Method of preparing a terminally heat sterilized plasma-like...

Details Method of preparing a terminally heat sterilized plasma-like... Method of preparing a terminally heat sterilized plasma-like...

1999-08-27

2002-05-14

Saucier, Sandra E. (Department: 1651)

Chemistry: molecular biology and microbiology

Differentiated tissue or organ other than blood, per se, or...

Including perfusion; composition therefor

C604S004010

Reexamination Certificate

active

06387612

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the field of aqueous solutions such as plasma-like solutions used to perfuse a living subject in need of perfusion and which act as effective substitutes for blood. The invention also relates to methods of preserving the biological integrity of the organs of a mammalian donor organism (as shown by superior anatomical integrity of cryopreserved organs and tissues of subjects perfused with the solution of the invention) and to methods of maintaining a partially or substantially completely exsanguinated subject at temperatures substantially below those normally maintained by a mammal.
BACKGROUND OF THE INVENTION
Two clinically applied preservation methods for organs are known: (1) initial perfusion for about 5 min with subsequent cold storage (2° C.), and (2) continuous perfusion using solutions containing albumin or plasma.
Many of the solutions used for initial perfusion with subsequent cold storage are based on the solutions of Collins et al. (1969) Lancet 2:1219 and Sacks et al. (1973) Lancet 1:1024. Ross et al. (1976) Transplantation 21:498 compared canine renal preservation following flushing and storage for 72 hours in various solutions. It was found that only kidneys preserved in a hypertonic citrate (HC) solution (comprising in part 80 mM K
+
, 55 mM citrate, 400 mOsmol/kg, pH 7.1) survived after 72 hours. The Collins and Sacks solutions in part contained 115-126 mM K
+
, 290-430 mOsmol/kg, pH 7.0-7.3. Wall et al. (1977) Transplantation 22:210 reports the hypothermic preservation of human livers for up to about 4 hours in a solution in part comprising 250 mg dextrose, and 15 mEq potassium phosphate. Bishop & Ross (1978) Transplantation 25:235 reported that renal function was preserved best in the HC solution of Ross et al. (1976) supra, rather than other available solutions. Fischer et al. (1985) Transplantation 39:122 found a new preservation solution for hypothermic ischemic storage (comprising in part 110 mM Na
+
, 115 mM K
+
, 400 mOsm/kg, solvent D
2
O, 110 mM HEPES) to be superior to other solutions in clinical use, including Collins, Sacks, and HC.
Among the solutions used for continuous organ perfusion, Belzer et al. (1985) Transplantation 39:118 reported a newly developed solution which preserved renal function when kidneys were perfused for 48 hours and stored for 24 hours,(comprising in part 80 mM sodium gluconate, 22 mEq/l K
+
, 128 mEq/l Na
+
, 4.9 mM adenosine, 10 mM HEPES, 3.0 mM glutathione, 3.75 g % albumin, pH 7.45). Kallerhoff et al. (1985) Transplantation 39:485 examined the effect of temperature on pH of organs continuously perfused with two different solutions (Euro-Collins: 10 mM Na
+
, 115 mM K
+
, 198 mM glucose, 406 mOsm/L, pH 7.2 at 20° C.; HTK: 15 mM Na
+
, 10 mM K
+
, 2.0 mM tryptophan, 180 mM histidine, 30 mM mannitol, 310 mOsm/L, pH 7.3 at 8° C.). At incubation temperatures between 5° C.-35° C., HTK solution maintained pH at consistently higher values than Euro-Collins solution.
Klebanoff & Phillips (1969) Cryobiology 6:121 describe hypothermic asanguinqus perfusion of dogs perfused with buffered Ringer's lactate at 7.1 to 16° C. Segall et al. (U.S. Pat. No. 4,923,442) describe a blood substitute capable of maintaining a subject and its organs at temperatures below 20° C. having four different solutions—a base solution, a cardioplegia-inducing solution, a cardioplegia-maintaining solution, and a recovery solution. The base solution contains electrolytes in physiological concentration, a macromolecular oncotic agent, a conventional biological buffer effective at physiological pH, sugar, and K
+
ranging from 4-5 mEq. The cardioplegia-inducing solution had a K
+
concentration of 25-45 mEq; the cardioplegia-maintenance solution had a K
+
concentration of 15-45 mEq; and the recovery solution had a K
+
concentration of 6-10 mEq. Segall et al. (U.S. Pat. No. 5,130,230) further described the four-solution system, where the recovery solution contains 0-10 mEq K
+
.
SUMMARY OF THE INVENTION
This invention features methods of using a single solution suitable to maintain a partially or substantially completely exsanguinated subject alive at normal temperatures or at temperatures substantially below those normally maintained by a mammal, generally less than 37-38° C. and greater than −2° C., comprising a sub- and/or physiological levels of K
+
and Mg
++
; physiological Na
+
, Ca
++
, Cl
−
; a macromolecular oncotic agent; an organic carboxylic acid or salt thereof; and a sugar.
The solution of the invention may be used as a plasma extender at normal body temperature. The solution of the invention is also useful to maintain the life or the biological integrity of a perfused subject and/or its organs during and after exposure to profound hypothermic conditions. The solution can also be used to maintain a euthermic subject in a pressurized environment with increased oxygen concentration up to 100% O
2
for time periods sufficient to permit adequate restoration of the subject's blood components.
The solution according to the invention may be used to perfuse and chill a mammalian subject to temperatures profoundly hypothermic to the subject's normal temperature. The solution can be used to maintain the subject in profound hypothermia for long periods of time, usually exceeding an hour, from which an intact subject can recover without apparent durable ill effects.
An important distinction of the solution of the present invention is that it does not require multiple solutions for it to be effectively administered to a subject for the purposes of blood substitution, or low temperature maintenance of a mammalian subject. The solution of the invention may be used at all phases of plasma extension or blood substitution.
Another important distinction of the solution of the present invention is the feature of a subphysiological amount of K
+
at all steps of administration. This requirement reduces the risk of hyperkalemia-induced heart sufficiency resulting in blood transfusion in primates and humans.
Another important distinction of the solution of the present invention is the absence of a conventional biological buffer. The absence of a conventional biological buffer in the solution confers the important medical advantage of allowing the solution to be terminally heat sterilized without degradation of solution components.
The solution of the present invention requires the presence of an organic carboxylic acid, salt, or short chain esters thereof. The organic carboxylic acid, salt or ester thereof is a component of the dynamic buffer system of the solution able to maintain a biologically appropriate pH range when used in a mammal.
The solution of the present invention requires the presence of a macromolecular oncotic agent sufficient to maintain physiological osmotic pressure. The macromolecular oncotic agent used in the solution of the present invention may be a protein(s) or starch(es).
An advantage of the solution is that it can be used in a mammalian subject during all phases of blood substitution from initial washout of the subject's blood through full substitution of all or substantially all circulating blood.
A feature of the invention is that it may be used to maintain a mammal without blood and also during reperfusion with blood.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a formulation” includes mixtures of different formulations and reference to “the method of treatment” includes reference to equivalent steps and methods known to those skilled in the art, and so forth.
Unless defined otherwise all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this i

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