Note: Descriptions are shown in the official language in which they were submitted.
6~
--1--
SYSTEM FOR BICARBONATE DIA~YSATE
DESC~IPTION
Field of the Invention
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
s~mi-permeable membrane.
~9~9~=
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 accomp!ished 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 tlle patient'~ blood to
the dialysate.
Dialysis is literally a life-saving process;
however, sometimes undesirable side effects such as
hypotension, fati~ue, nausea, and the like, are
encounteredO 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. r
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 probo
lems, as well as problems encountered by precipitate
~ormation when calcium and/or magnesium salts are
.
,
.
;9~i6
also present in ~he dialysate, sodium acetate was
substituted for sodium bicarbonate as an alkaliziny
agent more than fifteen years ago. Even today
dialysis solutions usually contain sodium acetate as
the alkalizing agentO Sodium acetate solutions are
more easily maintained than sodium bicarbonate
solutions in a state of sterility; sodium acetate
being subsequently metabolized in ~he bloodstream to
sodium bicarbonate.
~owever, with the increasing acceptance and
use of large surface area dialysis equipment, see
Babb et al., TransO AmerO Soc. Artif. IntO Organs
VIIo81-91 (1971), evidence is accumulating that the
increased transfer o 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 thepatients 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 o~ bicarbonate ions is
generated ~fter dialysis, producing alkalosis.
Rirkendol et al., TransO Am. SocO Artif. Intern.
Organs XXIIIo 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
--3--
of Internal Medicine 880332-336, 1978, disclose that
sodium bicarbonate-containing dialysate fluid
produces less nausea, headache, vomiting, post-
dialysis fatigue, hypo-tension, disorientation and
S dizziness than sodium acetate-containing fluid, when
used in a high-efficiency 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 QUt above, sodium bicarbonate solutions
present practical problems because these solutions
are not bacteriostatic and thus may present sterility
problems.
Aqueous sodium bicarbonate solutions, unlike
20 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 prolif~rate in sodium bicarbonate
solutions; and inrec~ion of the patient is thus
possible when there is even a m:inor and inadvertent
: departure from s~erile technique in ~he handling of
the dialysis process.
~: Summary of the Inven~ion
: The present invention permits the in situ
preparation of a bicarbonate-containing dialysate
suitahle for use in a dialysis machine from bacterio-
static starting solutions and also contemplates a
proportioning system for such preparation. In the
propor~ioning system, an aqueous hydrochloric acid-
containing solution and an aqueous carbonate-ion
.
.
'' ~ .
:
~6~
containing solution are combined, and the
conductivity as well as the hydrogen ion activity of
the produ~ed, bicarbonate-containing dialysate is
monitored.
Thi~ 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 li~uid prior to use is
avoided, rather the sodium bicarbonate is prepared in
~itu in a desired concentration shortly be~ore the
dialysate liquid contacts the dialysis membrane.
The formulation of sodium bicarbonate by the
reaction of sodium carbonate witA hydrochloric acid
or acetic acid is a well known chemical reaction
which proceeds by the following equations:
Na2C03 + ~C1 ~ NaCl ~ NaHC03
Na2C03 ~ HAc ~ NaAc + NaXCO
: ~ 3
\ (by metabolism)
NaE~C03
Aqueous acetic acid solutions are
bacteriostatic and self-sterilizing, and therefore
contaminant-free prior to blend.ing 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, a~ueous sodium
carbonate solutions having a sodium carbonate
concentra~ion o less than about 20 grams per liter
of solution (calculated a~ anhydrous Na2CO33 axe
capable of supporting bacterial growth. Such dilute
aqueous sodium carbonate solutions can be used to
~66~
generate sodium bicarbonate in 5itU when freshly
prepared; however, ~hese dilute solutions are not
sui~able for extended storage and shipment from a
manufacturing facility to the intended end use
S 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
solu~ion 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 uni~s that are suitable as
unitary dosages for each dialysis se~sion, each unit
containing a predetermined quanti~y calculated to
produce the desir~d therapeutic effect when diluted
and combined to produce a hemodialysis dialysate.
The preferred unit dosaye 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 2U 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 oncentrate, a source of
physiologlcally 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 potentlometric means for monitoring
hydrogen ion activity in the produced dialysate and
15 providing an output indicative of the hydrogen ion
activity (e.g~, a pH probe or meter3 7 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 ~o interrupt normal flow of the
produced dialysate when the value of either of ~hese
outputs deviates from a set magnitude by a
predetermined amount.
~ Drawin~
In the drawings-
FIGURE 1 is a block diagram illustrating asystem embodying the present inven~ion;
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
i
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 Preerred Embo~iments
To prepare a dialysate, ~he concentrated
bacteriostatic sodium carbonate solution is first
diluted with water, preferably deionized or ~empered
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 ~olution~
and that can form insoluble carbonates. The
lS bacteriostatic~ concentrated sodium carbonate
solution can contain sodium carbonate in an amount of
about 2Q 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
hermetlcally 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 dialysa~e compounded using
the aforementioned bacterio~tatic sodium carbonate
solution~ Prolonged existence of sodium bicarbonate
in the dialysate liquid prior to use is avoided;
~6~;~3~i~
--8~
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 proportiGning 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 ~ay 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. ~owever,
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 dialy ate solutions now
used inasmuch as the total concentration of bi~ar-
bonate ion in the patient9s 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
ac.id, will produce the desired amount of sodium
S bicarbonate for the patients who have the minimum
level requirement for bicarbonate ionsO For patients
with bicarbonate ion requirements above the minimum~
the necessary difference in bicarbonate ion require-
ment can ~hen be readily supplied by substituting
acetic acid for part of the hydrochloric acid while
using the ~ame 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 immediately 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 solutiorl may be selected to
produce 30 or 35 milliequivalenl:s of sodium
:~ bicarbonate ion per liter when l:he sodium carbonate
is diluted and then reacted with hydrochloric acid.
For patients requiring minimum sodium bicarbonate
~:~ levels the standard sodium carbonate solution would
be reac~ed wi~h an aqueous acid solution containing
only hydrochloric acid.
For other patients who mi~ht 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 substitu~ing acetic acid for the
hydrochloric acid equivalent of five milliequivalents
.~ .
~6~
--10--
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
tnat are reacted.
The amounts of other constituents of the
dialysate fluid desired for proper electrolyte
balance, e.g., NaCl, KCl, CaC12, MgC12, etc. are
based on clinical requirements. These salts may be
dissolved in the concentrated acid-containing
solution, or may be supplied as a third soluti~n, as
desired.
The aqueous acid concentrate solutions
within the purview of the present invention can be
prepared by dissolving the solid salts in water,
pre~erably deionized or ~empered water, and adding
hydrochloric acid~ The relative amounts of constit-
uents are selected so as to provide in ~he concen-
trated solution a chloride ion concentration of abo-lt
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 2Ø
Additionally, the aqueous acid concentrate
can contain the acetate group in a concentration up
~166~?~
to about 0.52S Molar, preferably in a concentr~tion
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 ~he 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 ~o
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) wat:er, e.g., tempered
water. Preferably, the sodium carbonate concentrate
and the tempered water are first combined; and the
~; dilu~ed 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
~3l~;i6~G~
2 -
the three liquid streams may be calcula~ed and
controlled by a suitable computex ox 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. PreEerably both the
conductivity and the pH of the obtained dialysate are
monitored.
It has been determined that a sodium
~icarbonate level of 35 milliequivalents per liter
usually is suitable for patients having a minimal
alkalizing re~uirement in their dialysate fluid. To
ohtain this level of sodium bicarbonate in the final
dialysate solution (after reaction with hydrochloric
acid and dilution), a standard~ bacteriostatic
concentr~ted 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 t to adjust bicarbonate
and pEI 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 ~ollowing Table.
HCO3 ionsHCl ~11.6N) HAc ~17.4~)
30Required ml/l ml/l
90.6 0
105.7
90.6 10.05
4~ 75.5 20.10
60.4 30.15
.: ~
In some instances it may be desirable to add hydro-
chloric acid in an amount that slightly exceeds the
stoicniometric 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 millie~uivalent per liter; and potassium
chloride dissolved in amounts of 0, 2~g2~ ~.85 and
8~76 grams produce potassium levels of 0, 1, 2 and 3
~ 20 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 provicling 40 milliequiva-
lents of bicarbonate ion, overall sodium levels of
130, 135 and 140 millie~uivalent:s per liter,
respectiYely~ can be obtained.
To produce a typical inal dialysate stream
of about 500 milliliters 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
,
.
696~
-14-
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-
S containing solution should be added only to khediluted 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 37C. (about 6000 micromhos per centi-
meter ancl 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 in~errupted due to equipment malfunction or for
some other reason.
Other illustrative concentrate compositions
for in situ generation of a sodium bicarbonate
dialysate are il1ustrated below.
6 ~ 6 6
-15-
To produce a dialysate having a pH of 7.2 to
7.4 and containing the constituents
Na 140 mEq/liter
HC03 35 mEq/liter
Cl 109 mEq/liter
Ca++ 3.5 ~q/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
HCl (11~6N~127.7 ml/liter
CaC12 2H2g.26 grams/liter
(mol.wt. 147.0)
9C12-6H2~1.83 grams/liter
~mol.wt. 203.3)
is preparedO The bacteriostatic aqueous sodium
. .
carbonate concentrate that is diluted 36-fold and
combined with the foregoing: acid concentrate after
approxlmate dilution contains 169.64 grams of
20: Na2C03-H20 (mol. wt. 124.01):p~.r lite~ which is
equivalent ~o abou:t 145 grams pier liter calculated on
the basis of anhydrous sodium c~arbonate~
The foregoing sodium carbonate concentrate
: can also be used at a 36-fold dilution to provide:a:
~dialysate having a~pEI o 702 to 7.4 and the following
: composition:
Na+ 140 mEq/liter
i::
3 35 mEq/liter
C2H302 5 mEq/liter
: :30 ~ Cl 104.5 mEq/liter
~ Ca ~ 3.~ mEq/liter
: ~ Mg~ O.5 mEq/liter
In the~latter case, the aqueous acid
35: conGentrate, again to be diluted 36:1, has the
-~ ollowing composition:
:,
.::
:: :
, ,
~66~3~;~
-16-
NaCl (mol.wt. 58.45) 13~.67 grams/liter
HCl (11.6N) 112.3 ml/liter
CH3CO2H (glacial) 10.2 ml/liter
Ca~l2o2H2O 9.26 grams/liter
(mol.wt. 147.0)
M9C12 6H2 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 s aled up or down accordingly within
their respective solubility limits.
Typical aqueous acid concentrate 501u-
tions suitable for the prepara~ion of hemodialysis
dialysate are illustrated below.
Preparatlon I
: NaCl 1~1 grams/liter
HCl (11.6 N) 122.6 ml/liter
KCl 10.5 grams/liter
~: 20 dextrose 70 grams/liter
water q~s.
Cl 3~804 Molar
Na 2.241 Molar
K 0.1403 Molar
dextrose 0O3532 Molar
'
Preparation II
NaCl 131 grams/liter
: HCl (11.6 M) 119 ml/liter
KCl 10.5 grams/liter
: dextrose 70 grams/llter
~: water ~.s.
Cl 3.7~2 Molar
Na+ ~241 Molar
K+ 0~1408 Molar
dextrose 0~3532 Molar
~17~
c~ t i ~
NaCl 159a6 grams/liter
HCl ~11.6 N) 98.7 ml/liter
KCl 10.5 grams/liter
dextrose 70 grams/liter
water q,g.
Cl 4.016 Molar
Na~ 2.730 Molar
K+ 0.1408 Molar
dextrose 0.3532 Molar
r ~
NaCl 159 ~ 6 grams/liter
: 15 HCl tll.6 N) 93.9 ml/liter
KCl 10.5 grams/liter
dextrose 70 grams/liter
Cl 3.961 Molar
Na+ 2.730 Molar
K+ 0.1408 Molar
dextro~e 0.3532 Molar
Preparation V
NaCl 134.67 gramsJliter
~5 HCl ~11.6N) 12707 ml/liter
. ~
CaC12 2H2 9.25 grams/liter
MgC12 ~2 1.83 grams/liter
: Water q.s.
Cl 3~857 Molar
: 30 Na+ 2.304 Molar
Ca+~ 0.06299 Molar
Mg 0.009001 Molar
., i
\
-18-
Pre~aration VI
NaCl 134.67 grams/liter
HCl (11.6N) l12.3 ml/liter
CH3GO2H (glacial) 10O2 ml/liter
CaC12 2H2 9.26 gramsjliter
M9Cl2 6 H2O 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.,
- Ba~illus cereus, Pseudomonas stutzeri as well as
yeasts, molds, and members of 5erratia and ~
OCOCCU9. In particular, sample~ of tbe concentra~ed
solutions were challenged by introducing about 1000
~: bacteria o 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 mem~er of ba~teria and
~ ~ periodically checked for growth to determine that the
; bac~eria used in each instance were viable (a
~: positive growth control). Additionally, an aliquot
of each solu~ion 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
bicarbona~e performed in the foregoing manner showed
that such solutions will support the growth of
yeasts, molds and Pseudomonas.
,. :::,, :,
19
The bacteriostatic proper~ies of the aqueous
sodium carbonate concentrate compositions embodying
the present invention are urther illustrated by ~he
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 solutions 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 ali~uots 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 concentrated
aqueous sodium carbonate solutions and are tabulated
in Table I, below.
~66~
--20--
TABLE I
RESULTS OF 50DIUM CARBONATE CONCENTRATE STUDY PROTOCOL
INCUBATI ON TIME
Day 1 Day 3 Day 7 Day 14
CONTROL
P. STUTZ. - - - -
SERRATIA
STAPH .
C . ALBI CANS - - -
MOLD - - - -
B. CEREUS
_ _
CONTROL
P. STUTZ. -- -- _ _
SERRATIA - - - --
STAPH .
C ~ ALBICANS
o MOLD
B. CEREUS - - -
E~ CONTROL
P. STUTZ.
E~ ~ SERRATIA - - - -
~ ~; STAPH. ~ -- ~
C) C . AI~BICANS
;~ ~D MOLD
B. CEREUS
CONTROL - - - -
P. STUTZ. - - - -
SERRATIA
STAPH~ - - -
C. ALBIC~IS
~ MOLD
L ~ B . CEREUS
o
u~ CONTROL - - - -
, ~ P. STUTZ. - - - _
SERRATIA - - - -
STAPH . - - -
O C. ~BICANS
o MOLD
B. CEREUS - - - -
CONTROL - -- - -
E~ P. STUTZ. + ~ + +
SERRATIA + ~ + +
x STA~PH. ~ + ~ +
~ C. ALBICANS + + + +
E-~ MOI.D ~ + ~ +
B. CEREUS ~ + + +
3~
--21~
To minimize the likelihood that the
presently contemplated bacterio~tatic aqueous sodium
carbonate solutions may freeze during refrigerated
storage or shipmentl an organic physiologically
acceptable freeæing 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 likej 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 illustxated in FIGURE
l~ An aqueous stream from carbonate source lO and an
aqueous stream from acid source 11 are combined in
mixing chamber 12. ~he carbonal~e source can be a
supply of a water-soluble, physiologically tolerable
alkali metal carbona~e, e.g., sodium carbonate in
anhydrous or hydrated form, dissolved in
physiologically tolerable water such as conditioned
water, e g., deionized wa~er, 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 o 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
a~etic acid in a predetermined ratio as prescribed by
~ ~6~
-22-
the attending physician~ Other constituents such as
sodium chloride, calcium chloride, magnesium
chloride, and the likel can also be dissolved with
the acid.
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
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
milliequivalents of sodium bicarbonate per liter, an
aqueous sodium carbonate solution (about 3.8 g/li~er)
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/mîn. continuing through line 114 and then
upwardly through line 116 into reservoir 117r Valves
118 and 119 in lines 112 and 116, respectively, are
used to balance the flow of aqueous ~odium carbonate
solution into the two reservoirs preferably in a
ratîo of about 9:1.
The sodium carbonate solution passing
through line 112 into reservoir 113 passes first into
sparger 1~1 comprising a tube, centrally located in
the reservoir, closed at its upper end and containing
side perforations which propel incoming solution
into the body of fluid contained in the reservoir.
Reservoir il7 contains a similar sparger 122 for
similar introduction of the sodium carbonate solution
from line 116.
~6~
-23-
The aqueous acidic solution, containirlg
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 stoichiometric to the flow of sodium carbonate
solution through line I10 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 carbonate introduced
therein i5 about 0.15 minutes. Reservoir 113
preerably is sized to provide a residence time of
about one-half minute (or about three half lives) for
the aqueou~ sodium carbonate solution introduced
therein 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
that includes reservoir 117, where the remaining,
unreacted sodium carbonate portion is introduced, the
residence time is about the same as in the first
sta~e (reservoir 113) and further conversion of
sodium carbonate to sodium 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 9B to 99 percent is obtained. In the
foregoing embodiment~ under the conditions prevailing
in reservoir 117 the pH never rises above about 7.4,
6~ ~ 6
-24-
and calciu~ carbonate is not formed in sufficient
quantity to come out of solution~
The produced bicarbonate-containing
dialysate is sonveyed through line 17 to a suitable
S hemodialysis apparatus, not shown.
It will be understood that more ~han 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
minutesO Preferably, at least about 80% of the total
sodium carbonate flow should be directed to the first
stage and the remainder to each subsequent stageO 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 ree 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. ar~icle discussed above, ~he preferred acid
solution for producing the dialysate is an aqueous
hydrochloric acid solution which produces no sodium
acetate. However, from the aforementioned chemical
,.. ~ ~ ,
25--
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 solu~ions 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.
W~ile 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 abou~ 6 and
subsequently again increases. This i5 schematically
illustrated in FIGURE 2. Inasmuch as dialysis is
usually carried out at abou~ physiological pH, and an
acidic dialysate is not only undesirable from a
therapeutic standpoint but may also dama~e the
dialysis membranes, it is important to guard against
a dialysate that is too acid~
To this e~d pH probe 13, (FIGURE 1) or a
similar potentiometric means for monitoring the
hydrogen ion activity of the aqueous solution leav~ng
~ixing chamber 12, is provided downstream from mixing
chamber 12 in addition to conductivity probe 14. p~
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 ou~puts are transmitted to valve
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
degree~ That is, under normal operating conditions
an aqueous bicarbonate-containing dialysate is
conveyed via conduit l7 to a dialysis cell ~not
shown), but a predetermined deviation in either pH or
conductivity will cause by~pass valve 16 to ~e
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
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 carb~nate solution together
with the indicator and control means for the entire
proportioning system embodying this invention while a
d i a ly s i s mach ine 21 may be equ ipped witll the
remainder of the necessary system components.
The functions performed by auxiliary unit 20
include metering of a controlled amount of
concentrated aqueous carbonate solution and combining
the metered amount with conditioned water, monitoring
of conductivity of ~he resulting dilute aqueous
carbonate solution, monitoring the hydrogen ion
- activity or pH of the dialysate produced, and
~ 35 protecting the patient against errors induced by
~ .0
-27-
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
2G, temperature~compensated conductivity probes 28
and 30, and appropriate indicators and controls in
module 32, including, for example, a conductivity
meter, a p~ 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 ~onstant
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 98F.
: 25 (37C.), to mixing tank 26 directly from an externa~
source (not shown) by means of a separate pump means
(not shown) via conduits 81, 82 and 38 ~hich together
with valves 83 and 84 foxm 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 wa~er
needed to ~onstitute the dialysate can be passed
through proportioning unit 40 with the amount needed
for preparing a dilute carbonate solute being pumped
:
.
-28-
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 ~o
maintain a substantially onstant carbonate ion
concentration in the diluted aqueous carbonate
solution. Inasmuch as conductivi~y 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 98F. (37C.).
Alternatively, the sigilal 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-
2S compensa~ed 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
35 provides a further assurance that the diluted
i. ~
~6~
_~9
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 ade~uate 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. Proportionlng 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. ~n 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 1:hrough 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. :[f 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 5Q 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 comblned streams are conveyed
further by means of conduit 62, equipped with air
S trap 59, to a dialysis cell ~ot 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
; 10 also the hydrogen ion activity thereof. For this
purpose p~ 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 contr~l module 42. Alternatively, both of these
output signals can be first transmitted to main
control module 42 and appropriate information
tnereafter 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 conduc~ivity of an aqueous
25 solution is a function of temperature, temperature
probe 68 is provided in conduit 62 and generates an
: output signal indicative of dialysa~e temperature at
the time the conduc~ivity 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. ~emperature probe 68
can be a thermistor, a thermocouple, or a similar
ternperature sensing device. The output signal from
~ .
.'~ ~,,,
-31-
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
conditîoned 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 Erom 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
30 present themselves to those skilled in the art.
