1. Field of the Invention
This invention lies in the field of in vivo techniques and compositions for replenishing fluid electrolytes and nutrients while regulating metabolic processes in living mammals.
2. State of the Art
The vital functions of highly developed organisms are closely dependent on the internal aqueous medium and on the maintenance in it of extreme constancy of chemical and physical properties.
It has long been recognized that all animal intracellular and extracellular body fluids contain inorganic electrolytes, and that these electrolytes are involved in, and profoundly influence, various life processes. Attempts to make artificial electrolyte fluids which may bathe tissues or be administered to the human blood stream have been known since about 1880, and, although modern analytical tools and procedures have clarified compositional details of blood electrolytes, the use of various aqueous electrolyte solutions for in vivo purposes in human medicine and related fields has been extent for approximately one hundred years.
Those inorganic electrolytes characteristically found in normal human blood serum at respective concentration levels above about 1 millimolar per liter of concentration are shown below in Table I. Also, for comparative purposes, in Table I are shown some representative compositions of various aqueous electrolyte solutions that have been previously prepared and used for in vivo purposes. In general, the philosophy behind the formulation of aqueous electrolyte solutions for in vivo use has been that such should mimic or closely resemble the chemical composition of electrolytes in blood and plasma. An electrolyte is a substance (usually a salt, acid or base) which in solution dissociates wholly or partly into electrically charged particles known as ions (the term is also sometimes used in the art to denote the solution itself, which has a high electrical conductivity than the pure solvent, e.g. water). The positively charged ions are termed cations while the negatively charged ions are termed anions. Strong and weak electrolytes are recognized. The dissociation of electrolytes is very markedly dependent on concentration; it increases with increasing dilution of the solution. The ions can be regarded as molecules in electrolyte solutions. Because of dissociation considerations, the term "sigma" or the greek letter for sigma (".SIGMA.") is sometimes employed herein as a prefix to designate the total presence of a specified material, such as an electrolyte, whether or not all of the material is in an ionic form complexed with a heavy metal, or regardless of charge on the material in a given solution. A pair of brackets ([]) indicates the free concentration of the substance indicated as opposed to that bound to tissue components, such as proteins. TBL3 TABLE I Prior Art Class 1c Normal Class 1a Class 1b 1. c. 4 Plasma 1. a. 1 1. a. 2 1. a. 3 1. b. 1 1. c. 1 1. c. 2 1. c. 3 Glucose + 1. c. 11 1. c. 13 Units N.E.J.M. Normal Normal Isotonic Isotonic 5% 5.25% Isotonic Na 1. c. 10 10% 1. c. 12 5% Fructose mmoles 283, 1285 0.9% Saline 0.95% Saline Na Lactate, NaHCO.sub.3.sup.-, Dextrose Dextrose Glucose 2 + Lactate + D-5-W Glucose + 2.5% Glucose in Electro- L fluid 1970 U.S. U.K. Salt Salt in H.sub.2 O, U.S. in H.sub.2 O, U.K. NaCl 1 NaCl 0.9% NaCl 0.9% NaCl 0.45% NaCl lyte 75 Na 136-145 155 162.5 160.3 160.3 54.1 53.4 154 154 77 40 K 3.5-5.0 35 Ca 2.1-2.6 free [Ca.sup.2+ ] [1.06] Mg 0.75-1.25 free [ Mg.sup.2+ ] [0.53] .SIGMA. mEq Cations 142.7-153.2 155 162.5 160.3 160.3 0 0 54.1 53.4 154 154 77 75 Cl 100-106 155 162.5 108.3 108.3 54.1 36.1 154 154 77 47.5 HCO.sub.3 26-28 52 .SIGMA. Pi 1-1.45 7.5H.sub.2 PO.sub.4.sup.- SO.sub.4 0.32-0.94 L-lactate 0.6-1.8 52.0 (d,l) 17.3 (d,l) 20 (d,l) pyruvate Lact/pyr oo oo oo D B OHbutyrate acetoacetate B HB/acac acetate Other .SIGMA. mEq anions 128.7-139.4 155 162.5 160.3 160.3 0 0 54.1 53.4 154 154 77 75 Na/Cl 1.28-1.45 1.00 1.00 1.48 1.48 1.00 1.48 1.00 1.00 1.00 0.84 Glucose 3.9-5.6 278 292 195 195 278 556 139 278 or others (Fructose) CO.sub.2 0.99-1.39 pH 7.35-7.45 5.5-6.5 5.5-6.5 .about.6.5 8.6 .about.6.5 .about.6.5 .about.6.5 .about. 6.5 .about.5.5-6.5 .about.5. 5-6.5 .about.5.5-6.5 .SIGMA. mOsa 285-295 310 325 321 321 278 292 301 302 564 813 293 428 Use: Prior Art Class 2a Normal 2. a. 12. Plasma 2. a. 1. 2. a. 3 2. a. 4. 2. a. 10 Isolyte S 2. a. 14. 2. a. 15. Units N.E.J.M. Ringer's 2. a. 2. Lactated Acetated 2. a. 5 Ionosol 2. a. 11. (McGaw) 2. a. 13. Delbecco's Kreb's 2. b. 1. mmole 283, 1285 Injection Lactated Ringer's Ringer's Lact/Acet D-CM Plasmalyte Polyionic Isolyte E Phosphate Ringer Krebs L fluid 1970 Class 1d U.S. Ringer's (Commercial) U.S. Ringer's (Abbott) (Travenol) 148 (Cutter) (McGaw) Saline Phosphate Henseleit Na 136-14 147 129.8 130 130 140 138 140 140 140 152.2 150.76 143 K 3.5-5.0 4 5.4 4 4 10 12 10 5 10 4.17 5.92 5.9 Ca 2.1- 2.6 2.5 0.9 1.5 1.5 2.5 2.5 2.5 2.5 0.9 2.54 2.5 free [Ca.sup.2+ ] [1.06] Mg 0.75-1.25 1.0 1.5 1.5 1.5 1.5 1.5 0.49 1.18 1.2 free [Mg.sup.2+ ] [0.53] .SIGMA. mEq Cations 142.7-153.2 156 139 137 137 158 158 158 148 2,158 159.15 164.12 156.3 Cl 100-106 156 111.8 109 109 103 108 103 98 103 140 131.51 127.8 HCO.sub.3 26-28 25 .SIGMA. Pi 1-1.45 9.83 17.38 1.18 SO.sub.4 0.32-0.94 0.48 2.36 1.18 L-lactate 0.6-1.8 27.8 (d,l) 28 (d,l) 27.5 (d,l) 50 (d,l) 8 (d,l) pyruvate Lact/pyr oo oo oo oo oo D B OHbutyrate acetoacetate B HB/acac acetate 28 27.5 47 27 49 Other 23 4 citrate (gluconate) .SIGMA. mEq anions 128.7-139.4 156 139 137 137 158 158 158 148 158 159.18 165.15 157.3 Na/Cl 1.28-1.45 0.94 1.16 1.19 1.19 1.36 1.28 1.36 1.43 1.40 1.08 1.15 1.12 Glucose 3.9-5.6 or others CO.sub.2 0.99-1.39 1.24 pH 7.35-7.45 7.4 7.4 7.4 .SIGMA. mOsa 285-295 309 276 272 272 312 312 312 294 315 308 311.16 308 Use: I.V. fluid I.V. fluid I.V. fluid I.V. fluid I.V. fluid I.V. I.V. electro- I.V. elec- I.V. Usually Biochemical Multiple electrolyte lyte trolyte electrolyte tissue experiments Biochemical therapy therapy therapy therapy culture, Uses sometimes cardiac surgery Prior Art Class 2c Normal 2. c. 6. Class 2d Plasma 2. c. 1 2. c. 2 2. c. 3. 2. c. 4. 2. c. 5. Peritoneal 2. c. 7. 2. d. 1 2. d. 2 Units N.E.J.M. Lactated 1/2 Strength Acetated Ionosol B + Dianeal + Dialysis + Dianeal K14 + Krebs Tyrode's 2. d. 3. 2. d. 4. mmoles 283, 1285 Ringer's + Lact-Ringer + Ringer's + 5% Glucose 1.5% Glucose 4.25% Glucose 4.25% Glucose Serum Solution 1 Tyrode's Locke's L fluid 1970 5% Glucose 2.5% Glucose Glucose (Abbott) (Travenol) (Am. McGaw) (Travenol) Substitute (Schimassek) Solution Solution Na 136-145 130 65 130 57 141 141.5 132 141 151.54 150.1 157.57 K 3.5-5.0 4 2 4 25 4 5.93 5.9 5.9 3.57 Ca 2.1-2.6 1.5 0.75 1.5 1.75 2.0 1.875 2.54 1.8 1.8 2.16 free [Ca.sup.2+ ] [1.06] Mg 0.75-1.25 2.5 0.75 0.75 0.75 1.18 0.45 0.45 0 free [Mg.sup.2+ ] [0.53] .SIGMA. mEq Cations 142.7-153.2 137 68.5 137 87 146 147 141 154.37 162.07 160.5 165.46 Cl 100-106 109 55 109 49 101 102.5 106 104.8 147.48 147.48 163.92 HCO.sub.3 26-28 24.9 11.9 11.9 3.57 .SIGMA. Pi 1-1.45 6.5 H.sub.2 PO.sub.4.sup.- 1.23 1.22 1.22 -- SO.sub.4 0.32-0.94 2.36 L-lactate 0.6-1.8 28 (d,l) 14 (d,l) 25 (d,l) 45 (dl) 35 (d,l) 1.33 pyruvate 4.9 0.09 Lact/pyr oo oo oo oo oo 14.8 D B OHbutyrate acetoacetate B HB/acac acetate 28 44.5 Other 2.45 glutamate.sup.- 5.4 fumarate.sup.2- .SIGMA. mEq anions 128.7-139.4 137 69 137 87 146 147 141 154.47 162.81 161.6 167.49 Na/Cl 1.28-1.45 1.19 1.18 1.19 1.16 1.40 1.38 1.25 1.35 1.03 1.02 0.96 Glucose 3.9-5.6 278 139 278 278 83 236 236 9.2 5.45 5.6 5.6-13.7 or others CO.sub.2 0.99-1.39 1.0 1.17 pH 7.35-7.45 .about.5.5-6.5 .about.5.5-6.5 .about.5.5-6.5 7.4 7.1 7.1 ? .SIGMA. mOsa 285-295 524 263 523 443 366 510 494 308.2 328 318.3 336 Use: I.V. fluid I.V. fluid same as Parenteral Peritoneal Peritoneal Peritoneal Artificial Liver nutrition & for de- 2. c. 1. Nutrition Dialysis Dialysis Dialysis Serum for Perfusion electrolytes hydration Tissue Slices Normal Na/Cl Class 1a Solutions Containing 1 or 2 Cations, no Nutrients and No HCO.sub.3.sup.- /CO.sub.2 1. a. 1. Most common U.S. I.V. electrolyte solution, Merck Manual. Causes hyperchloremic acidosis with Na/Cl = 1.00. See Black DAK. Lancet i, 353, 1952. 1. a. 2. Used as "normal" saline in U.K. and Canada. Geigy Handbook. 1. a. 3. Darrow et al. J. Am. Med. Ass. 143: 365, 432, 1944. Normal Na/Cl ratio but causes abnormalitie s. Class 1b. Solutions Containing 1 or 2 Cations, HCO.sub.3.sup.-, and No Nutrients. 1. b. 1. Darrow et al. J. Am. Med. Ass. 143: 365, 432, 1944. Use of bicarbonate alone to correct Na/Cl ratio gives a solution with an abnormal pH, and one which will cause Ca.sup.2+ or Mg.sup.2+ added to the solution to precipitate as MgCO.sub.3 or CaCO.sub.3, is the common alternative to Na lactate, salt; 1. a. 3. Class 1c Solutions Containing 1 or 2 Cations, with Non-ionic Nutrients. Typically 2.5%, 5%, 10%, 20%, Glucose or Fructose in the U.S. and 2.62%, 5.25%, 10.5%, 20% Glucose or Fructose in the U.K. 1. c. 1. Most used I.V. solution in the U.S. Merck Handbook, 1966, p. 1867. This is combined with NaCl in varying proportions so long as the osmolarity is not below 270 mOsa. 1. c. 2. Same solution in the U.K., where "isotonic" differs. Geigy Handbook, 1970, p. 334. 1. c. 3. Geigy Handbook, 1970, p. 334, has Na/Cl = 1.00 1. c. 4. Geigy Handbook, 1970, p. 334, has reasonable Na/Cl ratio but induces an abnormal redox state. 1. c. 10. throught 1. c. 12. See Facts and Comparisons p. 51, Oct. '81, Lippincott 1. c. 13. Facts and Comparisons p. 52, Aug. '83, Lippincott. Used in parenteral nutrition. Class 1d Solutions Containing 1 or 2 Cations, Nutrients, and HCO.sub.3.su p.- /CO.sub.2. None in prior art. Class 2a Electrolyte Fluids Containing 3 or 4 Cations Suitable for Contacting Cells, Containing No HCO.sub.3.sup .- /CO.sub.2 and No Glucose; eg. after S. J. Ringer, Physiol 4: 29, 223, 1883. 2. a. 1. Facts and Comparisons p 50, Oct '81, Lippincott 2. a. 2. Hartmann AF. J. Am. Med. Ass. 103: 1349, 1934. 2. a. 3. Facts and Comparisons p 50, Oct '81, Lippincott. 2. a. 4. Facts and Comparisons p 50, Oct '81, Lippincott. 2. a. 5. Fox et al. J. Am. Med. Ass. 148: 827, 1952. 2. a. 10. Facts and Comparisons p 50, Oct '81, Lippincott. 2. a. 11. Facts and Comparisons p 50, Oct '81, Lippincott. 2. a. 12. Facts and Comparisons p 50, Oct '81, Lippincott. 2. a. 14. Delbecco R, Vogt M. J Exp Med 1954; 99: 167-182 2. a. 13. Facts and Comparisons Oct, 1981, p. 50, Lippincott, St. Louis 2. a. 15. Krebs HA. Hoppe S 2 Physiol Chem 1953; 217: 193 Class 2b Solutions Containing 3 or 4 Cations, HCO.sub.3.su p.- /CO.sub.2 and No Glucose or Other Non-Ionic Nutrients. 2. b. 1. Krebs HA, Henseleit K. Hoppe-Seyle's 2 Physiol Chem 1932; 210: 33-66. This is the second major advance in fluids after S. J. Ringer, Physiol 1883; 4: 29, 223. This fluid became the basis for most tissue culture "balanced salt mixtures", was used in dialysis. It is known to contain twice too much Ca and Mg. It also has an abnormal Na/Cl ratio which Krebs himself unsuccessfully attempted to correct in 1950. (See Krebs HA. B B A 1950; 4: 249-269, or Table I class 2d.) Class 2c Solutions Containing 3 or 4 Cations, No HCO.sub.3.sup.- /CO.sub.2 to Which is Added Non-Ionic Nutrients. 2. c. 1. Multiple Manufacterer's. Facts and Comparisons p. 52, Oct 81 2. c. 2. Multiple Manufacterer's Facts and Comparisons p 52. Oct 81 2. c. 3. Multiple Manufacterer's Facts and Comparisons p 52, Oct 81 2. c. 4. (Abbott) Facts and Comparisons p 52b, Aug '83 2. c. 5. (Travenol) Facts and Comparisons p 704, Oct '82 2. c. 6. (American McGaw) Facts and Comparisons p 704, Oct '82 2. c. 7. (Travenol) Facts and Comparisons p 704, Oct '82 Class 2d Solutions Containing 3 or 4 Cations, Plus Non-Ionic Nutrients and HCO.sub.3.sup.- /CO.sub.2 2. d. 1. Krebs HA, B.B.A. 4: 249-269, 1950. Not used in vivo but presented for comparison of composition. 2. d. 2. Tyrodes's solution as modified for liver perfusion by Schimassek H, Biochem Z 336: 460, 1963. Not used in vivo but presented to show prior art in composition. Same for 2. d. 3, Tyrode's, and 2. d. 4, Locke's. 2. d. 3. Tryrode MV, Arch Int Pharmacodya Ther 20: 205-223, 1910. 2. d. 4. Locke FS, Zeatbl Physiol 14: 670-672, 1900.
Contemporarily, a large number of different aqueous electrolyte solutions are prepared, sold in commerce, and used as in vivo fluids, such as for electrolyte and fluid replacement, parenteral nutrition, and dialysis (both hemo-and peritoneal).
Even a cursory examination of Table I will confirm the medical dicta that "plasma is an unmakable solution". The solutions listed in Table 1 illustrate this belief. The essential problem is that plasma contains, in addition to major inorganic electrolytes, trace quantities of various electrolytes plus various metabolites including plasma proteins. In practice, it has not been possible to construct synthetically a replication of plasma because of it complexity. Blood, extracellular fluid, and even plasma can be regarded as tissues.
In most prior art electrolyte solutions, the concentration of chloride anions (Cl.sup.-) is higher than in human plasma or serum. For example, the Krebs Henseleit solution (see Table I) contains a concentration of Cl.sup.- which is about 20% higher than in human serum. This anion gap, that is, the difference between the positive cations and the negative anions, is now known to be due largely to the anionic metabolites in normal plasma plus the contribution of acidic amino acid groups found on plasma proteins. Referring to Table I, it is seen that the total positive cations in plasma is 142-154 meq/l while the total anions is only about 128-137 meq/l leaving a deficit of about 14-17 meq/l of anions. For convenience, the anion gap in human plasma can be expressed as the ratio of sodium cation milliequivalents per liter to chloride anion milliequivalents per liter.
From Table I, it is clear that the Krebs Serum substitute (Krebs, H. A. Biochem. Biophys. Acta 4, 249-269, 1950) comes closest to approximating the electrolyte composition of human plasma. In this solution, Krebs attempted to correct the excessive Cl.sup.- content in Krebs Henseleit solution (Hoppe-S Z. Physiol. Chem. 210, 33-66, 1932) using metabolic experiments with tissue slices. Because of the law of electrical neutrality, Na.sup.+ cannot be added to a solution without some anion (such as Cl.sup.-) being added also; the sum of cations and anions must be equal in any solution. In his 1950 attempt, Krebs chose pyruvate.sup.-, 1--glutamate.sup.-, and fumarate.sup.2- as anions to be added.
An alternative to Krebs selection of anions came about at the same time. In 1949, the use of high concentrations of acetate as a metabolizable organic anion was advocated (Mudge G. H. Mannining, J. A. Gilman A.; Proc. Soc. Exptl. Biol. Med. 71, 136-138, 1949). This idea led in 1964 to the advocacy of the use of 35-45 mM (millimolar) acetate in commercial hemodialysis fluids (Mion C. M., Hegstrom R. M., Boen S. T., Scribner B. H.; Trans. Am. Soc. Artif. Internal Organs 10, 110-113, 1964).
In addition to the above organic anions, the current reference work "Facts and Comparisons" indicates various commercial electrolyte fluids which contain lactate anion.
All of the prior art electrolyte solutions (with or without nutrients) as exemplified in Table I are now believed to lead to undesirable and pathological consequences particularly through extended usage. As regards acetate, editorials recently appearing in the British Medical Journal, 287, 308-309, 1983) present evidence that acetate leads to fatigue, nausea, malaise, sudden hypertension, increased atherosclerosis, hypoventilation, and hypoxia. Also, the originator of acetate dialysis now advocates its use only in "healthy" patients (Pagel M. D., Ahmed S, Vizzo J. E. and Scribner B. H.; Kidney Int. 21, 513-518, 1982).
Krebs choice of glutamate.sup.- and fumarate.sup.2- is incorrect because these anions do not penetrate cell membranes in a predictable manner, but, like citrate.sup.3-, exhibit severe gradients of six fold or greater between plasma H.sub.2 O and cell H.sub.2 O. The alternate use of d,l-lactate.sup.- (Hartmann AF. J Am Med Asso 103 1349-1354, 1934) is now known to induce severe abnormalities, particularly coma at levels far below the 28 to 35 mM d,l-lactate contained in these solutions (Oh MS et al, N Eng J Med 301 249 251, 1979; Stolberg L, et al N Eng J Med 306: 1344-1348, 1982; Ballabriga A, et al Helv Paediatr Acta 25:25-34, 1970) in to the induction severe abnormalities in redox and phosphorylation state induced by the use of 1-lactate alone. The use of gluconate.sup.- induces abnormalities in the hexosemonophosphate pathway. Indeed, all previous used organic ions violate the "safe entry points" or the normal Na:Cl ratio as herein defined.
In addition to the use of d,l-lactate, gluconate, fumarate, glutamate, pyruvate, and citrate anions in current commercially available prior art electrolyte fluids, and wherein such anions are typically employed at levels above those found in the (plasma or serum) of healthy humans, many such prior art commercial fluids also employ high levels of nonionic metabolites, such as fructose and glycerol, which induce separate redox state and phosphorylation potential abnormalities in phosphorylation potential with rapid destruction of liver purine nucleotides and their release into blood sometimes leading to renal shutdown due to uric acid deposition in the kidneys (see Woods H. F., Eggleston L. V. and Krebs H. A.; Biochem. J. 119, 501-510, 1970). Fructose in plasma above 0.2 mM must be considered to violate the "safe entry point". Likewise, use of intravenous glycerol at levels above 5 mM/l as currently practiced leads, in tissue containing glycerol kinase, such as kidney and liver, to accumulation of 10 mM glycerol phosphate (over 100 times normal). See Burch H. B. et al.; J. Biol. Chem. 257, 3676-3679, 1982).
In addition to failing to solve the anion gap problem (or to provide a normal milliequivalent ratio of sodium cation to chloride anions) without causing profound and adverse physiological effects (including disruption of normal redox state and normal phosphorylation potential), many prior art aqueous electrolyte solutions for in vivo usage fail to have a pH which approximates the pH of mammalian intracellular and extracellular fluids, especially, plasma or serum.
Mammalian systems normally operate at temperatures between about 37.degree.-38.degree. C. where, by common thermodynamic convention, neutral pH is taken to be about 7 at 25 C. It is clear that changes in pH, (the negative log 10 of [H.sup.+ ] concentration) necessarily affect the fundamental energetic relationships occurring in living cells. Also, enzymes have sharply defined ranges of "H.sup.+ ] concentration in which they perform their catalytic functions in a normal manner. Deviation of mammalian plasma pH down to 6.9 or above 7.7 from its normal range of 7.35-7.45 is therefore fatal to most mammalian organisms. Massive changes in the cellular redox and phosphorylation states also disorder cellular homeostasis.
The pH of human plasma is normally maintained by the human body in the range from about 7.35 to 7.45 while the pH of human cellular cytoplasm is about 7.2 (see Veech et al in J. Biol. Chem. 254, 6538-6547, 1979). If blood pH drops to 6.8 in man, then death ensues from cardiac arrest, and if blood pH increases to above pH 7.7, then death ensues from convulsions.
The major chemical system maintaining body pH within this narrow normal range is the [CO.sub.2 ]/[HCO.sub.3.sup.- ] buffer system. The [CO.sub.2 ] of blood is maintained minute to minute by a portion of the mammalian brain called the respiratory center which senses brain cell pH and adjusts the depth and speed of respiration to change pH by increasing or decreasing [CO.sub.2 ] according to the famous Henderson Hasselbalch equation (Henderson L. J., Silliman Lectures, Yale U. Press, New Haven, 1928).
Even though pH is thus seen to be a critical factor in mammalian blood, many commercial electrolyte solutions as administered have pH values which deviate substantially from normal. Others give excessive Cl.sup.- relative to Na.sup.+ which results in hyperchloremic acidosis, (Black D.A.K.; Lancet i 305-12, 1953), or give organic anions in a manner which causes measurable deviations from normal in the metabolic processes of the cell. Also, many commercially available electrolyte solutions contain no carbon dioxide which can result in a loss of respiratory drive and consequent hypoxia in patients.
The compositions and methods of the present invention overcome the above indicated prior art problems. These compositions and methods employ definite ratios of [bicarbonate.sup.- ]/[carbon dioxide], [1-lactate.sup.- ]/[pyruvate.sup.- ], and [d-betahydroxybutyrate.sup.- ]/[acetoacetate.sup.- ]. Each of these mixtures constitute a near equilibrium couple which is known to be a normal constituent of mammalian plasma. While each of these pairs of components has been previously employed at lease on a laboratory basis in solutions used for animal (mammalian) experiments, these mixture pairs have never previously been used in an electrolyte solution to obtain a normal Na:Cl milliequivalent ratio or to solve the anion gap problem.
All previous electrolyte solutions, and plasma substitutes, induce severe and measurable pathogenic abnormalities and no prior art electrolyte solution or plasma substitute has both (a) employed at least one of the three mixture pairs of this invention and (b) achieved a normal Na:Cl milliequivalent ratio as taught herein. Thus, for example, the Krebs Henseleit solution contains the [HCO.sub.3.sup.- ]/[CO.sub.2 ] buffer system (but contains excessive chloride ions). Schimassek (Schimassek H.; Bio. Chem. Z, 336, 460, 1963) added about normal blood levels of lactate and pyruvate to what is essentially Tyrode's solution (see Tyrode, M. J.; Arch Int. Pharmacodyn 20, 205, 1910) containing 2.5% albumin in an attempt to create a physiological solution for perfusion. It should be noted that Schimassek added 1.33 mM/L D-L-lactate, which is definitely abnormal (see normal blood lactate levels shown in Table 1). Further, the Na.sup.+ of 151 mM/l and Cl.sup.- of 147.5 mM/l in Schimassek's modified Tyrode's solution approximates the concentration of 155 mM/l Na and 155 mM/l Cl in so-called normal (0.9T) saline, the most widely used electrolyte infusion solution, and thus obtained a grossly abnormal Na:Cl milliequivalent ratio of about 1.24-1.45 with a mean of about 1.38. Infusions of electrolyte solutions with a Na:Cl milliequivalent ratio of less than about 1.38 have long been known to cause hyperchloremic acidosis in the treated organism. (See Levinsky N. G. in Harrison's Textbook of Medicine pp 230-236, McGraw-Hill, N.Y., 1983). It is the attempt to avoid this problem that leads to the wide use of such solutions as Ringer's lactate or acetate dialysis fluids which overcome the Na:Cl ratio problem, but which in turn create gross abnormalities of other types. It is the attainment of a normal Na:Cl milliequivalent ratio in a manner which avoids the pathological consequences inherent in all currently known or practiced methods which is a major part of the invention herein disclosed.
The making of a Krebs Henseleit electrolyte solution (or other prior art electrolyte solution) and the incorporation thereinto of a mixture of L-lactate and pyruvate anions, or of a mixture of D-betahydroxybutyrate and acetoacetate anions did not, and could not, result in the making of an electrolyte solution wherein the anion gap problem was overcome (or wherein the milliequivalent ratio of sodium cations to chloride anions was normalized), in accordance with the teachings of the present invention, because each of such resulting solutions would still contain excessive chloride anions and so would inevitably cause hyperchloremia if an when used in human or mammalian therapy.
In general summary, the prior art describes a series of electrolyte solutions typically of about 270-320 milliosmoles (or higher) comprised of: (a) 1 to 4 metallic cations of sodium, potassium, magnesium, and calcium in amounts greater than 0.5 mM/L, (b) 1 to 5 inorganic anions of chloride plus also HPO.sub.4.sup.2-), (c) 0 to several organic carboxylic or bicarbonate anions, (d) 0 to 5 nonionic materials in concentrations of greater than about 0.5 mM/L from the group comprising CO.sub.2 gas, glucose, urea, glutamine, and others, and (e) sometimes one or more high molecular weight substances, such as albumin, hemocel, and the like. None of these solutions, for the reasons herein above explained, either normalize the milliequivalent ratio of Na:Cl at all, or normalize this ratio without causing profound and adverse physiological consequences. In the present invention, there are provided processes and compositions of a complex fluid nature for in vivo usage which can substantially completely eliminate all of such prior art problems. While the components of these new solution compositions are known solution components, no one has heretofore formulated the solutions of the present invention which not only tend to achieve a normal plasma milliequivalent ratio of sodium cations to chloride anions, but also tend to achieve a normalization of plasma pH and a normalization of the cellular redox state and the cellular phosphorylation potential. Also, these new solutions permit one to avoid usage of the previously employed carboxylic anions, as acetate, or lactate alone, which cause adverse effects.
USPTO Backgrounds
USPTO Backgrounds