CA2180455A1 - Hemofiltration and plasmafiltration devices and methods - Google Patents

Abstract

Devices and methods for providing extracorporeal treatment of blood for effective plasmafiltration or hemofiltration are disclosed. The device incorporates a hollow fiber membrane device (HFD) connected in series with a parallel plate dialyzer (PPD). Sorbent suspension from a sorbent bag (101) first passes through the sorbent inlet (102) of the PPD, exits through sorbent outlet (103), is drawn into accumulator reservoir (104), is expelled from accumulator reservoir (104) and passes through check valve (105) in response to alternating positive pressure and negative pressure applied to the accumulator reservoir (104). The sorbent suspension then passes into HFD inlet (106) and through the outer chamber of the HFD, thus agitating and mixing the sorbent suspension into contact with exterior surfaces of the hollow fibers (107) in the HFD. Sorbent suspension exits the HFD from outlet (108) and passes through blood leak detector (109) and back into the sorbent bag (101).

Description

~WO95/18671 2~a;¢~s ElEMOFlLTRATION ANn PLASMAFILTRATlON
DE~V~ CES AND METHODS
R~ TO RELATED APPLICATION
Tllis is a co11ti11uation-in-part applicatior1 of U.S.
Patent Application Serial No. 07/332,030 filed February 6, 1992, now pendi11g.
BACKGROUND OF THli INVENTION
Tllis invention general 1y relates to devices and met11ods for extracorporeally treating blood OI blood fractions s~1c1 10 as blood iltrate or plasma to selectively remove toxil1s t11eref rom.
By way of background, extellsive e~forts llave bee11 made to discover safe and effective methods for removing toxins from ~atients by extracorporeal treatment o their blood.
15 Tlle6e efforts have included many studies directed i:o met11ods for extracorporeal treatme11t of ~1epatic failure d11e to irlfection, cirrhosis, toxin damage or other causes. Many methods l1ave been proposed witl1 the goal of removing small molecular toxins, protein-bound molecules or larger 20 molecules thought to be responsible for the coma arld i~lness of ~1epatic failure. Thus far, evidence has been presented s~lpporting adverse effects caused by non-protein bound small molecules such as ammonia, phenols, mercapta1ls, s~1ort chai fatty acids, aromatic amino-acids, neural in~1ibil:ors (GABA, 25 glutamate), false neural transmitters (octopamine) a11d bile salts. Among tllese, p~lenols and mercaptans, along witll .

WO 95/18671 F~ ~
~ 80~S5 . .

bilirubin and bacterial endotoxins, also occur as strol~(J
proteill-bo~ d toxins and are~tllus more di~ficult to effectively remove from t~le blood. In addition, t~lere are a variety of middle molecular weigllt toxins of liver failure havirlg molecular weig~lts of about 300 to about 10,000 whicl are difficult to effectively remove.
As to specific modes of treatment, those previously proposed and used have included blood perfusioll over heterogeneous liver pieces or past membranes which contact hepatocytes. Also proposed and used have been hemoperfusion tllrougtl columns of coated activated carbon or macroreticular resins, blood exchange, plasmapheresis with plasma replacemerlt, plasmaplleresis witll plasma perfusion t~lrougll bilirubin-binding and aromatic amino acid-bindillg sorbents, standard hemodialysis, standard hemodialysis with an amino acid dialysate and plasma exchange, high permeability ~lemodialysis, dialysis with charcoal-impregnated membranes, continuous llemofiltration, peritoneal dialysis, oral sorbellts and many other therapies.
Wllile some of these previously proposed treatments have produced neurological improvement in stage 2 or 3 coma and ~lave aided llepatic regeneration after injury, they have rlot provided muc~l clillical improvement in patients in stage 4 coma on respirators. Additionally, these diverse treatmellts each produce adverse effects on the patient, offsetting benefits. See, generally, Ash, S.R., Treatment of Acute llepatic Failure Witll Encephalopathy: A Review, Int. J. of ATtiL. Orq~nc~ Vol. 14, pp. 191--195 (1991) .
For example, althougll daily cl~arcoal llemoperfusion llas been sllown to provide neurologic and physiologic improvelnent of patients witil llepatic failure alld coma, Wincllester, J.F., llellloperfusion, in Replacanent of Rerlal ~unction by Dialysis ~ WO9S/18671 2 1 8 0 ~ 55 ; ` 111 C., C
(Ma~ler, J.F., ed. ), I)ordrecllt:Kl~lwer Academic PublislleLs, p~). 439-~59, (1989), hemoperfusion nevertlleless requires systemic anticoag~llation and also depletes coagulation fac~ors and platelets from tlle bloo~. Moreover, tlle 5 rela~ively large sorbent gral-ules used in ~ler~loperfusiorl columns have limited surface area (about 1000-10, 000 n~2) .
Conseq~lently, the available sorbent sura;ce area is saturated within a few hours, clearance of bound cllemicals rapidly diminishes, and a new column must be used.
Furtllermore, clirlical beneLits of charcoal ~lemoperLusiu may be offset by deleterious effects of bio-incompatibility. In one instance, a controlled study of patiellts witl~ fulminaLIt ~lepatic failure, all treated wiLII
aggressive isltensive care including intracerebral pressure 15 Inonitoring, demonstrated that patients treated by llemoperfusion llad a gerlerally lower survival rates tllall those treated with aggressive intensive care alone. Tlle only exception was noted in patients having fulmillant hepatic failure due to slepatitis A or B, for whom there was 20 reported a "trend toward improved survival" when treated with charcoal perfusion. O'Grady, J.G. et al., Controlled Trials of Cllarcoal l~emoper~usion and Prognostic Factors in Fulrllinant ~lepatic Failure, GastroenteroloqY. Vol. 9~1, pp.
1186-92 tl988).
As mentioner], standarrl }lemodialysis (i.e. dialysis of s~lood against only a dialysate solution) ~las also been s~udied as a possible treatment for hepatic failure.
Ilowever, beneits of hemodialysis may be similarly obscured by removal of substances (e.g. urea) known not to be toxins of slepatic failure. Additionally, hemodialysis requires tlle ~Ise of large volusnes of dialysate solution which lirllits tlle mobility and increases tlle complexity of tsle machines, or alternatively, it requir~s Llle provision of a sorbent colulnn ~o "regenera~e" tlle dialysate.

W095118671 r~lllJ.~
2180~5 Ill ligllt of tllis extensive background, tilere ren~a needs for improved devices alld methods for the extracorporeal treatment of blood or of blood f ractions tQ
effectively remove toxins, includillg both soluble and s proLein-bound toxins. The present invention addresses tllese needs .

W0 95/18671 _ r~ -~u.,,s~r~ ~5 ~;UMMARY OF TilE INVENTION
T~!e presellt inventioll E~rovides a unique filtratioll process (e.g. a llemofiltration or plasmafiltration process) w~lich is ~lighly ef~ect:ive in removing protein-bound and 5 middle molecular weight toxins. The inventive process includes the steps of passing a fluid, sucll as blood, containing protein-bound or middle molecular weigllt blood toxirls, throug~l the interior of a hollow fiber membrane, alld during the passage of blood, circulating a sorbellt 10 suspension against exterior surfaces of the hollow fiber melnbrane. As a further step, durill~ the passage of blood and circlllatiorl of sorbellt suspension, the plasma fractioll of the blood is caused to a] ternately exit arld re-erl~er t~le interior of the membrane. Thereby, blood plasma contacts 15 tlle sorbent suspensiorl upon exit from the interior of tlle membrane, so as to effectuate removal of tlle tOxills frorn ~lle blood. Tllis embodiment of tlle invention is applied witll preference to whole blood; however, the invention is not so limited, as it will be applicahle as well to the treatment 20 of ot~ler fluids containing middle molecular weigllt and/or proteirl bound blood toxins, e.g. blood fractions SUC~I as isolated blood plasma or other blood toxin-containing fluids s~lch as blood filtrate.
Anotller preferred embodiment of t!le present illverl~ion 2s provides a device whic~l is lligllly efective for removing protein-bound or middle molecular weig}lt toxins from fluids SUC~I as blood, blood plasma or blood f iltrate. T~le preferred device of the inverltion includes a rlollow fiber melllbrane, arld a p~lmp fluidly connected to ~lle irl~erior of 30 t~le }lollow fiber membrane and adapted to pass blood (or ano~ler fluid containing the toxins) t~lrough ~lle interior.
Tlle device fur tller includes a cilalllber surroundillg ~he ~lollow fiber memb~ane, ~he cllall~er also beirlg fluidly connec~ed to Wo 95/18671 21 8 ~ ~ 5 ~ r~

a supply of sorbent suspension colltaining solid particulaLe adsorbellt. A p~lmp is adapte~ to circulate the sorbetlt suspension tl~rougll tlle cl~amber alld against exterior surfaces of tlle hollow fiber membrane. Means for causillg tlle blood 5 or ot:ller I luid or a=fractioll tllereof passing tllrougll tlle interior of tlle menlbrane to alternately exit and re-enter t}le illterior of the ~lollow fiber membrane are also provided.
Still another preferred en~bodiment of tlle presellt inverltion provides a method for circulating a sorbent 10 suspension in a device for extracorporeal treatment of blood or a blood fraction. Tlle metllod of the invention includes a step of providing ~lle device having a sorbent circulation circuit alld a blood circulation circuit separated by melllbrarles, the membranes being compliantly formed to expalll:!
15 and contract in response to alternating positive pressure and !legative pressure applied to the sorbellt circulation circuit arld tllereby advance a sorbent suspension tllrou~ll tlle sorbent suspension circulation circuit. An accumulator reservoir is provided and fluidly connected to tlle sorbellt 20 circulation circuit, and is operable to alternately accumulate and expel sorbent suspension in response to alternating negative pressure and positive pressure ap~lied to tlle acc~lmulator reservior. Thereby, the accumulator reservoir colnununicates the alternating negative and positive 25 pressure to the sorbent circulation circuit. The metllod furtller includes applying alternating positive pressure arld negative pressure to the accumulator reservoir so as to conunurlicate tlle same to the sorbent circulation circuit alld cause ~lle compliant membranes to expand and contract, 30 w~lereby tlle sorbent suspension is advanced t}lrollgh ~he sorbent suspension circuit.
Still anot~ler preferred embodimellt of ~rle invelltion provides a device for extracorporeal treatment of blood or a ~ wo 95118671 ~ 1 8 0 4 5 5 . ~IIU_ 5~C

blood fraction. Tllis device llas a sorberlt circulatio circuit and a blood circula~ion circuit separated by IllelllbrAnes, wlle~ein ~lle membranes are complialltly fornled to expalld and corltract in response to alternating positive 5 pressure and negative press~lre applied to tlle sorbent circulatioll circuit and thereby advallce a sorbent suspensio tllroug~l tl~e sorbellt suspension circulation circuit. An accumulator reservoir is fluidly connected to the sorbent circulaLion circuit all~ operable to alternately accumulate 10 and expel sorbent suspension in response o alternatillg negative pressure and positive pressure applied to the accllmulator reservior, tlle acculllulator reservoir tllereby commullicating the alternatirlg negative arld positive pressule to tlle sorbent circulation circuit. Tlle device also 15 illcluules a source o positive pressure and of rlegative pressure 1uidly conl~ected to the accumlllator reservoir.
Wllell alternating positive pressure and negative pressllre al.e alternately applied to tlle accumulator reservior, L~le same is communicated to the sorbent circulation circuit to cause 20 ~I~e comE~lial~t membranes to expand and contract, wllereby ~lle sorbent suspensioll is advanced ~hrough the sorbent suspellsioll circuit.
The invention l:lIUS provides methods and devices by wllich greater removal of protein-bollnd and middle molecular weigllt 25 I~lood toxins fronl blood, blood plasma or blood filtrate can be acllieved, and wllereby eficient circulation of sorbents on tlle sorbellt side of a variety of different types of extracorporeal treatment devices is effectuated. Additiol~Al objects, features and adva~ltages of ~he present illvention 30 will be apparent from tlle description wllicll follows.
: .

- PeTlUS 95 / ~ C ~ 9 5 ~18 0 ~ ~ 5 IPEA/us Og AUS 1995 BRIE~F D~SCRIPTION OF TH~ FIGUR~S
Figure 1 is a perspective view of a preferred pressure/vacuum operated dialysis system which can be used in ~he irlvention.
Figure 2 is a schematic representation of the hydraulic system of tt~e dialysis system of Figure 1.
Figure 3 is a schematic representation of the mechanics of operation of the preferred direct pressure/vacuum operateù
dialysis system of Figure 1 during the first part of blood inflow (Fig. 3A) and during the remainder of blood inflow and blood outf low (Fig . 3B) .
Figllre 4 is a schematic representation of the hydraulic circuit of a combined device incorporating the system of Figure 1 in series with a hollow fiber plasmafilter.
Figure 5(a) shows t~le blood-side pressure curve between tlle system of Figure 1 and the plasmafilter in the combined device of Figure 4, during several inflow-outflow cycles.
Figure S(b) shows the sorbent-side pressure curve witllin the plasmafilter membrane package of the combined device of Figure 4. Mean blood-sorbent pressure difference is approximately zero Figure 6(a) shows a Langmuir isotllerm for bindillg of bromsulphthalein (BSP) ~rom saline (top line) and from porcine plasma (bottom line) to which it was first bound to cllarcoal .
Figure 6(b) sllows a Langmuir isotllerm for binding of unconjugated bilirubin from porcine plasma to whicll it was first bound to charcoal.

WO 9~/18671 ~! l 8 0 4 S ~ PCT/US9S/0039S
~ .:
_g_ LIESCRIE`TION OF T1~E l'REFERRED EMBOL)lME~T
For ~11e purposes of promo~ g an understa11dil1g of ~I~e principles of the invention, reference will now be made to certain embodiments and specific language will be used to S describe tlle same. It will neverLheless be understood ~llat no limitation sf tlle scope of the invention i.s tllereby intended, such alterations, further modifications and applications of t11e principles of ~1le inve1ltion as described -herein l)eing cor1templated as would 1lormally occur to olle 10 skilled in the art to which the invention relates.
As i11dicated above, one preferre~ embodilnent of t}lis invention relates to a method which can be used for e2~tracorporeal treatmerlt of blood or a blood fractioll by filtration, e.g. plasmafiltration (wherein plasma is 15 filtered across a membrane) or hemofiltration (wherein middle molecular weig}lt molecules (i.e. having molecular weigll~s of about 300 to about 10,000) are ~ ered across a membrane), in a manner w}lich provides the safe, consistellt and effective removal of toxins, including protein-bound 20 blood toxins and Illiddle molecular weigllt blood to2~ir1s. Tllis filtration cal1 be used alone, or in connection wit11 dialysis of tlle blood or blood fraction, for example using dialysis devices and met11ods as described ill my prior U.S. Pate1~t Application Serial No. 07/832,080 filed February 6, 1992, 25 which is hereby incorporated by reference in its entirety.
Likewise, tlle advantageous sorbent circulation system arld method described in t}lis prior application is effective o advance sorbent suspension througll ~1ollow fiber plasmaril~ers and r1emofilters, and is generally applicaole 30 to adval1ce sorbel1t suspel1sion t~1rougll a va~iety of extracorporeal treatment devices 11aving blood and sorberlt sides separa~ed by a membrarle, and thus also fornls a paLt oL
L11e applicant ' s i1lventis~l.

Wo ss/l867~ ' ~ r~
21~0 4~5 Tlle soIbent susLlellsiorl used i~ e inventioll cal~ lude powdered surface adsorptive agents, physiologic electrolytes and Inacromolecular flow ind~1Ging agents. In general, these compol~e11Ls are present in eLfective amou11ts ~o ac11ieve ~11e desired removal of substances from and electrolyte balal1ce in the blood of the patient while maintaining the stability and f luidity of the sorbent suspension . Because plasmafiltration membranes as used in t}le inventior1 ca potentially pass endotoxins, it is preferred tllat tlle sorbellt suspension be free from meas~1rable elldotoxins.
W~lile general sorbel1t suspension production tecll11iques 11ave been sufficient for these purposes, if necessary, measures can be l.aken sallitize or sterilize tlle suspension, for exal11ple usi11g 11eat or radiation (e.g. ga111ma-radiation), ~o assure tllat the sorbent suspension is substantially free f rom bacteria or otller mi.crobial growl:h whicl1 could poterltially generate endotoxins or ot}ler 11armLul subs t ances .
Tlle powdered surface adsorptive agent can be any olle o~
many Jcnown to tllose practiced in this area, but is preferably powdered activated charcoal. Furtller, tl1e powdered surface adsorptive agent preferably 11as a11 average particle dia1neter of not greater t}lan about lO0 microns.
More preferably, this average particle diameter is less tllan abou~ 50 I11icrol1s, wi tl1 90% or more of the particles llavillg dian~eters not greater than about 75 microns. Particles ~ree~ling 75 n~icrolls in diameter can be screened if necessary. As ol1e example, a suitable finely powdered activated cllarcoal is available fronl American Norit Con1pa11y, Inc. of Jacksol1ville, Florida, U.S.A., which cal1 be screened to remove particles larger ~llal1 tllose desired.
Tlle macromolecular ~ow il1d11cing agents f~1nction to ~ WOgS/1~671 218045a l~l" c ,5 mairltairl ~lle stability of the sorbent suspension formula~ior~
(i.e. Ilelps ~o prevent solids ~rom se~tlirlg out o~
suspensiol~) and Inaintaill tlle ~low properties of ~lle suspension. One desirable flow inducing agent is a 5 noniollic, llydroxyl-containiny polymer SUCII as a glycol derivaLive. Suitable agell~s of this type are available frorn sASF Wyandotte of Parsippany, New Jersey, U.S.A. under tlle trademark "Pluronic" polyols. These Pluronic polyols are polyoxyalkylene derivatives of propylene glycol. To date, 10 aE)plicant ~las used ~luronic F6~, which functions bo-h as a flow inducing agent and a defoaming agent. Anotller flow ~gellt Lllat llas been included in preferred suspensions is macroreticular polyvinylpyrrolidolle.
Tlle types and amounts of electrolytes included ill tlle 15 suspension Lormulation will depend upon tlle specific needs of the patient and will be readily determinable by physicians or oth~rs skilled in the area. Typically, tlle elec~rolytes will include sodium and cilloride (e.g.
op~iollally provided as sodi~lm cllloride), and can also 20 illclude bicarbonate, potassium, calcium, or any other electrolytes to be reyulated in tlle patient. As indicated, however, ~le types alld amoullts of electrolytes may vary widely depending on patient needs.
T~le sorbellt s~lspensioll formulation may also include all 2s ion-excllalluer to billd ionic cllemicals, e.g. ammonium, etc., whic~l may occur in the patient ' s blood. Many suitable ion excllangers includillg botll resins and other materials sucll as zeolites are kllown in tl1e art. When included, the ion-excllanger is pre~erably a catioll-excllange resin, wllicll 30 is desirably loaded with sodiuln or calcium. For example, ~o date, sodiulll polystyrene sulfonate llas been a preferred material .

Wo 95118671 r~l,t ,. -~ s.~ ~
218~

Tlle surface adsorptive agent, electrolytes, flow inducing agt~nts and any other additives will usually comptise about 5% to 30% by weigllt of ~he sorberLt suspensio formulatioll as a wtlole, Wil~ll the relnainder beillg water.
S Typically, solid sorbents will comprise about 2% to 25% by weiyllt of ~lle suspension ormulation, and electrolytes will comprise about about 1% to 5% of tlle suspension form~l1ation. Within these parameters, more preferred sorbent suspension form~llations comprise about 2% to 20%
10 powdered surface adsorptive agen~, up to about 10%
ion-exchanger, and up to about 1% f low agent suc!l as s polyol and/or polyvinylpyrrolidone.
~ rlle sorbellt suspension can also include viable hepatic cells, e.g. xenogenic or allogenic cells, alone or in 15 combillation wi~h one or more o t~le solid adsorbents alld ottler materials de5cribed above, to assist in the effective removal of toxins. For example, hepatocytes can be isola~ed from suitable donor tissue, purified and microencapsulated in polylner as described by Dixit et al., lle~atolo~y 1990:
20 12: 1342. Tllese microencapsulated cells can t~len be used directly ill tlle sorbent suspension, or can be cryopreservetl until use, for example as described by Dixit et al., ~ransr~lantatioll 1993; 55: 616-22. When hepatic cells are so usetl, plasma is effectively separated from the blood by 25 passage t'tlrougll t~!e plasmafilter membrane, allù proteirls a toxins are convected irlto contact witll the cells circulati exterior of tlle menlbrane . Af ter the cells llave acted ~pOII
tlle toxins, tlle plasma is returned ttlrougll tlle memt~rane alltl back into tlle patient.
Ill collnecLioll wi~ll plasmafiltratioll or helllofiltratio devices antl metllods, Lllere are many sllitable ~lollow fiber menlbranes WlliCII are kllowr~ for use in plasmafi] ~ratioll or 2~04~

llemofiltratior1 o blood, an~ tllose sl~illed in t~le area will be readily able to select al1d utilize a suitable membrsnes i[l tlle presellt irlvell~iorl. Such mel[lbranes can be, for example, cellulosic membranes (e.g. cellulose acetates), al1d 5 will llave pore sizes suLiciently large to allow passage o~
plasma pro~eil~s (e.g. in plasl~afiltrat;ion) and/or middle molecular weig11t blood toxirls (e.g. in hemofiltratior1), suitably l1avillg molecular weiQht cuto~s of abo~lt 50,000 or above, e.g. 50,000 to 6,000,000. Suitable plasmafiltratio lO al1d ~le~nofiltration membranes include, for example, those known under the desigllations F-80 (50,000 m.w. cuto~f, Fresellius USA, Inc ., Walnut Cree}~, CA), Altrex 140 (70, 000 m.w. cutoff, Altllill Medical, Inc., Miami Lakes, FL)), CTl90G
(60,000 m.w. clltoff, 13axter, Deerfield, IL), and L'lasmal~lo 15 AP-05t~(L) (about l,000,000 m.w. cutoff, Asaili Medical Co., Ltd., Tokyo, Japan). More preferred plasmafiltration or l1emofiltration n1embranes will have pore sizes WlliCt1 transmit albllmin or middle molecular weight molecules with selecl:ivity over larger molecules, and thus will provide 20 removal of toxins while mil1i1nizing potential interference with other blood functions. For example, the Plasmaf~ow AP-05H(L) plasma separator (0.5 scluare meters) has about a 596 rejection of albumin during unidirectional filtratioll, but about an 80% rejec~ion of macroglobulil1s.
Ill connecl:ion with dialysis when used in the presellt il1vention, there are many dialyzer me1nbranes w11ich are know for ~Ise in dialyziny body fluids such as blood, al1d those skilled in the area will be readily a~le to select and utilize a suitable membranes ill the eresent invention. O11e suitable melnbrane is a cellulosic mell1brane, particularly c~11e composed o regenerated cuproammonium cellulose (Cuprop~lan) .
Ill circumstances wllere ollly plasmafiltration or WO 9~/18671 r ~ ss 2~ 8~455 hemofilkratiorl (and llot dialysis) of tlle blood or other fl~lid is desired, the membrane irl the dialysis instrumellt need IIOt be a dialysis membrane, and trlus may be olle wllicll is in~permeable to blood an~ its components, e.g. a membrane 5 formed from a suitable compli ant plastic film. Moreover, where only plasmafiltration or hemofiltration is desired, tlle dialysis instrllmeilt lleeLI not be employed at all, al~d ally means of circulating the sorbent suspension against the exterior of t'ile llollow fiber Inembralles wllile passirlg tl!e 10 blood or otller f luid tllrough the interior o the membranes (witll bidirectiollal flow of t~le blood or fluid across tlle membranes) will be suitable. For example, the hollow ~iber membrarle cartridge could have sorbellt side coimections to a container filled Wit~l sorbellt suspension. W~lile tile sorbent 15 s~lsperlsion is circulated tllroug~l tlle cartridge, for exsmple by a roller p~lmp, the pressure changes in the blood side (created alltonlatically by roller p~lmps) would creste the desired bidirectional flow of plasma or other fluid across the membranes. Such systems will provide high clearance of 20 protein-bound or middle molecular weight toxins with great sim~licity arld low cost.
The inventive plasmafiltration or hemofi~tration metllods of the invention are advantageously performed in connection with a preferred, dialysis instrument including a parallel 25 ~-late dialyzer and moving the sorbent suspension formulatio in a co~lllter-current mode by t~le direct application of altelllating negative pressure alld positive pressure on tlle dialysate side, as described in more detail in Examples 1 and 2 i~elow. Tlle preferred system also creates a sligllt 30 back an~i fortll Illotion of tlle sorbe~lt suspension formulatioll, wllicll agitates, locally mixes, and helps to prevent settlillg of tlle sllsE)ension.
Extracorporeal blood~reatmerlts of tl-e illvention call be ~ W095/18671 ~180~55 used to saLely alla efEec~ively treat tlle coma alld illness or llepa~ic failure alld ~o improve a patie~L ' s clillical condition as evidenced by improved physiologic and neurologic patiellt status. Metllods of tllis invention can 5 also be successfully used in treating drug overdose, evell witll ilighly-protein-bound drugs (i.e. drugs wllich are 75% or more proteil~ bound). It is also expected tllat me~lods and devices of tlle illvenLion wilL be efective ill treating patients witll renal failure, uremia, or otller conditiolls 10 benefited by removal of to~ins from the blood. Further, plasmaEiltral:ioll alld/or dialysis metllods of tlle invention can be used ill llemofiltratioll to treat alld remove tOXills frol~ tlle hemofiltration ultrailtrate, alld return the treated ultrafiltrate to blood. Ill Lhis mallrler, the use of 15 large volumes of sterile replacement flllid can be an~eliorated or eliminated.
Tlle invell~iorl will now be described wiLII reference to tlle following specific Examples which are illustrative, and not limiting, of the invention.
E~AMPI,E 1 Operation and C ~ ~nents of Preferred Vacuum/Pressure C)perated Flow-Throuyh Dialysis Systelll Fig~lre l is a perspective view of a preferred dialysis system 11 sitting on a standard hospital cart, which can 25 be used in metllods of the invention. Generally, tlle preferred dialysis system 11 is similar in some respects to tlle dialysis instrument disclosed in my earlier U.S.
Patellt l~o. 4,661,246 issued April 28, 1987, wllicll is llereby incorporated llerein by reference in its entirety.
30 llowever, to fill alld em~ty ~lle dialyzer of blood, ~lle present system uses tlle direct application of pressure alld vacuu~ o give positive and negative pressure cilallges in ~lle dialysate. This increases tlle blood flow and ellhallces WO 95/18671 2 1 8 11 ~ s .

~lle Illixillg of tlle soLi~erlt suspellsion formulatioll, as well as llelps to maintain op~imal chemical gradients across tile dialysis melllbrane.
Wi~ll coll~inued re~erence to Figure 1, tl-e dialysis system 11 includes a machille iJase 12, reservoir tank 13 Witll cover 14, a sorbellt bag 15 containing sorberlt suspension materials, disposable pack 16 (illcluding tlle plate dialyzer), and power supply 17 (providing vacllllm, pressure, and DC power to tlle maciline base). Referring now also to Figures 2 and 3, Figure 2 is a hydraulic scllematic of tlle dialysis system, and Figure 3 provides in parts ~ and B a sum~nary of tlle mechanics and hydraulics of opera~ion of tile system dllring blood illflow and outfIow, respec~ively. Generally, ill the following discussion, ~lle nllnlbers 20-47 will be used to designate components on tlle disposable pack 16, wllereas numbers 50 and above will designate components of tile maciline base 12. In Figure 1, tlle maclline base 12 and disposable r~ack 16 are shown separated. Of course, in use together, tile pack 16 is mo~lrlted to maclline base 12 and their respective componellts assembled general]y as follows.
Vac~lum/pressure lille 20 from top port 21 of accumulator 22 is connected to vacuum pressllre port 50 on machille base 12 WlliCII feeds vacuum an~i pressure from tlle respective sources tilereof in power s~pply 17. rrime ~ube 23 is seated i nto ~he upper side of prime/rinse clamp 51 and tllrougll i~rime fluid serlsor 52. Tlle blood inflow tube 24 is seated into tlle lower side of prime rinse clan~p 51, blood i~lf low clamp 53 and tlle blood illf low sensor 54 . Tlle b1Ood outflow tube 25 is seated into blood outflow clalnp 55 and blood ou~flow sellsor 56, and fluid level sensor 57 is placed ollto acc~l~nulator 22_ Reinrusate t~lbe 26 is loaded into reinfusate pfflnp 58 and reinfusate f luid sensor -`~
~ WO95/18671 2180~i5 r~"~ s _17--59. Dialysate tube 27 (prior to the "Y" split) is loaded into dialysate pump 60 and its end connected to water port 61. 13rancll of dialysa~e ~ube 2~3 (after the "Y" split) wllict~ connects to tl~e dialysate inlet 29 of dialyzer 30 is 5 seateù into dialysate-in clamp 62. Filtrate line 31 is loaded irlto filtrate p~lmp 53 and into filtrate fluid sensor 64. Filtrate line 31 is also connected to filtrate disposal bag 32 which is vented. Three liters of sterile water are added to reservoir tank 13. Sorbent bag 15 is 10 sllspe~lded froln reservoir covel 14. Tubes 33 (leading to dialysate inlet 29) and 34 (leading to trle exit port of acculllulator 23 and also connected to dialysate ouLlet 35 via lille 36) are connected to lines 37 and 38 provided o and leading illtO sorbent bag 15.
ï'lle followillcJ steps are conducted under sterile colldi~ions. Blood illflow line 24 and blood ouL~low line 25 are connected to blood inlet 39 and blood outlet 40 of dialyzer 30, respectively. ReinEusate solutiorl (e.g.
CaC12 solution and appropriate amounts of r~Cl and/or 20 NaCl solution) i8 injected into reinfusate bag 41.
Reillfusate line 26 is connected to reinfusate bag 41 arld a drip ctlamber ill the line is partially Eilled. Prime tube 23 is connected to prime bottle 42 containing priming fluid, e.g. 5% dextrose. If desired, replacement fluid 25 can be provided via fluid replacement line 43.
~ llus, af ter ttle above assembly, ~lle blood in~low 24 alld blood outElow 25 tubes pass Lrom a single access lirle 44 througll clamps 53 and 55 and optical monitors 54 and 5G
to collnect to the top 39 alld bottom 40 openings of ttle 30 t~lood side of tlle dialyzer 30. Cylirldrical accurllulator 22 attaclles to ttle dialysate space at ttle top opening 35 of ttle dialysate side of dialyzer 30, ancd alterllating s~ron~
vacuuln (i.e. Ilegative pressure) and llodest positive Wo 95/1~671 1 ~" ~ ~ ~
~18~45~
pres3~lre ill accumulator 22 (provided by line 20 Lhrougll port 21 above ~he fluid level) alterna~ely draws dialysaLe into and expels dialysate ron~ accumulator 22, wllici~
expallds alld compresses tlle membranes of dialyzer 30 (as 5 illustrate by ~lle arrows, Fig. 5), wllile the automatically controlled i~lood inflow and out10w clarllps 53 and 55 asnure ~ilat blood passes unidirectionally tllro~lgll the dialyzer 30, at all average rate of up to 250 ml/lllin (irl 5 cycles). Tile ra~io o inflow/out10w cycle times 10 determines tlle ultrafiltration rate, from a minimum of about 200 ml/llr at a ratio of about 1.45, to about 600 ml/hr at a ratio of 2 . 45 .
In tlle preferred dialysis system 11 utilized ill the specific Examples, the dialyzer was a 1.6m COBE
15 parallel screen-plate dialyzer having dialysis membranes composed of regenerated cuproammoniurn cellulose (Cupropllan) and ilaving a functional molecular weigilt cut-off of about 3000 daltons, i.e. only molecules of abollt 3000 daltons or less will pass ~hrough the 20 membrane.
As opposed to many previously-krlowrl dialysis systems, tile syste~ Ised in ~ile invention contaills a sorbent suspension in tlle dialysate instead of merely a dialysis solution. Flow of the suspension is generally 25 coullter-currellt, and is both bidirectiollal between the accumulator 22 and dialyzer 30, and circular between the dialyzer 30 arld sorbent reservoir lS.
lrl sullul~ary, during the first part of i~lood inrlow (see particularly Fig. 3A), clamp 62 on the dialysate il~flow 30 lille 33 opens, allowing sorbellt suspension to flow froll~
tile sorbent reservoir 15 tilrougll tlle entire dialyzer 30, fillillg the accumulator ~2 to tile level o sensor 57.

~ WO 9SJI8671 2 1 8 ~ 4 ~

~lamp 52 tllen closes and remaills closed durillg ~lle remainder o~ inflow and all of outflow (see particularly Fig. 313), wllell pressure in ~I~e accumulator Z2 returlls some suspellsion to the dialyzer 30 and passes some ~ilrougl S o~le-way valve 45 to return ~o ~ile reservoir 15 via dialysate return lille 34. In l:ypical operation, eacl minute, about 900 ml of sorbellt suspension flows into accumulator 30 (ill 5 cycles). 600 llll of sori~ellt suspension ~lows back illtO ti~e dialyzer 30, ~Ind 300 ml l0 Llows Lroln the accllm~lator 22 into tlle sorbent reservoir 15. Tllis, alollg witll he expansion atld contractiorl of ~ile dialyzer melllbranes, keeps tlle sorbent suspension well mixed at the dialyzer membrane surface~ Typical blood side and dialysate side i~ressure, and tlle blood volume o8 lS t]le dialyzer over tin~e durillg sucil operation are sllown i Figllre 9. As can be seen, both the blood side and dialysate side pressures alternate betweerl positive and negative pressure, while the spring action o the plate dialyzer membranes ensures tllat tilere is constantly a 20 positive pressure gradierlt from blood side to dialysate side .
In one suitable system, sorbent bag 15 initially contairls dry sori~ent materials to wilich tlle systelll alltomatically adds 1.5 liters of sterile water from 2s reservoir tank 13 via port 61 durirlg priming. This operation is powered by dialysate pump 60. For the ~xamples givell }~elow, ~le sorbent Illaterials in bag 15 were as ollows:
-140 grams powdered activated cllarcoal (300, 000 sqllale 30 Illeters surface area, between 5 and 53 micron mean par~icle diameLer, 70 microrl Illaximlllll particle diameter) -80 grams catioll exciratlger (sodillm i?olystyrene sulollate, E'SS, fullctional bindil~g of 80 mL~q).
... . . . _ .. ..... .. . . . . _ .

2180~55 -20--1.5 grams Pluronic F6B.

-3.0 yralTls polyvillylpyrrolidone (PVP).
-sodi~lm bicarbonate and sodi~m cllloride to result i pllysiologic star~ing concerltrations il~ e dialysate 5 sorbent suspension after prin~iny (sodium=190 mEq~L, bicarbonate_35 mLq/L, cllloride=105 m~q/L).
Tlle priming fluid for tlle blood side of the dialysis systcln was one liter of 5% dextrose from container 42 a~l:aclled to blood illflow tule 24 via tube 23. During 10 prillling, priming/rinse clamp automatically opens prilne tube 23 wlli le closing blood inf low tube 24 . l riming f luid is tl~ls pulled illto the system rather than blood. Gl~lcose passes across the membrarles of the dialyzer 30, and 20 grams binds to the charcoal, w~lile sodium cllloride, and 15 bicarbonate pass from tlle suspension into tlle primillg rluid. During dialysis, glucose disassociates fro~ he charcoal and returns to the patiellt (unless the patient s glucose is very hig~l). A reinfusate of sterile calcium cllloride alld Eotassium cllloride was pumped by reinusate 20 pllmp 5~ f ro~n reillfusate container 41 throug~l tube 26 illtO
tlle olltf low line 25 at a dimillishing rate througl!out ~lle trea~ ellt, to offset removal by the cation excllanger.~
Tlle system also includes a variety of sensors to make opera~ion safe, simple and ~ligllly automated, including:
-a scale to weigll t~le erltire top of tlle mac~lille, to measure vol~lllles ~ rafil~ered rrom and reLurned ~o ~lle patiell~;
-blood sellsors (54 a~d 56) ~o meas~lre foam, bubL)les, Wo 95/18671 ~ 1 8 0 4 5 5 ... . . .

particles of blood irl tlle ill~low and outflow lilles 24 a 25, and to Ineasure f low rate on tlle inf low line 24;
-llelnoglobill sensor 46 to cllemically detect lIemoglobiII
within tI1e sorbent suspenslon if there is a men~brarle blood 5 leak. For tIIis function, a filtrate collector 47 provides a solid-free sample of tlle dialysa~e fluid to hemoglobin sensor tape wl1icI1 cllanges color i hemoglobin is present.
T~le ~ape is automatically wetted Witll samples of dialysate, adval~ced aIld monitored for color cllange by a 10 reflectometer. The wetting of the tape is controlled by filtrate pllmp 63 wllich furt~Ier pumps excess filtrate via tube 31 illtO collection colItainer 32.
-empty line sensors on all fluid-illed lines;
-temperature sensor for f luid in the reservoi r tank 13 15 surroullding tlle sorberlt bag 15 (optimally lleated to about 37 to 40C by heating elements also provided in tlle mac~ e).
TIIe computers of tlle systeln automate many of tl1e s~eps of treatment, including:
-priIIIing of tlIe macIIine, observing lines to determilIe t~Iat all air is removed;
-re~url1ing luid to the patient wllen desired final weigllt is obtained or on command (or tlle latter, automatically adjusting ultrafiltraLion to reacll desired fiIlal weiglI~).
-rinsi ng tI1e dialy~er aIld blood lines at the end of trea~menl; and Wo 95/18671 , r~
218045~

-recordil1g, storillg and ~ransferri11g da~a co1~cer11ir erogress of each treatrnen~.
E~AMPI.E 2 COMBINED DIALYSIS~PL.ASMAFILTER or HEMOFILTER DEVICE
Figl1re 4 provides a sc11ema~ic diagram sllowing ~11e ydraulics of a combined dialysis/plaslnafilter device i accordance with the invention. As shown, the device incoreorates a parallel plate dialyzer ("Pl?D") connected in series Wit~l a 11ollow fiber membra1le device ("E~FD"). I
this regard, it will be understood tllat the present invention is not limited to suci1 a combined device, and t11at Lile 11FD could be used as the sole ayent for treatme of the blood. Furtller, wher1 used in combirlation with t11e L'PD, the ilFL) can be incorporated in any suitable location witllin Lhe sorbent circulation side of the PE'D.
Preferably, tlle 1~FD will be il1corporated to as to achieve 11igh bidirectional plasma flow across the membranes of t~1e E~FD, wit11 a net flow of about zero to prevent increasi11g sorbel~t volume (w~1ic11 would increase the volunle of distribution for albumin and increase loss of albumin froln L1le patient) . The 1~FD is also desirably incorL orated so as Lo provide blood treatment rates over 150 ml/1llin., to allow iligh filtration rates across the membranes and E)ermit lligll clearance of protein-bound or middle molecular weiyllt substances.
I11 L~le illustrated arrallyement, t:lle 1~FD is colll~ected ill series Witll t1~e PPD suc11 I:hat sorbent suspellsio exiting the sorbent reservior f irst passes tllroug~ lle 1'`E'L~
and L11en tlle 11FD. More partic~llarly, sorbent is first drawl1 fro1n solbe11t bag 10l arld into sorbent irllet 102 o t~le PE'D. Sorbellt e~its ~orbent outlet 103 and is drawl~

~ Wo 9~18671 2 1 8 0 4 S ~ s illLo accun~Illator reservior 104, wllereafter i~ is expelled fronl accumulator reservior 10~ and ~asses ~IIrougII cIIeck valve 105. Tlle sorbent susl?ensioll t~len passes irlto I~FD
inlet 106 and throuy~I t~Ie outer c~IaIober of tlle IIFD, tllus 5 passing illtO contact Wit~I exterior surfaces of the hollow fibers 107 in the IIFD package. Sorbent suspension exits the HFD from outlet 108, and passes ~hrougII blood leak detector 109 arla back into sorbent bag 101. T}le PPD ca be suitably operated as described in FxaTnple 1 above. 1 10 this manner, the sorberlt suspension is also effectively a~7itated and mixed at t~le surface of the membranes iI~ tile I~FI). Additionally, when alternating positive alld negative pressure is applied to t~le sorbent circuit via tlle accumulator reservior 104, checl~ valve 105 prevents l5 negative pressure frorn beilIg applied to ~he I~FD sorbeIlt side, and creal.es only intermittent positive pressure (Figure 5tb))- IIl this system, the blood-side (see Figure 5(a)) aIld dialysate-side pressures vary witII eacII cycle, bl~t are balanced on average, tlIus crea~ing a bidirec~ioIlal 20 flow in eacII cycle but with zero net filtration (there is rlet sorbent to blood filtration in the EIFD, offsetting ultrafiltration of the PPD, several hundred ml/Ilr.).
On tlle blood side, blood passes from the patiellt access and into blood inlet 110 of the E'PD, with the 25 in~ermediate addition of saline from reservior lll. WIIere a dialysis membrane (as opposed to an impermeable membrane) is irlstalled iII tlle E'PD, tlle blood is dialyzed in ~lle E~E'D as described above. Bloo~L then exits tlle PE~D
tllrougII outlet 112 arld passes i~ltO interior c~lannels of 30 ~Ie IIollow fibers of the IIFD (commercial ~IFD devices have a r~ckaye including a plurality of ~Iollow fiber membraIIes)~ ~t ~Ilis point, t~Ie alternatiny positive aIId negative pressure apE~lied on t~Ie sorl)ent side causes a bidirectioIlal flow of pl~sllla across tlle hollow fiber WO 95/18671 ~ ~ r~ l / u. ~ .
~181~5~

erllbranes, ~lIat is, ~lle 3aloou plasrna exits alld ~lIell re-enters t~le Ilollow fiber membranes. WIlile exterior of tIle llemofilter or plasmafilter membranes, middle molecular wei~tlt toxirIs and/or plasnla proteins, includirlg proteins 5 to Wl~iCIl toxic substances are bound, come into contact witll the sorbent sllspension. The toxic substances are adsocbed to tlle adsorben~s, and ill t~le case of plasmafiltration, the proteins, now free of toxins, are passed back into t~le hollow fiber membranes. Thus, 10 effectiYe E~laslllaEiltratioll or I~emofiltration of ~IIe blood is ac~lieved as tIIe blood passes through tlle HFD. Blood exits Lhe IIFD via outlet 113, and is ret~lrned to the patielIt tllrougII tlle patient access.
The pressures of the blood-side and sorbent-side will 15 vary witll tlle particular MFD devices employed. TIlus, wi~I
a particular IIFD device, in vitro tests carl be done to measIIre filtratioll rate, and the vacuum and pressure opera~ing tlle sysLeln will be adjusted to aLtain zero llet Liltration. Moreover, to optimize blood flow, adjust~nents 20 to tlle ratio of inflow/outflow times can be made. TIle combined PE'D/IIFD system will, like the system described in Example 1, measure ~IIe rate of ultra~iltratioll by weigIIill~J
tIle entire top of tIIe device, including ~he sorberlt ba~.
But, since tlle goal is net ultrafiltration of about zero, 2~ tllere is no need for the long inflow times of tlle system of r~xample i. Better blood flow will be obtained using approximately equal inflow and outflow times. During i viLro tests, Lor example witll pig blood, tlle drivillg pressures can be adjuste-l as above, and tlle llet blood f low 30 determine~ (by change of weigllt of tlle 3 liter corItaiIler duril~g eac~l cycle). TIle illflow-ou~flow tiIIIes can tIIen be adjusted ~o give maxiIIIulll blood flow. ~'reEerably, tlle 20U-225 ml/mill average blood f low of the system oil Exannple 1 is IIIaiIltailled.

~WO 95/113671 2 1 8 ~ /t) r, EXAMPI.~ 3 BLOOD TI~EATMENT WITII I~IALYSIS/
- PLASMAFILTER OR IIEMOFlLTER DEvlCE
Cllarcoal has ~lle capacity to very effect:ively adsorb 5 middle molecular weigl~t molecules and protein-bound toxins (see, e.g., Figs. 6(a) and 6(b) wllicil provide Langmllir isotllerms of tlle adsorpLioll o BSP fro~ lasma alld saline alld of ~ ubin from plaslna). In ~lle following studies, the rE'D/IIE'D device described in Example 2 was used to 10 deterrnine clearallce ra-es of sollle proteill-boulld arld middle molecular weigllt substances f rorn blood. 3 liters of f resi pig blood were spiked with various substances (Sl-own in Talale 1 below), anrl ~lle blood was treaLed usillg ~lle PPD/IIFD
device. D~lring several ~lollrs of treatmer~t, the blood was 15 colltilluously infused with the sllbstallces at a rate desiglled to mairltain a constallt concentration (calculated by the predicted clearance of tlle system). The clearances were then determined by dividing the rate of infusion by the s~eady-state concentratioll of the substance. If ~lle blood 20 volume challged, ~llell the cllange was included ill tlle calcula~ioll of clearallce. The results are shown in Ta~le 1, in whicll "Creat" ~ creatinine, "~ili" = bilirubin, BSE', alld "Vallco" - vancomycin. Among these, creatinine is a small, non-protein boulld substance, bilirubill, Elavil all~ BSP are small, llighly protein-bound molecules, and vancomycin is a ~iddle mclecular wei~lht, noo-ir~tein bound substallce.

WO95/18671 .~I/lJ,,. 'l 75 21 8~S~

BLOOD FLOW AND CLEAR~NCES (ml/~in) Ave r~ ' r ~ re at ~ lanCQ
S PPD orlly 200 140 0 0 12 O
F-80 150 130 ~12 n/a 40 Altrex 140 180 130 5 n/a - -(70K) ~ltllin* 140 90 :5 n/a lg 37 l0CT19OG 160 85 0 - - 62 ~lasmaflo 140 95 ~43 n/a n/a 35 AP-05H(L) - (dash) - no data 15 n/a . data not currently available * develo~mental filter from Althin Medical, Inc., m.w.
cutof f - 100, 000 .
As can be seen, use of tlle HFD can provide significalll:
increases in t~le clearance of middle molecular weight and 20 pro~ein-bound substances, and can be used in connection Witl ~!le PPD to provide effective overall clearance of small an~
larger substances, both protein-bound and non-protein-bound .

~ Wo 95/18671 2 1 8 0 4 ~
. .

Wllile Lile irlvelltiorl llas Lleell illustraLed all~ ~escrii)ed in detail in tile dra~ gs and foregoing description, the same is to be considered as illustrative and not restricLive ill cllaracter, it beillg urlderstood tilat only ~ile preerre(1 S embodiments have been shown and described and t~lat all cllanges arld modiications that come witl~ the sl irit o ~I~e inverltion are desired to i~e protected.

Claims (10)

WHAT IS CLAIMED IS:

1. A filtration process for removing blood toxins, comprising:
passing a fluid containing protein bound and/or middle molecular weight blood toxins through the interior of a hollow fiber membrane;
during said passing, circulating a sorbent suspension against exterior surfaces of the hollow fiber membrane;
during said passing and circulating, applying intermittent pulses of positive pressure to said sorbent suspension so that the fluid or a fraction thereof alternately exits and re-enters the interior of the hollow fiber membrane, wherein said fluid or fraction which exits the interior of the hollow fiber membrane contains the protein bound and/or middle molecular weight toxins which contact said sorbent suspension so as to effectuate removal of said toxins from said fluid and delivery of said toxins into said sorbent suspension.

2. The process of claim 1, wherein said hollow fiber membrane is a hemofiltration membrane, whereby middle molecular weight toxins are removed from said fluid.

3. The process of claim 1, wherein said hollow fiber membrane is a plasmafiltration membrane, whereby middle molecular weight toxins and protein-bound toxins are removed from said fluid.

4. The process of claim 1, wherein said fluid is blood.

5. The process of claim 3, wherein said plasmafiltration membrane transmits albumin with selectivity over larger proteins.

6. A blood dialysis device which comprises:
a hollow fiber membrane;
a pump fluidly connected to the interior of said hollow fiber membrane and adapted to pass a fluid containing middle molecular weight and/or protein-bound blood toxins through the interior of said hollow fiber membrane;
a chamber surrounding said hollow fiber membrane, said chamber further being fluidly connected to a supply of sorbent suspension;
a pump adapted to circulate said sorbent suspension through said chamber and against exterior surfaces of said hollow fiber membrane; and means for causing said fluid or fractions thereof passing through the interior of the hollow fiber membrane to alternately exit and re-enter said interior.

7. The device of claim 6, wherein said hollow fiber membrane is a hemofiltration membrane.

8. The device of claim 6, wherein said hollow fiber membrane is a plasmafiltration membrane.

9. The device of claim 8, wherein said plasmafiltration membrane transmits albumin with selectivity over larger proteins.

10. The device of claim 6, further comprising a dialysis instrument adapted to dialyze said fluid fluidly connected in series with the interior of said hollow fiber membrane.