CA1121738A

CA1121738A - Automated intermittent blood purification process

Info

Publication number: CA1121738A
Application number: CA000305132A
Authority: CA
Inventors: William P. Murphy, Jr.; Frank A. Gotch; Bennie J. Lipps
Original assignee: Cordis Dow Corp
Current assignee: Althin Medical Inc
Priority date: 1977-06-10
Filing date: 1978-06-09
Publication date: 1982-04-13
Also published as: AU518734B2; JPS546397A; IT1105139B; IT7849795A0; AU3632078A; DE2825134A1

Abstract

AUTOMATED INTERMITTENT BLOOD PURIFICATION PROCESS

Abstract of the Disclosure An automated blood purification process, preferably hemodialysis, which establishes the operating parameters of rate, and time based upon blood analysis shortly prior to, and during, said process to insure attainment of physician controlled objectives for each patient in minimum time. The process optionally automates preparation of the extracorporeal circuit, including the artificial kidney, for use and at the end of the treatment automatically flushes blood in the extracorporeal circuit back into the patient and con-currently prepares the artificial kidney for possible reuse.

Description

Background o the Invention This invention relates broadly to the removal of wastes from blood and particularly to the dialysis of blood. More speci-fically, this inventi~n concerns an improved ~utomated process for dialyzing the blood of chronic or acute renal patients hav;ng little or no residual normal kidney functioningD
The process of hemodialysis is relativ~ly new9 having effectively started in lg43 when clinical use was first made of an artificial Xidney device employing cellulose tubes mounted on a drum rotating in a pool of dialysate solution. Since then, hemo-dialysis has been increasingly accepted ~y doctors and patients in the *reatment of renal insufficiencies and is in wide use at the present time. Various improvements in semi-permeable membranes and artificial kidney constructions contributed to such acceptance, both in the clinic and in home use. Notable advances include the disposable coil-type kidneys of the middle 19501s; improved blood access means, particularly arteriovenous shunts and a variety of ~ 73 ~

platc-type kidneys in the 1960's; and the hollow iber artificial ~idneys ~hich were first introduced commercially in tlle United Sl:ates in the early 197~'s. At the present time, hollo-~ fiber arLificial kidneys appear to be increasingly displacing the earlier types, although coil and plate types are still in use.
Irrespecti~e of the particular type of artiicial kidney that is used, the hemodialysis process heretofore performed is basically the same. In that process, a portion of ~he patient's blood is continuously externally circulated through an artificial i kidney which transfers from the blood to a dialysate solution certaln of the toxic components normally excreted in the urine of a healthy person; the thus purified blood is continuously return~d ~o the patient. As initially practiced, a clinical hemodialysis treatment required from about 7 to 20 hou.s with an average of about 12 hours~
Improvements in membranes, kidney construction, and methodol~gy decreased the time required to the range of a~out eigh~ hours; at the present time using the best currently available ar~ificiâl kidney constructions and the best procedures in current clinical use, hemodialysis requires fTom about 4 to 6 hours three times per ~o ~eek for efective maintenance of patients with chronic or acute renal insufficiencies. While this reduction in time required per hemodialysis is significant and important to the parties~ hemo-dialysis remains a debilitating process which interrupts the paticnt~ 5 entire life scheme because it consumes from S ~o 8 hours, or so, duTirlg three out of the five ordinar)r wor~ days during each weeX.
Time, in addition to the actual dialysis time oE four ~o six hours, is required in travel to and from a clinic, and both in clinics or in home dialysis substantial time is rcquired in prc-paring the extracorporeal circuit ~cgments including the artificial ~idney for use and the ~idney and associatcd segrnents for storage un~il the next dialysis~ ~hich m~y include preparation of the kidne~

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fjor reuse. l~itll artificial kidneys heretofore available prepara-tion for use has involved a series o-f complex steps with such exacting requirements that most patients are unable to collduct their own hemodialysis and technical assistance of trained personnel is necessary. Complications in the preparation of the extracorporeal circuit exist in rinsing the kidney with sterile saline in prepara-tion for priming with the patient's blood; in transferring blood lines from the sterile saline source to the blood access in the patient's arm ~nd priming the extracorpore~l circuit, and in anti-coagulant addition prior to the commencement of on-stream dialysis, etc. Complications also arise during dialysis as a result of patient's sickness, substantial blood pressure changes~ substantial fluid ingestion and the like and, particularly for home patients, these problems in the absence of promp-t correction lead to extremely serious consequences up to and including death~ Mrareover~ renal-insuf~iciency patients tend to progressively develop a preoccupation with the effects and complications of dialysis which stem -fTom the discomforts caused by ~he repeated, persistent therapy that includes burdensome dietary requirements between dialysis treatments and emotional variations as wastes build up and then are speedily and unnaturally removed from the body -fluid.
A majority of renal-insufici.ency patients are thus unable to work on a full tlme basis and only a portion of pa-tients on inter-mittent maintenance dialysis are able to discharge the duties of part tirne emlloyment. I`he expense of clinical, or home, hemodial~sis in addition to tlle loss of earnirlg capac;ty for the renal-insuffi-ciency patient represents a tragcdy to the patient and his family;
it is, theTefore, apparent that irnprovements in the hemodialysis process W}licll would make it possible for such patient on intermitten~
dialysis to receive sufi.cient dialysi.s to maintain health and yet permit him to Te-enter tlle regular worX force would be extremely valuable and highly desirable. It is one of the prim~ry objectives of this in~ention to provide a process which automatically performs ~ 7 3~

at least some of the complex preparation and tcrmination steps which havc heretofore required s~illed technician assis~ance to perform, and thereby reduces the total time that is required.
Extensi~e reseaTch on kidney diseases and the hemodialysis process has been conducted continuously since the early 1940's.
Nevertheless, it is currently recognized by those skilled in the hemodialysis art that the functions performed by healthy kidneys are extremely complex, and the best informed researchers and workers in the art acknowledge that there is still much which is unknown.
For example, some of the many compounds which are formed from protein in the energy generation process in the body and carried by the blood to the kidneys and excreted in the urine by healthy kidneys are yet to be identified. Semi-permeable membranes which have been used clinically in hemodialysis to date are known to remove low molecular weight components such as urea, creatinine, uric acid, etc.~ and to leave higher molecular weight components such as albumin in the blood;
however, it is not known for certain ~hether compounds having inter-media~e molecular weights are~ or should be, removed by the hemo-dialysis membrane, Clinical evidence has shown that removal of excess water and certain of the most concentrated low molecular ~eight catabolites, such as urea, will sustain a renal-insufficiency patient for a number of years. Nevertheless, those best informed readily acknowledge that clinical intermittent hemodialysis, as currently practiced, using the best artificial ~idneys that are available and the best controls alld procedures kno~n is still a relatively crude process, provides only a partial substitute for the Fullctions per-formed by healthy kidneys, and needs further improvement.
~ detailed description of the hemodialysis process as currently practiced in advanced clinics in the Ullited States, is ~ 73 contained in Chapter 41 of the treatisc entitled Thc ~
~olume 2, entitled "Hemodialysis: Technical and Kinetic Considera-tions"~ by Frank A. Gotch, 1976. That description identifies a number of important problems that exist iJI the bes~ devised proce-dures used in deciding, at the beginning of each dialysis, the ~ime or length, of the hemodialysis and the rate of watèr and l~aste or solute removals during that dialysis; These control parameters of time and rate are selected by the doctor or clinical technicial and represent the best available estimates for each pa~ient but it is ~,o Xnown that they are based upon values of ~ater and blood solutes to be removed that are inexact. I~ater to be removed is established by weighing the patient and assuming that the excess over a prior normal weîght for that patient is WateT that should be removed. The quan-tity of solute to be removed, such as urea, creatinine J uric acid~
etc~, is based upon an empirical assumption that blood urea nitrogen ~BUN) maintained below about 80 milligram per cent is an acceptable level for adequate dialysis therapy and îs determined by COmpaTing the approximate 80 milligram percent value ~ith a BUN value obtained by analysis on a sample of the patient's blood taXen sometime during 2~ the month prior to the hemodialysis being started. The difference in these BUN values is used as the determinant fo~ establishing operating conditions which control the amount and t]~e rate at l~hich ~aste solutes are removed during hcmodialysis, but the thus establishc~
difference is erroneous to the de~ree that the patient's BUN value at the time o the hemodialysis beislg commenced difEcrs rom the earlier detQrmined BUN value. It is Xno~n that the BUN valucs 1uctuate rapidly and subs~antiall~ ith protein intakc, residual kidney function, etc., and it is probable that the assumcd ~U~ value at the time any ~iven hemodialysis is started is erroncous ~o some degree.

1~5 Using thc quantities of water and ~UN to be removed which are established as above described, certain other assumptions must be made before the length of the hemodialysis and rate of water and solute removal can be established. The first, and most impor-tant, assumption is that the rate of withdral~al of blood -Erom the patient and rate of blood flow through the artificial kidney will be constant for the entire four to six hours hemodialysis period. This ideal situation assumption introduces a substantial error because blood flow rate is never constant or the entire hemodialysis and 20~ to 40% error may occur; such errors occur because blood pumps and blood flow rate measuring means currently available are known to be subject to gross variations~ Moreover, patient-caused inter-ruptions are common at some time during the 4 to 6 hour dialysis interval and such interruptions may or may not be appropriately offset or corrected before dialysis is discontinued.
A second assumption which is made is that the flow rate, pressure and composition of the dialysate solutîon flo-~ing on the side of the semipermeable membrane oppos;te the blood side will be constant throughout the hemodialysis, cur~ently available equipment is incapable of assuring such constant conditions. The last aspect of this problem of the pTe-set operating conditions is that opera-tional variations which do occur may be disregarded or go undetected during the hemodialysis, and a final assumption is made at the con-clusion of the hemodialysis that the intended quantities o~ water and solutes have in fact been removed, and in the majority of cases that assumption is ~nost likely incorrect to some degree.
Other aspects of hemodialysis still in need of improve-ment relate to access to the blood of the patient, blood sampling and analysis procedures, anti-coagulant therapy control and prepara-tion of the artificial kidney for possible reuse. During hemodialysi~
operating controls nol~ exist to protect against health injurious failures in the blood access means or the kidney or dialysate supply means 3 but the currently practiced process does not include _~, ( operatin~ parameter changes durin~ dialysis which reflect mcasurc-ment of actual water and solute clearance to insure optimum conform-ance ~ith patient needs, the original pre-set operational eontrol parameters, OT to perform the treatment in minimum time.
It is, therefore~ another important object of this invention to proviae a process for purifying blood which improves the quality, or adequacy of hemodialysis relative to hereto-Eore available hemodialysis processes used in commercially accep~able clinics 9 and does so in minimum time with a minimum of assistance to fTom skilled technicians in preparation for~ during and at the con-clusion of the hemodialysis treatment.

Summary of the Invention and Brief DescTiption of the Process and Drawin~s This invention pTovides an automated blood purification hemodialysis process which samples and analyzes the blood of a renal patient shortly prior to initiation of the purific~tion process such as hemodialysis and automatically establishes optimized operat-ing conditions $or the process based upon the analysis results, in view of predetermined medical objectives supplied by the patient's physician for the treatment. The ~rocess monitors water removal rate, pressures and flow rates of blood and dialysate~ and the acidity of dialyzed blood and the dialysate~ and analy~es at least once during d;alysis at least one of the dialyzed blood ~nd spent dialysate to determine the rate of rcmo~al of at l~ast one control solute; based upon this interim an~lysis, needed adjustments are automatically made to insure attainment of the preselected post dialysis control solute concentration in the lcast possi~le time.
The process optionally includes steps or automatically prcparing the ext~ac~rporcal blood-contacting components for conncction to th~

ir-'J~
~ 71 patient~s bl~od ac~ess means, steps for purifyin~ spent dial~sate and ~ecirculating the same, and steps for flushing and stcrilizing an a~tificial kidney to conserve the patient's blood and in prepara-tion for possible reuse thereof. Th~ proc~ss oTdina~ily includes the step of post-dialysis determina*ion ~ the concentration of the control solute and based upon that analysis and in comparis~n with physician input based thereon provides instructions to ~he patient for diet control in the interim period prior to the next contemplated hemodialysisO
The process may als~ include steps fo~ automatic~lly establishing blood~clotting time at the beginning of o~ during a tTeatment and based upon the clotting time results establishing ~he necessary anti-coagulant addition therapy prior to initiation o~ the hemodialysis, and for addition of anticoagulant duTing the hemodialysis a~ well as determination of time for cessa tion of anti-coagulant addit;on during dialysis .or the time and amount of coagulant addition ~so *hereby Testore normal clotting time to the blood by the end of the ~ialysis.
In another aspect the invention provides a combination in means for removing waste from blood and for effecting intermittent hemodialysis comprising (l) an artificial kidney;
~ 2) extracorporeal circuit means including blood and dialysate circuits for circulating blood and dialysate respectively through said artific.ial kidney, (a) said artificial kidney having a membrane for separatirlg said ci.rcuits and for removing waste products Erom said blood when said blood and dialysate are circulated through said kidney, (b) said blood circuit having inlet and outlet port means for supplying arterial blood to said artificial kidney and for rem~ving dialyzed blood from said artificial kidney, SI
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(3~ ~ source of fresh dialysate subs~antially free of pre-selected control solute:
(4) said dialysate circuit having inlet dialysate port means for supplying fresh dialysate from said source to said artificial kidney and outlet dialysate por-t means for removing spent dialysate from said artificial kidney;
(5) pumping means for effecting dialysis by circulating said arterial blood and fresh dialysate to opposite sides of said membrane and through said artificial kidney to produce dialyzed blood and spent dialysate containing increased amounts of control solute;
(6) analyzing means including predialysis bloocl analyzing means for analyzing said arterial ~lood prior to said dialysis and for transmitting predialysis signals corresponding to values determining ~ a) the guantity of ~ater in said arterial blood d (b) the concentration of at least one control solute in said arterial blood, (c) and the concentration or partial pressure of at least one of the normal components in said arterial blood;
(7) computer means responsive to said predialysis signals for comparing said values with at least one corresponding pre~estahlished post-dialysis value for said control solute, water and components to establish (a) the dialyzing time for said hemodialysis, (b) the quantity of said water, components and control solute to be removed during said hemodialysis, (c) and the dialyzing rate of removal to attain said post-dialysis value in minimum time; and - 8a -.~

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(8) contr~l means associated with said computer means for controlling said pumping means in response to the established dialyzing time and rate of rer.~val to obtain flow rates for said blood and dialysate and the pressure of at least one of said blood and said dialysate to effect the transmembrane pressure necessary to provide said dialyzing rate;
~ 9~ said analyæing means also comprising means for analy2ing at l~ast once during said hemodialysis at least one of ~aid blood and said dialysa~e for th~ concentration of said control solute and for transmitting concentration signals corresponding to said control solute concentrations;
(10) said ~omput~r means also comprising means responsive ~o ~he control~olute concentration signals for comparing the control solute concentrations with preprogrammed post-dialysis control solute concentratiDn data, the op~rational characteristics of said circuit means/ and ~n integrated performance profile ~or ~aid circuits ~or transmitting corrective signals;
(11) 6aid control means also including means cooperable with said circuits and responsive to said corrective signals for substantially maintaining said pro~ile.
The basic distinction between the process of this inven-tion and heTetofore practiced blood purification processes, parti-cularly hemodialysis, resides in the steps of analysis of thc blood s~ortly prior to, during and after the hemodialysis and then basin~ the operational parameter settings of the segments in the extracorporeal circuit on the analysis results after comparison thereof with post-dialysis ~bject;ves supplied by the attendinl~, physician~ and in view of the tcc}lnic~l operational capabilities of the kidney and supporting extracorporeal segments bein~ uscd.
The improved process maXes use of highly sens;tivc analy-tical means which require extrcmely small amounts of the ~atien~'s blood and compute~s capable of instan~aneously comparing thc analy-tical resul~s~ as obtained~ with thc val~es for water, blood ~.., I
8b -components and control solute pre-progralllmed into the computer or central processing unit. The computer is pre-programmed for each instant of the hemodialysis on the basis that steady-state conditions will exist throughout the 4 to 6 hour contemplated treatment; such reference hemodialysis is defined by the formulae set forth in Chapter 41 by Gotch9 identified above.
The thus determined differences from the steady-state contemplated performance become the basis ~or correcting signals from the central processing uni.t to the appropriate extracorporeat ~ circuit segment to change the necessa~y operational parameters to correct such deficiency and assure attainment of the post-dialysis objectives for patient content of water, blood components and control solute in minlmum operational time.
As used in this specification and in the claims the expression blood "components" refers to solutes present in the blood, other ~han metabolic waste solutes, including sodium, potassium, calcium, magnesium, dissolved oxygen, dissolved carbon dioxide, bicarbonate, acetate and resultant pH; the express;on "control solute" refers to an endogenous or exogenous substance in a body liquid, or to a measurable physiological response W}liC}I directly, or indirectly reflects or correlates with a change in concentration of waste metabolites or catabolites being removed from the blood.
This expression contemplates na-turally present solutes in the blood such as urea, creatinine, uric acid, etc , or solutes in lymph fluids or other parts of the hurnan body as well as exogenous substances, for example, tracer elements, colored or color-producing materials l~hen in the body, etc. The expression also contemplates any response which may be measured that is made by the body and ~hich quantita-tively reflects the progress of removal of l~astes from the blood during the purifica~ion process, for example~ measurable nerve response changes, etc 7~

The principles of this invention are applicable to various specific procedures for purifying, or removing wastes from, blood including, for example, peritoneal dialysis, adsorp-tion, absorption and hemodialysis which is the preferred procedure. When applied to hemodialysis, the process of this invention may be performed by using any of -the heretofore avail-able types of artificial kidneys including flat plate, coil or preferably hollow fiber types. A new, hollow fi.ber artificial kidney which is particularly well suited for use in the process of this invention, and thus preferred, is disclosed in the com-monly owned U.S. Patent of B.J. Lipps et al, No. 4,211,597, issued July 8, 1980 entitled "Improved Artificial Kidney and Method ~or Making Same."
This invention will be described in some of its detailed aspects by referring to certain of the preferred embodiments of that patent.
Figure 1 is a perspective view showing a hollow fiber type artificial kidney mounted on and associated with a dialy-sate supply and control device and attached to a renal-insufficiency patient in typical fashion :Eor the practice of the process of this invention.
Figure 2 is a top view of a preferred embodimen-t of a hollow fiber artificial kidney particularly adapted for use in the process of this invention.
Figu~e 3 is a top vi.ew of another pre-.Eerred artific:ial kidney construction having i.ntegral segments adapted to enable performance of the improved hemodialysis process of this in-vention including certain of the optional steps thereof.
Figuxe 4 schematically i.llustrates component elements and control means suitable to automatically effect the basic process of this in~ention and certain of its optional embo~iments-Figure 5 shows the schematic arrangement of Figure 4modified to enable practice of other optional embodiments of the process of this invention.

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Figure 6 is a Elow sheet representation of the automated steps, in preferred time sequence order, which characterize the preferred hemodialysis form of the process o~ this invention.

Detailed Description of the Process In its detailed aspects the process is best understood by referring primarily to the flow diagram shown in Figure 6, and secondarily to the schematic illustration of the relation-ship of the extracorporeal circuit segments to the analyzer and control processing unit as shown in Figures 4 and 5.
As may be seen in Figure 6 the more important, or primary, automated steps are shown in full line box formation, indicating time sequence process performance ln the direction of the arrows;
secondary automated steps that may be included are contained in dotted line boxes and connected with dotted lines to the primary step boxes in approximate time sequences. Figure 6, as shown, assumes prior connection of t~e artificial kidney 10 to a dialysate supply and control machine, generally designated 12, as may be seen in ~igure 1. Artificial kidney 10, as illus-trated, is of the hollow fiber type and advantageously may have the form and include extracorporeal segments of the type shown in either of Figures 2 or 3. The particular artificial kidneyconstructions shown in Figures 2 and 3 are disclosed in detail in Lipps et al, U.S. Patent No. 4,211,597, issued July 8, 1980 and are included herein as illustrative kidney embodimen-ts which are particularly well suited for use as the kidney 10 shown in the ex-tracorporeal circuit of Figures 4 and 5.

Automatic Steps Prior to ~Iemodialysis Start-Up Refe:rring again to Flgllre 6, the first of the essential steps of the automated process of this invention is sampling the patient's blood and supplying that sample to the Analyzer.

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Prior to this essential first step, other preliminary steps of preparing the extracorporeal circuit for use must have occurred and these steps, which are illustrated as optionally automatic in Figure 6 include - lla -t73~

rinsing with saline and priming witll the patient's blood. Sterile saline rinsing is necessary unless the segments are saline filled as received froJn the manufacturer and, typically, extracorporeal circuit segments and some artificial ~idneys are supplied in dry packaged form; other hollow fiber artificial kidneys are supplied filled ~ith an aqueous solution of formaldehyde. While the steps o~ rinsing and priming are ordinarily performed by the clinical technician, automatic performance is illustrated in Figures 4 and 5 and will now be described. ~enous blood line 14 and saline return line 15 are connected by valve 16; arterial blood line 18 and saline supply line 19 are connected by valve 20 and sterile saline lines 19 and 15, respectively~ receive saline ~rom, and return saline to~ saline tank 22~ After valves 167 20 are actuated to connect saline lines 15, 19 into the circuit~ blood pump 24 is started to pull saline from tank 22 and propel same through blood pressure sensol~ 25, blood flowmeter 26, the ibers in artificial kidney 10~ ~lood sensor 27~ constant venting air trap and filter 28, bubble sensor 30 and back to saline tank 22~ This circulation is continued for a preset time, for example 10 to 20 minutes, and at the end of the preselected time period, bubble sensor 30 is activated by signal from the central processing unit (CPU) 32 *o determine whether all gaseous bubbles have been cleared from the circuit.
As soon as sensor 30, which has ~he capability of detecting the presence or absence Or gas bubbles and during the rinse cycle is normally set to detect the absence o bubb:les, detects the absonce of bubbles for a preset 2 to 3 minutes interval, the rinse cycle is terminated arld valves 16, 20 actuated to place blood lines 14, 18 in the operational circuit.
After attachment of blood lines 145 lB to the pat;ent, blood pump 24 is actuated to assist blood ~low and prime~ or fill, the extracorporeal circuit ~ith the patient's blood, sensor 30 having been reversed to its normal hemodialysis pos;tion to detect t~
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the presence of bubbles and automatically close valve 34 upon such detectiorl to thereby prevent infusion o gas bubbles in*o a patient's vein. When the extracorporeal circuit is primed9 and by signal from the CPU, a sample of arterial blood is withdrawn and conveyed to the Analyzer 36, as for example through non-thrombogenic capillary tubing 38. Analyzer 36 is physically located in close adjacency to the rear surface of kidney 10 and within the housing of control machine 12 and tubing 38 withdraws blood from blood line 18 at site 40, as may be seen in Figure 2.
In response to signal from the memory bank of CPU 32, based upon physician input for the particular patien~, a bolus o anticoagulant, typically heparin, is infused into the arterial blood line 18 by infusion means 42 which may be phy-sically located in kidney 10 at site 44, Figure 2.
As shown in Pigure 6, analyzer 36 analyzes the patient's blood for the concentration of sodium, potassium, calcium, magnesium~
chloride, bicarbonate, acetate, dissolved oxygen, dissolved carbon dioxide and determines acidity or pH. ~issol~ed oxygen, dissolved carbon dioxide, bicarbonate and pH are determinable -from a single micro sample of blood, e.g., 175 to 500 microliters~ within seconds after the sample is introduced to automatic means which form a part of analyzer 36 such as those available from Corning Medical of Medfield, Massachusetts, and Instrumentation Laboratory7 Inc. of Lexington, Mass. A portion of the blood sample is filtered through a Inicroporous filter and a small sample of about 0.3 milliliters of the resultant plasma is analyzed using ion selective electrodes for sodium, potassium~ bicarbonate and chloride, such electrodes and circuitry comprising another portion of analyzer 36, being of the type available from Photovolt Corporation, of New York~ The concen-tration of calcium and magnesium is analyzed in a similar manner ~ith ion specific electrodes and CiTCUitry av3ilable from Orion Research Incorporated of Cambridge, Massachuset~s. Urea, or blood 17~3~
urea nitrogcn (r,UN), which has becn ~idely used as a control solute in ad~anced clinics employins thc system elucidated by Gotch in Chap~er 41 o ~ , is dctermined from a 20 microliter sample using an ammOTIiUm-Sensitive electrode and components, which form a further por~ion of analyzer 36, that are a~ailable from ~imble Instruments of Toledo, Ohio. Clotting time is determined on a small sample of ~hole blood using any of the available thromboplastin time t~st reagents, such as~Thrombofax~*in a direct time reading instru-ment such as the~Fibrometer~available from Becton-Dicki~son Co.
~ ater in the patient's body is determined by ~eighing the patient before hemodialysis is started ~hile seated in chair 42 which is supported on scales 44 thctt are interconnected IYith CPU 32 to provide instantaneous ~eight readings tXroughout the dialysis.
Satisfactory scales 44 for this use are availa~le from Aimex Co.
of Boston, Massachusetts.
Analyzer 36 transmits the results of the above described individual analyses to CPU 32 ~hich has been pre-programmed to con~ain in its various memory banks a first set of aata relating to the blood purification objectives for the hemodialysis treatment being started as supplied by the physician, a sccond set of data definitive o the extracorporeal circuit operational characteristics, and a t:hird set constituting the program which integrates the composite CPU inputs into an instant ~y instant performance profile for the 4 to ~ hours treatment; this program is based on the above reerred to premise of st~ady state operat;.on throughout the treatment and consists of appropriate ormulae of the t.y~e described in detail by ~otch in Chapter 41 of The ~idney, as ~ill be apparent to on~ s~illed in .
the art. The C~U patient prof~le data importantly includes pos~-dialysis concentrations for componcnts, control solute and t~at~r content o the patient.
* Trademarl~;
** Trademar.

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Central ~rocessin~ unit 32 substantially instantaneously, or in a short time, completes the comparison between tne blood analyses and post dialysis concentrations far components and activates circuit means 46 for formulating the optimized dialysate composition;
this circuit includes a tzp water source 48, pressure regulator 50, a heater 52 and for the single-pass dialysate system shown in Figure 4 a heat exchanger 54, dialysate flow control valve 56J
deaeration means including coil 58 and deaeration pump 60 and cons~an~
venting air t~ap 62. In the dialysate circuit of Figure 5 which ro includes dialysate regeneration means 64~ CPU 32 pxovides appropriate information to modiy the previously regenerated dialysate compos~tion to the op~imized composition in view of the patient~s blood analysis for components. As dialysate is formed, circulation is start~d in the circuit which by-passes the artificial ~idnc)r dialyzer ln; t~is circuit is controlled by by-pass valve 66 and includes ba~k pressure regula~or 68, dialysate temperature sensor 69, dialysate pr~ssure sensor 70, dialysate pressure pump 72 and blood leaX detector 74.
IYhen sufficient dialysate is formulated in the case of the single pass system of Figure 4, and upo~ actuation in the case of the 2~ regeneration system of ~igure 5, b~-pass valve 66 is actuated to feed dialysate through dialyzer 10.

Automatic Steps At tart-Up To commence hemodialysis, the CPU program establishes the length of the hemodialysis b~ comparing the control solute analysis value ~ith the pos-t-dialysis p]lysician input value~ after integration of controlling extracorporeal circuit parameters includins blood 1OW rate capabilities o~ thc ~atient's blood ~ccess and the clearance capabilities for the control solu~e of thc dialyzer as a function of flux and blood flo~ r~te. Typically, blood flnw rates approximate 200 ml/minute but ~ith improved blood acccss devices substantially higher rates up to ~bout 5~0 ml/minu,c may be used 15.

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with certain patients or for ]imited t;me periods within the treat-ment. With the length of hemodialysis estabiished~ the CPU then transmits control signals to the dialysate pressure pump 72, dialysate flowmeter 76, pressure regulators 68 and 70, and blood pump ~4, blood -flowmeter 26 and venous blood pressure sensor 27 to modify rates of flow and pressures from the stand-by conditions extant during blood sample analysis to thereby establish the transmembrane pressure necessary to remove water, by ultrafiltration7 from the blood at the appropriate rate; such rate is the result obtained ~y ~he CPU
i~ from the co~paTisan of the patient~s weight, as sea~ed in chalr 42, and the physician prescribed post-dialysis weight, a~ter integration reflecting patient rate capabilities to avoid undesirable blocd pressuIe reactions, and the ultrafiltration capacity of the ~idney at the blood flow rate es~ablished to insure clearance of the control solute in the time allotted.
. CPU signals also activate dialysate temperature sensor 69, ultrafiltrate co~stant-monitoring flowmeter 76 in the dialysate input line, and corresponding ultrafiltrate flowmeter 78 in the dialysate output line. In the dialysate regeneration circuit of Figure 5, ultrafiltrate is also visually measured by ultrafiltTate over-flo~
meter 80 and ultrafiltrate collection tank ,5Z.
Based upon the clotting time results, the CP~ establishes the need for, or lack of need for, infusion of anti~coagulant, in addition to that in~used in the initial bolus; ~hen needed the CPU establishes the appropriate rate of infusion as a function of the pre-selected blood 10~ rate~ and actuatcs anticoagulant pump 42 -to commence the established in~usion at th~ instant~ or shortly therea~ter, that blood pump 24 is actuated to cffect its star~-up operational blood flo-Y rate.

16.

7~3 Automatic Ste s Durin~ Di~l sis ~ J~
During dialysis the ccntral processing unit is supplied continuous operating data with respect to in vi~o blood pressure in ~he arterial blood line from sensor 25 and in t~.e venous blood line from sensor 27. In vivo patient blood pressure is satisfactorily monitored by using one of the many commercially available arm or leg attached devices, such for example as the programmed~Electro-Sphygmomanometer PE-30~,"available rom NARCO Bio-Systems, Inc.
In vivo blood pressure is monitored so as to pre~ent variations ,~v more than about ~ 35 millimeters o~ mercury and the CPU reacts when variations reach about + 25 mm to lo~er the transmembrane pressure and thus decrease water removal Tate until the patient's in vivo blood pressure returns to normal, that is, about + 10 mm of mercury ~ariation from the'patient's blood pressure at start-up. Transmembrane pressure is preferably reduced by corrective signals, from ~U 32 to dialy-s~te pressure pump 72 but may include concurrent corrective signals to blood pump 24 as well in emergencies.
The CPU also con~inuously receives instantaneous dialysate temperature data from dialysate sensor 69, and by correcting signals to heater 52, and/or heat exchanger 54 maintains the dialysate temperature in the range of 37 C. ~ 3 C., or signals to actuate ~y-pass valve 66 in extreme temper~ture ris~ situatiolls.
Water removal rate is constantly monitored by UFR flo-~-meters 76 and 78 ~hich supply cons~ant rate data to ~U 32 for co~
son with the instantaneous perfortnance profile. I~here variations are detected, appropriate corrcctive signals to dialysate pressure pump 72 establish the needed ch~nge in transmernbrane pressure.
~er-all patient ~eight is also constantly monitored by data fed froln scales 44 to the CPU.
Dialysate composition is continuously monitored and or this purpose the CPU is su~rlicd componen~ analytical data from ~ 7; TradPmar~ 17.

.

7~

the above described ion selective electrodes; alterna-tively, continuously monitored conductivity da~a from conventional apparatus may by supplied to indicate maintenance of the desired dialysate composition. Variations are instantaneously corrected by corrective signals from the CPU to dialysate formulation means 46 or dialysate regenerator 64.
For best control and most accurate attainment of th~e pre-programmed performance profile for the control solute, for example BUN r continuous analysis of, or frequent analysis of, 10 blood samples is made. For this purpose, a sample of arterial blood from line 18 at site 40, and a simultaneous sample of venous, or dialyzed blood from line 14 at site 84 (see Fig. 2), is delivered to analyser 36 through capillary lines 38 and 86, respectively. After analyzer 36 completes the ammonium anode analysis and transmits the results to the CPU 32, an instantan-eous comparison is made to the pre-programmed instantaneous values or the performance profile. Variations from the expected profile are corrected by signals to blood pump 24 to al-ter blood flow rate as needed. Even though extremely small size 20 blood samples are required for this purpose, it is more desir-able to monitor the control solute continuously by analyzing dialysate samples taken from the exit dialysate line 88 at site 90 that are supplied to analyzer 36 through sample line 92.
Simultarleously, an input dialysate sample is taken from 94 at site 96 and forwarded to analyæer 36 throuyh l:ine 98. After receiving the analysis results, the CPU supplies appropriate corrective signals to blood pump 24, and where the control so]ute removal rate exceeds the expected profiled rates, the length of the treatment may be modified by the CP[J to shorten 30 the pre-programmed treatment -time and vice versa.

While continuous, or frequent, control solute analysis 3L'73!b~

is desirable, -the process of this invention produces the desired lmprovemen-t, relative to prior hemodialysis treatments when one control solute analysis is made during the dialysis and changes in operational - 18a -k' parameters of the thus indica~ed extracorporeal segments are made in response to those analytical results. In.Tnany cases 1 to 4 control solute analyses during the treatment are suf~icient to provide atta;n-ment of post-dialysate goals l~hich closely approximate the results obtainable from more frequent or continuous analyses of instantaneous control solute concentTakions, and are thus preferred :Erom the practical standpoint.
Periodic clotting time tests of the above described t~pe, for example, one to four tests, aTe desirable during the dialysis treatment. As clotting time changes are detected~ the CPU corrects the anticoagulant addition rate with signals to aTlticoagulant pump 42v CPU supplied signals, based on the clotting time test after 2 or 3 hours of the dialysis, terminate addition of anticoagulant at such time that the blood will be restored to its approximate normal clotting time by the end of the pre-programmed dialysis treatment; when neces-sary, the CPU actuates coagulan~ pump 100 to supply the requisite quantity of coagulant to offset the previously added anticoagulant, again for the purpose of restoring blood to its approximate normal clotting time by the end of the dialysis.

Automatic Ste s After Dialysi.s Terminated P - .
When the CPU receives control solute analytical data indicating attainment of the post-dialysis control solute concentra-tion, appropriate signals are dispatcl~ed to terminate blood ~low and dialysate flow and to inactivate thosc associated control segments that weTe automatically activated by CPU signals at start up. An arterial blood sample is taken at site 40 and delivered to analyzer 36 through line 38 to establish clotting time, concentration of blood componentS and final blood solute concentration.

19 .

~ 3~ ' The next step~ which may be optionally automatic, is to flush blood rom the extracorporeal circuit back to the patient. An improved artificial kidney 10 which enables automatic flushing is shown in Figure 3. The kidney of Figure 3 is generally similar to the kidney shown in Figure 2 and referred to above but is further modified to include integral means to pe~lit such flushing.
As there shown a sterile saline pouch 102 is located adjacent the common inlet and outlet bloo'd port 104 which receives inlet blood line 18 and outlet blood line 14. Pouch 102 has a flexible upper surface layer and is expansible to receive varying quantities of sterile saline, and is separated from inlet blood line 18 by valve 106.
After termination and with blood pump 24 ffa valve 106 is opened on signal from the CPU, and pouch 102 is flattened or depressed *o expel the contained saline to thereby return the blood in the hollow fibers of kidney 10, blood lines 18, 14 and associated segments 40, 42 back into the patient's vein. The quantity of salinc used in flusing may be all or a CPU controlled portion thereof, as desired.
Analytical information obtained on the arterial blood samplc taken at termination and a resume of data regarding the completed dialysis treatment as to length, water content of patient at termination 7 and~ for example, abnormalities of patient reactions relative to operating parameters at the time of such reactions which are relevant ~o physician input for succeeding treatments, are relayed by any suitable means to the,attending physician. One pre-ferred method is automatic telephonic transmission to a magnetic or punch card receiver of the same type used by the physician to supply data to the CPU. A print out of such data in the physicianls office~ for review and immediate, or subsequent physician response and relay to the CPU increases overall cfficiency in the process.

. 2~

~ 3~

Patient instructions as to diet, particularly water and prote;n in~ake, for the interim period prior to the next dialysis treatment may be supplied as CPU print outs directly to the patient to reflect standing or modified physicial instructions; objectives for the succeeding dialysis are advantageously supplied to the memory banks of the CPU at the same time and in a similar fashion.
The last step of the process which is optionally au~omatic is that of sterilizing the kidney 10 for possible reuse. Satisfactory sterilization is obtained by the use of recirculating steam for about 30-60 minutes~ Other sterilants may be used if desired~ -While the abo~e described steps may be advantageouslycarried out with the illustrative apparatus shown in Figures 1 to 3 inclusive, and in the sequence illustrated in Figures 4 to 6 inclus-ive, ;t is to be understood that otheT apparatus and other conditions suitable for use therewith may be employed, and that modi~ications in step sequence may also be made satisfactorily, without thereby departing from the invention.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A combination in means for removing waste from blood and for effecting intermittent hemodialysis comprising (1) an artificial kidney;
(2) extracorporeal circuit means including blood and dialysate circuits for circulating blood and dialysate respectively through said artificial kidney, (a) said artificial kidney having a membrane for separating said circuits and for removing waste products from said blood when said blood and dialysate are circulated through said kidney, (b) said blood circuit having inlet and outlet port means for supplying arterial blood to said artificial kidney and for removing dialyzed blood from said artificial kidney;
(3) a source of fresh dialysate substantially free of pre-selected control solute;
(4) said dialysate circuit having inlet dialysate port means for supplying fresh dialysate from said source to said artificial kidney and outlet dialysate port means for removing spent dialysate from said artificial kidney;
(5) pumping means for effecting dialysis by circulating said arterial blood and fresh dialysate to opposite sides of said membrane and through said artificial kidney to produce dialyzed blood and spent dialysate containing increased amounts of control solute;
(6) analyzing means including predialysis blood analyzing means for analyzing said arterial blood prior to said dialysis and for transmitting predialysis signals corresponding to values determining (a) the quantity of water in said arterial blood, (b) the concentration of at least one control solute in said arterial blood, (c) and the concentration or partial pressure of at least one of the normal components in said arterial blood;
(7) computer means responsive to said predialysis signals for comparing said values with at least one corresponding pre-established post-dialysis value for said control solute, water and components to establish (a) the dialyzing time for said hemodialysis, (b) the quantity of said water, components and control solute to be removed during said hemodialysis, (c) and the dialyzing rate of removal to attain said post-dialysis value in minimum time; and (8) control means associated with said computer means for controlling said pumping means in response to the established dialyzing time and rate of removal to obtain flow rates for said blood and dialysate and the pressure of at least one of said blood and said dialysate to effect the transmembrane pressure necessary to provide said dialyzing rate;
(9) said analyzing means also comprising means for analyzing at least once during said hemodialysis at least one of said blood and said dialysate for the concentration of said control solute and for transmitting concentration signals corresponding to said control solute concentrations;
(10) said computer means also comprising means responsive to the controlsolute concentration signals for comparing the controlsolute concentrations with preprogrammed post-dialysis control solute concentration data, the operational characteristics of said circuit means, and an integrated performance profile for said circuits for transmitting corrective signals;

(11) said control means also including means cooperable with said circuits and responsive to said corrective signals for substantially maintaining said profile.

2. A combination in accordance with claim 1, wherein the values for said normal components of paragraph (6) include the concentration of sodium, potassium, calcium, magnesium, chloride, bicarbonate, acetate in said arterial blood and the partial pressures of dissolved oxygen and carbon dioxide in said arterial blood.

3. A combination in accordance with claim 1 wherein said control means responsive to said established dialyzing time and rate of removal also comprises means for effecting the composition of the fresh dialysate for said hemodialysis to optimize removal of unwanted wastes in said blood during said hemodialysis.

4. A combination in accordance with claim 1 wherein said preselected control solute of paragraph (3) includes at least one control solute recurring naturally in said arterial blood, said control solute of paragraph (6) includes a control solute selected from the group consisting of blood urea nitrogen, creatinine uric acid, and naturally occurring blood solutes having a molecular weight less than 59,000, said analyzing means comprising means for analyzing at least one of said dialyzed blood and said spent dialysate during said hemo-dialysis and for transmitting concentration signals corresponding to the concentration of at least one solute selected from sodium, potassium, calcium, magnesium, chloride, acetate, oxygen and carbon dioxide, said computer means comprising means responsive to the last named signals for comparing the concentration of the selected solute with the concentration of said preprogrammed post-dialysis control solute data and for transmitting said corrective signals, and said control means including means responsive to said corrective signals for automatically adjusting at least one of said blood flow rate, dialysate flow rate, and dialysis composition to attain said post-dialysis control solute concentration in minimum time.

5. A combination in accordance with claim 1,2 or 3 wherein said membrane comprises hollow fibers.

6. A combination in accordance with claim 1 wherein said analyzing means also comprises means for automatically analyzing one of said blood and said dialysate to determine the rate of water removal from said blood during said dialysis and for transmitting water removal signals corresponding to said determined rate of water removal, said control means comprising means responsive to said water removal signals for automatically adjusting at least one of said blood flow rate, dialysate flow rate and the pressure of said blood and dialysate to maintain said rate of water removal at substantially the rate established in paragraph (8).

7. A combination in accordance with claim 1 wherein said analyzing means comprises means for analyzing during said hemodialysis at least one of said dialyzed blood and spent dialysate to determine the concentration of at least one solute selected as a control solute in claim 4 and for transmitting concentration signals corresponding to the last named concentration, and said control means comprising means responsive to the last named concentration for automatically adjusting at least one of said blood flow rate, dialysate flow rate, and dialysate composition to effect said post-dialysate value of paragraph (7) in minimum time.

8. A combination according to claim 1 wherein the analyzing means comprises means for effecting the analysis and transmitting the signals of paragraph (9) at repeated intervals during said hemodialysis.

9. A combination according to claim 1 wherein the analyzing means comprises means for effecting the analysis, and transmitting the water removal signals of claim 6 continuously during said hemodialysis.