WO1986000239A1 - Procedes et solutions d'hemodialyse - Google Patents

Procedes et solutions d'hemodialyse Download PDF

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Publication number
WO1986000239A1
WO1986000239A1 PCT/US1985/001205 US8501205W WO8600239A1 WO 1986000239 A1 WO1986000239 A1 WO 1986000239A1 US 8501205 W US8501205 W US 8501205W WO 8600239 A1 WO8600239 A1 WO 8600239A1
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Prior art keywords
fluid
hemodialysis
blood
dialysis
solution
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PCT/US1985/001205
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English (en)
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Richard L. Veech
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Veech Richard L
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Publication of WO1986000239A1 publication Critical patent/WO1986000239A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1654—Dialysates therefor
    • A61M1/1656—Apparatus for preparing dialysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1601—Control or regulation
    • A61M1/1603—Regulation parameters
    • A61M1/1605—Physical characteristics of the dialysate fluid
    • A61M1/1609—Physical characteristics of the dialysate fluid after use, i.e. downstream of dialyser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1654—Dialysates therefor
    • A61M1/1656—Apparatus for preparing dialysates
    • A61M1/1666—Apparatus for preparing dialysates by dissolving solids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1654—Dialysates therefor
    • A61M1/1676—Dialysates therefor containing proteins, e.g. albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3607—Regulation parameters
    • A61M1/3609—Physical characteristics of the blood, e.g. haematocrit, urea
    • A61M1/361—Physical characteristics of the blood, e.g. haematocrit, urea before treatment

Definitions

  • This invention lies in the field of techniques and compositions for hemodialysis and related matters.
  • inorganic electrolytes characteristically found in normal human blood serum at respective concentration levels above about 1 millimolar per liter of concentration are shown below in Table 1.
  • Table II are shown some representative compositions of various aqueous electrolyte solutions that have been previously prepared and used for in vivo (including dialysis) purposes.
  • the philosophy behind the formulation of aqueous electrolyte solutions for in vivo use has been that such should mimic or closely resemble the chemical composition of electrolytes in blood and plasma.
  • An electrolyte is a substance (usually a salt, acid or base) which in solution dissociates wholly or partly into electrically charged particles known as ions (the term is also sometimes used in the art to denote the solution itself, which has a higher elec rical conductivity than the pure solvent, e.g. water).
  • the positively charged ions are termed cations while the negatively charged ions are termed anions. Strong and weak electrolytes are recognized. The dissociation of electrolytes is very markedly dependent on concentration; it increases with increasing dilution of the solutions.
  • sigma or the greek letter for sigma (“ ⁇ ") is sometimes employed herein as a prefix to designate the total presence of a specified material, such as an electrolyte, whether or not all of the material is in an ionic form complexed with a heavy metal, or regardless of charge on the material in a given solution.
  • a pair of brackets ( [ ] ) indicates the free concentration of the substance indicated as opposed to that bound to tissue components, such as proteins.
  • aqueous electrolyte solutions are prepared, sold in commerce, and used as in vivo fluids, including dialysis (both hemo- and peritoneal).
  • dialysis both hemo- and peritoneal
  • the original hemodialysis solutions attempts were made to duplicate Krebs-Henseleit as Table I shows. These original hemodialysis systems were open however and loss of CO 2 lead to precipitation of Ca as CaCO 3 .
  • the original dialysis solutions contained excessive Cl- ion in excess of Na to overcome the "anion gap".
  • anion gap is used to connote the difference in milliequivalents/ liter between the apparent sum of routinely measured in- organic cations in plasma and the apparent sum of routinely measured inorganic anions in plasma.
  • the law of electrical neutrality of solutions states that such a term has no real physical meaning, but the term is widely used and accepted.
  • electrolyte solutions and methods described in such copending application utilize, as above indicated, individual electrolyte concentrations which, in accord with prior art practice, closely resemble (and are in fact intended to closely resemble) the chemical composition of electrolytes in mammalian blood and plasma.
  • composition of dialysis fluid in the future should resemble that of intercellular fluid (See Parson, F.M. & Stewart, W.K. in Replacement of Renal Function by Dialysis (1983) (Drukker, W., Parsons, F.M. & Maher, J.F. eds) pp 148-170, Martin Nijhoff, Hingham).
  • hemodialysis fluid electrolyte composition which will always contact the body cells by the media of blood plasma, must contain a precisely calculated degree of deviation from normal in order to achieve electrolyte normality in plasma after blood hemodialysis.
  • the extent and direction of that deviation is determined by the charge and concentration of the non-permeant (Donnan- active) material on the inside (blood side) of the dialysis membrane.
  • dialysis membranes have pores of average size of 10,000 M.W.
  • the only charged non-permeant material left inside the dialysis cartridge (on the blood side) in a counter-current dialysis are the plasma proteins albumins, globulin and blood cells.
  • This invention relates to the discovery that the concentrations and distributions of electrolytes in, respectively: (a) the freshly hemodialyzed blood of a patient, and (b) the hemodialysis solution used for the hemodialysis of that patient's blood, are defined by certain mathematical relationships which closely approximate such concentrations and distributions in each of the hemodialyzed blood and the hemodialysis solution.
  • This discovery permits one to practice various new and very useful processes in the field of hemodialysis.
  • One such process involves preparing an aqueous hemodialysis solution which when used for hemodialysis of a given patient will produce in the blood (plasma) being returned to such patient after hemodialysis thereof a desired or predicted composition of electrolytes.
  • Another such process relates to estimating (or predicting) the concentration of various blood (plasma) electrolyte components present in the blood being returned to a patient after hemodialysis of such blood with a given aqueous hemodialysis solution.
  • Another such process involves regulating the anionic charge associated with a patient's own polyanionic blood proteins of predetermined and variable charge (especially albumin) for purposes of filling the anion gap, normalizing the Na:Cl milliequivalent ratio, or the like.
  • predetermined and variable charge especially albumin
  • This discovery additionally permits one to prepare new and useful aqueous electrolyte solutions.
  • the solutions of this invention use polyanions of predetermined and variable charge present in a patient's own blood (especially albumin) to fill the anion gap and to normalize the Na:Cl milliequivalent ratio in the patient's own blood (plasma).
  • hemodialysis solutions of the present invention are provided which have abnormal respective concentrations of electrolytes whereas previous fluids attempted to mimic plasma concentrations of electrolytes. Yet when such solutions are used for hemodialysis, they tend to result inherently in normalization of the concentrations and distributions of electrolytes in the blood (plasma) of a patient hemodialyzed therewith. In other words, in order to achieve normality in concentration and distribution of electrolytes in blood (plasma), one employs hemodialysis solutions of the present invention wherein abnormal, relative to normal blood (plasma), concentrations of electrolytes are incorporated in a rationally predictable manner.
  • a patient's own albumin is employed to normalize the Na:Cl milliequivalent ratio present in that patient's blood.
  • additional features For example, one can utilize in the practice of this invention aqueous solutions for hemodialysis wherein:
  • compositions described in my above identified copending U.S. patent application can be achieved in the practice of my present invention, but, in addition, hy taking into consideration the hereindescribed mathematical relationships existing between hemodialysis solution and blood being, or to be, dialyzed therewith, regulation of blood and hemodialysis solution (as desired) inorganic electrolyte concentrations is achievable as is regulation of a patient's own polyanionic blood protein charge.
  • the present invention provides compositions and methods for correcting the anion gap, and such processes and compositions and methods take into account the special Donnan Forces operating during hemodialysis.
  • the present invention makes possible the preparation of electrolyte solutions for various special purposes, such as in situations where a patient is to be hemodialyzed to achieve changes in blood composition not associated with or caused by renal failure, as herein described and exemplified, including acidosis, poisoning, hyperkalemia, and the like.
  • the present invention provides techniques for achieving solutions from the mathematical formulae described below showing the relationship between the electrolytes and non-permeant charged material on patient's blood and the charged electrolytes in a hemodialysis fluid to be or being used to hemodialyze that blood.
  • the present invention provides a general process for estimating the concentration of electrolytes in a solution containing at least one non-permeant- ionically charged material after such solution has been dialyzed through an inert membrane structure, and, conversely, the present invention provides a general process for estimating the concentration of electrolytes needed in a starting solution which is to be used to dialyze a solution containing at least one non- permeant ionically charged material in order to achieve a desired or predetermined electrolyte composition in the latter solution.
  • Examples of practical applications include preparing dried plasma protein in an electrolyte solution ready for I.V. infusion, and the like.
  • This invention further relates to the discovery that, in a dialysis, one can control the rate of change in concentration of a diffusible material in a fluid on one side of an inert dialysis membrane relative to another fluid on the opposing side of such membrane.
  • the rate is preferably, in accord with this invention, linearized, but may be made to be hyperbolic or any other mathematically definite shape.
  • the rate of change in any dialyzable component may be regulated by changing the concentration of that component over time in the dialysis fluid. Control of the rate of change, allows the physician to either decrease the morbidity induced by a rapid initial change characteristic of present dialysis (1st order rate) or to shorten the length of time required for dialysis in those patients, able to tolerate rapid changes.
  • control of rate of change of concentration in accord with the teachings of the present invention makes possible many new and improved dialysis techniques where a given dialysis procedure can be varied to meet a physician determined optimized dialysis rate and time for a given patient, thereby to maximize benefits to that patient.
  • This discovery thus provides processes for regulating the concentrations and distribution of electrolytes in living animal cells which are being treated (contacted) with an electrolyte containing fluid by systematically changing (altering) the electrolyte composition of such fluid over a predetermined (selected) interval of time.
  • the rate of change that is, the slope and the shape of the curve of rate of change versus time slapsed, is variable, but the final fluid composition and the starting fluid composition can be regarded as predeterminable.
  • the present processes make possible the achievement of electrolyte compositional changes in extracellular fluids which cannot be achieved by the conventional method of merely admixing (or exposing) a particular extracellular fluid to an electrolyte composition of fixed (predetermined) electrolyte components as respects type and weight.
  • Such conventional method results in a fixed and predictable rate of change with respect to time that is fully defined by a simple first order (hyperbolic) rate equation.
  • the invention further provides an embodiment of apparatus for practicing such methods wherein a plurality of separately stored master components or batches (or equivalent) of pre-chosen starting materials are automatically blended together in a prechosen sequence and/or at prechosen rate(s) so as to produce product electrolyte compositions that is continuously (or discontinuously, if desired) systematically varied as to component concentration and/or component selection.
  • the invention further relates to compositions and fluids useful in the practice of such processes and in the operation of such apparatus.
  • the present invention can be used for various application, such as, for examples: (1) in human dialysis (especially hemodialysis) to control the rate of electrolyte change in a patient's blood,
  • An optional fixture of the present invention is that one can, by the practice of this invention, regulate the electrolyte composition properties of human blood or plasma in a living patient by changing in a predetermined systematic manner over a predetermined interval of time one or more of such blood electrolyte compositional variables or characteristics such as:
  • polyanionic protein charge on blood being dialyzed (2) concentration of one or more major blood cations and/or anions. (3) concentration of diffusible non-ionics and the like.
  • Another optional feature of the present invention is that one can avoid the use of acetate anions in a dialysis fluid or in a parenteral fluid (including intravenous fluids) because use of acetate or d,1 lactate ions alone as is conventionally practiced in the art has definable pathological consequences.
  • Another optional feature of the present invention is that one can incorporate bicarbonate/CO 2 into an electrolyte solution in variable quantities.
  • Another optional feature of the present invention is that one can use cell permeant near-equilibrium couples in an electrolyte solution (so as to regulate intracellular redox and phosphorylation states ) .
  • Another feature of this invention is that one may regulate the charge on a non-permeant polyionic substance by regulation of pH metal content and concentration of other effectors of charge.
  • the specified milliequivalent ratio of sodium to chloride in normal mammalian blood generally is believed to be in the range from about 1.24:1 to 1.47:1.
  • Ratios about 1.47, i.e. from about 1.47 to about 1.6 can be used within the spirit and scope of this invention as when it is the physician's conscience intention to create an abnormal Na:Cl ratio as, for example, to create an excess of alkali reserve; however, such higher ratios are generally not presently preferred for general usage.
  • the Na:Cl ratio can range to 1.55.
  • the total quantity, or sum (sigma), of bicarbonate anions and carbon dioxide present in a solution of this invention ranges from 0 to about 55 millimoles per liter of solution.
  • the ratio of bicarbonate milliequivalents per liter to dissolved carbon dioxide milliequivalents per liter in a solution of this invention can range from about 1:1 to 55:0.1 and preferably 11:1 to 24:1. More preferably, such total ranges from about 10 to 45 mM/1 and such ratio ranges from about 18:1 to 26:1, and still more preferably such total ranges from about 23 to 35 roM/1 while such ratio ranges from about 19:1 to 21:1.
  • a ratio of 19.95 for [HCO 3 -]/[CO 2 ] gives a pH of 7.4 which is presently particularly preferred.
  • the total quantity, or sum (sigma) of l-lactate anions and pyruvate anions present in a solution of this invention ranges from 0 to about 55 millimoles per liter of solution.
  • the ratio of L-lactate anion milliequi- valents per liter to pyruvate anion milliequivalents per liter in a solution of this invention can range from about 20:1 to 1:1.
  • such total quantity ranges from about 0.5 to 10 mM/1 and such ratio ranges from about 3:1 to 15:1, and more preferably such total quantity ranges from about 2 to 8 mM/1 while such ratio ranges from about 5:1 to 12:1.
  • the total quantity, or sum (sigma) of d-betahydroxybutyrate anions and acetoacetate anions present in a solution of this invention ranges from .about 0 to about 55 millimoles per liter of solution.
  • the ratio of d- betahydroxybutyrate anion milliequivalents per liter to acetoacetate milliequivalents per liter in a solution of this invention can range from about 6:1 to 0.5:1.
  • such total ranges from about 1 to 10 mM/1 and such ratio ranges from about 4:1 to 1:1, and more preferably such total ranges from about 2 to 5 mM/1 while such ratio ranges from about 3:1 to 1.5:1.
  • milliequivalent ratio as sometimes used herein, reference is had the ratio of milliequivalents per liter of one substance to milliequivalents per liter of another substance in a aqueous medium.
  • bicarbonate-/carbon dioxide couple tends, as used in this invention, to regulate the concentration of hydrogen ions in blood
  • each such near equilibrium couple when used as herein described constitutes a safe entry point into the metabolic system of a mammal.
  • safe entry point as used herein reference is generally had to a metabolite which, in living tissue or cells:
  • each such above described near equilibrium couple in this invention exhibits a distribution or permeability between intracellular fluid and extracellular fluid such that the ratio of the concentrations in, respectively, intracellular fluid to extracellular fluid ranges from about 1.0:1 to 1.5:1 in most all mammalian cells.
  • Osmotically active substances preferably non ionic
  • Osmotically active substances incorporated with the solutions of this invention preferably should each constitute a safe entry point.
  • glucose about 13 mM/1 is higher than ever occurs under normal physiological conditions in a healthy man.
  • Use of glucose above 13mM/l (as in the widely used 5% glucose solution) as a calorie source is, apart from consideration of the source of pathology, and apart from the carboxylate couples considered herein to be an acceptable source of calories.
  • the extreme ability of the mammalian body to regulate its glucose metabolism makes it far to be preferred over other possible nonionics, such as fructose or glycerol, which enter the metabolic system in an uncontrolled manner causing pathologic changes such as are already referenced, and so such are not safe entry points.
  • a solution used in the practice of this invention contains from about 120 to 165 millimoles per liter of sodium cations, and more preferably from about 129 to 163.5 mM/1 and most preferably from about 136 to- 145 mM/1.
  • a solution contains sufficient chloride anions to produce a milliequivalent ratio of sodium cations to chloride anions in the range above defined.
  • a solution of this invention can contain one or more of the following additional metallic cations each in a respective quantity as below indicated:
  • Quantity range cation (millimoles per liter) component Broad perferred Potassium 0-40 0-5 calcium 0-10 0-1.5 magnesium 0-10 0-1
  • a solution of this invention can have additionally incorporated (dissolved) therein from 0 to about 855 millimoles per liter of at least one substantially nonionic (including zwitterionic) osmotically active substance (which is preferably metabolizable).
  • a solution used in the practice of this invention is further characterized by generally having: (1) sufficient total substances dissolved therein to produce and osmolarity ranging from about 260 to 850 milliosmoles (mOs), and preferably from about 265 to 550 mOs, and most preferably from about 280 to 320 in mOs;
  • mOs milliosmoles
  • the relationship between total (dissolved) ionic substances is such that the pH ranges from about 5 to 9, and preferably from about 6.9 to 8.6; and most preferably from about 7.35 to 7.55;
  • the minimum total concentration of all such near equilibrium couple (s) present is at least about 0.1 millimoles per liter, and preferably is at least about 0.5 mM/1, and more preferably about 2 mM/1, while the maximum concentration thereof is preferably not more than about 80 and more preferably is not more than about 61 mM/1 and most preferably is not more than about 50 mM/1.
  • examples of usable such nonionic substances include glucose, glycerol, fructose, sorbitol, and the like. Glucose is presently most preferred.
  • the processes and the solutions of the present invention find use in a wide variety of therapeutic applications, such as in electrolyte and fluid replacement, parenteral nutrition, and dialysis.
  • Figure 1 is a flow chart of one embodiment of a computer program for solving in a hemodialysis application the multicomponent interrelationships involved in the distribution of charged ions in a multicomponent Donnan equilibrium situation involving a permeant membrane the present program being capable of identifying the plasma composition which will be achieved in a given patient who is to be hemodialyzed with a particular, predetermined hemodialysis fluid composition;
  • Figure 2 illustrates one embodiment of another computer program which can be used for solving the multicomponent interrelationships herein presented the present program being capable of identifying the composition of a hemodialysis fluid to be used for the hemodialysis of a patient based upon the desired or anticipated patient plasma electrolyte composition of the freshly hemodialyzed blood of that patient;
  • Figure 3 is a diagrammatic plat of change in concentration of one diffusible component of the patient's plasma as ordinates versus time as abscissae (the plot illustrates a first order rate equation);
  • Figure 4 is a diagrammatic plot, similar to Fig. 3 except concentration is plotted as the natural logarithm;
  • Figure 5 is an illustration of various rates of change for one diffusible component here potassium (K), in a patient's blood undergoing hemodialysis, the plot for any given rate of change being dependent upon whether the rate of change is accomplished linearly or hyperbolically.
  • K potassium
  • Figure 6 is a diagrammatic illustration of one embodiment of apparatus suitable for the practice of the present invention when one desires to continuously vary the electrolyte composition of a hemodialysis solution being used for hemodialysis during the time period of that hemodialysis involving the blood of a given mammal, thereby to linearize the rate of change of composition of the plasma electrolytes of that mammal during such hemodialysis; and
  • Figure 7 is a diagrammatic illustration of one embodiment of a hemodialysis apparatus wherein dialysis fluid composition can be varied, either batchwise from one patient to another, or continuously during the dialysis of a given patient to achieve a desired rate of change in the patient's blood electrolyte concentration or both if desired.
  • the net osmolar movement of eqn 7a is 2 osmoles --- ⁇ outside.
  • the net movement of eqn 7b is 3 osmoles --- ⁇ inside, requiring the Na + /K + ATPase to cycle 3 times for each 2 times the Na + /Ca 2+ exchange mechanism operates in order to maintain osmotic equilibrium.
  • the gradient [Ca 2+ ] i /[Ca 2 +] o is thus a direct function of the [Na + ] o 3 /[Na + ] i 3 , (the [Cl-] o /[Cl-] i ), and a function of the phosphorylation and entropy state of the cell.
  • the present invention in one aspect provides a process for preparing an aqueous hemodialysis solution which when used in hemodialysis will produce a desired electrolyte compostition in hemodialyzed blood.
  • a process for preparing an aqueous hemodialysis solution which when used in hemodialysis will produce a desired electrolyte compostition in hemodialyzed blood.
  • Various techniques are available for measuring albumin content in mammalian blood and any convenient such technique can be employed in the practice of this invention.
  • total blood protein can be determined using a plasma sample of the patient's blood. From the total blood protein and an electrophoresis of such protein, an estimate of the albumin and globulin content of the total blood protein can be made.
  • albumin is known to have a molecular weight of approximately 68,500. It has previously been established that albumin has a variable anionic charge which is dependent upon the pH of the solution wherein the albumin is dissolved (see Tanford, C.S. J. Am. Chem. Soc. 72, 441-451, 1950). For example, at the physiological pH value of 7.4, albumin has a valance of approximately 20 mEq/mole. The hydrogen ion equilibria in native human serum albumin was measured and desribed (Tanford, C.S. J. Am. Chem. Soc. 72, 441-451, 1950). Thus, from the published information, the valence of albumin at pH values over the physiological range are established. By selecting particular pH value for a desired hemodialysis solution, the approximate anionic valence of albumin at this pH value becomes determined and can be estimated by the supervising physician.
  • albumin is the principal polyanionic material present in plasma (blood), and since the valence of albumin is variable according to hydrogen ion concentration (or pH) , the pH of the dialysis solution contacting plasma during hemodialysis controls the pH of the plasma and the charge on the plasma albumin.
  • the approximate molar concentration of albumin is the only knowledge about the patient's blood (plasma) that is needed in order to prepare an aqueous hemodialysis solution which will be suitable to the individual needs of a patient undergoing hemodialysis.
  • the attending physician has the means for the first time to produce in the patient's plasma as returned to such patient after hemodialysis thereof a desired or specified composition of electrolytes which meet the special needs of that patient in an economically feasible manner which produces for less toxicity than any existing solution.
  • the physician selects initially the approximate concentration desired for each of the following specified plasma electrolyte components in the freshly hemodialyzed blood to be returned to the patient after hemodialysis of the patient's blood with the desired solution: sodium, potassium, calcium, magnesium, chloride, bicarbonate, sigma phosphate, L-lactate, pyruvate, D-betahydroxybutyrate, and acetoacetate according to such conditions as: the reasons for dialysis, the patient's general disease, his faithfulness in following instructions, the periods between dialysis, and other such individual factors; depending upon what components are to be included in a starting hemodialysis fluid.
  • composition of the desired hemodialysis solution is then calculated after which the desired solution is prepared.
  • conventional methods of electrolyte solution preparation can be employed which are well known to those of ordinary skill in the art.
  • the present invention provides a process for predicting accurately the plasma electrolyte content of freshly hemodialyzed mammalian blood when that blood is hemodialyzed with a hemodialysis solution of known fixed starting composition.
  • a process for predicting accurately the plasma electrolyte content of freshly hemodialyzed mammalian blood when that blood is hemodialyzed with a hemodialysis solution of known fixed starting composition one measures the approximate molar concentration of the albumin initially present in the blood of the patient to be hemodialyzed, as explained above in connection with the foregoing process. Then one substitutes the concentration values for each electrolyte values in the plasma of the blood to be hemodialyzed.
  • the equations 2 permit one to approximate the concentrations and distributions in each of hemodialyzed blood and hemodialysis solution.
  • the cations present in this solution will usually comprise from two to four metals selected from the group consisting of sodium, potassium, calcium and magnesium, while the anions present in such a solution will typically comprise chloride and possibly bicarbonate and inorganic phosphate.
  • the designation "Pi” is used herein, for convenience, to designate inorganic phosphate ions.
  • the valence of Pi at pH 7.4 is taken, for exemplary purposes herein, to be -1.8/mole.
  • a dialysis starting soltuion may contain dissolved therein any one of three different near equilibrium couples (identified respectively as bicarbonate anion and CO 2 . L-lactate anion and pyruvate anion, and D-betahydroxybutyrate anion and acetoacetate anion).
  • L-lactate anion and pyruvate anion and D-betahydroxybutyrate anion and acetoacetate anion.
  • Equation 2b2 is then a statement of electrical neutrality in the plasma.
  • the foregoing operations are illustrated in Figure 1 as process boxes 1, 2, and 3, respectively.
  • the computer is set to solve sub-elements of equation 2e, knowing the relationships in 2c and 2d.
  • the signal received by switch "A” is fed into process box 6 where an initial adjustment of sodium level in equation 2e is undertaken using a predetermined sodium factor.
  • the result of the calculation in process box 6 is fed back into process box 5 where a new, tentative solution to equation 2e is reached.
  • decision switch "A” which, at this point, permits the signal to be passed through to process box 7 wherein a temporary absolute value for equation 2e is calculated.
  • the signal is allowed to flow through to decision point or decision switch "B" where a determination is made as to whether or not the initial tentative solution in process box 5 is less than the adjusted tentative solution to equation 2 achieved in process box 5 on the second pass there through.
  • the signal is shunted into process box 8 where a register reset for the temporary absolute value of equation 2e is calculated.
  • the program flow from process box 8 next occurs back to process box 6.
  • process box 6 the repetitive recalculation above described occurs and the cycle is repeated.
  • the reiterative process is continued until an immediately prior solution to equation 2e is finally found to be equal to or greater than a current temporary solution to equation 2e.
  • the signal is fed into decision switch "C" for comparison of a temporary absolute value of equation 2e against an acceptable deviance.
  • the signal is permitted to move to process box 9, when and if the absolute value of equation 2e is equal to or greater than the accepted, predetermined, deviant or constant.
  • the sodium adjustment factor is reduced by a predetermined selected quantity or factor after which the signal is returned to process box 5 where a new, tentative equation 2e solution is produced.
  • decision switch "C” shows that an immediately preceding solution to equation 2e is within the acceptable (predetermined) deviant or constant.
  • the final output from decision switch "C” is fed to process box 10 where comments, as from a physician or technician, are conveniently entered. The comments entered generally relate to the results displayed, as those familiar with the art will readily appreciate.
  • the signal passes into process box 121 where a title arrangement is printed (or displayed, if desired).
  • equation 2 results for sodium are printed (or displayed, if desired).
  • the signal is then passed to decision switch "D".
  • decision switch "D" equation 2 results are checked for potassium level. If the potassium level is zero, then it is not printed as in a subsequent process box 13. On the other hand, if the potassium level is other than zero, the process box 13, is activated, and the potassium detail is printed. Thus, the equation 2 results for potassium are printed (or displayed, if desired).
  • the patient's albumin concentration and charge is printed or displayed by process box 23, after being entered by the physician (see box 3).
  • Process box 24 marks the end of processing and completion of the program.
  • a program such as is shown in Figure 2 and as is herein described in the accompanying text:
  • anions which may be regarded as reasonably typical, comprise chloride, bicarbonate and inorganic phosphate.
  • the albumin molar concentration and charge associated with the particular patient who is to be hemodialyzed are then entered into process box 7.
  • the charge to be given the albumin typically between -5 /mole albumin at pH 5.5 or /mole albumin at pH 8.4 is chosen by the physician. This choice determines the pH (and HCO 3 -/CO 2 ratio) of the dialysis fluid in accordance with the Henderson-Hasselbalch equation (equation 1).
  • the value of Z [Prot -z ] is needed to solve equation 2b2 (see box 8)*.
  • the total anion charges are adjusted with the albumin molar concentration and charge, as shown in process box 8; after which the total charge of anions is subtracted from the total charge of cations, as shown in process box 9.
  • decision switch "A” is activated. If the absolute value of the difference shown by process box 9 is less than a predetermined fixed value, then the difference is set to zero, as accomplished in process box 10. If the difference is greater than the predetermined value, then program flow proceeds from switch “A” to switch "B". It is necessary to have the total charges of cations equal the total charges of anions because of the law of electrical neutrality. In the present program, if electrical neutrality has been achieved by equivalence between anion and cation charges, or if the difference is so small there between as to be considered acceptable (negligible), then the program flow proceeds to decision switch "B".
  • process box 12 is activated.
  • the technician is informed that there is an anion deficit in the plasma make-up or composition. And such technician or physician is asked if he wishes to make up the difference with a near equilibrium couple such as l-lactate and pyruvate anion mixture. If the operator makes the decision to include l-lactate and pyruvate, then decision switch "D" permits the program to flow through to process box 13. If on the other hand, the decision of the operator is not to include lactate/pyruvate mixture, then decision switch "D" bypasses process box 13, 14, 15, and 16 (and their associated decision switches E, F, and G are bypassed).
  • process box 13 if such is activated, the operator is asked to enter his total chosen concentration of lactate/pyruvate mixture in an amount sufficient to achieve electrical neutrality in the contemplated or desired electrolyte solution being formulated. After this information is input by the operator the program proceeds to decision switch "E". Here a computer check is made of the input achieved in process box 11. If electrical neutrality is in fact achieved, then process box 15 is activated. If on the other hand, if electrical neutrality is not produced by the input in process box 13, then decision switch "E” activated process box 14. In process box 14 , an error message is printed and the operator is asked for corrected instructions to be input back into process box 13. This process is repeated until the amount of lactate/pyruvate entered is sufficient to produce electrical neutrality. In process box 15, in effect the anion gap is filled with the adjusted molar concentration of lactate/ pyruvate selected in process box 15.
  • decision point F is activated. Here one tests to see whether or not the adjusted anion gap is within acceptable limits. If this adjustment is not acceptable, one passes form decision point F to decision switch G and on through to process box 17. On the other hand, if this adjustment is satisfactory (within defined limits), then process box 16 is activated, and this process box sets the anion gap to zero, whereupon the process flow proceeds into decision switch G.
  • decision switch G a decision is made as to whether or not electrical neutrality has in fact been achieved. If electrical neutrality has not been achieved, then the program flow proceeds on through into process box 17. If, on the other hand, electrical neutrality has been achieved, then the program flow proceeds from decision switch G to process box 23. In process box 17, if electircal neutrality has not been achieved, then the operator is notified by a print, and the operator is asked if he wants to make it up with acetoacetate anion and betahydroxybutyrate anion. If the operator affirmatively indicates that he wishes to add a mixture of acetoacetate and d-betahydroxybutyrate, then the program proceeds through decision switch H into process box 18.
  • decision switch H passes the control to process box 22.
  • decision switch H controls the decision is to be compensated with a mixture of acetoacetate and betahydroxybutyrate or not.
  • Process box 18 asks the operator a question to the effect: "Since you want to include a mixture of acetoacetate and betahydroxybutyrate, how much of such mixture do you wish to add?" From process box 18 the program is sent to decision switch I, wherein a decision is made: "Is the quantity of ketone bodies added greater than what is needed to satisfy the anion gap?" If it is, then decision point I activates process box 19, and an error message is printed for the operator and also control returns to process box 18, where the operator must input appropriate corrections. When the amount is equal to or less than the anion gap, decision point I activates process box 20 and in process box 20 the anion gap is filled with the amount of ketone bodies entered in process box 18.
  • decision point J Program flow now enters decision point J wherein a decision is made to see whether or not the anion gap is within acceptable limits. If it is, then process box 21 is activated and the anion gap is set to zero. If on the other hand, if it is not then the process flow proceeds directly to process box 22 passing through decision point K. In decision point K, a decision is made: "Is the anion gap zero?" If it is, then process flow proceeds directly from decision point K to process box 23. If it is not, then process flow proceeds from decision point K to process box 22.
  • a print occurs wherein the operator is informed that there still remains an anion deficit in the propsed plasma composition, and further the operator is asked: "What ion do you wish to use to make up the remaining deficit?"
  • process will proceed to process box 23 wherein a display is made showing the entire plasma composition.
  • decision point M a decision is made as to whether or not to test the previous value (or temporary value) of equation 2e against a new temporary value for equation 2e. To meet the yes condition, the previous temporary value of equation 2e must be less than the currently determined value of equation 2e. If the decision is "no, then program control passes to decision switch N. In decision point N, the computer asks: "Is the absolute value of equation 2e less than an acceptable
  • the sodium scaling factor (which is a predetermined constant) is incrementally adjusted, after which program flow returns from process box 27 to process box 25 and a new absolute value for equation 2e is achieved.
  • Process box 28 involves the use of a register reset of the absolute value for equation 2e whereby process flow returns to process box 28 in an iterative mode continues until decision switch N produces a yes. When this occurs, then process box 29 is activated. In process box 29, the program output title is printed (and optionally displayed). Also, in process box 29 the sodium value is reduced by 0.935, which is the water adjustment factor. Thus the total sodium adjustment is known.
  • the computer asks if the potassium molar concentration is zero or not. If this concentration is not zero, then the potassium level is printed in process box 31.
  • a similar sequence of decision points and print details occurs for each of calcium, magnesium, chloride, bicarbonate, and phosphate, all as shown below. Ion Decision Point Print Process No.
  • decision point U the question is asked: "Was the quantity of mixture of lactate plus pyruvate zero?" If the answer is yes, then process flow proceeds from decision point U to decision point Z. If no, then process flow proceeds from decision point U to process box 37, where a lactate quantity is printed. Then next, process box 38 is activated where a pyruvate is printed (and/or displayed if desired).
  • process control passes to decision point V where a decision is made as to whether or not the quantity of mixture of betahydroxybutyrate and acetoacetate is zero or not. If zero, then process control passes on through to decision point W. If not, successively, process boxes 39 and 40 are activated, wherein, respectively, betahydroxybutyrate detail is printed followed by the printing of acetoacetate detail. In decision point W a decision is made as to whether or not the ion gap has been closed. If so, then program control proceeds through to process box 42. If not, then the process box 41 is activated and process box 41 prints the identity of the particular ion to be used to fill the anion gap.
  • process box 42 the computer prints (and/or displays, if desired) the value of plasma albumin (in terms of molar concentration) and albumin charge (z).
  • process box 43 the program is terminated.
  • the Rate of Change in Electrolyte Concentration By regulating the rate of change in plasma electrolyte composition during, for example, hemodialysis, one can also minimize and even eliminate the so-called disequilibrium syndrome and effects associated with the occurrence thereof in a patient.
  • the disequilibrium syndrome is believed to be associated with rapid changes in a patient's electrolyte and tissue H 2 O composition during the course of hemodialysis.
  • a patient is hemodialyzed with a dialysis fluid having an electrolyte composition which is different from the patient's own plasma
  • the patient's electrolyte composition changes, and approaches the composition of electrolytes in the fluid being used for the hemodialysis.
  • Freshly hemodialyzed blood is returned to the patient and mixes with the patient's blood. Over the time period of the hemodialysis, measurable and significant alteration of the patient's blood (plasma) electrolyte composition results.
  • C is approximately equal to the concentration of any substance in the patient's blood (plasma) at any time;
  • the final form of the curve produced by plotting equation (1) (above) is illustrated in Figure 3. Referring to Figure 3 the curve 10 is seen to be hyperbolic in form. The point where the concentration is midway between C o
  • FIG. 5 there is seen an example of the situation which exists in conventional hemodialysis.
  • time is shown along the abscissa while the ordinate is used to show, for this illustration, the level of plasma potassium (K) in milliequivalents per liter.
  • the patient is assumed to have an initial plasma level of 6 mEq/1, and the patient is to have a final plasma level of 3 mEq/1.
  • the C o level is 6 mEq/1 for potassium.
  • the time C o /2 required to achieve plasma K of 4.5 mEq/L is marked by dotted line 13 when the change in concentration rate follows that shown in the first order rate equation curve 15.
  • any convenient means may be employed to practice the process of the present invention with regard to achieving a desired linearization of the change in concentration of plasma relative to hemodialysis with a pre-chosen hemodialysis fluid.
  • a rate change in hemodialysis may be accomplished by associating a mixing device with existing dialysis equipment. While any convenient such device may be employed, a simple embodiment is shown in Figure 6 in association with hemodialysis equipment.
  • the mixing device is herein designated by the numeral 20 and is seen to incorporate two chambers, 21 and 22, respectively.
  • the apparatus employed is obtainable commercially from Bethesda Research Laboratories, Inc., in Rockville, Maryland, under the trade designation "BRL Gradient Former".
  • the chamber 22 and the chamber 21 are cylindrical in configuration with chamber 22 being generally coaxial with respect to chamber 21; thus, the outer walls of chamber 22 conform the inner walls of chamber 21.
  • An initial hemodialysis fluid or solution which approximates in composition the patient's initial plasma composition is charged into chamber 22 at predetermined fill level so that the weights of the two solutions are equal.
  • Chamber 21 is filled to a similar level with a hemodialysis solution composition which preferably is slightly lower in electrolyte content than the physician wishes to have at the termination of hemodialysis. Dialysis then proceeds as is described in apparatus in CRC Critical Reviews in Biomedical Engineering 9, 201-244, 1983.
  • pump 23 is actuated and valve 24 is opened, fluid through line 25 commences.
  • the fluid in line 25 is comprised of a mixture of the respective fluids in chambers 21 and 22.
  • the composition in line 25 continuously changes as fluid drains from gradient former 20, with the fluid composition in line 25 forming a linear gradient such that the rate of mixing of fluid in chamber 21 with the fluid in 22 is essentially linear as represented by, for example, one of the linear plots 16, 17, 18 or 19 in Figure 5.
  • appropriate mixing procedures can be employed.
  • a magnetic stirrer 27 actuated by a magnetic stirring plate 28 are provided for the apparatus 20 in the embodiment shown.
  • the output from the pump 23 is fed through a line
  • a dialyzer unit 32 which may be of the conventional type; for example, a hollow fiber dialyzer, or the like.
  • the fluid in line 29 passes through a heater 31, which maintains the temperature in line 29 at a predetermined value.
  • the temperature gauge 33 is provided for monitoring fluid temperature.
  • a throttling valve 34 is employed to regulate flow rate at the line pressure associated with fluid in line 29.
  • a flow meter 35 is incorporated into the system for monitoring purposes.
  • a safety valve 36 is provided conventionally.
  • the dialysis delivery system shown delivers dialysis to hemodialyzer 32 under appropriate conditions of concentration, temperature, pressure, and flow, and monitors and alarms (not detailed) are incorporated into the system to measure and/or control hydrostatic pressures across the dialyzer membrane for fluid removal.
  • dialyzer blood leaks as with the aid of a blood leak detector 37
  • the blood circuit is of conventional design and operation and is not detailed herein.
  • a blood pump, heparin infusion, and air/foam detector are preferably built into the system with provisions for appropriate connections to, and positioning of, the blood tubing.
  • the design utilized in Figure 6 is of the single pass, single patient system type. After the dialysis fluid leaves the dialyzer 32, it is discharged into a drain by a dialysate flow pump 39.
  • the above described gradient former can be replaced by a device which produces an output at a constant flow rate and variable composition.
  • a device which produces an output at a constant flow rate and variable composition.
  • One such device is available commercially from Waters Associates,
  • a pump B delivers a predetermined outflow which is less than the total volume of flow desired.
  • Pump A produces a flow or fluid volume which is equal to the total outflow minus the flow rate of pump B.
  • the total flow is a composite of the flows from each of the respective pumps A and B.
  • the pumps A and B are themselves controlled by a programmer which permits one to adjust the composite flow rate and composition so that, for example, the flow rate can be constant but the composition variable.
  • This device can be used for the purpose of obtaining the desired linearity associated with the practice of the present invention.
  • Figure 7 is given a rudimentary outline of a device with multiple entry points for concentrates which can be mixed in accordance with the concentrations dictated by equation 2 herein.
  • the beginning and ending concentrations of the dialysis fluid need not be the same.
  • any shape of curve may be obtained by appropriate programming.
  • the curve can be linear as in Figure 5.
  • the dialysis fluids can not only be varied during administration to achieve the desired rate of change, but also nay have different compostions depending upon the attending physician's evaluation of a patient's particular needs.
  • a non-permeant (impermeant) charged material of variable charge in the solution being dialyzed is used so as to create a Donnan equilibrium situation of a variable and controlable intensity wherein the distribution of the activity of the permeant ions on both sides of the dialysis membrane may be controlled, and thereby, the ionic composition of the dialyzed fluid is regulated.
  • this aspect of this invention has a wide variety of applications, it is particularly well suited for use in hemodialysis where the charges on the impermeant materials in the blood (particularly albumin, but also to a lesser extent the blood cells themselves and to an even lesser extent the globulins have charges which can create a Donnan effect) are used to create the ionic composition of the blood itself.
  • the ionic compostiion of a dialyzable fluid such as blood is regulated by the ionic composition of the dialyzing fluid and the charge on the impermeant charged material in the dialyzable fluid so as to determine the concentration of permeant ions in the dialysable fluid being dialyzed.
  • the charge of said non-permeant charged material in said dialyzable fluid is regulated by varying at least one of the following: (a) the pH of said dialysing fluid,
  • such dialyzable fluid comprises blood of a mammal, and the charge associated with non-permeant charged material in said blood is so regulated by: (a) varying the pH of said dialyzing fluid,
  • compositions An illustrative class of electrolyte solutions usable for hemodialysis, whose compositions are determined by applying equation 2 can be characterized as shown in the following Table IV. In solving equation 2, each patient's albumin molar concentration and charge is determined, and decisions are made respecting the concentrations of individual electrolytes desired in the patients plasma at the termination of hemodialysis, as indicated above.
  • compositions of the dialyzing solutions can be conventionally prepared by hand from avialable salts metals, gases and the like, the apparatus provided herein permits automatic preparation of some general solutions which are designed to meet the specific needs of particular patients from those specific groups which comprise the major groups undergoing hemodialysis.
  • An osmotically active material may be added in absence of ultrafiltration as a means of removing excess H 2 O from patients in those set ups not equipped with newer pressure sustaining dialysis cartridges.
  • glucose is preferred.
  • a physician desires to use any one or more of the near equilibrium couples as defined herein, then one can change the individual ratios at the discretion of the physician to achieve different chemical potentials. In the present illustrative examples, these ratios are set using the assumption of normal operating conditions.
  • FIG. 7 Shown in Figure 7 is one embodiment of apparatus of the present invention with functional capability as previously indicated.
  • concentrates are prepared and stored in vessels A, B...N, as shown in Fig. 7.
  • Each vessel A, B...N is interconnected with a mixing chamber
  • conduit means respectively designated as a, b...n.
  • a computer 110, or master control device, is interconnected with each of the porporationating pumps
  • a source (not detailed) of purified water input as labeled is provided and in the input line 115 is located a flow regulator 116 which is functionally interconnected with the computer 110, as shown.
  • Output past the flow regulator 116 in conduit 115 is input into an aerator 117 and in the aerator 117 inter mixing of carbon dioxide gas with the water is achieved so as to achieve dissolution of carbon dioxide in the water.
  • a conventional aerator of the lung type is illustrated.
  • Carbon dioxide is input past a gas feed regulator 120, the regulator 120 being functionally inter-connected with the computer 110 as shown; excess (undissolved) CO 2 is discharged.
  • the water containing dissolved carbon dioxide exits through conduit 121 and passes through a flow regulator 122 which is functionally interconnected with the computer 110. Flow through conduit 121 proceeds into mixing chamber 100. Thus, in mixing chamber 100 water containing a measured quantity of dissolved carbon dioxide is intermixed with individual ones of concentrates so as to produce an electrolyte solution wherein the exact composition of individual electrolyte components is controlled.
  • the solution from mixture chamber 124 exits through conduit
  • each regulator such as regulator 125
  • the fluid from mixing chamber 100 is fed to the dialyzer unit 130 which can be of conventional construction and here is preferably of the type which can be pressurized in the conventional prior art manner so as to achieve the processing effect in hemodialysis known as hyperfiltration to those skilled in the art.
  • the mixing chamber 100 can incorporate more than one mixing device so as to assure that the output from mixing chamber 100 is uniform in composition and physical characteristics.
  • compositional examples from the prior art illustrating the results obtaining from solving equation 2 so as to predict what the concentration of plasma electrolytes will be in the blood of a patient being returned to him from the dialysis machine assuming a normal human albumin concentration of 0.65mM/l.
  • the albumin charge changes depending upon the pH of the particular dialysis use being used. This latter point was not appreciated in the prior art since no attention was paid to the careful regulation pH nor was there any understanding as to why this regulation was important.
  • Initial plasma electrolytes are given simulating the clinical conditions described.
  • a dialysis fluid is created from equation 2 to achieve the final plasma electrolytes concentrations desired in the treatment of the condition.
  • the blood of the patient is sampled during dialysis and it is noticed that the blood urea drops at a roughly constant rate during dialysis ending at about 10mM at four hours.

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Abstract

Techniques de prédiction des concentrations et répartitions respectives de matériaux diffusibles dans des solutions sur les côtés opposés d'une membrane semi-perméable. Compositions uniques pour une hémodialyse utilisant les relations mathématiques impliquées. Procédé de régulation de la vitesse de modification de la concentration d'un matériau diffusible d'un fluide à un autre fluide sur un côté opposé d'une membrane semi-perméable. Appareil pour réaliser de tels procédés.
PCT/US1985/001205 1984-06-22 1985-06-24 Procedes et solutions d'hemodialyse WO1986000239A1 (fr)

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Cited By (8)

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US4649050A (en) * 1984-06-22 1987-03-10 Veech Richard L Electrolyte solutions containing polyanionic materials
US4663289A (en) * 1984-06-22 1987-05-05 Veech Richard L Electrolyte solutions and in vitro use thereof
US4668400A (en) * 1984-06-22 1987-05-26 Veech Richard L Hemodialysis processes and hemodialysis solutions
EP0437274A1 (fr) * 1990-01-12 1991-07-17 Bartz, Volker Solution pour l'infusion et la dialyse contenant du bicarbonate et du calcium
EP0547025A1 (fr) * 1988-03-03 1993-06-16 Gambro Ab Méthode pour déterminer la concentration d'une substance dans le sang ou la dialysance d'un dialyseur.
USRE38604E1 (en) 1984-06-22 2004-09-28 Btg International Limited Fluid therapy with L-lactate and/or pyruvate anions
US7445801B2 (en) 2002-06-07 2008-11-04 Baxter International Inc. Stable bicarbonate-based solution in a single container
EP2483304B1 (fr) 2009-09-29 2016-05-04 F.Hoffmann-La Roche Ag Réglage de filtration préalable de solutés issus de tampon pour la preparation a forte teneur en immunoglobuline

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* Cited by examiner, † Cited by third party
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AU627141B3 (en) * 1991-09-13 1992-06-26 Baxter International Inc. Peritoneal dialysis solution

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DE2825134A1 (de) * 1977-06-10 1978-12-21 Cordis Dow Corp Automatisches intermittierendes blutreinigungsverfahren
US4336881A (en) * 1979-06-14 1982-06-29 Diachem, Inc. Aqueous acid concentrate for hemodialysis dialysate
US4366051A (en) * 1976-11-19 1982-12-28 Halbert Fischel Hemodialysis system
US4489535A (en) * 1980-10-02 1984-12-25 Veltman Preston Leonard Materials and method for preparing dialysis solutions containing bicarbonate ions

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US4366051A (en) * 1976-11-19 1982-12-28 Halbert Fischel Hemodialysis system
DE2825134A1 (de) * 1977-06-10 1978-12-21 Cordis Dow Corp Automatisches intermittierendes blutreinigungsverfahren
US4336881A (en) * 1979-06-14 1982-06-29 Diachem, Inc. Aqueous acid concentrate for hemodialysis dialysate
US4489535A (en) * 1980-10-02 1984-12-25 Veltman Preston Leonard Materials and method for preparing dialysis solutions containing bicarbonate ions

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649050A (en) * 1984-06-22 1987-03-10 Veech Richard L Electrolyte solutions containing polyanionic materials
US4663289A (en) * 1984-06-22 1987-05-05 Veech Richard L Electrolyte solutions and in vitro use thereof
US4663166A (en) * 1984-06-22 1987-05-05 Veech Richard L Electrolyte solutions and in vivo use thereof
US4668400A (en) * 1984-06-22 1987-05-26 Veech Richard L Hemodialysis processes and hemodialysis solutions
USRE38604E1 (en) 1984-06-22 2004-09-28 Btg International Limited Fluid therapy with L-lactate and/or pyruvate anions
EP0547025A1 (fr) * 1988-03-03 1993-06-16 Gambro Ab Méthode pour déterminer la concentration d'une substance dans le sang ou la dialysance d'un dialyseur.
EP0437274A1 (fr) * 1990-01-12 1991-07-17 Bartz, Volker Solution pour l'infusion et la dialyse contenant du bicarbonate et du calcium
WO1991010457A1 (fr) * 1990-01-12 1991-07-25 Nephro-Medica Pharmazeutische Vertriebsgesellschaft Mbh Solution d'infusion et de dialyse contenant du bicarbonate et du calcium
US7445801B2 (en) 2002-06-07 2008-11-04 Baxter International Inc. Stable bicarbonate-based solution in a single container
EP2483304B1 (fr) 2009-09-29 2016-05-04 F.Hoffmann-La Roche Ag Réglage de filtration préalable de solutés issus de tampon pour la preparation a forte teneur en immunoglobuline

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CA1263072A (fr) 1989-11-21
EP0185089A4 (en) 1988-06-08
JPS61502942A (ja) 1986-12-18
EP0185089A1 (fr) 1986-06-25
AU4605585A (en) 1986-01-24

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