U.S. patent application number 10/207114 was filed with the patent office on 2003-01-16 for fluid therapy with l-lactate and/or pyruvate anions.
This patent application is currently assigned to BTG International Limited. Invention is credited to Veech, Richard L..
Application Number | 20030013765 10/207114 |
Document ID | / |
Family ID | 27542005 |
Filed Date | 2003-01-16 |
United States Patent
Application |
20030013765 |
Kind Code |
A1 |
Veech, Richard L. |
January 16, 2003 |
Fluid therapy with l-lactate and/or pyruvate anions
Abstract
Electrolyte solutions are provided which are useful in
electrolyte and fluid therapy, parenteral nutrition and dialysis.
The Na:Cl ratio is normalized, plasma and cellular pH are
normalized and cellular cofactor ratios are normalized in a manner
which decreases toxicity over prior art solutions.
Inventors: |
Veech, Richard L.;
(Rockville, MD) |
Correspondence
Address: |
NIXON & VANDERHYE P.C.
8th Floor
1100 North Glebe Road
Arlington
VA
22201-4714
US
|
Assignee: |
BTG International Limited
|
Family ID: |
27542005 |
Appl. No.: |
10/207114 |
Filed: |
July 30, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10207114 |
Jul 30, 2002 |
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09917772 |
Jul 31, 2001 |
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09917772 |
Jul 31, 2001 |
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09433716 |
Nov 4, 1999 |
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09433716 |
Nov 4, 1999 |
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08179880 |
Jan 11, 1994 |
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6020007 |
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08179880 |
Jan 11, 1994 |
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07846081 |
Mar 5, 1992 |
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07846081 |
Mar 5, 1992 |
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06940333 |
Dec 17, 1986 |
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5100677 |
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06940333 |
Dec 17, 1986 |
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06810918 |
Dec 18, 1985 |
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06810918 |
Dec 18, 1985 |
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06748232 |
Jun 24, 1985 |
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4663166 |
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06748232 |
Jun 24, 1985 |
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06623102 |
Jun 22, 1984 |
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Current U.S.
Class: |
514/557 |
Current CPC
Class: |
A61K 33/00 20130101;
A61K 2300/00 20130101; A61K 33/00 20130101; A61K 31/19 20130101;
A61K 2300/00 20130101; A61K 33/00 20130101; A61K 33/06 20130101;
A61K 31/19 20130101; A61K 33/06 20130101; A61K 31/19 20130101; A61K
2300/00 20130101; A61K 33/14 20130101; A61K 33/06 20130101; A61K
31/19 20130101; A61K 33/06 20130101; A61M 1/287 20130101; A61K
33/10 20130101; A61K 33/10 20130101; A61K 33/14 20130101; C12N
5/0018 20130101; C12N 2500/12 20130101; A61K 33/06 20130101; A61M
1/1654 20130101; A61K 33/14 20130101; A61K 33/10 20130101 |
Class at
Publication: |
514/557 |
International
Class: |
A61K 031/19 |
Claims
I claim:
1. A process for accomplishing fluid therapy in a living human
comprising the step of introducing into the body of such human an
aqueous solution containing at least one anion species selected
from the group consisting of 1-lactate, pyruvate,
d-betahydroxybutyrate, acetoacetate, and mixtures thereof, the
total concentration of said anions in said solution being in the
range from about 0.01 to 1400 millimoles per liter.
2. The process of claim 1 wherein said introducing is accomplished
parenterally.
3. The process of claim 1 wherein said total concentration of said
anions ranges from about 1 to 1000 millimoles per liter.
4. The process of claim 1 wherein said anions present in said
solution comprise 1-lactate anions.
5. The process of claim 1 wherein said anions present in solution
comprise pyruvate anions.
6. The process of claim 1 wherein said anions present in said
solution comprise d-betahydroxybutyrate.
7. The process of claim 1 wherein said anions present in said
solution comprise acetoacetate.
8. The process of claim 1 wherein said anions present in said
solution comprise a mixture of 1-lactate anions and pyruvate
anions.
9. The process of claim 1 wherein said anions present in said
solution comprise a mixture of d-betahydroxybutyrate and
acetoacetate anions.
10. The process of claim 1 wherein said anions present in said
solution comprise a mixture of 1-lactate, pyruvate,
d-betahydroxybutyrate and acetoacetate anions.
11. The process of claim 1 wherein said solution contains at least
one cation selected from the group consisting of sodium, potassium,
calcium, magnesium, ammonium, and mixtures thereof, the total
milliequivalent quantity of such cations in said solution being
equal to the total milliequivalent quantity said anion(s).
12. The process of claim 1 wherein the cations present in said
solution comprise sodium.
13. The process of claim 1 wherein said solution contains at least
one of the following mixtures: (a) 1-lactate anions and pyruvate
anions in a milliequivalent ratio of from about 20:1 to 1:1, and
(b) d-betahydroxybutyrate anions and acetoacetate anions in a
milliequivalent ratio of from about 6:1 to 0.5:1, and further
contains sodium-cations and chloride anions, and the
milliequivalent ratio of sodium to chloride in either below 1.24 or
above 1.6.
14. The process of claim 1 wherein said introducing is accomplished
by irrigation.
15. The process of claim 1 wherein said introducing is accomplished
by hemodialysis.
16. The process of claim 1 wherein said introducing is accomplished
by peritoneal dialysis.
17. The process of claim 1 wherein said introducing is accomplished
by oral ingestion.
18. The process of claim 1 wherein said solution additionally
contains bicarbonate anions and the Ph of said solution is adjusted
to a desired 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 1-lactic, d-betahydroxybutyric, acetoacetic, and
pyruvic in an amount sufficient to give such desired Ph.
19. In an improved process for accomplishing treatment of metabolic
acidosis in a living human, the step of introducing into said human
a solution comprising water having dissolved therein the following
components in the respective amounts indicated:
5 Quantity Component (in mM) Cations Na.sup.+ 0-2400 K.sup.+ 0-60
C.sup.2+ 0-4 Mg.sup.2+ 0-3 Anions 1-lactate 0-2400 pyruvate 0-2400
d-betahydroxybutyrate 0-2400 acetoacetate 0-2400
provided that the total amount of 1-lactate, pyruvate,
d-betahydroxybutyrate and/or acetoacetate anions present in any
given solution ranges from about 0.1 to 2400 mM with the total
amount of said cations being such as to achieve electrical
neutrality in such given solution, and further provided that said
solution has a pH ranging from about 5 to 8.2.
20. A fluid composition for treatment of metabolic acidosis in a
living human comprising water having dissolved therein the
following components in the respective amounts indicated:
6 Quantity Component (in mM) Cations Na.sup.+ 0-2400 K.sup.+ 0-60
Ca.sup.2+ 0-4 Mg.sup.2+ 0-3 Anions 1-lactate 0-2400 pyruvate 0-2400
d-betahydroxybutyrate 0-2400 acetoacetate 0-2400
provided that the total amount of 1-lactate, pyruvate,
d-betahydroxybutyrate and/or acetoacetate anions present in any
given solution ranges from about 0.1 to 2400 mM with the total
amount of said cations being such as to achieve electrical
neutrality in such given solution, and further provided that said
solution has a pH ranging from about 5 to 8.2.
21. In an improved process for accomplishing rehydration,
electrolyte replacement, and nutrition in a living human suffering
prom fluid, electrolyte, and nutritional depletion, the step of
introducing into said human a solution comprising water having
dissolved therein the following components in the respective
quantities indicated:
7 Quantity Component (in mM) Cations Na.sup.+ 130-160 K.sup.+ 2-10
Ca.sup.2+ 0.5-2.5 Mg.sup.2+ 0-1.5 Anions Cl-- 90-115 1-lactate 0-55
pyruvate 0-55 d-betahydroxybutyrate 0-55 acetoacetate 0-55
provided that in any given said solution, the total amount of
1-lactate, pyruvate, d-betahydroxybutyrate and/or acetoacetate
anions present ranges from about 0.1 to 55 mM with the total amount
of said cations being such as to achieve electrical neutrality in
any given said solution, and further provided that said solution
has a pH ranging from about 6.0 to 7.5.
22. A solution for rehydration, electrolyte replacement, and
nutrition comprising water having dissolved therein the following
components in the respective quantities indicated:
8 Quantity Components (in mM) Cations Na.sup.+ 130-160 K.sup.+ 2-10
Ca.sup.2+ 0.5-2.5 Mg.sup.2+ 0-1.5 Anions Cl-- 90-115 1-lactate 0-55
pyruvate 0-55 d-betahydroxybutyrate 0-55 acetoacetate 0-55
provided that in any given said solution, the total amount of
1-lactate, pyruvate, d-betahydroxybutyrate and/or acetoacetate
anions present ranges from about 0.1 to 55 mM with the total amount
of said cations being such as to achieve electrical neutrality in
any given said solution, and further provided that said solution
has a pH ranging from about 6.0 to 7.5.
23. In an improved process for replacing at least in part the renal
function of a living human patient by dialysis by allowing said
patient's blood to pass over one face of a semipermeable membrane
while a dialysis fluid contacts the opposite face, the improvement
which comprises employing as said dialysis fluid an aqueous
solution comprising water which has dissolved therein the following
components in the respective amounts indicated:
9 Quantity Component (in mM) Cations Na.sup.+ 130-145 K.sup.+ 0-4
Ca.sup.2+ 0.5-2.0 Mg.sup.2+ 0-1.0 Anions Cl-- 90-120 1-lactate 0-55
pyruvate 0-55 d-betahydroxybutyrate 0-55 acetoacetate 0-55
provided that in any given such solution the total amount of
1-lactate, pyruvate, d-betahydroxybutyrate and/or acetoacetate
anion present ranges from about 0.1 to 55 mM with the total number
of indicated cations present being such as to achieve electrical
neutrality with the total number of anions present, and also
provided that said solution has a pH ranging from about 5 to 8.2,
and further provided that said solution has a milliosmolarity
ranging from about 250 to 600 mOs/l.
24. A solution for dialysis therapy comprising water having
dissolved therein the following components in the respective
amounts indicated:
10 Quantity Components (in mM) Cations Na.sup.+ 130-145 with
substantially no d-lactate K.sup.+ 0-4 Ca.sup.2+ 0.5-2.0 Mg.sup.2+
0-1.0 Anions Cl-- 90-120 1-lactate- 0-55 pyruvate 0-55
d-betahydroxybutyrate 0-55 acetoacetate 0-55
provided that the total amount of 1-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, and also provided that said solution has a pH ranging
from about 5 to 8.2.
25. The process of claim 23 wherein said process comprises
hemodialysis and where said solution additionally contains from
about 20 to 55 mM of bicarbonate anions and wherein said solution
also contains a sufficient portion of at least one of said
1-lactate, pyruvate, d-betahydroxybutyrate, and/or acetoacetate
anions which are derived at least in part from the addition to said
solution of, respectively, at least one of 1-lactic acid, pyruvic
acid, d-betahydroxybutyric acid and/or acetoacetic acid in a total
amount which is sufficient to produce a pH in the range from about
5 to 8.2, and said solution contains sufficient nonionic dissolved
nutrients to achieve a solution milliosmolarity of from about 260
to 540 mOsmoles/Liter.
26. The solution of claim 24 wherein said solution additionally
contains from about 20 to 55 mM of bicarbonate anions and wherein
said solution also contains a sufficient portion of at least one of
said 1-lactate, pyruvate, d-betahydroxybutyrate and/or acetoacetate
anions which are derived at least in part from the addition to said
solution of, respectively, at least one of 1-lactic acid, pyruvic
acid, d-betahydroxybutyric acid and/or acetoacetic acid in a total
amount which is sufficient to produce a pH in the range from about
5 to 8.2, and said solution contains sufficient nonionic dissolved
nutrients to achieve a solution milliosmolarity of from about 250
to 550 mOsmoles/Liter.
27. The process claim 23 wherein said process comprises peritoneal
dialysis and wherein said fluid is infused into the peritoneal
cavity of said patient, allowed to dwell there for a time ranging
from about 1/2 to four hours, and then is drained off, wherein said
solution additionally contains from about 20 to 55 mM/l of
bicarbonate anions, and wherein said solution also contains a
sufficient portion of at least one of said 1-lactate, pyruvate,
d-betahydroxybutyrate, and/or acetoacetate anions derived from the
addition to said solution of, respectively, at least one of
1-lactic acid, pyruvic acid, d-betahydroxybutyric acid and/or
acetoacetic acid in a total amount which is sufficient to produce a
pH in the range from about 5.5 to 7.5, and said solution also
contains sufficient nonionic dissolved nutrients to achieve a
solution milliosmolarity of from about 260 to 550
mOsmoles/Liters.
28. The solution of claim 24 wherein said solution additionally
contains from about 20 to 55 mM of bicarbonate anions and wherein
said solution also contains a sufficient portion of at least one of
said 1-lactate, pyruvate, d-betahydroxybutyrate, and/or
acetoacetate anions derived from the addition to said solution of,
respectively, at least one of 1-lactic acid, pyruvic acid,
d-betahydroxy-butyric acid and/or acetoacetic acid in a total
amount which is sufficient to produce a pH in the range from about
5.5 to 7.5, and said solution also contains sufficient nonionic
dissolved nutrients to achieve a solution milliosmolarity of from
about 260 to 550 mOsmoles/Liter.
29. The process of claim 21 wherein said introduction is
accomplished parenterally and wherein said solution additionally
contains from about 20 to 55 mM of bicarbonate anions and wherein
said solution also contains a sufficient portion of at least one of
said 1-lactate, pyruvate, d-betahydroxybutyrate, and/or
acetoacetate anions derived from the addition to said solution of,
respectively, at least one of 1-lactic acid, pyruvic acid,
d-betahydroxybutyric acid and/or acetoacetic acid in a total amount
which is sufficient to produce a pH in the range from about 5.5 to
7.5, and said solution also contains sufficient nonionic dissolved
nutrients to achieve a solution milliosmolarity of from about 260
to 550 mOsmoles/Liter.
30. The process of claim 1 wherein said solution additionally
contains at least one 1-amino acid.
31. The process of claim 1 wherein said solution has an osmolarity
ranging from about 240 to 2400 mOsmoles per liter.
Description
RELATED APPLICATION
[0001] This present application is a continuation-in-part of my
copending U.S. patent application Ser. No. 810,918, filed Dec. 18,
1985, which in turn is a continuation-in-part of my copending U.S.
patent application Ser. No. 748,232, filed Jun. 24, 1985, which in
turn is a continuation-in-part of U.S. patent application Ser. No.
623,102 filed Jun. 22, 1984, now abandoned.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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 1-lactate anions, pyruvate anions,
d-betahydroxybutyrate anions, acetoacetate anions, or mixtures
thereof in combination with selected cations.
[0004] 2. Prior Art
[0005] Previously, I have provided improved electrolyte solutions
for in vivo and in vitro usage which contain 1-lactate and pyruvate
anions, and/or d-betahydroxybutyrate and acetoacetate anions in
respective defined ratios in combination with defined Na:Cl ratios;
see my copending U.S. patent applications Ser. Nos. 748,232 and
747,792, both filed Jun. 24, 1985, and also my copending U.S.
patent application Ser. Nos. 747,858 and 748,184, also filed on
such date. However, it is now appreciated that the benefits of
using 1-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.
[0006] The prior art indicated in the "Background" sections of
these earlier patent applications is incorporated by reference into
the present application.
[0007] 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.
[0008] 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,1-lactate mixture. Hence, the d,1-lactate
is the form used in contemporary pharmaceutical practice. The
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.
[0009] The toxicity of d-lactate has been described in humans (see
Oh M S et al N Eng J Med 301: 249-251, 1979; Perlmutter, D H et al
J Pediatrics 102: 234-238, 1983; Stolberg, L et al N Eng J Med 306:
1344-1348, 1982). Thus, the d-form has now been discovered to cause
adverse and toxic effects when administered to mammals. For
example, when an aqueous 20 mM/l d-lactate (or d-lactic 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 amount of K.sup.+. With continued
administration, coma develops, the cerebral edema worsens and death
ensues. In contrast, when 1-lactate is similarly administered, the
differential concentration of 1-lactate between intracellular and
extracellular fluid does not cause coma or death. For another
example, Veech et al. (Veech, R L and Fowler, R C., "Cerebral
Dysfunction and Respiratory Alkalosis During Peritoneal Dialysis
with d-Lactate Containing Peritoneal Dialysis Fluids". Am. J. 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,1-lactate in routine dialysis fluids. Because
of such encephalopathological results, parenteral solutions
containing the racemic d,1-lactate anions should not be
administered for therapeutic purposes.
[0010] 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,1-lactate solution is
used parenterally as an alkalinizing 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 solutions. In
addition, it could also be used in current hemodialysis to replace
the acetate anion, or, in its H.sup.+ form, as an acid to be added
to a bicarbonate hemodialysis fluid.
[0011] Prior to the teachings contained in my afore referenced U.S.
Ser. No 748,232, pyruvate anions d-betahydroxybutyrate anions, and
acetoacetate anions in aqueous solution, so far as is now known,
were never used in human therapeutic fluids.
BRIEF SUMMARY OF THE INVENTION
[0012] This invention relates to a process for accomplishing 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 containing at least one permeant mono-anionic
metabolite selected from the group consisting of 1-lactate anions,
pyruvate anions, d-betahydroxybutyrate anions, acetoacetate anions,
or mixtures of such anions.
[0013] Here, 1-lactate is defined as that form of lactate anion
found in mammalian tissues and designated 1 or L-lactate. It is
identified by its ability to react with NAD.sup.+ to form pyruvate
in a reaction catalyzed by mammalian lactate dehydrogenase (EC
1.1.1.27). The form of 1-lactate which is dextrorotatory in aqueous
solution is designated 1-(+) while the salts of 1-lactate which in
aqueous solution are levorotatory are designated 1-(-)lactate (see
US Dispensatory. Osol, A, Pratt, R, Gennar, A R, eds. p 658. J R
Lippcott. Philadelphia, 1973). Pyruvate and acetoacetate have no
sterospecificity.
[0014] 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 aqueous 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 1-lactate, pyruvate, d-betahydroxybutyrate or
acetoacetic acid, preferably 1-lactate, and/or (e) irrigation
therapy.
[0015] 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
1-lactate (or one of the other metabolite anions herein identified
and used in the practice of this invention) in place of racemic
d-1-lactate, but also the substitution of, for example, 1-lactate
for d-1-lactate, in solutions employed in fluid therapy, does not
cause any change in the heretofore known beneficial physiological
or pharmacological effectiveness of such fluids.
[0016] In general, a solution containing at least one such anion is
administerable for generally the same purposes that prior art
parenteral fluids or dialysis fluids are used which contain racemic
d-1-lactate anions. For examples, such a solution can be used to
treat acidosis, dehydration, blood electrolyte depletion, shock,
malnutrition, uremia and the like.
[0017] Because mixtures of 1-lactate anions and pyruvate anions,
and mixtures of d-betahydroxybutyrate anions and acetoacetate
anions, in solutions each constitute near-equilibrium couples,
which can vary widely in concentration under normal physiological
conditions, as explained, for example, in my aforereferenced U.S.
patent application Ser. No. 748,232, 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 maintain a normal plasma milliequivalent ratio of sodium
cations to chloride anions, (b) thus tends to prevent
hyperchloremic acidosis, and (c) accomplishes electrolyte and fluid
and resuscitation therapy. The anions taught by this invention
permit one to avoid the known untoward effects of high levels of
the d-lactate anion (see Veech, R L, Fowler, R C, op. cited above)
or of acetate anion which are now the major organic anions
conventionally added to parenteral fluids (See Veech R L. The toxic
impact of parenteral solutions on the metabolism of cells: a
hypothesis for physiological parenteral therapy. Am J Clin Nutr 44:
519-551, 1986).
[0018] Other and further objects, aims, purposes, features,
advantages, 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
[0019] For the fluid therapy purposes of my present invention, any
conventional administration procedure is suitable, although
parenteral (particularly intravenous) administration during hemo or
peritoneal dialysis is presently preferred.
[0020] For example, sodium 1-lactate aqueous solutions, which are
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 dissolved 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 1-lactate, and 1 g sodium
1-lactate corresponds to about 0.75 g sodium bicarbonate. The
bicarbonate or 1-lactate solutions are preferrably administered
diluted with glucose solution or distilled water. The alkalizing
action of sodium 1-lactate is diminished in severe liver damage
since its breakdown is retarded. See, for example, Documenta Geigy
6th ed, pp. 331-332, Geigy, Manchester, 1962.
[0021] In practice, the calculation of the quantity of an
alkalizing infusion solution required for adults is based on an
average value for the water content of the body of 50% by weight
and on a uniform intra- and extra-cellular distribution of
bicarbonate, 1-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,
for example, 1-lactate, bicarbonate or d-betahydroxybutyrate anions
of 70.times.6.times.0.5=210 mEq must be administered. In order to
avoid the danger of an acidosis becoming converted into an
alkalosis, it is advisable not to attempt a complete normalization
of the alkali reserve by means of an alkalizing solution, and such
solutions should never be administered without supplementary
potassium.
[0022] 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.
[0023] 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 1-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.
[0024] When using solutions such as "Lactated Ringer's" (see, for
example, my aforereferenced U.S. Ser. No. 748,232) to replete body
water and electrolytes, the 28 mM d,1-lactate of the prior art is
replaced with, for example, 28 mM 1-lactate. In this way, the Na:Cl
ratio, in such an-1-lactate solution, is moved, if desired, towards
a normal ratio of 1.36 as found in normal human plasma. Thus,
hyperchloremic acidosis resulting from large infusions of normal
sodium chloride solutions is avoided. The same considerations apply
to use of such solutions in dialysis (see, for example, my
aforereferenced U.S. patent applications Ser. Nos. 748,232 and
748,184).
[0025] Alternatively, in all the present new solutions,
d-betahydroxybutyrate anions, for example, can be used
alternatively in place of 1-lactate anions. Additional benefits may
accrue from the use alternate or combined use of pyruvate and
acetoacetate.
[0026] A preferred application for this invention involves usage of
a mixture of anions of 1-lactate and pyruvate, or a mixture of
anions d-betahydroxybutyrate and acetoacetate, as indicated, in
solutions. 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 aqueous solutions presents a practical problem,
use of 1-lactate or d-betahydroxybutyrate alone confers stability
on the solution and is to be preferred over the currently used
d,1-lactate or acetate.
[0027] 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/L,
then 70.times.6.times.0.5 or 210 mEq is infused with a fluid of
this invention containing bicarbonate anions and 1-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.
[0028] For a second example, a liter of solution of the composition
of the current Ringer's lactate (for the composition thereof, see
my afore referenced U.S. Ser. No. 748,232) may be infused over a
four hour period into a dehydrated 70 kg man with the exception
that the d,1-lactate used is replaced with 1-lactate.
[0029] For a third example, the prior art accomplishment of
peritoneal dialysis by infusion into the peritoneum of 2L of a
conventional d,1-lactate based or acetate based peritoneal dialysis
solution, is changed in that the 35-45 mM d,1-lactate or acetate is
altered and replaced by 35-45 mM 1-lactate. After remaining in the
peritoneum for about 1/2 hour, the fluid is drained off and the
process repeated until the blood urea nitrogen (BUN) is decreased
to the level desired.
[0030] In parenteral therapy, the total concentration of anions
selected from the above indicated anion group, a present preference
being 1-lactate, pyruvate, and/or mixtures thereof, can range from
about 0.01 to 2400 millimoles 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, for example, d,1-lactate.
[0031] A present preference is to employ, for fluid therapy, an
aqueous solution wherein the total concentration of 1-lactate or
pyruvate anions ranges from about 1 Molar to 1 millimolar. In a
more preferred form, from about 28 to 45 millimoles (total) of such
anions are present (such as in an improved Ringer's lactate or in
improved peritoneal dialysis fluids).
[0032] Although a solution taught by the present invention may
contain either 1-lactate or pyruvate alone, as essentially the sole
organic metabolic anion, a mixture of 1-lactate anions and pyruvate
anions may also be used, and 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 millieguivalent ratio of 1-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.
[0033] The 1-lactic, pyruvic, d-betahydroxybutyric, and acetoacetic
acids themselves as such, may be used. For example, such can be
used in combination with aqueous bicarbonate anions; for instance,
in sodium bicarbonate containing solutions. Also, one can employ,
in the starting solutions used in the processes of present
invention, aqueous solutions which contain, along with such
metabolite anions as taught in this invention, at least one cation
selected from the group consisting of sodium, potassium, calcium,
magnesium, and ammonium. Preferably, from about 0.01 to 2400
millimoles per liter of such anions are present.
[0034] Inorganic physiologically acceptable anions, besides
bicarbonate, may also be present, such as chloride, phosphate, and
sulfate, if desired, and if such are present, the respective
quantities present are preferably similar to corresponding
physiologic levels. A difference between the total milliequvalents
of the cations present in a solution and the total milliequivalents
of the organic anions of the specified group employed in the
practice of this invention (1-lactate, pyruvate,
d-betahydroxybutyrate, and acetoacetate) can be provided by other
physiologically acceptable anions.
[0035] It is considered to be physiologically advantageous and it
is generally preferred in the practice of this invention, to
maintain the levels of 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,1-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.
[0036] 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,1-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.
[0037] 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 present in current commercial amino
acid formulations (which lead to metabolic bone disease) can be
replaced by such anions. See, for example, my copending U.S. patent
application Ser. No. 810,916, filed Dec. 18, 1985, and its
continuation-in-part application filed on even date herewith, all
the teachings of which are entirely incorporated hereinto by
reference.
[0038] Also preferably, a starting solution used in the practice of
this invention has a pH in the range from about 5 to 9, although
for the contemplated human usage, a most preferred pH is about
7.4.
[0039] Additional cations and anions may be present in a starting
solution as taught, for example, in my aforereferenced U.S. Ser.
No. 748,232.
[0040] 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 1-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 1-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: 1 pH = pK a ' - log [ HCO 3 - ] 2 (
[ HCO 3 - ] - [ HA ] ) - 1 2
[0041] where:
[0042] HA is the concentration of carboxylic acid in
moles/liter,
[0043] pK.sub.a'=6.10 at 38.degree. C. (see Hastings, A B, et al.,
J. Biol. Chem. 79:183-192, 1928).
[0044] In preferred applications of this sort, such as applications
which can incorporate from about 28 to 40 mM/l HCO.sub.3.sup.-,
about 2 to 9 mM/l 1-lactic, pyruvic, d-betahydroxy-butyric acid
and/or acetoacetatic acid may generally be added. Such solutions
are presently preferred for peritoneal or hemodialysis over
existing fluids containing acetic acid or d,1-lactate because of
the toxicity of the presently used acids.
[0045] Optionally, carbon dioxide may additionally be dissolved in
such a solution, for example, in a range such as taught in my
aforereferenced U.S. Ser. No. 748,232.
[0046] For purposes of practicing the present invention, only when
both 1-lactate and pyruvate anions are present in a milliequivalent
ratio of from about 20:1 to 1:1, and/or both d-betahydroxybutyrate
and acetoacetate anions are present in a milliequivalent ratio of
from about 6:1 to 0.5:1 are present in admixture in a starting
solution, and only when both sodium cations and chloride anions are
also present in such a starting solution, then the milliequivalent
ratio of Na.sup.+ cation to Cl.sup.- 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 used individually. Also, such practice
does not require the use of a narrowly specifed range of Na.sup.+
to Cl.sup.- milliequivalent ratios (when such inorganic ions are
both present).
[0047] Thus, as taught herein, therapy (including 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 or more of various
anions herein taught in a starting solution wherein the cations are
selected from among hydrogen, sodium, potassium, calcium,
magnesium, and ammonium.
[0048] However, in the practice of this invention, 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,1-lactate
as is currently used, for example, in ambulatory parential dialysis
fluids. The use of 1-lactate in conjunction with other inorganic
anions, but in the absence of the unstable ketoacid pyruvate,
results in a fluid which has as long a chemical stability as the
currently used d,1-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 anions only 1-lactate anions and/or
d-betahydroxybutyrate anions and is termed herein Class I for
convenience. This class is particularly useful where long term
fluid storage is desirable. Another class of solutions, for
example, contains 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 1-lactate anions and pyruvate anions, or only a mixture
of d-betahydroxybutyrate anions and acetoacetate anions, which is
useful when redox control is desired, and is termed herein Class
III for convenience. Table I illustrates various embodiments of
such exemplary classes.
1 TABLE I Range of Concentration in mMoles/Liter Com- Item No.
ponent Class I Class II Class III 1 l-lactater 0.01-2400 or beta-
hydroxy butyrate 2 pyruvate 0.01-2400 or acetoace- tate 3 l-lactate
0.01-2400 plus pyruvate and/or d-beta- hydroxy- butyrate and
acetoace- tate 4 (cations) 10.sup.-5-10.sup.-9 10.sup.-5-10.sup.-9
10.sup.-5-10.sup.-9 (hydro- 0-2400 0-2400 0-2400 gen) sodium 0-2400
0-2400 0-2400 potassium 0-1200 0-1200 0-1200 calcium 0-1200 0-1200
0-1200 mag- 0-1200 0-1200 0-1200 nesium ammon- 0-10 0-10 0-10
ium
[0049] Table II describes four 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,1-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,1-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 ingestion, such as under conditions requiring therapy where
close patient monitoring is not possible.
[0050] For example, one can accomplish treatment of 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.
[0051] For example, one can accomplish parenteral fluid therapy
with improved 1-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.
[0052] 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 employable with the improved fluids 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 membrane.
[0053] 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 least one of 1-lactic acid,
pyruvic acid, d-betahydroxybutyric acid and/or acetoacetic acid in
a total amount which is sufficient to produce a pH in the range
from about 5.5 to 8.2, such solution also has a milliosmolarity of
from about 250 to 310 mOs/l.
[0054] 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.
[0055] 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.
[0056] It will be appreciated that the designation mM and mM/l are
used herein in their conventional manner to designate millimoles
per liter.
2 TABLE II Preferred Solutions (New) units in mMoles/Liter solution
Component Type A.sup.(1) Type B.sup.(2) Type C.sup.(3) Type
D.sup.(4) Cations Na.sup.+ 0-2400 130-160 130-145 130-145 K.sup.+
0-60 .2-10 0-4 0-4 Ca.sup.2+ 0-4 0.5-2.5 0.5-2.0 0-2 Mg.sup.2+ 0-3
0-1.5 0-1.0 0-1 Anions Cl.sup.- 0-2000 90-115 90-120 95-110
HCO.sub.3.sup.- 0-2000 0 0-40 20-55 Pi.sup.-1.8 0-50. 0 0
SO.sub.4.sup.2- 0-1.2 0 d-lactate.sup.- 0 0 0 acetate.sup.- 0 0 0
l-lactate.sup.- 0-2400 0-55 0-55 0-20 pyruvate.sup.- 0-2400 0-55
0-55 0-20 d-betahydroxy- butyrate.sup.- 0-2400 0-55 0-55 0-20
acetoacetate.sup.- 0-2400 0-55 0-55 0-20 Nonanionics Glucose 0-278
0-280 0-240 0-240 pH 5-8.2 6.0-7.5 5-8.2 5.5-8.2
[0057] Table II Footnotes:
[0058] (1) The total amount of 1-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.
[0059] (2) The total amount of 1-lactate, pyruvate,
d-betabhydroxybutyrate, 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. The milliosmolarity ranges from 270 to 450
mOsmoles/Liter.
[0060] (3) The total amount of 1-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.
[0061] (4) The total amount of 1-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 indicated 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 from about 280 to 540
milliosmoles per liter when such solutions are used for peritoneal
dialysis. Such a solution has a pH ranging from about 5.5 to
7.5.
Embodiments
[0062] The following examples are merely illustrative of the
present invention and are not intended as a limitation upon the
scope thereof.
EXAMPLES 1-4
[0063] The following Table III illustrates particular solutions of
this invention:
3TABLE III (Values are in mMoles/Liter) Com- Ex. No. ponent Class I
Class II Class III 1 l-lactate.sup.(1) 1000 Na.sup.+ 1000 2
pyruvate.sup.(2) 1000 Na.sup.+ 1000 3 l-lactate.sup.(3) 900
pyruvate 100 Na.sup.+ 1000 4 l-lactic 5 acid Table III footnotes:
.sup.(1)For treatment of acidosis see Merck Handbook p 1866 12th
edition. .sup.(2)For treatment of acidosis when severe reduction of
[NAD.sup.+]/[NADH] is present (see USSN 748,232). .sup.(3)For
treatment of acidosis when redox balance is desired (see USSN
748,232). .sup.(4)For use as an additive to a bicarbonate
containing solution (see USSN 748,232).
EXAMPLES 5-12
[0064] Illustrative examples of various physiological abnormalities
which are treatable by using various starting solutions of the
present invention are shown in Table IV below:
4TABLE IV Exemplary Useages Condition Useful and Fluid Composition
Route of solution common Cation(s) Anion(s) Administration, name in
mMoles/liter and Dose 5. Dehydration Na.sup.+130 Cl.sup.-109
Parenteral, (L-lactated K.sup.+ 3 l-lactate 28 500 ml to 3
Ringers).sup.(1) Ca.sup.2+ 1.5 liters per day depending on severity
and cause 6. Peritoneal Na.sup.30 141 Cl.sup.31 101
Intraperitoneal, Dialysis Ca.sup.2+ 1.75 l-lactate.sup.- 45 4 to 8,
2 liter (Dianeal.sup.(2) w/1.5% Mg.sup.2+ 0.75 bags per day
Dextrose, Travenol).sup.(3) (also dextrose 83) 7. Metabolic
Na.sup.+ 156.1 l-lactate 156.1 Parenteral or Acidosis oral, 10 ml
to (Isotonic sodium 1 L depending l-lactate solution).sup.(4) on
size of patient 8. Cardiac Reper- Na.sup.+ 145 Cl.sup.- 115
Intracoronary fusion Fluid.sup.(5) Ca.sup.2+ 0.5 HCO.sub.3.sup.- 25
infusion after Mg.sup.2+ 0.75 pyruvate.sup.-11.5 cardiac arrest
K.sup.+ 4 (also glucose 10 and CO.sub.2 1.2) 9. Dehydration and
Na.sup.+ 120.2 Cl.sup.- 104.7 Parenternal or potassium Loss.sup.(6)
K.sup.+ 36.2 l-lactate.sup.- 51.7 oral.sup.(8). in Diarrhea, Keto-
(may be acidosis or Stress diluted with (Improved Darrow's 2
volumes Solution).sup.(7) of 278 mMolar glucose for pediatric use)
10. Hemodialysis Na.sup.+ 135 Cl.sup.- 106.5 Hemodialysis with
Bicarbonate K.sup.+ 2 HCO.sub.3.sup.- 33 without un- and l-lactic
Ca.sup.2+ 1.5 l-lactic physiolocal acid.sup.(9) Mg.sup.2+ 40.375
acid 2 levels of acetate.sup.(10) 11. Electrolyte Na.sup.+ 140
Cl.sup.- 103 Alternative to Replacement K.sup.+ 10 l-lactate 27.5
Fox's acetate HBDH-Ringer's Ca.sup.2+ 2.5 d-betahy- 27.5 Ringer's
Mg 1.5 droxybutyrate for electrolyte replacement.sup.(11)
[0065] Table IV Footnotes
[0066] (1) Hartmann A F. Theory and practice of parenteral fluid
administration. JAMA 1934; 103: 1349-1354.
[0067] (2) Dianeal is a trade mark of Travenol Laboratories,
Deerfield Ill.
[0068] (3) Facts and Comparisons. St. Louis: J B Lippincott,
October 1981-August 1983: 35d-53.
[0069] (4) Essellier A F, Jeanneret P. Agueous
solutions--parenteral infusion therapy. Documenta Geigy 6th
edition. Manchester: Geigy, 1962: 324-334
[0070] (5) The period of reperfusion of heart following, for
example coronary by pass can be critical and may result in
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
1-lactate or glucose alone (See Kobayshi K, Neely J R. The control
of maximum rates of glycolysis in rat cardiac muscle. Circ Res
1979; 44: 166-175.
[0071] (6) Essellier A F, Jeanneret P. Aqueous
solutions--parenteral infusion therapy. Documenta Geigy 6th
edition. Manchester: Geigy, 1962: 332-333
[0072] (7) Darrow and Pratt. JAMA 1950; 143: 365-ff and 432-ff.
[0073] (8) Martin et al. JAMA 1951; 147: 24-ff.
[0074] (9) See Table XI, Prior Art Hemodialysis Fluids. WO
86/00227
[0075] (10) Blood acetate levels above the physiological level of
0.2 mM are associated with metabolic bone disease. Veech R L. Am J
Clin Nutr 44: 544, 1986.
[0076] (11) Fox C L. JAMA 1952; 148: 827-833.
[0077] 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.
* * * * *