Note: Descriptions are shown in the official language in which they were submitted.
~3~ 88
61253-6315
BACKGROuND OF THE INV~NTION
Field of the Invention
This invention lies in the field of fluid therapy
in humans, and more particularly in the field of aqueous
solutions for parenteral, oral, dialysis, and irrigation
therapy which employ at least one of l-lactate anions,
pyruvate anions, d- betahydrox~butyrate anions, acetoacetate
anions or mixtures thereof in combination with selected
cations.
Prior Art
Previously, I have provided improved electrolyte
solutions for _ vivo and in vitro usage wich conatain
l-lactate and pyruvate anions, and/or d-betahydroxybutyrate
and acetoacetate anions in respective defined ratios in
combination with defined Na:Cl rations. However, it is now
appreciated that the benefits of using l-lactate, pyruvate,
d-betahydroxybutyrate, and/or acetoacetate anions need not
be restricted by these previously taught relationships of
anion pair ratios to Na:Cl ratios.
Previously, only racemic mixtures of lactate anions
containing both d~ and 1- forms of lactate have been used in
aqueous solutions for human parenteral therapy. The other
major organic anion used in human parenteral fluids has been
acetate. So far as is now known, the natural 1- form of
lactate anion has heretofore never been used, apart from the
unnatural d- form, in human fluid therapy.
Sodium lactate solutions, used in pharmaceutical
practices, are not specified in terms of isomeric
structure. In the U.S. and British Pharmacopeias, lactate
is defined and approval was duly granted for use of the d,
l-lactate mixture. Hence, the d, 1 lactate is recognized to
be the physiologically predominant form which is metabolized
by different pathways and with different effects than is the
d-lactate.
The toxicity of d-lactate has been described in
humans (see Ch MS et al N. En~. J. Med. 301: 249-251, 1979;
Perlmutter, DH et al J. Pediatrics 102: 234-1348, 1982).
Thus, the d- form has now been discovered to cause adverse
and toxid effects when administered to mammals. For
example, when an aqueous 20 mM/l d-lactate (or d-lactate
acid) is administered parenterally to a rat, swelling of
brain tissue is observed because the brain takes in the
slowly metabolized d-lactate plus an equivalent of K+-
With continued administration, coma develops, the cerebraledema worsens and death ensues. In contrast, when l~lactate
is similarly administered, the differential concentration of
l-lactate between intracellular and extracellular fluid does
not cause coma or death. For another example, Veech et al.
(Veech, RL and Fowler, RC., "Cerebral Dysfunction and
Respiratory Alkalosis Duriny Peritoneal Dialysis with d-
Lactate Containing Peritoneal ~i.alysis Fluids". Am. 3.
Med., 1987 (in press)) points out that the severe recurrent
metabolic alkelemia described by Kenamond et al. ("Severe
Recurrent Alkalemia in a Patient Undergoing Continuous
Cyclic Peritoneal Dialysis". Am. J. Med., 548-550, 1986) was
secondary to an encephalopathy caused by the inclusion of
d,l-lactate in routine dialysis fluids. Because of such
encephalopathological results, parenteral solutions
containing the racemic d,l-lactate anions should not be
administered for therapeutic purposes.
All previous commercial formulations of fluids for
human therapy use lactate or lactic acid in the racemic d,l
form as defined in the United States or British Pharmacopeia
(see the United States Pharmacopeia 21st edition, January
1985,~p 581, 945-946, 1186; United States Pharmacopeia
Convention, Rockville, and British Pharmacopeia 1980, p 250,
666, 667, Her Majesty's Stationary Office, London). Sodium
d,1-lactate solutions are currently and conventionally used
for three major purposes in current medical practice.
First, sodium d,l-lactate solution is used parenterally as
an alkaliniziny agent to correct acidosis. Secondly, it is
used in parenteral fluid therapy to normalize the Na:Cl
ratio from the 1:1 ratio found in normal saline. Thirdly,
it is used as the counter ion in peritoneal dialysis
~304~;88
61~3-~315
solutions. In addition, it could also be used in current
hemodialysis to replace the acetate anlon, or, in its H form,
as an acid to be added to a blcarbonate hemodialysis fluid.
Prior to my own teachings, pyruvate anion~ d-
betahydroxybutyrate anions, and acetoacetate anions in aqueous
solution, so far as is now known, were never used in human
therapeutic fluids.
8~IEF SUMMARY OF THE INV~NTION
This invention relates to a process for aacomplishing
fluid therapy without encephalopathy or metabolic bone disease
and other complications resulting from use of present fluid
formulations in a living human involving the introduction into
the body of such human an aqueous solution con~aining at least
one permeant monoanionic metabolite selected from the group
consisting of l-lactate anions, pyruvate anions, d-
betahydroxybutyrate anions, acetoacetate anlons, or mixtures of
such anions.
The present invention therefore provides use of an
aqueous solution containing at leaat one anion species selected
from the group consisting of pyruvate in an amount so that the
concentration of pyruvate anions ln solution is in the range of
about .01 to 40 milllmoles per liter, l-lactate, d-
betahydroxybutyrate, acetoacetate, and mixtures thereof, and at
least one cation selected from the group consisting of sodium ,
potassium , magnesium 2 , calcium2 , hydrogen and ammonium+
and mixtures thereof, the total concentrakion of all of said
anions ln said solution being in the range from about 0.01 to
2400 millimoles per liter for ~luid therapy ln a human.
~ The invention further provi.des a commeraial package
comprising an aquèous solution containlng at least one anlon
species selected from the group conslstlng of pyruvate ln an
`~i
.
~30~ 8
612~3-~315
amount so that the concentration of pyruva~e anlons in solution
is in the range of about .01 to 40 millimoles per liter, l-
lactate, d-betahydroxybutyrate, acetoacetate, and mixtures
thereof, and at least one cation selected from the group
consisting of sodlum , potassium , magnesium 2 , calcium2 ,
hydrogen and ammonium and mixtures thereof, the total
concentration of all of said anions in said solution being in
the range from about 0.01 to 2400 millimoles per lit~r together
with instructions for use thereof in fluid therapy of a human.
The solutions o~ the invention may contain at least
one anion species comprising l-lactate or d-betahydroxybutyrate
or acetoacetate.
Here, l-lactate is de~ined as that form o~ lactate
anion found in mammalian tissues and designated l or L-lactate. -
It is identified by itæ ability to react with NAD to form
pyruvate in a reaction catalyzed by mammalian lactate
dehydrogenase (~C 1.1.1.27). The form of l-lactate which is
dextrorotatory in aqueous solution is designated 1-(+) while
the salts of l-lactate which in aqueous solution are
levorotatory are designated l-(-) lactate (see US Dispensatory.
Osol, A. Pratt, R. Gennar, AR, eds. p. 658. JR Lippcott,
Philadelphia, 1973). Pyruvate and acetoacetate have no
sterospecificity.
5a
~3~61!~1~
More particularly, this invention is directed to
improved methods and optionally stable fluids for
conventional administration to humans such as, (a) oral
ingestion of an aqueous solution containing at least one of
such anions, or a mixture of such anions, (b) parenteral
therapy involving, for example, the intravenous
administration of an a~ueous solution containing at least
one of such anions, or a mixture thereof, (c) dialysis
therapy (hemo or peritoneal) using aqueous solutions
containing at least one of such anions, (d) dialysis therapy
(hemo or peritoneal) where acetic acid is replaced with at
least one acid of the group consisting of l-lactate,
pyruvate, d-betahydroxybutyrate or acetoacetic acid,
preferably l-lactate, and/or (e) irrigation therapy.
One presently preferred such anion comprises 1-
lactate. Thus, surprisingly, encephalopathy, metabolic bone
disease, and many other complications are not only
completely avoided by using l-lactate (or one of the other
metabolite anions herein identified and used in the practice
of this invention) in place of racemic d-l-lactate, but also
the substitution of, for example, l-lactate for d-l-lactate,
in solutions employed in fluid therapy, does not cause any
change in the heretofore known beneficial physiological or
pharmacological effectiveness of such fluids.
In general, a solution containing at least one
such anion is administerable for generally the same purposes
that prlor~art parenteral fluids or dialysis fluids are used
which contain racemic d-l-lactate anions. For examples,
such a solution can be used to treat acidosis, dehydration,
blood electrolyte depletion, shock, malnutrition, uremia and
the like.
~046~
secause mixtures of l-lactate anions and pyruv~te
anions, and mixtures of d-betahydroxybutyrate anions and
equilibrium couples, which can vary widely in concentration
under normal physiological conditions. These anions can be
employed with little or no adverse side effects in
parenteral fluids and the like. Moreover, the therapeutic
use of these anion couples ~a tends to maintian a normal
plasma milliequivalent ratio of sodium cations to chloride
anions, (b) thus tends to prevent hyperchloremic acidosis,
and (c) accomplishes electrolye and fluid and resuscitation
thereapy. The anions taught by this invention permit one to
avoid the known untoward effects of high levels of the d-
lactate anion (see Veech, RL Fowler, RC, op. cited above) or
of acetate anion which are now the major organic anions
conventionally added to parenteral solutions on the
metabolism of cells: a hypothesis for physiological
parenteral therapy. Am J Clin Nutr 44: 519-551, 1986).
Other and further objects, aims, purposes,
features, advantagesl embodiments, applications, and the
like will be apparent to those skilled in the art from the
teachings of the present specification taken together with
the claims.
DETAILED DESCRIPTION
For the fluid therapy purposes of my present
invention, any conventional administration procedure is
~ ~ .
~o~
suitable, although parenteral (particularly intravenous)
administration duriny hemo or perikoneal dialysis i~
presently preferred.
For example, sodium l-lactate aqueous solutions,
which a~e stable and easily sterilized, can be used in
infusion fluids in place of sodium bicarbonate for treatment
for acidosis. For example, the bicarbonate may be ~issolved
immediately before use in the infusion fluid by light
agitation and preferably warmed to body temperature. In
such a replacement, 1 g sodium bicarbonate corresponds to
about 1.33 g sodium l-lactate, and 1 g sodium l-lactate
corresponds to about 0.75 g sodium bicarbonate. The
bicarbonate or l-lactate solutions are preferrably
administered diluted with glucose solution or distilled
water. The alkalizing action of sodium l-lactate is
diminlshed in severe liver damage since its breakdown is
retarded. See, for example, Documenta Geigy 6th ed, pp.
331-332, Geigy, Manchester, 1962.
In practice, the calculation of the quantity of an
alkalizinq infusion solution required for adults is based on
an average value for the water content of the body of 50% by
wsight and on a uniform intra- and extra-cellular
distribution of bicarbonate, l-lactate, d-
betahydroxybutyrate, and other aforementioned permeant
monovalent anionic metabolites. This method naturally
yields only rough figures. The calculation can be
simplified by reckoning in milliequivalents desired change
in the alkali reserve. For example, in order to increase or
decrease the alkali reserve in a patient weighing 70 kg by 5
mEq, a quantity of, ~or example, l-lactate, bicarbonate or
d-betahydroxybutyrate anions of 70x6x0.5 = 210 mEq must be
~L30ALlEi88
administered~ In order to avoid the danger of an acidosis
becoming converted into an alkalosisl it is advisable not to
attampt a complete normali~ation o~ the alkali reserve by
means o~ an alkalizing solution, and such solutions should
never be administered without supplementary potassium.
In children, a higher water content of about 66%
must be reckoned with, so that the calculation yields
relatively high infusion quantities. The differences
between the calculated and observed effects of alkalizing
and of acidifying compounds can be considerable since the
above approximate calculation ignores a number of important
factors.
In diabetic acidosis, many authors consider it is
inadvisable to administer large quantities of sodium salts
without potassium salts. On the other hand, extremely good
results have been reported in the intensive lactate
treatment of diabetic coma. There is no doubt that a
moderate alkali therapy with l-lactate and/or pyruvate is
indicated in diabetic ketosis with very much lowered alkali
reserve, since it has been shown that insulin activity is
inhibited by acidosis and that acidosis increases the blood
sugar. Clearly use of d-betahydroxybutyrate or acetoacetate
would not be suitable for use in diabetic ketoacidosis. As
those skilled in the art will also appreciate, the ketone
bodies would not be appropriate for use in pregnant women.
When using solutions such as "Lactated Ringer's" to
replete body water and electrolytes, the 28 mM d,l-lactate
of the prior art is replaced with, for example, 28 mM 1-
lactate. In this way, the Na:Cl ratio, in such an l-lactate
solutions, is moved, if desired, towards a normal ratio of
~` '
13[)~L61!~
1.36 as found in normal human plasma. Thus, hypercloremic
acidosis resulting from large infusions of normal sodium
chloride solutions is avoided. The same considerations
apply to use of such solutions in dialysis.
Alternatively, in all the present new solutions, d-
betahydroxybutyrate anions, for example, can be used
alterntively inplace of l-lactate anions. Additional
benefits may accrue from the use alternate or combined used
of pyruvate and acetoacetate.
A preferred application for this invention involves
usage of a mixture of anions of l-lactate and pyruvate, or a
mixture of anions d-betahydroxybutyrate and acetoacetate, as
indicated, in solutionsO Under special circumstances, use
of one or the other of such anions alone may be preferred,
such as in cases of severe reduction of the pyridine
nucleotide systems where administration of pyruvate anions
may be preferred. In conditions where long stability of
mixed a~ueous solutions presents a practical problem, use of
l-lactate of d-betahydroxybutyrate alone confers stability
on the solution and is to be preferred over the currrently
used dj l-lactate or acetate.
For one example, to correct an acidosis wherein a
70 kg man is 6 mEq below the normal plasma bicarbonate level
of 26-30 mEq/Lm then 70x6x0.5 or 210 mEq is infused wlth a
fluid of this invention containing bicarbonate anions and l-
lactate anions as described hereinbelow, over a 2 to 4 hour
period. Other dosages and rates of infusion may be used, if
desired, depending on the clinical situation.
~,` 10
'.,.
,
61253~6315
For a second example, a llter of 501utlon of the
colnposition oE the current l~inger's lactate may be lnfused
over a four hour period lnto a dehydrated 70 kg man with the
exception that ~he d, l-lactate used is replaced with 1-
lactate.
For a third example, the peior art accomplishment
o perltoneal dialysis by infusion into the peritoneum of 2L
oE a conventional d, l-lactate based or acetate based
peritoneal dialysis solution, is change in that the 35-45 mM
l-lactate. After remaining in the peritoneum for about 1/2
hour, the fluid is drained of~ and the process repeated
until the blood urea nitrogen (BUN) is decreased to the
level desired.
In parenteral therapy, the total concentration of
anions selected Erom the above indicated anion group, a
present preference being l-lactate, pyruvate, and/or
mixtures thereof, can range from about 0.01 to 2400
milllmoles per liter, though larger and smaller quantities
can be used depending upon circumstances. The rate of
introduction into a human patient, and the dosage used, are
generally the same as are conventionally used in solutions
containing, or example, d, l-lactate.
~ present preference ls to employ, for 1uid
therapy, an aqueous solutlon wherein the total concentration
of l-lactate or pyruvate anlons ranges from about 1 Molar to
1 milllmOlar. In a more preferred form, from about 28 to 45
millimoles ~total) of such anions are present (such as in an
lmproved ~inger's laotate or in lmproved peritoneal dialys~s
Eluids).
`~i
i~` ~
~L3~4~;88
Although a solution tauyht by the present
invention may contain either l~lactate or pyruvate alone, as
essentially the sole organic metabolic anion, a mixture of
l-lactate anions and pyruvate anions may also be used, an~
similarly a mixture of d-betahydroxybutyrate anions and
acetoacetate anions may be used. When such an anion redox
couple is employed, it is presently preferred to employ a
milliequivalent ratio of l-lactate anions to pyruvate anions
in the range from about 20:1 to 1:1, and a milliequivalent
ratio of d-betahydroxybutyrate anions to acetoacetate anions
in the range from about 6:1 to 0.5:1.
The l-lactic, pyruvic, d-betahydroxybutyric, an~
acetoacetic acids themselves as such, may be used. For
examplej such can be used in combination with aqueous
bicarbonate anions; for instance, in sodium bicarbonate
containing~solutions. Also, one can employ, in the starting
solutlons used in the processes of present invention~
aqueous solutions which contain, along with such metabolite
anlons a: taught in this invention, :t least one cation
selected from the group consisting of sodiuffl, potassium,
o:loium,~ magnesium, and ammonium. Preferably, from about
0.01 to 2400 millimoles per liter of such anions are
present.
~ Inorganic physiologically acceptable anions,
besides bicarbonate, may also be present, such as chloride,
pho:phat:, and~sulfate, if desired, and if such are present,
the re:pective ~uantities present are preferably similar to
; corresponding phy5iologic levels. A difference between the
total millie~uvalents of the cations present in a solution
a~d the total milliequivalents of the organlc anions of the
specified gFOup employed in the practice of this invention
12
~: :
~309LS~8
~l-lactate, pyruvate, d-bet~hydroxybu~yrate, and
acetoacetate) can be provided by other physiologically
acceptable anions.
It is considered to he physiologically
advantageous and it is generally preferred in the practice
of this invention, to maintain the levels o~ the respective
organic metabolite anions employed at values which are
approximately physiologic. Also, when a mixture of the
monocarboxylic metabolic anions is employed in a given
solution, it is not necessary to employ redox couple anion
pairs since this use of these defined monocarboxylic
metabolite anions does not produce the toxic effects
resulting from the present use of d,l-lactate or acetate.
Further, it appears to be desirable to employ such anionic
metabolites in combination with bicarbonate anions in
conditions where large volumes of fluid are to be used and
administration of calories is not desired, such as in
peritoneal dialysis.
Additionally and preferably, such a solution may
contain dissolved therein at least one osmotically active,
substantially nonionic substance in accord with, for
example, teachings for prior art d,l-lactate and acetate
containing solutions. Examples of suitable such nonionic
substances include glucose (preferred), fructose, glycerol,
sorbitol, and the like. Typically, and preferably, such a
solution has an osmolarity ranging from about 240 to 2400
mOsmoles/liter.
In addition, formulations containing ionic
nutrients, such as 1- amino acids, can benefit from the
addition of at least one of the metabolite monocarboxylic
acid anions taught herein. For example, the acetate anions
13
.13q:~46131S
present in current commercial aminoacid formulations (which
lead to metabolic bone disease) can be replaced by sùch
anions. See, for example, my copending Canadian Patent
application Serial No. 525,697, filed Dec. 18, 1986.
Also preferably, a starting solution used in the
practice of this invention has a pH in the range from about
S to 9, although for the contemplated human usage, a most
preferred pH is about 7.4.
Thus, and as indicated above, such a solution can
additionally contain bicarbonate anions. The pH of the
resulting solution is adjustable to a desired value, such as
a preferred value in the range from about 6 to 8.4. by the
addition of the hydrogen form of at least one acid selected
from the group consisting of l-lactic. d-betahydroxybutyric,
acetoacetic, and pyruvic in an amount sufficient to give
such desired value. For example, when an anion of an acid
such as l-lactic acid, pyruvate acid, d-betahydroxybutyrate
acid, or acetoacetic acid is to be added to a bicarbonate
containing starting solution, a desired pH of such solution
for use in human hemodialysis, or the like, is given by
following the formula:
P-~ = Px2~ - lc~ ~C03 1 _
2([~C03 ~-[HA~) 2
where:
HA is the concentration of carboxylic acid in moles/liter,
` A 14
~304688
61253-6~15
pKa, = 6.10 at 3~ ~see ilastings, AB, et al., J. siOl. Chem.
79:183-192, 192~).
In preferred appllcatlons of thl~ sort, ~uch a3
appllcations which can incorporate from 2~ to 40 nM/l IIC03 ,
about 2 to 9 nM/l l-lactlc, pyruvic, d-betahydroxy-
butyric acid and/or acetoacetatic acid may generally be
added. Such solutions are presently preferred for
perltoneal or hemodialysis over existing flulds containing
acetic acid or d, l-lactate because Oe ~he toxiclty of t
presently uscd aclds.
Optionally, carbon dioxide may additionally be
dlssolved in such a solutlon.
For purposes of practicing the present invention,
only when both l-lactate and pyruvate anions 3re present in
a milllequivalent ratio of from about 20:1 to l:l, and/or
both d-betahydroxybutycate and acetoacetate anions are
present in a milliequivalent ratio of rom about 6:1 to
0.;:1 are present in admixture in a starting solution, and
only when both sodium catlons and chloride anions are also
present in such a starting solution, then the
milliequivalent ratio of Na~ cation to Cl- anions is always
preferably below 1.24 or`above 1.6. Thus, the practice of
the methods of this invention does not require, in any given
starting solution, both members of a redox active, near-
equilibrium monocarboxylic acid couple; either member can be
use~ individually. Also, such practice does not require the
use of a narrowly specified range of Na+ to Cl
mllliequivalent ratlos (when such inocganic ions are both
presènt).
13~88
Thus, as taught herein, therapy (includiny
correction of acidosis, dialysis and/or fluid, electrolyte
or nutrient replacement, and the like) in accord with the
present invention can be accomplished through the use of any
one ox more of various anions herein taught in a starting
solution wherein the cations are selected from among
hydrogen, sodium, potassium, calcium, magnesium, and
ammonium.
However, in the practice of this ~nvention,
preferrably only one monoanionic permeant metabolite (1-
lactate, pyruvate, d-betahydroxybutyrate, and acetoacetate)
is present in a solution at any one time. Thus, improvement
in existing parenteral fluids can be achieved by use of 1-
lactate alone rather than d,l-lactate as is currently used,
for example, in ambulatory parential dialysis fluids. The
use of l-lactate in conjunction with other inorganic anions,
but in the absence of the unsta~le ketoacid pyruvate,
results in a fluid which has as long a chemical stability as
the currently used d,l-lactate, but avoids the toxic effects
resulting from the inclusion of the unnatural d-isomer.
Thus, for example, one class of solutions, which has
characteristically long shelf life and stability, contains
as ànions only l-lactate anions and/or d-betahydroxybutyrate
anions and lS termed herein Class I for convenience. This
class is particularly useful where long term fluid storage
is desirable. Another class of solutions, for example,
c~ntains as anions only pyruvate anions and/or acetoacetate
anions and is termed herein Class II for convenience.
Another class of solutions, for example, contains as anions
only a mixture of l-lactate anions and pyruvate anions, or
only a mixture of d-betahydroxybutyrate anions and
acetoacetate anions, which is use~ul when redox control is
desired, and is termed herein Cla~s III for convenience.
Table I illustrates various embodiments o~ such exemplary
classes.
:
~L3~
TABLE I
Range of Concentration in mMoles/Liter
Item No. component Class I class II Class ~II
1 l-lactate or
betahydroxy-
butyrate 0.01-2400
2 pyruvate or
acetoacetate 0.01-2400
3 l-lactate plus
pyruvate and/or 0.01-2400
d-betahydroxy-
butyrate and
acetoacetate
4 (cations) 10-5-10-9 10-5-10-9 10-5-10-9
(hydrogen)0 - 2400 0 - 2400 0 - 2400
sodium 0 - 2400 0 - 2400 0 - 2400
potassium 0 - 1200 0 - 1200 0 - 12bO
calcium 0 - 1200 0 - 1200 0 - 1200
magnesium 0 - 1200 0 - 1200 0 - 1200
ammonium 0- 10 0 - 10 0 - 10
i304~i1~
Table II describes ~our classes of physiologic
permeant monoanionic metabolite solutions suitable for each
of three major fields of application. The genus class is
described in Type A solutions of Table II, where d,l-lactate
was previously used, and such improved solutions are
suitable for use in treatment of certain forms of metabolic
acidosis. For oral or parenteral use in resuscitation or
the treatment of acidosis or severe fluid loss in diarrhea,
the milliosmolarity of the solutions can vary widely from
about 240 mOsmoles/L to 4800 mOsmoles/L. Prior art
hypertonic sodium chloride solutions or hypertonic Ringer's
lactate solutions have been widely used in resuscitation;
such solutions can be reformulated as Type A solutions of
this invention. Type B solutions of Table II are suitable
for rehydration, electrolyte replacement, and/or nutrition.
Type C solutions of Table II, are suitable for use as
peritoneal dialysis and hemodialysis fluids. Type D
solutions can be regarded as being similar in use to Type C
solutions, but such include the permeant monoanionic
metabolites in their hydrogen form in solutions which
contain bicarbonate so as to achieve a desired pH in a
manner which avoids the current toxic effects of high levels
of acetate or d,l-lactate. These class D solutions are
particularly suitable for use where it is desirable to avoid
high levels of monocarboxylic acids. By using normal
metabolites, these new fluids improve the corresponding
prior art fluids, such as Ringer's lactate, hemodialysis
fluids, and the like. With appropriate dosage, these fluids
are also suitable for oral inyestion, such as under
conditions requiring therapy where close patient monitoring
is not possible.
,j .
- -
~L3~)4688
For example, one can accomplish treatment o~
metabolic acidosis or resuscitation with improved sodium 1-
lactate or other Type A solutions as described in Table II.
For treatment of acidosis, initial parenteral administration
followed by oral administration is often preferred.
For example, one can accomplish parenteral fluid
therapy with improved l-lactated Ringer's-type solutions
(Type B) using the present invention in a human patient
suffering from fluid, electrolyte, and/or nutritional
depletion. Such a fluid may optionally contain non-ionic
dissolved nutrients, usually glucose, from 0 to 280
mmoles/liter.
For another example, one can accomplish dialysis
fluid therapy with an improved dialysis solution (Type C)
using the present invention in a living human patient. The
conventional techniques of hemo- and peritoneal dialysis
known to the prior art are employabIe with the improved
flulds of this type. Thus, the renal function of a living
human patient is replaced at least in part by passing the
blood~of the patient over one face of a dialysis membrane
while a dialysis fluid is passed over the opposite face of
such membrsns.
In hemodialysis, it is preferable to use a
dialysis solution of Type D containing from about 20 to 55
mM/l~of bicarbonate anions, such solution also contains a
sufficient portion of anions of at least one of said 1-
~:
lactate, pyruvate, d-betahydroxybutyrate, and/or
acetoacetate anions which are derived from the addition to
said solution of, respectively, at lea~t one of l-lactic
acid, pyruvic acld, d-betahydroxybutyric acid and/or
acetoacstic acid in a total amount which is su~ficient to
::::
.-
~3~q;8~
produce a p~ in the range from about 5.5 to 8.2, such
solution also has a milliosmolarity of from about 250 to 310
mOs/l.
Similarly, when peritoneal dialysis is being
practiced, a Type D solution containing bicarbonate can be
used and the carboxylic metabolite acid material(s) as above
described is/are (as the case may be) also present, but here
in an amount sufficient to produce a pH ranging from about
5.5 to 7.5. The milliosmolarity ranges from about 280 to
550 mOs/l achieved by disolution in such solution of
sufficient nonionic nutrients.
Type D solutions are also adapted for parenteral
administration, and for such purposes, a suitable
composition of Type D is similar to that above indicated for
peritoneal dialysis.
It will be appreciated that the designation mM and
mM/l are used herein in their conventional manner to
designate millimoles per liter.
)41~
TABLE II
Pre~erred Solutions (New)
units in mMoles/Liter solution
Component Type A(l) Type B(2) Type C(3) Type :D(4)
Cations
Na+ 0-2400130-160 130-145 130-145
K+ 0-60 2-10 0-4 0-4
Ca2+ 0-40.5-2.5 0.5-2.0 0-2
Mg2+ 0 30-1.5 0-1.0 0-1
Anions
Cl 0-200090-115 90-120 95-110
HC03 0-2000 0 0-40 20-55
Pi 1.8 0-50. 0 0
so4 0-1.2 0
d-lactate~ 0 0 0
acetate~ 0 0 0
l-lactate~ 0-24000-55 0-55 0-20
pyruvate~ 0-24000~55 0-55 0-20
d-betahydroxy-
butyrate 0-24000-55 0-55 0-20
acetoacetate~0-2400 0-55 0-55 0-20
Nonanionics
Glucose 0-2780-280 0-240 0-240
pH 5-8.26.0-7.5 5-8.2 5.5-8.2
:
22
4!~88
Table II Footnotes:
(1) ~he total amount of l-lactate, pyruvate, d-
betahydroxybutyrate, and/or acetoacetate anions present in
any given solution ranges from about 0.1 to 2400 mM with the
total number of indicated cations present being such as to
achieve electrical neutrality. However for most uses, 140-
160 mM of total cations and correspondingly 140-160 mM total
anions is preferred.
(2) The total amount of l-lactate, pyruvate, d-
betabhydroxybutyrate, and/or acetoacetate anions present in
any given solution ranges ~rom about 0.1 to 55 mM with the
total number of indicated cations present being such as to
achieve electrical neutrality. The milliosmolarity ranges
from 270 to 450 mOsmoles/~iter.
(3) The total amount of l-lactate, pyruvate, d-
betahydroxybutyrate, and/or acetoacetate. anions present~in
any given solution ranges from about 0.1 to 55 mM with the
total number of indicated cations present being such as to
achieve electrical neutrality. Such a solution preferably
also contains sufficient dissolved nonionics (such as
glucose) to produce a desired physiological milliosmolarity
from about 250 to 600 mOsmoles/Liter.
:(4) The total amount of I-lactate, pyruvate, d-
betahydroxybutyrate, and/or acetoacetate anions present in
any given solution ranges from about 0.5 to 20, and more
preferably~from about 1-10 mM with the total number of
indloated anions present being such as to achieve electrical
neutrality. Preferably for hemodialysis, such solutions has
a pH ranging from about 5.5 to 8.2. Optionally, the
quantity of nonionics dissolved in such solution is
sufficient to achieve ~rom about 280 to 540 milliosmoles per
~ 23
~041~8
liter when such solutions are used for peritoneal dialysis.
Such a solution has a pH ranging from about 5.5 to 7.5.
EMBODIMEMTS
` The following examples are merely illustrative of
the present invention and are not intended as a limitation
upon the scope thereof.
Examples 1-4
The following Table III illustrates particular
solutions of this invention:
24
~30~il!38
TABLE III
(Values are in mMoles/Liter)
Ex. No. Component Class I Class II Class III
1 l-lactate~l) 1000
Na~ 1000
.. . ... .
2 py+ruvate(2) 1000
Na 1000
3 1-lactate(3) goo
pyruvate 100
Na 1000
4 l-lactic acid 5
Table III footnotes:
(1) For treatment of acidosis see Merck Handbook p 1866
12th edition.
(2) ~or +reatment of acidosis_when severe reduction of
[NAD ]/[NADH] is present
(3) For treatment of acidosis when redox balance is desired
: (4) F~r use as ~n additive to a bicarhonate containing
.
Examples 5-12
Illustrative examples of various physiological
abnormalities which are treatable by using various starting
solutions of the present invention are shown in Table IV
below:
i
t
:
~ A
:::
:
-
13~
TABLE IV
Exemplary Usea~es
Condition Where Fluid Composi~ion Route of
Useful and Cation(s) Anion(s) Administration,
solution common in mMoles/liter and Dose
name
5. Dehydration Na+ 130 Cl 109 Parenteral,
(L-lacta~ç~ K+ 3 l-lactate28 500 ml to 3
Ringers)~l) Ca2+ 1.5 liters per day
depending on
severity and
cause
6. Peritoneal Na+ 141 Cl 101 Intraperitoneal,
Dialysi~s Ca~+ 1.75 l-lactate 45 4 to 8, 2 liter
(Dianeal~2J w/1.5% ~2+ 0.75 bags per day
Dextrose, Travenol)( (also dextrose 83)
7. Metabolic Na+ 156.1 l-lactate 156.1 Parenteral br
Acidosis oral, 10 ml to
(Isotonic sodium lL depending on
l-lactate solution)(4) size of patient
8. Cardiac Reper- Na+ 145 Cl 115 Intracoronary
fusion Fluid (5) Ca2+ 0.5HCO3 25 infusion after
M~2+ 0.75 pyruvate 11.5 cardiac arrest
K 4
(also glucose 10 and
C2 1.2)
9. Dehydration a(~ Na+ 120.2 Cl 104.7 Paren~8 al or
Potassium Loss K+ 36.2 1-lactate 51.7 oral ( ~.
in Diarrhea, Keto- (may be diluted with
acidosis or Stress 2 volumes of 278 mMolar
(Improved ~arrow's glucose for pediatric
Solutlon)( J use)
lO. Hemodialysis N+a+ 135 Cl 106.5 Hemodialysis
with Bicarbonate K 2 HC03 33 without un-
and l-~actic Ca2++ 1.5 l-lactic physiolocal
acid ( I Mg 0.375 acid 2 levels ~0)
11. Electrolyte Na+ 140 Cl 103 Alternative to
Replacement K* 10 l-lactate 27.5 Fox~s acetate
HBDH-Ringer~s Ca2+ 2.5 d-betahy- 27.5 Ringer's
Mg 1.5 droxybutyrate for electro~y~e
replacement~ J
26
~3~)468 !3
Table IV ~ootnotes
(1) Hartmann AF. Theory and practice of parenteral fluid
administration. JAMA 1934; 103: 1349-1354,
(2) Dianeal is a trade mark of Travenol Laboratories,
Deerfield Illinois
(3) Facts and Comparisons. St. Louis: JB Lippincott, oct
1981-Aug 1983: 35d-53.
(4) Essellier AF, Jeanneret P. Agueous solutions -
parenteral infusion therapy. Documenta Geigy 6th edition.
Manchester: Geigy, 1962: 324-334
(5) The period of reperfusion of heart following, for
example coronary by pass can be critical and may result ih
permanent heart damage due to excessive calcium loading.
Pyruvate is the preferred substrate for heart under these
conditions giving maximal efficiency of cardiac work over
either glucose plus l-lactate or ylucose alone (See Kobayshi
K, Neely JR. The control of maximum rates of glycolysis in
rat cardiac muscle. Circ Res 1979; 44: 166-175.
(6) Essellier AF, Jeanneret P. Aqueous solutions -
parenteral infusion therapy. Documenta Geigy 6th edition.
Manchester: Geigy, 1962: 332-333
(7) Darrow and Pratt. JAMA 1950; 143: 365-ff and 432-ff.
(8) Martin et al. JAMA 1951; 147: 24-ff.
~9) 5ee Table XI, Prior Art Hemodialysis Fluids. WO 86/00227
(lO) Blood acetate levels above the physiological level of
0.2 mM~are associated with metabolic bone disease. Veech RL.
Am J Clln Nutr 44: 544, 1986.
(11~ Fox CL. JAMA~1952; 148: 827-833.
~ 27
-
~3~4~
It is to be understood that the invention is not
limited to the features and embodiments hereinabove
specifically set forth, but can be carried out in other ways
and manners without departure from its spirit,
28
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