Blood substitute

• US 4,923,442 A
• Filed: 04/26/1989
• Issued: 05/08/1990
• Est. Priority Date: 05/02/1988
• Status: Expired

• Current Assignee: Biolife Solutions, Inc.
• Original Assignee: Cryomedical Sciences Inc.
• Inventors: Segall, Paul E., Waitz, Harold D., Sternberg, Hal
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): Witz, Jean C.
• Application Number:
  US07/343,850
• Time in Patent Office: 377 Days
• Field of Search: 424/677, 424/679, 424/680, 424/681, 424/682, 424/692, 524/23, 524/56, 524/59, 128/897, 128/898, 604/49, 604/51, 604/52, 604/53
• US Class Current: 604/522
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/14 Alkali metal chlorides; Alkaline earth metal chlorides
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender

Abstract

A blood substitute suitable for replacing blood in mammalian subjects when performance of surgical procedures at hypothermic temperatures is described. The blood substitute comprises water, electrolytes at physiological concentration, dextran 40 at a concentration sufficient for the blood substitute to achieve a colloidal suspension having a fluid osmotic pressure essentially equivalent to mammalian plasma, HEPES buffer at a physiological pH, dextrose, magnesium ion at a concentration of about 0.01M and potassium ion at a concentration greater than 10 mEq per liter sufficient to prevent or arrest cardiac fibrillation. In one embodiment the blood substitute is a multi-solution system wherein the solutions comprise differing levels of the above-indicated componants and are administered sequentially to completely replace a subjects circulating blood.

Claims

1. A blood substitute capable of maintaining a subject and its organs at temperatures below 20°

C. comprising a base solution comprising water, electrolytes in physiological concentration, a macromolecular oncotic agent, a biological buffer effective at physiological pH, simple sugar, and potassium ion in a concentration range of 4-5 mEq,

a cardioplegia induction solution comprising said base solution and wherein the concentration of potassium ion is in a range of 25-45 mEq,

a cardioplegia maintenance solution comprising said base solution and wherein the concentration of potassium ion is in a range of 15-45 mEq,

and a recovery solution comprising said base solution and wherein the concentration of potassium ion is in a range of 6-10 mEq.

2. The blood substitute of claim 1 wherein the macromolecular oncotic agent comprises an impermeate polysaccharide.

3. The blood substitute of claim 1 wherein said polysaccharide is dextran.

4. The blood substitute of claim 3 wherein said dextran is at a concentration sufficient for the blood substitute to achieve a colloidal suspension having an oncotic pressure essentially a colloidal suspension having an oncotic pressure essentially equivalent to mammalian plasma.

5. The blood substitute of claim 4 wherein said dextran is dextran 40.

6. The blood substitute of claim 4 wherein said dextran is dextran 70.

7. The blood substitute of claim 1 wherein said base solution and said recovery solution but not said cardioplegia induction solution and said cardioplegia maintenance solution, further comprise about 25 mM NaHCO₃.

8. The blood substitute of claim 1 wherein said base solution and said recovery solution but not said cardioplegia induction solution and said cardioplegia maintenance solution, comprise glucose in a concentration from 0-5 mM.

9. The blood substitute of claim 1 wherein said cardioplegia induction solution and said cardioplegia maintenance solution, comprise about 10 mM glucose.

10. The blood substitute of claim 1 wherein said base solution and said recovery solution but not said cardioplegia induction solution and said cardioplegia maintenance solution, comprise magnesium ion in a concentration of about 1-2mEq.

11. The blood substitute of claim 1 wherein said cardioplegia induction solution and said cardioplegia maintenance solution, comprise magnesium ion in a concentration of about 10 mEq.

12. The blood substitute of claim 1 wherein said base solution and said recovery solution but not said cardioplegia induction solution and said cardioplegia maintenance solution, comprise CaC1₂ in a concentration range of 2.5-3 mM.

13. The blood substitute of claim 1 wherein said cardioplegia induction solution and said cardioplegia maintenance solution, comprise CaC1₂ in a concentration range of 1.5-2 mM.

14. The method, of performing a bloodless hypothermic procedure upon a non-living euthermic subject comprising the steps of:

(a) lowering the subject'"'"'s core body temperature to a temperature above ice point and insufficient to cause cardiac fibrillation;

(b) placing the subject'"'"'s circulation on by-pass.

(c) perfusing the subject with an amount of a first perfusate sufficient to remove essentially all of the subject'"'"'s circulating blood said first perfusate comprising, water, electrolytes in physiological concentration, a macromolecular oncotic agent, a biological buffer effective at physiological pH, simple sugar, magnesium ion in a concentration sufficient to substitute for calcium ion in membrane calcium ion channels;

(d) when the subject'"'"'s temperature is substantially hypothermic but before cardiac fibrillation occurs, perfusing the subject with an amount of a second perfusate sufficient to replace essentially all of the circulating first perfusate, said second perfusate comprising, water, electrolytes in physiological concentration, a macromolecular oncotic agent, a biological buffer effective at physiological pH, simple sugar, magnesium ion in a concentration sufficient to substitute for calcium ion in membrane calcium ion channels and a cardioplegic agent in a concentration sufficient to prevent or arrest cardiac fibrillation or contraction.

15. The method of claim 14 wherein prior to perfusing the subject with said first perfusate, removing an amount in the range from 1/3 to 1/2 of the subject'"'"'s blood.

16. The method of claim 14 wherein subsequent to perfusing the subject with said second perfusate when the subject'"'"'s temperature is below that at which cardiac fibrillation or regular cardiac contraction can occur, perfusing the patient with a sufficient amount of said first perfusate to wash out the cardioplegic agent.

17. The method of claim 14 further comprising the steps of rewarming the subject, perfusing the subject with a sufficient amount of said first perfusate to wash out the cardioplegic agent, and perfusing the subject with sufficient whole blood or packed blood cells to wash out said first perfusate and raise the subjects hematocrit to about 20 at a core body temperature of about 25 degrees C. and a hematocrit to about 30 at a core body temperature of about 35 degrees C.

18. The method of claim 16 comprising rewarming the subject and perfusing the subject with sufficient whole blood or packed blood cells to wash out said first perfusate and raise the subjects hematocrit to about 20 at a core body temperature of about 25 degrees C. and a hematocrit to about 30 at a core body temperature of about 35 degrees C.

19. The method of claim 14 wherein the subject is subjected to hyperbaric oxygen tension prior to or while the first or second or first and second perfusate are administered.

20. The method of claim 17 wherein the subject is subjected to hyperbaric oxygen tension prior to or while the first or second or first and second perfusate are administered or while the subject is recovering.

25. The method of claim 14 wherein the amount and rate of introduction of any fluid into the subject is controlled by removing from the subject'"'"'s circulation sufficient fluid to maintain the pulmonary arterial wedge pressure at 5 mm Hg or less.

21. The method of performing a bloodless hypothermic procedure upon a euthermic subject in need thereof comprising the steps of:

(a) lowering the subject'"'"'s core body temperature to a temperature above ice point and insufficient to cause cardiac fibrillation;

(b) placing the subject'"'"'s circulation on by-pass;

(c) perfusing the subject with an amount of a first perfusate sufficient to remove essentially all of the subject'"'"'s circulating blood said first perfusate comprising, water, electrolytes in physiological concentration, a macromolecular oncotic agent, a biological buffer effective at physiological pH, simple sugar, and potassium ion in a concentration range of 4-5 mEq;

(d) when the subject'"'"'s temperature is substantially hypothermic but before cardiac fibrillation occurs, perfusing the subject with an amount of a second perfusate sufficient to replace essentially all of the circulating first perfusate, said second perfusate comprising, water, electrolytes in physiological concentration, a macromolecular oncotic agent, a biological buffer effective at physiological pH, simple sugar;

(e) after cardiac contractile activity stops replacing essentially all of said circualting second perfusate with a third perfusate comprising water, electrolytes in physiological concentration, a macromolecular oncotic agent, a biological buffer effective at physiological pH, simple sugar, and potassium ion in a concentration range of 15-45 mEq;

(f) prior to reintroducing blood into the subject, replacing essentially all of the circulating third perfusate with a fourth perfusate comprising water, electrolytes in physiological concentration, a macromolecular oncotic agent, a biological buffer effective at physiological pH, simple sugar, and potassium ion in a concentration range of 6-10 mEq.

22. The method of claim 21 wherein prior to perfusing the subject with said first perfusate, removing an amount in the range from 1/3 to 1/2 of the subject'"'"'s blood.

23. The method of claim 21 further comprising the steps of initiating rewarming the subject, while perfusing the subject with a sufficient amount of said fourth perfusate to wash out the third perfusate and perfusing the subject with sufficient whole blood or packed blood cells to wash out said fourth perfusate and raise the subjects hematocrit to about 20 at a core body temperature of about 25 degrees C. and a hematocrit to about 30 at a core body temperature of about 35 degrees C.

24. The method of claim 21 wherein the subject is subjected to hyperbaric oxygen tension while at least one of the first, second, third, or fourth perfusate is circulated in the subject.

26. The method of claim 21 wherein the amount and rate of introduction of any fluid into the subject is controlled by removing from the subject'"'"'s circulation sufficient fluid to maintain the pulmonary arterial wedge pressure at 5 mm Hg or less.