In FIG. 2, ~ s~ule ports 134, 135, 136, 137, W<:l 97r32653 PCT/US97/04126 and 138 are for m~e~lring, respectively, hemoconcentrator inlet ~les~ulc, hemoconce~ dtor outlet pressure and solute removal device inlet plcs~urc, solute removal device plasma pressure, solute removal device outlet ~c~u,e, and hemoconrentr~tQr vacuum prcs~ulc. A shunt line 139 from line ~2 to line 54 permits the solute removal device 64 to be bypassed. For example, clamping lines 52 and 54 at sites 58 and 60 proximal to the solute removal device permits blood to flow through the shunt line directly from the hemoconcelllldtor to the blood reservoir. In this configuration, multiple cyclesof hemoconcentration can be ~clÇulllled without passing through the solute removal device. Opening such clarnps at sites 58 and 60, and clamping the shunt line at site 62 causes the blood to flow through the solute removal device.
Thus, the system shown in FIG. 2 permits operation in selected operational modes, such as (1) allowing the blood to flow through the solute removal device each time the blood flows through the hemoconcen~ld~or (.~imnlt~nPous mode), or (2) allowing the blood to flow through the hemo~;ollcc;~ d~ur for several cycles and then to flow through the solute removal device (seqllenti~l mode).
A ~lcfcllcd hemoconcclllld~or for use in the present invention is a BIOFIL~ER 140 ~Research Medical, Inc., Midvale, Utah) co..l;.i..il~g a porous hollow fiber, cçllnlose (li~et~t~ clllbl~e. Other suitable ll~-lll,l~e materials2 0 include polyacrylonitrile, polysulfone, polymethylmethacrylate, cellulose acetate, cellulose tri~et~t~, and the like. Preferably, the hemocollce.l~ldtor is ul~s~leam of the solute removal device 64 so that blood passing through the hemocollcellLI~lol is hel)alil.i~ed and has less likelihood of foll~ g clots than if the hemoconcentrator were placed dowl~LI~dlll of the solute removal device, 2 5 particularly where such solute removal device is a heparin removal device.
Placing the hemocollcclllldlor dowllsllcdlll of the heparin removal device increases the likelihood of clots collecting in the hemoconcentrator. Moreover, concell~d~illg the blood also concell~la~es the targeted solute, e.g. heparin, which makes the solute removal device operate more efficiently.
3 0 Although the present invention is shown in ler~ ce to a CPB circuit, the invention can also be used by conn~octing the blood salvage circuit to the cardiotomy circuit or by connecting the blood salvage circuit directly to the patient for processing of patient blood.
Another illustrative embodiment of the present invention is shown in FIG. 4. This system 200 comprises a hemoconcclllr~tor 204 and a pair of selected solute removal devices 208 and 212 coupled to a blood reservoir 216.
The blood reservoir could be a cardiotomy reservoir, a CPB circuit, a patient, or the like. The blood rcs~lvoil is coupled to device 208 by line 220. A roller pump 224 is disposed on line 220 for pumping the blood through the system.
One end of line 220 is coupled to the imet port ~8 of device 208, and the other 1 0 end of the line 220 is coupled to the blood reservoir. ~nother line 232 is coupled at one end to the outlet port 236 of device 208 and at the other end to the inlet port 240 of device 212. Line 244 is coupled at one end to the outlet port 248 of device 212 and at the other end to the blood reservoir. The plasma port 252 of device 208 is coupled by line 256 to the inlet port 260 of the hemoeollcel,lla~or 204, and the outlet port 264 of the hemoconce~lLlalol is coupled to the plasma port 268 of device 212 by line 272. The vacuum port 276 of the hemoconcentrator 204 is coupled to a vacuum line 280, which is coupled to a collection vessel 284 and a vacuum pump 288. For experimental purposes, ple~,~ule ports 290, 292, 294, 296, 298, and 300 are placed in the 2 0 system as shown for taking pressure measurements. The pressure measurements taken at ports 290, 292, 294, 296, 298, and 300 represent, respecti~ely, ~LeS~Ule at the imet port 228 of device 208, pressure at the outlet port 236 of device 208 and at the inlet port 240 of device 212,1,lcs~,ule at theplasma cha-nbt;l 304 of device 208 and ~lcs~ulc of inlet port 260 of the hemoconcentrator 204, pressure at the plasma chamber 308 of device 212, plcssulc at the outlet port 248 of device 212, and vacuum plcs~ule at the vacuum port 276 of the hemoconcenll~lor 204. A flow probe 312 in line 256 measures the plasma filtration rate of device 208.
In this configuration, blood is pumped through the first solute removal 3 0 device 208, and the plasma that is separated from the blood cells is con~ ete(l to the hemoconc~ r. In the hemocc,llcen~lator, water and low molecular weight solutes are removed from the plasma and con~ t~l to a collection vessel. The concentrated plasma that exits the hemoconce"~ld~or is then conducted into the plasma chamber of the second solute removal device, where the plasma is combined with blood cells again after refiltration. The blood thatexits the second device has thus been subjected to both hemoconcentration and affinity removal of a selected solute.
Not all of tne plasma separated from tae blood in the first solute removal device 208 passes through the hemoconc~llL,~lol. A portion of the plasma lc~nl~l~. the hollow fiber m~n,l,l~lle by refiltration for ,~...;x;..~ with the blood cells, exits the device at outlet port 236, and is transported tnrough line 232 to the second solute removal device 212. In the second solute removal device 212, the plasma can again pass through the pores in the hollow fiber membranes into the plasma ch~mh~r 308. In the plasma chamber 308 there can be mixing of plasma with concentrated plasma from the hemoconcentrator and additional affinity removal of selected solutes. The plasma can then return to the hollow fiber mell,b,~,e by refiltration, where it is mixed with the blood cells, and eventual retllrn~od to the blood lt:StlVOil. Preferably, a fine mesh screen is placed at port 252 of device 208 and at port 268 of device 212 to retain sorbentin the plasrna chambers.
A variant of the embodiment shown in FIG. 4 is illustrated in FIG. S, 2 0 where like reference numbers are used to indicate similar parts. The dirrt;,~.lces between FIG. 4 and FIG. S are in how the plasma and the water removed thele~lolll pass through the hemoco"c~"Ll~lor. In FIG. 4, the plasma enters the h~ml-con~P..~.alor into the chamber that ~wl~ullds the hollow fibers,and the water and low molecular weight solutes pass from the chamber through 2 5 the pores in the hollow fiber ultrafiltration membrane into the lumens of the hollow fibers and then into the vacuum line for collection in the collection vessel. In contrast, in the system 316 shown in FIG. 5, the plasma enters the - hemoconcentrator into the lumens of the hollow fibers, and the water and low molecular weight solutes pass from the lumens of the hollow fibers through the 3 0 pores in the hollow fibers into the chamber and then into the vacuum line for collection in the collection vessel.
In FIG. 6 there is shown a coll~bilLalion device 142 for carrying out the processes of hemoconc~l-L-~tion and selective removal of a targeted solute. The co~ h aLion device 142 is placed in a blood salvage circuit 140 coupled to a CPB circuit 144, as in FIG. 1. The blood salvage circuit comprises a pump 148 for pumping blood from the CPB circuit 144 through the co~ ion device 142 and optionally through a separate hemocollc~ k)r 152. The colllbi~lion device comprises a hollow ~lber plasma-sepal~tillg lllellll,l~e 156 coupled to an inlet port 160 and an outlet port 164. The hollow fiber plasma-sepal~illg m~lllbla-le 156 is enclosed in a housing 168 that encomr~ses a plasma chamber 172 Cont~;nin~ a plasma chamber solution 176 and a selective sorbent 180. The hollow ffbers have pore sizes in the range of about 0.01 ,~m to 1.0 ,um, as described above. Also contained within the plasma chamber 172 is an ultrafiltration membrane 184 having an outlet port 188. This ultrafiltration membrane is also made of hollow fibers having a molecular weight cut-off in the range of about 10,000 to 10Q,000, as described above in conn~ction with the hemoconce,lllalol. Not only can vacuum be applied to enh~nre hemoconcentration, but the system also accommodates countervalent or dialysis solutions.
Blood is pumped into the c~lllbill~Lion device 142 such that the blood 2 o enters at the inlet arm 160. The blood passes through the lumens of the hollow fiber membranes, and the plasma and solutes pass through the pores of the .le,l.l,.~e into the plasma chamber solution co..~ g a selective sorbent.
When selected solutes contact the sorbent, the selected solutes bind to the sorbent, thus depleting the concentration of the select~(l solute in the plasma. If the outlet port 188 of the ultrafiltration mem~l~e is closed, then the selected-solute-depleted plasma passes through the pores of the hollow fiber plasma-st;l)a~ g ~ e 156 by refiltration and passes out of the device 142 into the blood salvage circuit 14û. The solute-depleted blood can optionally be passed through a separate hemoconcentrator 152, where water, fluids, and low 3 0 molecular weight solutes are removed by ultrafiltration, or can pass directly into the CPB circuit 144. In this configuration, the blood can be subjected to ,simlllt~n~ous or sequential hemoconcentration and solute depletion.
-CA 0224703l l998-08-l8 By opening the outlet port 188 of the ultrafiltration membrane 184, solute-depleted plasma can be subjected to hemoconcentration in the con~ ion device. Preferably, the outlet port 188 is coupled to a vacuum line, similar to what is shown in FIGS. 2, 4, and 5. Water, fluids, and low molecular weight molecules pass through the ultra~filtration membrane 184 and are drawn out of the device 142 through the outlet port 188 for coTl~octiQn The pore size of the ultrafiltration ~n~ l)ldl~e 184 can be selected such that the size of the low molecular weight mfllec~lles removed is select~ble. Typically, the molecular weight cut-off is in the range of about 10,000 to about 100,000. The concentrated plasma in the plasma chamber let;~ the hollow fiber plasma-s~alaLillg membrane 156 by refiltration, mixes with blood cells in the lumens of the hollow fibers, and passes out of the device through the outlet arm 164.
As with the blood salvage circuit of FIGS. 2, 4, and 5, the collll,hl~ion device can be used by c.-nn~ction to the CPB circuit, the cardiotomy circuit, orby connection ~lilc;-;~ly with the patient for processing of patient blood.
The co"~ alion device possesses a number of advantages that are not otherwise obtained. For example, the Collll)ilk-lion device permits blood salvage and targeted solute removal in a single, low cost device. Also, higher pressures can be used for ultrafiltration than are otherwise possible because the 2 0 ultrafiltration is done in the plasma phase rather than the whole blood phase.
Such higher pressures are not possible in the whole blood phase because of the res-lltin~ lysis of blood cells. Further, the colllbillation device provides for a quick and easy means for responding to the systemic infl~mm~tory response that accc ,ll~allies cardiopulmonary bypass in a significant proportion of patients. This systemic jnfl~,l""~loly response is believed to result from the rapid release of certain cytokines into the blood. These cytokines can be removed by using selected sorbents, such as immobilized immnn(>globulins, - receptors, and/or whole cells, for specific binding of the cytokines. Removal of the cytokines from the blood of a patient undergoing systemic infl~ y 3 0 response is believed to alleviate such response.
, Further advantages of the present invention derive from the lack of high tr~n~m~,mhrane pressure in the plasma separating and sorbent-co~ g device.
This relatively low tr~n~m~--mhrane pressure results in improved rheology as compared to other devices known in the art such ~at the present system can be operated at higher flow throughputs. This higher rate of flow results in less tirne being needed to process the blood, and con~eqll~ntly less time is needed to treat a patient.
Example 1 In this e~mrle, ~,1~s~ul~ and flow data were d~;le, .. ~ for a plasma separation and sorbent-co~ device similar to the plasma sorbent system described in U.S. Patent No. 5,211,850 to Shetti~r & McRea and illu~lla~;d in PIG. 3.
In this exarnple, a plasma sorbent system col.~ .;..g a heparin-speci~lc sorbent (HRD, Research Medical Inc., Midvale, UT) was tested to deterrnine inlet pressure (P;n)~ outlet ~res~ul~ (PoU~~ plasma ~ s~ule (Pp,asma), arld tran~m~,lnhrane ~l.,ssule (TMP). Pressure mea~ulelllell~ were taken at the inletline 87, outlet line 89, and plasma port 82. TMP was calculated as the average of inlet and plasma pressures less plasma l~leS~U'e [(Pin + Pplasma)/2 - PplasmJ2 0 Table 1 shows the results of such an experiment using porcine whole blood as the m~-1inm Blood was pumped through the HRD using a SARNS 5000 blood pump.
Table 1 25Flow (ml/min) Pin P0ut Pplasma TMP
(mm Hg) (mm Hg) (mm Hg) (mm Hg) sOo 380 95 210 100 , WO 97J3~653 PCT/US97~04126 These data show that the inlet blood pressure (Pjn) increases with the increase in blood flow rate through the hollow fiber lumen. The plCS'.Ule in the~ plasma ~h~mher (Pplasma) also increases proportionately, while the outlet blood pressure (Pout) increases at a much slower rate. The tr~nem~mhrane pressure (TMP) is a direct measure of the driving force for the filtration rate of fluid from the blood in the inlet arm of the plasma-sepaLa~ g m~lllbld,le into the plasma ch~mher. This driving force is seen to be increasing with the increase in the blood flow rate. This test demonstrates that as the Pplasma increases with the increase in Pin, two di~r~relll regions of mass transfer are created. In theinlet arm of the plasma-separating membrane where Pin > Pp,asma, there is a positive convection of mass L,~.rt;r across the m~m~ ule through its pores into the plasma chamber solution. However, in the outlet arrn of the plasma-sepal~lhlg membrane where Pout < Pp,asma, this causes a negative or reverse convective mass L,~u~.r~ across the membrane through its pores frorn the plasma chamber solution into the lumen.
Example 2 In this ~x~mple, a hemoconc~ or (BIOFILTER 140, Research 2 0 Medical Inc., Midvale, UT) was tested to ~lelr~ vacuum ples .ur~ (PVacuum), inlet pressure (Pin), outlet pressure (Pout)~ tr~n.~m~...l.l~le prc~s~ c (TMP), and ultrafiltration rate (UFR~ at three ~liLr :renl flow rates using human blood in human clinical trials. TMP was det~rmin~d as the average of inlet and outlet pressures less va~uum pressure [(Pin + PoUt)/2 - PVacuum]. Blood was pumped 2 5 with a roller pump from a cardiotomy reservoir or cardioplllmnn~ry bypass circuit into the hemoconcentrator through the inlet port. Water and solutes having a molecular weight lower than that of the molecular weight cut-off of theultrafiltration ~ nll),~le passed from the lumens of the hollow fibers through the pores of the membrane into the chamber defined by the housing. A ~a~;uum 3 o line was coupled to a port in the housing and to a collection flask and a vacuum pump for applying reduce pressure to the chamber. Concentrated whole blood passed through the outlet port for return to the cardiotomy reservoir or CPB
eircuit. Tables 2-4 show the results of such t~ climents at hemoconcentrator flow rates of 200 ml/min, 300 mlfmin, and 400 ml/min, respectively.
Table 2 HemocollcellLI~tor Flow Rate = 200 ml/min Pvacuum Pin Pout TMP ~JFR
(mmHg~ (mmHg) (mm Hg) (mm Hg)(ml/min) Table 3 ~T~moconcentrator Flow Rate = 300 ml/min Pvacuum Pin Pout TMP UFR
(mm Hg) (mm Hg) (mm Hg) (mm Hg)(ml/min) _ Table 4 Hemoconcenll~lol Flow Rate = 400 ml/min Pvacuum Pin Pout TMP UFR
(mm Hg~ (mm Hg) (mm Hg~ (mm Hg)(ml/min) These results show ultr~filtr~ n rates can be manipulated by varying flow rates and vacuum pr~s~ures. At a given flow rate, the ultrafiltration rate can generally be increased by increasing the vacuum ~)lc;S~
Example 3 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 2, wherein hemocon~entr~tion and heparin removal were carried out simlllt~n~.ously. The hemocollcell~l~lor was a BIOFILTER 140 and the solute removal device was an HRD for removing 2 0 heparin. The shunt line was clamped such that blood passed through the hemoconcentrator and the solute removal device in each passage through the circuit.
In this ex~mple, bovine whole blood was recirculated through the system at a flow rate of 500 ml/min for 60 ll~illul~s. The pn,~u,e, ultrafiltration rate, 2 5 and heparin removal data from this experiment are shown in Table 5.
Table 5 Example 3 Exa!nple 4Example Hemo Pjn (mmHg) 538 238 NA
5Hemo PoUt/HRD Pin (mm Hg) 348 42 314 HRD Pout (mm Hg) 2 NA 290 HRD Pplasma (rnm Hg) 131 NA -34 Pvacuum (mm Hg) NA -172 -300 Hemo TMP (mm Hg) 477 312 NA
10HRD TMP (mm Hg) 118 118 162 UFR (ml/min) 122 95 15 % HeparinRemoved/Pass 15 16 17 Example 4 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 2 and according to the procedure of Example 3 except that at the begh~ lg of the expwi ~ l the shunt was used to bypass the heparin removal device until a selected volume was removed, and 2 0 then the blood was caused to circulate through the heparin removal device.
Thus, this example shows that hemoconct;nlldlioll and heparin removal can be carried out seqll~nti~lly. It is ~le~lled to perform the hemoconrentration priorto heparin removal, because pelrull,lillg heparin removal prior to hemoconcentration leads to a greater likelihood of clot formation.
2 5 In this ex~mp1e, bovine whole blood was recirculated through the system at a flow rate of S00 rnl/min for 60 millules. The pressure, ultrafiltration rate, and heparin removal data from this experiment are shown in Table S.
Example 5 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 6, wherein hemoconcentration and selected solute removal were carried out in a single device combining a hemoconcell~ralol- and a solute removal device. Pressure measurements were taken so that inlet pressure (P;~), plasma chamber pressure (Pp,~ma), outlet pressure (Pout), and vacuum pressure (PVaCuum) were determined In this example, bovine whole blood was recirculated through the system at a flow rate of 500 ml/min for 60 m;mlt~s. The ~lCS;iUle, ultrafiltration rate, and heparin removal data from this experiment are shown in Table 5.
Example 6 This example shows an illustrative embodiment of the present invention according to the system shown in FIG. 4. Pl~s~,ule measu~ Ls were taken at ports 290, 292, 294, 296, 298, and 300, which ~ senl, respectively, pressure at the inlet port of device 208, ~)lCS~7Ule at the outlet port of device 208 and at the inlet port of device 212, pressure at the plasma chamber of device 208, ;7'57Ule at the plasma chamber of device 212, pl~S~,Ule at the outlet port of 2 0 device 212, and vacuum ~ S'7ule at the vacuum port of the hemoconc~llll~Lc l .
A flow probe 312 in line 256 measured the plasma filtration rate of device 208.
In this example, 3 liters of bovine whole blood at 30~C and a hematocrit of 0.26 was used in the system. The roller pump was a Masterflex Model 7524-00, and the vacuum pump was a GAST Model DOA-P104-AA. The selected solute removal devices were heparin removal devices (HRD, Research Medical Inc.), and the hemoconcelllraLor was a Biofilter 140 (Research Medical Inc.). Tygon tubing (S-50-HL Class VI, 6.35 mm x 1.59 mrn and 4.77 mm x 1.59 mm). The flow probe was a Transonic flow probe No. H6X117 used with a Transonic HT109R flowmeter and 6.35 mm x 1.59 mm tubing. Pressure 3 0 measurements were taken with a Deltran Disposable Ple,,~ulc; Tr~nedllcer (Utah Medical, Midvale, Utah). Data collection was with an HP 75000 system.
The results of these f;~elilllents are shown in Tables 6 and 7.
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Opcll 11- air 4()() 173 70 J() 11 17 0.29 -Il)(~ 111~l1l)4()() 172 66 Ztl lJ 16 ~.32 -200 mlmlll 400 198 R5 264 25 18 0.35 -:IINI mlllll~ 4110 210 94 3(15 30 19 0.37 1IIIII11l 4(1(~ 222 1~1 4. 1 3t~ 1') 11.41 V;lc C losc I 5('(' 22G 87 129 0 14 0.26 ()l~cn l~ Dir 50(1 239 93 111 10 15 0.2-) -1110 ~ 51N1 2S1 11)2 21NI IS 16 0.31 -2~)0 ~Illl11177~ $~ 259 1 1(~ 2 ~() 21 16 ~).33 -3lXI nllllll~ 51N1 265 114 374 25 IG 11.35 -41J0 u~ Slul275 123 458 30 IG 11.37 VDC (~losc~ )() 280 108 176 () 17 11.26 ~ co ~o uir ~ou 2NI 1()) 1(3 Il) 17 0.2-) -IINI lulllll~ t~lUI 2J1 117 23() 15 17 1\.31 -20~ 2~ 18 17 ~ 12 -3()(~ 1llllllll (()() 31~ 12~ 423 23 19 ~).31 -4"" """"U '~"" 3'7 13~1 518 28 1-) ().36 Vneel~lsc) 700 3161 113 2.14 0 1(~ ().26 ())~cn lo uir 700 334 13() 1)0 11 17 0 2) 7~)0 345 135 275 15 18 ~.31 -21~ . 71)1~ 3-19 141~ 3(18 1-) 19 0.3~
1llllllll 7~ 3S4 1 1~ 4t 1 22 2~ ~).33 -41)0 1IIIII11~ 71N)375 ~5% 5.52 25 2() 0.35 Example 7 In this example, the system was configured according to FIG. 5, and the procedure was as in Example 6. The results were similar to those of Example 6.
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Vac CluseO (~(N) 733 392173101 177 14 -I 0 I.)llcll lu :lir G()() 71938(1157 102 IG2 13 -3 GO
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-4~)0 111111)18 7()~ 4fi215213) 147 IS -4(~2 175 , WO 97/326~;3 rCT/US97/04126 T/~ 7 V~ slilo;l~c(l l~eree~ e Vol. Ilcl of Illc 11100~l T 1\11 of 'I MI' ~-r 'I'MI' ~-r wulcr lI--w l~crcccla~c c~lh l-lomi II~IW l~l7~ ) D2 llc~u-leolle.1- Ill(ltl~IDSII~8 rUIW t(7 8r~Cr ISt Vacuull~ l'or~ c(ll~ 8 llll~lll~ mllllll ll~w % bllt~l~l nuw % I-ass Vac cl~ls~:~l 2013 72 30 ~12 0 23 1).2-()l~cn ~n air 21H1 76 32 33 7 19 t).28 81 37 1 8 2-1 17 ().34 -2UI) Ullllll~ 2()0 9.5 48 ?13 33 18 0 3) 3l)0 1~ 2~ l7 788 48 21 o.so .11)(1 ~Il 2~)() 1~14 3.; 3~ () 2~ s2 V;le ~ I lsc l 4~1() 1~15 ~13 1~).$ ~) 1(1 ~).7~
Opcll 11- air 4()() 173 70 J() 11 17 0.29 -Il)(~ 111~l1l)4()() 172 66 Ztl lJ 16 ~.32 -200 mlmlll 400 198 R5 264 25 18 0.35 -:IINI mlllll~ 4110 210 94 3(15 30 19 0.37 1IIIII11l 4(1(~ 222 1~1 4. 1 3t~ 1') 11.41 V;lc C losc I 5('(' 22G 87 129 0 14 0.26 ()l~cn l~ Dir 50(1 239 93 111 10 15 0.2-) -1110 ~ 51N1 2S1 11)2 21NI IS 16 0.31 -2~)0 ~Illl11177~ $~ 259 1 1(~ 2 ~() 21 16 ~).33 -3lXI nllllll~ 51N1 265 114 374 25 IG 11.35 -41J0 u~ Slul275 123 458 30 IG 11.37 VDC (~losc~ )() 280 108 176 () 17 11.26 ~ co ~o uir ~ou 2NI 1()) 1(3 Il) 17 0.2-) -IINI lulllll~ t~lUI 2J1 117 23() 15 17 1\.31 -20~ 2~ 18 17 ~ 12 -3()(~ 1llllllll (()() 31~ 12~ 423 23 19 ~).31 -4"" """"U '~"" 3'7 13~1 518 28 1-) ().36 Vneel~lsc) 700 3161 113 2.14 0 1(~ ().26 ())~cn lo uir 700 334 13() 1)0 11 17 0 2) 7~)0 345 135 275 15 18 ~.31 -21~ . 71)1~ 3-19 141~ 3(18 1-) 19 0.3~
1llllllll 7~ 3S4 1 1~ 4t 1 22 2~ ~).33 -41)0 1IIIII11~ 71N)375 ~5% 5.52 25 2() 0.35 Example 7 In this example, the system was configured according to FIG. 5, and the procedure was as in Example 6. The results were similar to those of Example 6.
Claims (42)
1. A system for salvaging blood from a patient for the selective removal of a targeted solute in the blood and the removal of water, fluids, and low molecular weight solutes comprising:
(a) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for retaining components selected from the group consisting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (b) a first solute removal device for selectively removing the targeted solute from blood by means of convective and diffusive transport of plasma from said blood across a hollow fiber plasma-separating membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood, comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) the hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating said blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm; and (c) means for coupling said hemoconcentrator to said first solute removal device to permit liquid communication therebetween and for coupling said homoncentrator and said first solute removal device to said patient to permit blood to be received from and returned to said patient.
(a) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for retaining components selected from the group consisting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (b) a first solute removal device for selectively removing the targeted solute from blood by means of convective and diffusive transport of plasma from said blood across a hollow fiber plasma-separating membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood, comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) the hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating said blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm; and (c) means for coupling said hemoconcentrator to said first solute removal device to permit liquid communication therebetween and for coupling said homoncentrator and said first solute removal device to said patient to permit blood to be received from and returned to said patient.
2. The system of claim 1 wherein said the porous ultrafiltration membrane of said hemoconcentrator comprises a plurality of hollow fibers.
3. The system of claim 2 wherein the molecular weight cut-off of said porous ultrafiltration membrane is in the range of about 10,000 to 100,000.
4. The system of claim 3 wherein said porous ultrafiltration membrane is made from a material selected from the group consisting of polyacrylonitrile, polysulfone, polynethylmethacrylate, cellulose acetate, cellulose diacetate, and cellulose triacetate.
5. The system of claim 1 wherein said hollow fiber plasma-separating membrane comprises a bundle of parallel hollow fibers.
6. The system of claim 5 wherein said sorbent is of a size and configuration such that said sorbent is not permeable to the plasma-separating membrane.
7. The system of claim 6 wherein said hollow fibers making up said plasma-separating membrane are constructed of a blood-compatible material having a suitable pore size to allow passage of plasma into the plasma chamber solution while retaining blood cells and platelets from the blood within the hollow fibers.
8. The system of claim 7 wherein the pore sizes in said membrane range between about 0.01 µm to 1.0 µm.
9. The system of claim 8 wherein said hollow fibers of said plasma-separating membrane are made from a material selected from the group consisting of polypropylene, cellulose diacetate, polycarbonate, polyvinylchloride, polyvinylalcohol, polymethylmethacrylate, polyethylene, polysulfone, and polyethylenevinylalcohol.
10. The system according to claim 9 wherein the sorbent comprises a ligand immobilized on a substrate and said ligand is a member selected from the group consisting of enzymes, living tissue, fragments of tissue, cells, antibodies, peptides, macromolecules, nucleic acids, lectins, carbohydrates, andchelating agents.
11. The system of claim 10 wherein said sorbent has affinity for heparin.
12. The system of claim 11 wherein the substrate is agarose.
13. The system of claim 12 wherein the sorbent is poly-L-lysine-coupled agarose.
14. The system of claim 1 wherein said homoconcentrator and said first solute removal device are configured for simultaneous hemoconcentration and removal of the targeted solute.
15. The system of claim 1 wherein said hemoconcentrator and said first solute removal device are configured for sequential hemoconcentration and removal of the targeted solute.
16. The system of claim 1 wherein said hemoconcentrator has an inlet port and an outlet port and said outlet port of said hemoconcentrator is coupled to the inlet arm of said first solute removal device such that blood passes through said hemoconcentrator for removal of water, fluids, and low molecular weight solutes to result in concentrated blood, which concentrated blood then passes through said first solute removal device for removal of the targeted solute.
17. The system of claim 1 wherein said hemoconcentrator has an inlet port and an outlet port and the outlet arm of said first solute removal device is coupled to the inlet port of said hemoconcentrator such that blood passes through said first solute removal device for removal of the targeted solute resulting in targeted-solute-depleted blood, which targeted-solute-depleted blood then passes through said hemoconcentrator for removal of water, fluids, and low molecular weight solutes.
18. The system of claim 1 wherein said plasma chamber solution is an electrolyte.
19. The system of claim 1 wherein said porous ultrafiltration membrane is contained in said closed plasma chamber such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration.
20. The system of claim 1 further comprising a second solute removal device, which comprises (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) a hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm;
wherein the plasma chamber of said first solute removal device is coupled to the inlet port of said hemoconcentrator and the outlet port of said hemoconcentrator is coupled to the plasma chamber of said second solute removal device such that plasma can flow from said first solute removal device through said hemoconcentrator to said second solute removal device such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration, and wherein said outlet arm of said first solute removal device is coupled to the inlet arm of said second solute removal device such that blood can flow therebetween.
(ii) a hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm;
wherein the plasma chamber of said first solute removal device is coupled to the inlet port of said hemoconcentrator and the outlet port of said hemoconcentrator is coupled to the plasma chamber of said second solute removal device such that plasma can flow from said first solute removal device through said hemoconcentrator to said second solute removal device such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration, and wherein said outlet arm of said first solute removal device is coupled to the inlet arm of said second solute removal device such that blood can flow therebetween.
21. An apparatus for selectively removing a targeted solute from blood by binding said targeted solute to an affinity sorbent and removing water,fluids, and low molecular weight solutes by ultrafiltration, comprising:
(a) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(b) a hollow fiber plasma-separating membrane having an inlet arm and an outlet arm and configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(c) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(d) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (e) a porous ultrafiltration membrane disposed in said closed plasma chamber and configured for being immersed in said plasma chamber solution, said ultrafiltration membrane having a selected molecular weight cut-off for allowing water, fluids, and solutes with a molecular weight lower than the cut-off to pass therethrough and for retaining solutes with a molecular weight greater than the cut-off and means for withdrawing said water, fluids, and solutes that pass through said ultrafiltration membrane; and (f) means for circulating said blood into said inlet arm such that plasma, including water, fluids, and low molecular weight solutes therein, is transported from said blood across said plasma-separating membrane by convective and diffusive transport into the plasma chamber solution where the selective removal of the targeted solute from non-targeted solutes using said affinity sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood and out through said outlet arm.
(a) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(b) a hollow fiber plasma-separating membrane having an inlet arm and an outlet arm and configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(c) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(d) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (e) a porous ultrafiltration membrane disposed in said closed plasma chamber and configured for being immersed in said plasma chamber solution, said ultrafiltration membrane having a selected molecular weight cut-off for allowing water, fluids, and solutes with a molecular weight lower than the cut-off to pass therethrough and for retaining solutes with a molecular weight greater than the cut-off and means for withdrawing said water, fluids, and solutes that pass through said ultrafiltration membrane; and (f) means for circulating said blood into said inlet arm such that plasma, including water, fluids, and low molecular weight solutes therein, is transported from said blood across said plasma-separating membrane by convective and diffusive transport into the plasma chamber solution where the selective removal of the targeted solute from non-targeted solutes using said affinity sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood and out through said outlet arm.
22. A system for salvaging blood from a patient for the selective removal of a targeted solute in the blood and the removal of water, fluids, and low molecular weight solutes comprising:
(a) a hemoconcentrator comprising an inlet port, an outlet port, and a porous ultrafiltration membrane having a selected molecular weight cut-off forretaining components selected from the group consisting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (b) first and second solute removal devices for selectively removing the targeted solute from blood by means of convective and diffusive transport ofplasma from said blood across a hollow fiber plasma-separating membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood, each said first and second solute removal device comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) the hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating said blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm;
(c) means for coupling the plasma chamber of said first solute removal device to the inlet port of said hemoconcentrator and means for coupling the outlet port of said hemoconcentrator to the plasma chamber of said second solute removal device such that plasma can flow from said first solute removal device through said hemoconcentrator to said second solute removal device such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration, and means for coupling the outlet arm of said first solute removal device to the inlet arm of said second solute removal device such that blood can flow therebetween; and (d) means for coupling said first and second solute removal devices to said patient to permit blood to be received from and returned to said patient.
(a) a hemoconcentrator comprising an inlet port, an outlet port, and a porous ultrafiltration membrane having a selected molecular weight cut-off forretaining components selected from the group consisting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (b) first and second solute removal devices for selectively removing the targeted solute from blood by means of convective and diffusive transport ofplasma from said blood across a hollow fiber plasma-separating membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood, each said first and second solute removal device comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) the hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating said blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm;
(c) means for coupling the plasma chamber of said first solute removal device to the inlet port of said hemoconcentrator and means for coupling the outlet port of said hemoconcentrator to the plasma chamber of said second solute removal device such that plasma can flow from said first solute removal device through said hemoconcentrator to said second solute removal device such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration, and means for coupling the outlet arm of said first solute removal device to the inlet arm of said second solute removal device such that blood can flow therebetween; and (d) means for coupling said first and second solute removal devices to said patient to permit blood to be received from and returned to said patient.
23. A method of selectively removing a targeted solute and water, fluids, and low molecular weight solutes from blood comprising:
(a) providing a system comprising:
(1) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for retaining components selected from the group consisting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (2) a first solute removal device for selectively removing the targeted solute from blood by means of convective and diffusive transport of plasma from said blood across a hollow fiber plasma-separating membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood, comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) the hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating said blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm; and (3) means for coupling said hemoconcentrator to said first solute removal device to permit liquid communication therebetween and for coupling said hemoncentrator and said first solute removal device to said patient to permit blood to be received from and returned to said patient;
(b) directing said blood from a source into said inlet arm by said means for circulating said blood, through said plasma-separating membrane and out said outlet arm at a volume and a velocity that permits convective and diffusive transport of plasma from said blood across said plasma-separating membrane along the inlet arm of said plasma-separating membrane into said plasma chamber solution;
(c) causing said plasma in said plasma chamber solution to come into contact with said sorbent such that said targeted solute is selectively bound tosaid sorbent;
(d) causing said non-targeted solutes to pass by diffusive and convective transport from said plasma chamber solution across the plasma-separating membrane into the blood retained by said plasma-separating membrane and out of said device;
(e) causing said blood or plasma to pass through said hemoconcentrator such that water, fluids, and solutes with a molecular weight less than said cut-off pass through said porous ultrafiltration membrane and arewithdrawn from said blood or plasma, and said ultrafiltration retains cells and solutes with a molecular weight greater than said cut-off in said blood or plasma.
(a) providing a system comprising:
(1) a hemoconcentrator comprising a porous ultrafiltration membrane having a selected molecular weight cut-off for retaining components selected from the group consisting of cells and solutes with a molecular weight greater than the cut-off and for allowing water, fluids, and solutes with a molecular weight less than the cut-off to be removed from blood or plasma; and (2) a first solute removal device for selectively removing the targeted solute from blood by means of convective and diffusive transport of plasma from said blood across a hollow fiber plasma-separating membrane into a plasma chamber where the selective removal of the targeted solute from non-targeted solutes using a sorbent is accomplished followed by the subsequent transport of the non-targeted solutes across the plasma-separating membrane back into the blood, comprising (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) the hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating said blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm; and (3) means for coupling said hemoconcentrator to said first solute removal device to permit liquid communication therebetween and for coupling said hemoncentrator and said first solute removal device to said patient to permit blood to be received from and returned to said patient;
(b) directing said blood from a source into said inlet arm by said means for circulating said blood, through said plasma-separating membrane and out said outlet arm at a volume and a velocity that permits convective and diffusive transport of plasma from said blood across said plasma-separating membrane along the inlet arm of said plasma-separating membrane into said plasma chamber solution;
(c) causing said plasma in said plasma chamber solution to come into contact with said sorbent such that said targeted solute is selectively bound tosaid sorbent;
(d) causing said non-targeted solutes to pass by diffusive and convective transport from said plasma chamber solution across the plasma-separating membrane into the blood retained by said plasma-separating membrane and out of said device;
(e) causing said blood or plasma to pass through said hemoconcentrator such that water, fluids, and solutes with a molecular weight less than said cut-off pass through said porous ultrafiltration membrane and arewithdrawn from said blood or plasma, and said ultrafiltration retains cells and solutes with a molecular weight greater than said cut-off in said blood or plasma.
24. The method of claim 23 wherein said the porous ultrafiltration membrane of said hemoconcentrator comprises a plurality of hollow fibers.
25. The method of claim 24 wherein the molecular weight cut-off of said porous ultrafiltration membrane is in the range of about 10,000 to 100,000.
26. The method of claim 25 wherein said porous ultrafiltration membrane is made from a material selected from the group consisting of polyacrylonitrile, polysulfone, polynethylmethacrylate, cellulose acetate, cellulose diacetate, and cellulose triacetate.
27. The method of claim 23 wherein said hollow fiber plasma-separating membrane comprises a bundle of parallel hollow fibers.
28. The method of claim 27 wherein said sorbent is of a size and configuration such that said sorbent is not permeable to the plasma-separating membrane.
29. The method of claim 28 wherein said hollow fibers making up said plasma-separating membrane are constructed of a blood-compatible material having a suitable pore size to allow passage of plasma into the plasma chamber solution while retaining blood cells and platelets from the blood withinthe hollow fibers.
30. The method of claim 29 wherein the pore sizes in said membrane range between about 0.01 µm to 1.0 µm.
31. The method of claim 30 wherein said hollow fibers of said plasma-separating membrane are made from a material selected from the group consisting of polypropylene, cellulose diacetate, polycarbonate, polyvinylchloride, polyvinylalcohol, polymethylmethacrylate, polyethylene, polysulfone, and polyethylenevinylalcohol.
32. The method according to claim 31 wherein the sorbent comprises a ligand immobilized on a substrate and said ligand is a member selected from the group consisting of enzymes, living tissue, fragments of tissue, cells, antibodies, peptides, macromolecules, nucleic acids, lectins, carbohydrates, andchelating agents.
33. The method of claim 32 wherein said sorbent has affinity for heparin.
34. The method of claim 33 wherein the substrate is agarose.
35. The method of claim 34 wherein the sorbent is poly-L-lysine-coupled agarose.
36. The method of claim 23 wherein said hemoconcentrator and said first solute removal device are configured for simultaneous hemoconcentration and removal of the targeted solute.
37. The method of claim 23 wherein said hemoconcentrator and said first solute removal device are configured for sequential hemoconcentration and removal of the targeted solute.
38. The method of claim 23 wherein said hemoconcentrator has an inlet port and an outlet port and said outlet port of said hemoconcentrator is coupled to the inlet arm of said first solute removal device such that blood passes through said hemoconcentrator for removal of water, fluids, and low molecular weight solutes to result in concentrated blood, which concentrated blood then passes through said first solute removal device for removal of the targeted solute.
39. The method of claim 23 wherein said hemoconcentrator has an inlet port and an outlet port and the outlet arm of said first solute removal device is coupled to the inlet port of said hemoconcentrator such that blood passes through said first solute removal device for removal of the targeted solute resulting in targeted-solute-depleted blood, which targeted-solute-depleted blood then passes through said hemoconcentrator for removal of water, fluids, and low molecular weight solutes.
40. The method of claim 23 wherein said plasma chamber solution is an electrolyte.
41. The methodo of claim 23 wherein said porous ultrafiltration membrane is contained in said closed plasma chamber such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration.
42. The method of claim 23 further comprising a second solute removal device, which comprises (i) a closed plasma chamber configured for being filled with a plasma chamber solution and to freely circulate, equilibrate, and interact plasma in said plasma chamber solution under relatively uniform pressure;
(ii) a hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm;
wherein the plasma chamber of said first solute removal device is coupled to the inlet port of said hemoconcentrator and the outlet port of said hemoconcentrator is coupled to the plasma chamber of said second solute removal device such that plasma can flow from said first solute removal device through said hemoconcentrator to said second solute removal device such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration, and wherein said outlet arm of said first solute removal device is coupled to the inlet arm of said second solute removal device such that blood can flow therebetween.
(ii) a hollow fiber plasma-separating membrane, wherein said plasma-separating membrane has an inlet arm and an outlet arm and is configured for being immersed in said plasma chamber solution in said closed plasma chamber;
(iii) at least one sorbent having an affinity for binding said targeted solute, wherein said sorbent is contained in said closed plasma chamber;
(iv) means for securing said inlet arm and outlet arm of said plasma-separating membrane in said plasma chamber and closing said chamber to maintain relatively uniform plasma chamber solution pressure; and (v) means for circulating blood into said inlet arm, through said plasma-separating membrane, and out through said outlet arm;
wherein the plasma chamber of said first solute removal device is coupled to the inlet port of said hemoconcentrator and the outlet port of said hemoconcentrator is coupled to the plasma chamber of said second solute removal device such that plasma can flow from said first solute removal device through said hemoconcentrator to said second solute removal device such that water, fluids, and low molecular weight solutes can be removed from said plasma by ultrafiltration, and wherein said outlet arm of said first solute removal device is coupled to the inlet arm of said second solute removal device such that blood can flow therebetween.
Applications Claiming Priority (2)
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US1313596P | 1996-03-08 | 1996-03-08 | |
US60/013,135 | 1996-03-08 |
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CA002247031A Abandoned CA2247031A1 (en) | 1996-03-08 | 1997-03-08 | Selective membrane/sorption techniques for salvaging blood |
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EP (1) | EP0892664A4 (en) |
JP (1) | JP2001524839A (en) |
AU (1) | AU2212897A (en) |
CA (1) | CA2247031A1 (en) |
WO (1) | WO1997032653A1 (en) |
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1997
- 1997-03-07 US US08/813,504 patent/US5858238A/en not_active Expired - Fee Related
- 1997-03-07 AU AU22128/97A patent/AU2212897A/en not_active Abandoned
- 1997-03-07 EP EP97915100A patent/EP0892664A4/en not_active Withdrawn
- 1997-03-07 WO PCT/US1997/004126 patent/WO1997032653A1/en not_active Application Discontinuation
- 1997-03-07 JP JP53203997A patent/JP2001524839A/en active Pending
- 1997-03-08 CA CA002247031A patent/CA2247031A1/en not_active Abandoned
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WO1997032653A1 (en) | 1997-09-12 |
EP0892664A1 (en) | 1999-01-27 |
EP0892664A4 (en) | 1999-09-15 |
US5858238A (en) | 1999-01-12 |
AU2212897A (en) | 1997-09-22 |
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