This invention relates to hemodialysis and, in particular, a system and compositions for the preparation of a bicarbonate-containing dialysate for dialyzing the blood of a patient across a semi-permeable membrane. Background of the Invention It has been recognized for some time that human blood may be conditioned through dialytic action with a selected exchange fluid.

Dialysis is performed on patients whose kidneys are not capable of adequate purification of blood and elimination of excess water. This is usually accomplished by circulating a portion of the patient's blood through a dialysis cell in which the patient's blood passes on one side of a semi-permeable membrane and a dialysate solution on the other side. The semi-permeable membrane passes waste materials and water from the patient's blood to the dialysate.

Dialysis is literally a life-saving process; however, sometimes undesirable side effects such as hypotension, fatigue, nausea, and the like, are encountered. Research is continuing to counter the adverse side effects and to further improve the efficacy of hemodialysis, including investigations to improve the composition of the exchange fluid, i.e., the composition of the dialysate.

Dialysate liquids must contain an alkaliz¬ ing salt. In the early days of dialysis development sodium bicarbonate was used as the alkalizing agent. However, because of shelf-life and stability prob- le s, as well as problems encountered by precipitate formation when calcium and/or magnesium salts are

also present in the dialysate, sodium acetate was substituted for sodium bicarbonate as an alkalizing agent more than fifteen years ago. Even today dialysis solutions usually contain sodium acetate as the alkalizing agent. Sodium r^etate solutions are more easily maintained than s- mm bicarbonate solutions in a state of sterility; sodium acetate being subsequently metabolized in the bloodstream to sodium bicarbonate. However, with the increasing acceptance and use of large surface area dialysis equipment, see Babb et al., Trans. Amer. Soc. Artif. Int. Organs XVII:81-91 (1971), evidence is accumulating that the increased transfer of acetate occurring in large surface dialyzers using sodium acetate dialysates is not without shortcomings.

It has been observed that patients dialyzed on large surface area dialyzers using a sodium acetate dialysate were rapidly depleted of bicarbo- nate ion during dialysis, thereby placing the patients in acidosis. Moreover, inasmuch as the influx rate of acetate ions into the patient's bloodstream during dialysis on a large surface area dialyzer usually is greater than the rate of metabo- lism of acetate ions to bicarbonate ions, a rela¬ tively large concentration of bicarbonate ions is generated after dialysis, producing alkalosis. Kirkendol et al., Trans. Am. Soc. Artif. Intern. Organs XXIII:399-403 (1977), recognized the drawbacks of sodium acetate dialysates as well as the impracti¬ cability of sodium bicarbonate dialysates and investigated other potential substitutes for sodium acetate.

Graefe et al., in an article entitled "Less Dialysis-Induced Morbidity and Vascular Instability with Bicarbonate in Dialyzate," published in Annals

of Internal Medicine 8J3:332-336, 1978, disclose that sodium bicarbonate-containing dialysate fluid produces less nausea, headache, vomiting, post- dialysis fatigue, hypo-tension, disorientation and dizziness than sodium acetate-containing fluid, when used in a high-efficienty large-surface-area dialyzer.

A beneficial effect of sodium bicarbonate- containing dialysates in reducing incidence of atherosclerosis is recognized in Kluge et al., Int. Soc. Art. Org. 3A, p. 23 (April 1979).

These articles would suggest that sodium bicarbonate, rather than sodium acetate should be the alkalizer of choice in dialysate liquids. However, as pointed out above, sodium bicarbonate solutions present practical problems because these solutions are not bacteriostatic and thus may present sterility problems.

Aqueous sodium bicarbonate solutions, unlike aqueous sodium acetate solutions, are not self-sterilizing and cannot be prepared in advance of their use for dialysis. Common infectious organisms can survive and proliferate in sodium bicarbonate solutions; and infection of the patient is thus possible when there is even a minor and inadvertent departure from sterile technique in the handling of the dialysis process. Summary of the Invention

The present invention permits the in situ preparation of a bicarbonate-containing dialysate suitable for use in a dialysis machine from bacterio¬ static starting solutions and also contemplates a proportioning system for such preparation. In the proportioning system, an aqueous hydrochloric acid- containing solution and an aqueous carbonate-ion

STITUTE SHΞΞT OMPI

containing solution are combined, and the conductivity as well as the hydrogen ion activity of the produced, bicarbonate-containing dialysate is monitored. This invention can be practiced using presently known dialysis equipment in conjunction with a dialysate compounded in two stages from two or three previously prepared bacteriostatic solutions. In this manner prolonged existence of sodium bicarbonate in the dialysate liquid prior to use is avoided, rather the sodium bicarbonate is prepared in situ in a desired concentration shortly before the dialysate liquid contacts the dialysis membrane.

The formulation of sodium bicarbonate by the reaction of sodium carbonate with hydrochloric acid or acetic acid is a well known chemical reqction which proceeds by the following equations:

Na ₂ C0 ₃ + HC1 > NaCl + NaHC0 ₃ a ₂ C0 ₃ + HAc — ^■ — NaAc + NaHC0 ₃ \ (by metabolism)

NaHC0 ₃ Aqueous acetic acid solutions are bacteriostatic and self-sterilizing, and therefore contaminant-free prior to blending with the sodium carbonate solution.

The aforementioned aqueous acid solutions are inherently bacteriostatic, but the aqueous sodium carbonate solutions are not bacteriostatic at all concentrations. In particular, aqueous sodium carbonate solutions having a sodium carbonate concentration of less than about 20 grams per liter of solution (calculated as anhydrous are capable of supporting bacterial growth. Such dilute aqueous sodium carbonate solutions can be used to

O

generate sodium bicarbonate in situ when freshly prepared; however, these dilute solutions are not suitable for extended storage and shipment from a manufacturing facility to the intended end use station. Surprisingly, and unpredictably, however, aqueous sodium carbonate solutions containing sodium carbonate in a concentration of about 20 grams or more per liter of solution are bacteriostatic.

Accordingly, the present invention contem- plates a bacteriostatic aqueous sodium carbonate solution and a concentrated aqueous hydrochloric acid solution that are suitable for the compounding of a hemodialysis dialysate. The sodium carbonate solution comprises water, and at least about 20 grams of sodium carbonate per liter of solution. The amount of sodium carbonate present is calculated as anhydrous sodium carbonate; however, the hydrated forms of sodium carbonate, e.g., sodium carbonate monohydrate or sodium carbonate hexahydrate, are also well suited for preparing the aforementioned sodium carbonate concentrates. For preparing highly concentrated sodium carbonate solutions it is preferable to use the more soluble forms of sodium carbonate. In one preferred embodiment, the bacteriostatic aqueous sodium carbonate solution and aqueous acid concentrate are in the form of physically discrete units that are suitable as unitary dosages for each dialysis session, each unit containing a predetermined quantity calculated to produce the desired therapeutic effect when diluted and combined to produce a hemodialysis dialysate. The preferred unit dosage forms are sealed unit dose containers, more preferably sealed, collapsible unit dose containers that can be emptied without the

need for venting. The sealed unit dose containers preferably contain about one liter to about 50 liters of the bacteriostatic solution or concentrate, more preferably about 2 liters to about 20 liters. A preferred embodiment of the system of this invention includes a source of aqueous carbonate ion concentrate, a source of aqueous hydrochloric acid-containing concentrate, a source of physiologically tolerable water, and means for commingling an aqueous stream from each of the aforementioned sources to produce a bicarbonate-containing dialysate. Additionally, the system includes a potentiometric means for monitoring hydrogen ion activity in the produced dialysate and providing an output indicative of the hydrogen ion activity (e.g., a pH probe or meter), conductivity sensing means for monitoring the conductivity of the produced dialysate and providing an output indicative of the conductivity thereof, and a flow control means that is responsive to both of the foregoing outputs and is adapted to interrupt normal flow of the produced dialysate when the value of either of these outputs deviates from a set magnitude by a predetermined amount. Brief Description of the Drawings In the drawings:

FIGURE 1 is a block diagram illustrating, a system embodying the present invention;

FIGURE 2 is a graphical representation of the conductivity and pH of an aqueous stream obtained by combining an aqueous sodium carbonate stream and an aqueous hydrochloric acid-containing stream; and

FIGURE 3 is a semi-schematic representation of a flow system designed to provide two reaction stages between the aqueous sodium carbonate and the

hydrochloric acid and to substantially prevent the formation of calcium carbonate precipitate when the reactants are mixed; and

FIGURE 4 is a block diagram of a preferred proportioning system embodying the present invention. Description of Preferred Embodiments

To prepare a dialysate, the concentrated bacteriostatic sodium carbonate solution is first diluted with water, preferably deionized or tempered water, to provide a carbonate ion concentration that is sufficiently low to avoid the precipitation of any cations that may be present as additional constituents in the aqueous acid concentrate solution and that can form insoluble carbonates. The bacteriostatic, concentrated sodium carbonate solution can contain sodium carbonate in an amount of about 20 grams per liter of solution up to about 150 grams per liter of solution, and preferably about 105 to about 115 grams per liter solution, .thus prior to use the concentrated sodium carbonate solution should be diluted sufficiently to avoid the formation of undesirable precipitates when combined with the aqueous acid concentrate. The bacteriostatic solution can be packaged in the aforementioned quantities in sealed containers, e.g., collapsible hermetically sealed containers, so as to avoid undesirable pick-up of carbon dioxide from ambient atmosphere. Preferably, the dissolved carbon dioxide concentration in the concentrated sodium carbonate solution is less than about 0.5 molar.

Presently known dialysis equipment can be used in conjunction with a dialysate compounded using the aforementioned bacteriostatic sodium carbonate solution. Prolonged existence of sodium bicarbonate in the dialysate liquid prior to use is avoided;

SUBSTΓ _ »— ^■ cr-.' _- -

instead, sodium bicarbonate is generated in a flowing stream in situ within the dialysis machine and in a desired concentration shortly before the dialysate liquid contacts the dialysis membrane. The proportioning systems available on present dialysis equipment vary, thus the dilution ratios for each of the concentrates that are to be combined to form the ultimate dialysate may be different and in some instances may be as high as 60:1. However, in all instances the produced bicarbonate-containing dialysate has a pH in the range of about 7:1 to about 7:4 and an osmolality of about 200 to about 280- milliosmoles.

Since sodium bicarbonate is the preferred alkalizing material for minimizing side effects during hemodialysis, the preferred acid solution for producing the dialysate is a hydrochloric acid solution which produces no sodium acetate. However, from the aforementioned chemical reactions it can be seen that acetic acid produces equimolar amounts of sodium bicarbon- .e and sodium acetate; and acetic and hydrochloric a . mixtures produce even less sodium acetate. Sue ^' jlutions are therefore preferable to the sodium aceuate-alkalized dialysate solutions now used inasmuch as the total concentration of bicar¬ bonate ion in the patient's bloodstream can be readily adjusted by the addition of minor amounts of acetate ion to the dialysate while the total concen¬ tration of acetate ion in the dialysate is minimized. The use of a small amount of acetic acid in combination with hydrochloric acid is helpful, however, when using a standardized bacteriostatic sodium carbonate stock solution. That is, in a standardized system for the dialysis of patients some of whom may require different levels of sodium

bicarbonate, it may be advantageous to make up a standard sodium carbonate solution, which, after suitable dilution and reaction with hydrochloric acid, will produce the desired amount of sodium bicarbonate for the patients who have the minimum level requirement for bicarbonate ions. For patients with bicarbonate ion requirements above the minimum, the necessary difference in bicarbonate ion require¬ ment can then be readily supplied by substituting acetic acid for part of the hydrochloric acid while using the same standard sodium carbonate solution. The additional bicarbonate production from the same level of sodium carbonate is possible because acetic acid can produce two bicarbonate ions from each molecule of sodium carbonate (one immedia ly and the other through metabolic action in the bloodstream) while hydrochloric acid produces only one.

For example, a minimum alkalizing level of 35 milliequivalents per liter of sodium bicarbonate may be taken as standard; and a level of sodium carbonate in a standard solution may be selected to produce 30 or 35 milliequivalents of sodium bicarbonate ion per liter when the sodium carbonate is diluted and then reacted with hydrochloric acid. For patients requiring minimum sodium bicarbonate levels the standard sodium carbonate solution would be reacted with an aqueous acid solution containing only hydrochloric acid.

For other patients who might require 40 milliequivalents of sodium bicarbonate per liter, for example, the additional five milliequivalents may be obtained from the same standard sodium carbonate solution that provides 35 milliequivalents of sodium bicarbonate by substituting acetic acid for the hydrochloric acid equivalent of five milliequivalents

per liter. The substituted acetic acid will react with the sodium carbonate not only to produce immediately the same amount of sodium bicarbonate as the hydrochloric acid that it replaces (5 milliequivalents per liter) but it will also produce 5 milliequivalents per liter of sodium acetate which converts in the body to sodium bicarbonate. Thus, partial substitution of acetic acid for hydrochloric acid in a reaction with a standard minimum sodium carbonate solution increases the ultimate level of sodium bicarbonate to the extent of such substitution on a mol for mol basis. Alternatively, the addition of acetic acid can be dispensed with by increasing the amounts of hydrochloric acid and sodium carbonate that are reacted.

The amount.*? of other constituents of the dialysate fluid δ d for proper electrolyte balance, e.g., Ne..--__, KC1, CaCl _2/ MgCl_, etc. are based on clinical requirements. Ther~* salts may be dissolved in the concentrated acid-" taining solution, or may be supplied as a t: ^' . solution, as desired.

The aqueous acid concentrate solutions within the purview of the present invention can be prepared by dissolving the solid salts in water, preferably deionized or tempered water, and adding hydrochloric acid. The relative amounts of constit¬ uents are selected so as to provide in the concen¬ trated solution a chloride ion concentration of about 3.5 to about 4.7 Molar, sodium ion concentration of about 1.9 to about 2.7 Molar, and a pH value of about 1 to about 2.5 Preferably, the pH value of the aqueous acid concentrate is about 1.8 to about 2.0. Additionally, the aqueous acid concentrate can contain the acetate group in a concentration up

to about 0.525 Molar, preferably in a concentration of about 0.15 Molar to about 0.35 Molar. Since aqueous solutions of acetate group-containing com¬ pounds contain ionized as well as unionized forms thereof, the term "acetate group" as used herein and in the appended claims includes both such forms.

Optionally, the aqueous acid concentrate can also contain potassium ion in a concentration up to about 0.14 Molar, calcium ion in a concentration up to about 0.125 Molar, and magnesium ion in a concen¬ tration up to about 0.09 Molar. Dextrose can be present in a concentration of about 0 to about 0.4 Molar, preferably in a concentration of about 0.2 to about 0.35 Molar. The dialysate is preferably provided to the membrane through a proportioning apparatus into which three liquids are directed as separate streams at controlled rates, namely (1) a bacteriostatic stock sodium carbonate concentrate, (2) a bacteriostatic acid concentrate containing the remaining dialysate solute constituents, and (3) water, e.g., tempered water. Preferably, the sodium carbonate concentrate and the tempered water are first combined; and the diluted sodium carbonate solution thus obtained is then combined with the acid concentrate, usually at a 34:1 or 36:1 dilution ratio. However, if desired, the acid concentrate may also be diluted to a predetermined concentration before the bicarbonate is generated. The dilution ratios in any given instance will depend on the type of dialysis equipment and associated proportioning devices that are used, and also on the particular concentrations of the aqueous sodium carbonate concentrate and the acid concentrate that are utilized in any given instance. The relative proportions and flow rates of

SUBSTSTUT

the three liquid streams may be calculated and controlled by a suitable computer or microprocessor device; and the operation of the system may be monitored by a continuous reading of either the conductivity or the pH value of the final composite stream to the dialysis unit. Preferably both the conductivity and the pH of the obtained dialysate are monitored.

It has been determined that a sodium bicarbonate level of 35 milliequivalents per liter usually is suitable for patients having a minimal alkalizing requirement in their dialysate fluid. To obtain this level of sodium bicarbonate in the final dialysate solution (after reaction with hydrochloric acid and dilution) , a standard, bacteriostatic concentrated sodium carbonate solution is prepared containing 1891 grams of sodium carbonate in a 4.5 U.S. gallon batch, i.e., containing 111 grams of sodium carbonate per liter of former solution, which is then diluted with tempered water in a water-to- concentrate volume ratio of about 28 to 1. This ratio may be varied, however, to adjust bicarbonate and pH levels as needed.

Suitable levels of hydrochloric acid and acetic acid in the acid-containing solution for patients requiring different levels of alkalizing bicarbonate are shown in the following Table.

HC0 ₃ ions HC1 (11.6N) HAc (17.4N)

Required ml/1 ml/1 mEq/1

30 90.6 0

35 105.7 0

40 90.6 10.05

45 75.5 20.10

50 60.4 30.15

P

In some instances it may be desirable to add hydro¬ chloric acid in an amount that slightly exceeds the stoichiometric amount needed for conversion of sodium carbonate to sodium bicarbonate and in other instances it may be desirable to increase the amount of sodium carbonate.

The remaining solute constituents of the dialysate solution as prescribed by the attending physician can be added to the acid-containing solution or can be provided to the dialysate as a stream of a separate solution.

In the case of a separate solution, for example, in each liter batch thereof, 6.45 grams of dissolved calcium chloride produces a calcium level of 3 milliequivalents per liter; 1.83 grams of dissolved magnesium chloride produces a magnesium level of 1 milliequivalent per liter; and potassium chloride dissolved in amounts of 0, 2.92, 5.85 and 8.76 grams produce potassium levels of 0, 1, 2 and 3 milliequivalents per liter, respectively. Typical sodium chloride levels in such a separate solution are 149.6, 155.7 and 161.1 grams per liter batch. In combination with the sodium from the aforementioned sodium carbonate solution providing 40 illiequiva- lents of bicarbonate ion, overall sodium levels of 130, 135 and 140 milliequivalents per liter, respectively, can be obtained.

To produce a typical final dialysate stream of about 500 illiliters per minute to the membrane, or so-called artificial kidney, having the consti¬ tuents proportioned as described above, the diluted sodium carbonate solution is combined with the aforementioned acid-containing solution in a volu¬ metric ratio of, for example, 34 to 1, i.e., 34 parts by volume of the diluted sodium carbonate solution to

one part by volume of the acid-containing solution. In instances where the acid-containing solution also contains the prescribed additional constituents needed for proper electrolyte balance, the acid- containing solution should be added only to the diluted sodium carbonate solution because otherwise a calcium carbonate and/or magnesium carbonate precipi¬ tates in the dialysate may be formed.

Proper proportioning of the dialysate constituents during hemodialysis can be readily monitored by a conductivity sensor because the conductivities of the diluted sodium carbonate solution and the dialysate solution are sufficiently different at 37°C. (about 6000 micromhos per centi- meter and about 13,000 micromhos per centimeter, respectively) so that any malfunction of the dilution system for the sodium carbonate concentrate and/or the metering system for the acid-containing solution can be immediately detected and appropriate remedial measures can be implemented. It is preferred to use a pH monitor in conjunction with the conductivity sensor to insure that undiluted acid concentrate does not come in contact with the dialysis membrane in the event the supply of diluted aqueous sodium carbonate solution that is to be combined therewith is reduced or interrupted due to equipment malfunction or for some other reason.

Other illustrative concentrate compositions for in situ generation of a sodium bicarbonate dialysate are illustrated below.

To produce a dialysate having a pH of 7.2 to

7.4 and containing the constituents

Na + 140 mEq/liter HCO ^" 35 mEq/liter

Cl 109 mEq/liter Ca ++ 3.5 mEq/liter Mg +"+' 0.5 mEq/liter an aqueous acid concentrate (for 36:1 dilution) having dissolved therein

NaCl (mol.wt. 58.45) 134.67 grams/liter HC1 (11.6N) 127.7 ml/liter

CaCl ₂ '2H ₂ 0 9.26 grams/liter

(mol.wt. 147.0)

MgCl ₂ '6H ₂ 0 1.83 grams/liter

(mol.wt. 203.3) is prepared. The bacteriostatic aqueous sodium carbonate concentrate that is diluted 36-fold and combined with the foregoing acid concentrate after approximate dilution contains 169.64 grams of Na ₂ C0 ₃ ^# H ₂ 0 (mol. wt. 124.01) per liter which is equivalent to about 145 grams per liter calculated on the basis of anhydrous sodium carbonate.

The foregoing sodium carbonate concentrate can also be used at a 36-fold dilution to provide a dialysate having a pH of 7.2 to 7.4 and the following composition:

Na 140 mEq/liter

HCO~ 35 mEq/liter

^C 2 ^H 3°2 5 mEq/liter Cl ^" 104.5 mEq/liter

Ca ++ 3.5 mEq/liter Mg ++ 0.5 mEq/liter

In the latter case, the aqueous acid concentrate, again to be diluted 36:1, has the following composition:

OMPI

NaCl (mol.wt. 58.45) 134.67 grams/liter

HC1 (11.6N) 112.3 ml/liter CH ₃ C0 ₂ H (glacial) 10.2 ml/liter CaCl ₂ »2H ₂ 0 9.26 grams/liter

(mol.wt. 147.0) MgCl ₂ ^» 6H ₂ 0 1.83 grams/liter

(mol.wt. 203.3)

The specific dilution ratios of each concentrate can be selected as desired, and the amounts of the constituents present in each concen¬ trate can be scaled up or down accordingly within their respective solubility limits.

Typical aqueous acid concentrate solu¬ tions suitable for the preparation of hemodialysis dialysate are illustrated below. Preparation I

NaCl 131 ^• grams/liter

HC1 (11.6 N) 122.6 ml/liter

KC1 10.5 grams/liter dextrose 70 grams/liter water q.s.

Cl ^" 3.804 Molar

Na ⁺ 2.241 Molar

K ⁺ 0.1408 Molar dextrose 0.3532 Molar

Preparation II

NaCl 131 grams/liter

HC1 (11.6 N) 119 ml/liter

KC1 10.5 grams/liter dextrose 70 grams/liter water q. s .

Cl ^" 3.762 Molar

Na ⁺ 2. 241 Molar

K ⁺ 0.1408 Molar dextrose 0.3532 Molar

TIT . O

Preparation III

NaCl 159.6 grams/liter

HC1 (11.6 N) 98.7 ml/liter

KC1 10.5 grams/liter dextrose 70 grams/liter water q.s.

Cl ^" 4.016 Molar

Na ⁺ 2.730 Molar

K ⁺ 0.1408 Molar dextrose 0.3532 Molar

Preparation IV

NaCl 159.6 grams/liter

HC1 (11.6 N) 93.9 ml/liter

KC1 10.5 grams/liter dextrose 70 grams/liter

Cl ^" 3.961 Molar

Na ⁺ 2.730 Molar

K ⁺ 0.1408 Molar dextrose 0.3532 Molar

Preparation V

NaCl 134.67 grams/liter

HC1 (11.6N) 127.7 ml/liter

CaCl ₂ 2H ₂ 0 9.26 grams/liter

MgCl ^■ 2. 6H ₂ 0 1.83 grams/liter

Waa1ter q.s.

Cl ^" 3.857 Molar

Na 2.304 Molar Ca ++

0.06299 Molar Mg++

0.009001 Molar

UBSTITUTE c ^~ -m ^ ^∑ Xi

Preparation VI

NaCl 134.67 grams/liter

HC1 (11.6N) 112.3 ml/liter

CH ₃ C0 ₂ H (glacial) 10.2 ml/liter

CaCl ₂ 2H ₂ 0 9.26 grams/liter

MgCl ₂ 6 H ₂ 0 1.83 grams/liter

Cl ^" 3.679 Molar

Na ⁺ 2.304 Molar

Ca ⁺⁺ 0.06299 Molar

Mg ⁺⁺ 0.009001 Molar acetate group 0.1775 Molar

Bacteriological testing of concentrated aqueous sodium carbonate solutions indicates that these solutions will not support the life of micro¬ organisms that can be potential contaminants, i.e.. Bacillus cereus, Pseudomonas stu'tzeri as well as yeasts, molds, and members of Serratia and Staphyl- ococcus. In particular, samples of the concentrated solutions were challenged by introducing about 1000 bacteria of a specific type and checking these samples periodically over a time period of several days. For each sample two types of control were also used. First a sample of nutrient broth was chal- lenged with the same type and member of bacteria and periodically checked for growth to determine that the bacteria used in each instance were viable (a positive growth control) . Additionally, an aliquot of each solution sample was left unchallenged but otherwise handled in the same manner as the chal¬ lenged samples (a negative growth control) .

Tests on aqueous solutions of sodium bicarbonate performed in the foregoing manner showed that such solutions will support the growth of yeasts, molds and Pseudomonas.

The bacteriostatic properties of the aqueous sodium carbonate concentrate compositions embodying the present invention are further illustrated by the following example. EXAMPLE: Evaluation of the Bacteriostaticity of

Aqueous Sodium Carbonate Solutions

Five aqueous sodium carbonate test solu¬ tions and a control were challenged with various microorganisms and cultured to ascertain whether these solutions support microorganism growth. The five test solutions contained sodium carbonate in the following concentrations: 20 grams/liter, 40 grams/liter, 60 grams/liter, 80 grams/liter, and 100 grams/liter. The five test -rolutions and TSY Broth were each divided into seven 20-milliliter aliquots and seeded with approximately 1000 microorganisms each. The microorganisms that were used were Pseudomonas stutzeri, Bacillus cereus, Candida albicans (a yeast) , members of Serratia and Staphylococcus, and a mold. The aliquots were then incubated at room temperature and subcultured at 1, 3, 7, and 14 days. An unseeded aliquot of each test solution served as the negative control, and an aliquot of TSY Broth seeded with each organism served as positive growth control.

Results of the foregoing evaluation demonstrate the bacteriostaticity of concentra-_ed aqueous sodium carbonate solutions and are tabulated in Table I, below.

tr ^> ~ r — _. '

OMPI

TABLE I RESULTS OF SODIUM CARBONATE CONCENTRATE STUDY PROTOCOL

INCUBATION TIME

Day 1 Day 3 Day 7 Day 1

CONTROL P. STUTZ. SERRATIA ε STAPH. - - - -

0"i C. ALBICANS - - - - o MOLD - - - —

B. CEREUS — — — —

CONTROL — — — —

. P. STUTZ. - - - -

SERRATIA - - - - ε STAPH. _ ^" - - -

Cπ C. ALBICANS - - - -

• P. STUTZ. - - - -

SERRATIA - — — — tn STAPH. - - — -

CONTROL __ _ «. _

EG EH P. STUTZ. + + + +

§ SERRATIA + + + + m STAPH. + + + +

WlS t ^* ', ^' -■ T ~ ^~ " ^~ y- ys - ^■

To minimize the likelihood that the presently contemplated bacteriostatic aqueous sodium carbonate solutions may freeze during refrigerated storage, or shipment, an organic physiologically acceptable freezing point depressant can be added thereto. Suitable freezing point depressants for this purpose are physiologically tolerable liquid mono- or polyhydric alcohols such as ethanol, propylene, glycol, glycerin, and the like, as well as mixtures of such alcohols. The amount of the freezing point depressant that is added will vary with the particular organic compound utilized and will depend also on the expected ambient temperatures during shipment and storage. The basic elements of a system to mix the bacteriostatic aqueous sodium carbonate solution and aqueous acid concentrate are illustrated in FIGURE 1. An aqueous stream from carbonate source 10 and an aqueous stream from acid source 11 are combined in mixing chamber 12. The carbonate source can be a supply of a water-soluble, physiologically tolerable alkali metal carbonate, e.g., sodium carbonate in anhydrous or hydrated form, dissolved in physiologically tolerable water such as conditioned water, e.g., deionized water, distilled water, or the like, at a concentration sufficiently dilute upon combination with the acid source so as not to bring about the precipitation of any insoluble carbonates upon addition of the aqueous acid solution that could otherwise result due to the presence of small amounts of cations such as calcium or magnesium that may be present in the acid solution.

The acid source can be a supply of hydro¬ chloric acid alone or hydrochloric acid admixed with acetic acid in a predetermined ratio as prescribed by

SUBSTi s U 2.---■ a.-y.j- .1 oMPi .. IPO .

the attending physician. Other constituents such as sodium chloride, calcium chloride, magnesium chloride, and the like, can also be dissolved with the acid.

5 Mixing chamber 12 is of sufficient holding capacity to provide adequate mixing and residence time for the carbonate-to-bicarbonate conversion to take place. If desired, a separate holding tank may be provided downstream of mixing chamber 12 for this

10 purpose.

In place of a single mixing chamber, a preferred system to mix the carbonate and acid solutions is shown in FIGURE 3. To generate a bicarbonate-containing dialysate containing about 35

15 milliequivalents of sodium bicarbonate per liter, an aqueous sodium carbonate solution (about 3.8 g/liter) is flowed through line 110 at the rate of about 500 ml/min. with a portion thereof, preferably about 450 ml/min. passing upwardly through line 112 into

20. reservoir 113 and another portion, preferably about 50 ml/min. continuing through line 114 and then upwardly through line 116 into reservoir 117. Valves 118 and 119 in lines 112 and 116, respectively, are used to balance the flow of aqueous sodium carbonate

25 solution into the two reservoirs preferably in a ratio of about 9:1.

The sodium carbonate solution passing through line 112 into reservoir 113 passes first into sparger 121 comprising a tube, centrally located in 0 the reservoir, closed at its upper end and containing side performations which propel incoming solution into the body of fluid contained in the reservoir. Reservoir 117 contains a similar sparger 122 for similar introduction of the sodium carbonate solution 5 from line 116.

_/ yξ\_ RE

OMP ^"

The aqu-jus a.. σ solution, containing hydrochloric acid (about 1.4 N) and other dialysate components is introduced through the closed upper end of reservoir 113 through line 111 at a flow rate of about 14 ml/min. The flow of acid through line 111 is stoichiomet ic to the flow of sodium carbonate solution through line 110 but is in excess of that needed to convert all of the sodium carbonate flowing into reservoir 113 to sodium bicarbonate. Under the conditions prevailing in reservoir 113, the half life of the sodium carbc ate in ^~ . oduce therein i' bou- 15 r ites. ^~~ .eseι ir 113 preferabl ~ s to vide res. :ce t. ^" of out one .f J te aboi hret .lf-li s) for :e aqueou . sodi...*. carbonate s* ition introduced .erein and constitutes the first conversation stage. Thus, about 89 to 90% of the sodium carbonate introduced into reservoir 113 is converted to sodium bicarbonate before the bicarbonate-containing liquid stream flows out of the reservoir 113 and into reservoir 117 through line 124.

The solution in reservoir 113 (first stage) remains acidic because some of the hydrochloric acid introduced remains unreacted. In a subsequent stage ^.hat includes reservoir 117, where the remaining, nreacted sodium carbo e portion is introduced, the esidence time is abou he same as in the first itage (reservoir 113) ; further conversion of sodium carbonate to soc am bicarbonate takes place, preferably a further 10-fold reduction in the carbonate concentration. In this manner an overall, conversion of sodium carbonate to sodium bicarbonate of about 98 to 99 percent is obtained. In the foregoing embodiment, under the conditions prevailing in reservoir 117 the pH never rises above about 7.4,

and calcium carbonate is not formed in sufficient quantity to come out of solution.

The produced bicarbonate-containing dialysate is conveyed through line 17 to a suitable hemodialysis apparatus, not shown.

It will be understood that more than the two stages above may be provided, if desired. It does not require the presence of well-defined holding vessels or reservoirs, but may be provided by an extended flow path such as in a coiled pipe. The average residence time in each carbonate conversation stage should preferably be at least about 0.45 to 0.6 minutes. Preferably, at least about 80% of the total sodium carbonate flow should be directed to the first stage and the remainder to each subsequent stage. In determining the residence time in each stage after the first stage the volume of the lines connecting the stages has to be taken into account of course. Under some conditions, the acidity in reservoir 113 may be sufficient to decompose some sodium bicarbonate and produce free carbonic acid in the reaction mixture. The amount of carbonic acid produced, however, is well below the solubility limit for carbon dioxide at ambient temperatures; and no carbon dioxide bubbles will form. Any carbonic acid in reservoir 113 will be converted back to sodium bicarbonate in reservoir 117 at the relatively higher pH prevailing therein.

Since sodium bicarbonate is the preferred alkalizing material for minimizing side effects during hemodialysis, in accordance with the Graefe et al. article discussed above, the preferred acid solution for producing the dialysate is an aqueous hydrochloric acid solution which produces no sodium acetate. However, from the aforementioned chemical

reactions it can be seen that acetic acid produces equimolar amounts of sodium bicarbonate and sodium acetate; and acetic and hydrochloric acid mixtures produce even less sodium acetate. Such solutions are therefore preferable to the sodium acetate-alkalized dialysate solutions now used inasmuch as the concentration of acetate ion in the dialysate is minimized or completely obviated. The use of a small amount of acetic acid in combination with hydrochloric acid is helpful, however, for adjustment of the desired bicarbonate ion concentration when using a standardized system for the dialysis of patients some of whom may require different levels of sodium bicarbonate as discussed above. While conductivity measurement usually provides a good indication of bicarbonate ion concen¬ tration in the solution that is used for hemodialysis, it has been found that the conductivity of the aqueous bicarbonate solution formed as a result in mixing chamber 12 (FIGURE 1) passes through a minimum as the hydrogen ion activity of the bicarbonate solution decreases in the range of an apparent pH value of about 4 to about 6 and subsequently again increases. This is schematically illustrated in FIGURE 2. Inasmuch as dialysis is usually carried out at about physiological pH, and an acidic dialysate is not only undesirable from a therapeutic standpoint but may also damage the dialysis membranes, it is important to guard against a dialysate that is too acid.

To this end pH probe 13, (FIGURE 1) or a similar potentiornetric means for monitoring the hydrogen ion activity of the aqueous solution leaving mixing chamber 12, is provided downstream from mixing chamber 12 in addition to conductivity probe 14. pH Probe 13 provides an output that is indicative of

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hydrogen ion activity in the produced solution, and conductivity probe 14, in turn, provides an output that indicates the conductivity of this solution. Both of these outputs are transmitted to valve

5 control means 15 which is suitably programmed to energize by-pass valve 16 so as to divert to drain any portion of the produced bicarbonate solution when the value of the outputs of either probe 13 or probe 14 deviates from a set magnitude by a predetermined

10 degree. That is, under normal operating conditions an aqueous bicarbonate-containing dialysate is conveyed via conduit 17 to a dialysis cell (not shown), but a predetermined deviation in either pH or. conductivity will cause by-pass valve 16 to be

15. energized so as to divert the dialysate to drain via conduit 18.

Another preferred proportioning system embodying the present invention that may be used in conjunction with an existing dialysis machine so as

20 to utilize some of the machine components that are already present is illustrated in FIGURE 4. To this end, auxiliary unit 20 may contain the dispensing system for the aqueous carbonate solution together with the indicator and control means for the entire

25 proportioning system embodying this invention while a dialysis machine 21 may be equipped with the remainder of the necessary system components.

The functions performed by auxiliary unit 20 include metering of a controlled amount of 0 concentrated aqueous carbonate solution and combining the metered amount with conditioned water, monitoring of conductivity of the resulting dilute aqueous carbonate solution, monitoring the hydrogen ion activity or pH of the dialysate produced, and 5 protecting the patient against errors induced by

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equipment malfunction, improper starting solutions, and the like occurrences.

Auxiliary unit 20 includes carbonate concen¬ trate pump 22, a metering pump usually having a capacity of zero to about 50 milliliters/minute, and associated pump control means 24, mixing unit or tank 26, temperature-compensated conductivity probes 28 and 30, and appropriate indicators and controls in module 32, including, for example, a conductivity meter, a pH meter, various indicator lights, audio alarms, and the like. Carbonate concentrate pump 22 communicates with carbonate concentrate source 34 by means of flexible conduit 36 and functions to convey a concentrated aqueous carbonate solution to mixing tank 26 via conduit 37. The concentrated aqueous carbonate solution is diluted in mixing tank 26 with conditioned water supplied through flexible conduit 38 at a predetermined, substantially constant volumetric rate. The resulting dilute aqueous carbonate solution (about 28:1 dilution in case of sodium carbonate monohydrate solution) is then fed to proportioning unit 40 in dialysis machine by means of conduit 39. Conditioned water can be supplied, usually at a constant temperature of about 98°F. (37°C), to mixing tank 26 directly from an external source (not shown) by means of a separate pump means (not shown) via conduits 81, 82 and 38 which together with valves 83 and 84 form a continuous confined flow passageway for the conditioned water. Alternatively, and depending on the particular proportioning unit 40 that is installed in the dialysis machine 21, all or a portion of the total amount of conditioned water needed to constitute the dialysate can be passed through proportioning unit 40 with the amount needed for preparing a dilute carbonate solute being pumped

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to mixing tank 26 via conduits 85 and 86 upon appropriate setting of valves 83 and 84 while utilizing the pumping device or devices normally present in proportioning unit 40. Temperature-compensated conductivity probe

28 is provided associated with mixing tank 26 and controls operation of pump 22 to produce the diluted aqueous carbonate solution. Probe 28 provides an output signal that is received by pump control means 24 and regulates the rate of introduction of the concentrated carbonate solution into mixing tank 26. The purpose of this conductivity control loop is to maintain a substantially constant carbonate ion concentration in the diluted aqueous carbonate solution. Inasmuch as conductivity is a function of concentration as well as solution temperature, a temperature-compensated signal to pump control 24 is desirable. Preferably, all conductivity values are referenced to 98°F. (37°C). Alternatively, the signal or signals emanating from probe 28 can be first transmitted to control circuitry module 32 and then an appropriate signal transmitted to pump control means 24.

Conductivity probe 30 is also temperature- compensated and provides an output signal that is received by indicator and control circuitry module 32 which, in turn, provides a visual and/or audio indication of the conductivity of the diluted carbonate solution stream leaving auxiliary unit 21, and flowing to proportioning unit 40, for example. Additionally, module 32 is operably connected and supplies information to main control circuitry module 42 via cable 44. The redundancy afforded by a pair of temperature-compensated conductivity probes provides a further assurance that the diluted

carbonate solution fed to dialysis machine 21 for further compounding into a dialysate solution has the desired concentration at all times.

Stabilization chamber or tank 58 is provided between probes 28 and 30 in order to stabilize the diluted carbonate solution and also to provide a reserve supply. A chamber volume of about 250 cubic centimeters is usually adequate for this purpose; however, larger or smaller volume chambers can be used as required in any given instance.

Aqueous acid concentrate source 46 supplies the aqueous acid concentrate to proportioning unit 40 by means of flexible conduit 48. Proportioning unit 40 meters the diluted carbonate solution and the acid concentrate solution to provide a stream of each solution in a predetermined volume ratio, usually about 34:1, to mixing tank 50. The volume ratio may vary, however, depending on the type of proportioning unit used and the concentration of the diluted aqueous carbonate solution used in any given instance. In any event, each stream is supplied to mixing tank 50 separately, e.g., the dilute carbonate stream is supplied through conduit 52 and the acid concentrate stream is supplied through conduit 54. Deaeration pump 56 can be optionally provided in conduit 52 to remove any air that may be present in the diluted carbonate stream. If desired, the aqueous acid concentrate can also be diluted with conditioned water in proportioning unit 40 before being combined with the dilute carbonate stream.

Also, with some dialysis machines conduit 39 can lead directly to pump 56, and conduit 52 can be eliminated between proportioning unit 40 and pump 56.

Mixing tank 50 can be a vortex-type mixing chamber so as to rapidly achieve good and thorough

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mixing of the incoming streams. Preferably, however, mixing tank 50 is the system shown in FIGURE 3. From mixing tank 50 the combined streams are conveyed further- by means of conduit 62, equipped with air trap 59, to a dialysis cell (not shown) for use in a dialysis cell or unit as the dialysate for dialyzing a patient.

As pointed out above, it is important not only to monitor the conductivity of the dialysate but also the hydrogen ion activity thereof. For this purpose pH sensor 64 and dialysate conductivity probe 66 are provided downstream from dialysate mixing tank 50 and air trap 59. An output signal generated by pH sensor 64 can be transmitted to indicator and control module 32, and an output signal generated by dialysate conductivity probe 66 is transmitted to main control module 42. Alternatively, both of these output signals can be first transmitted to main control module 42 and appropriate information thereafter transmitted to indicator and control module 32 via cable 44. Depending on the type of pH sensor utilized, a temperature sensor-compensator may also be desirable for the pH sensor.

Inasmuch as the conductivity of an aqueous solution is a function of temperature, temperature probe 68 is provided in conduit 62 and generates an output signal indicative of dialysate temperature at the time the conductivity thereof is measured. The output signal from temperature probe 68 is also transmitted to control module 42 where it is integrated with the other received signals using appropriate circuitry, e.g., a suitably programmed microprocessor, or the like. Temperature probe 68 can be a thermistor, a thermocouple, or a similar temperature sensing device. The output signal from

temperature probe 68 can also be used to compensate the output signal from pH probe or sensor 64 as well as to regulate the heat input to the stream of conditioned water that enters the present system via conduit 81.

The output signal from pH sensor 64 can be further utilized to control the operation of carbonate concentrate pump 22 alone or together with the output signal from conductivity and temperature probe 28, as desired.

By-pass valve 70 is positioned in conduit 62 downstream of probes 64, 66.and 68 and is operably associated with control module 42 so that any deviation from normal operating conditions or dialysate characteristics will cause by-pass valve 70 to be actuated so as to divert the dialysate stream passing through conduit 62 to drain via drain passageway 72 and to interrupt the dialysate flow to a dialysis cell (not shown) . Turbidity detector 87 in drain passageway 72 serves to detect any undesirable precipitate that may be present. Detector 87 can be a conventional blood leak detector usually present in dialysis machines. The foregoing description and the accompanying drawings are intended as illustrative and are not to be taken as limiting. Still other variations and rearrangements of system components without departure from the spirit and scope of the present invention are possible and will readily present themselves to those skilled in the art.

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