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Forty-one dog livers were preserved with cold, lactated Ringer’s, plasma, or intracellular (Collins) solutions. Consistent survival was obtained with all three solutions for 9 hr. After 18 hr, the plasma and Collins solutions permitted survival, with the Collins solution having a slight overall advantage. The method using Collins solution has been used to preserve seven human livers in Los Angeles, to transport the organs to Denver, and to transport them as orthotopic grafts from 6 hr, 45 min to 10 hr later.
It has been well known for a decade that the preservation of whole animal and human livers is possible for many hr, as proved by subsequent life-sustaining function of the hepatic grafts in recipients (1–4, 7, 8, 10). The preservation methods can be divided into the more complicated ones involving continuous or intermittent perfusion (1–4), and those using simple intravascular infusion of cold solutions (7, 8, 11, 13) followed by cold storage.
In this investigation, infusion solutions have been compared in cold storage experiments to determine the extent, if any, that the infusion fluid composition affects the outcome. The results have been used to design a successful clinical trial of liver graft preservation and transport over long distances.
With preservation times of 9 and 18 hr, three solution types were compared. After removal, the livers were washed free of blood with 500 to 800 ml of lactated Ringer’s solution at 4 C. The fluid was delivered through the portal vein at 100 cm H2o pressure. This was followed with 400 to 600 ml of the test solution at 4 C. After placing it in a plastic bag, the organ had more test solution poured over it. The plastic bag was kept cold by packing it in ice, as it standard practice with kidney preservation (5, 6).
There were 41 experiments that were divided into 7 groups depending upon the solutions used and the time of preservation (Table 1). As the graft vessels were being anastomosed to the recipient structures, the preservation fluid was washed out with a slow final infusion of cold, lactated Ringer’s solution. The transplantation technique was the one originally described in our laboratories (11), as slightly modified later (10). No immunosuppression was given postoperatively.
The seven livers were removed in six different Los Angeles hospitals under conditions of heart-beating brain death. Preservation was with Collins solution, using the same technique as described in dogs but with adjustments of infusing volume according to the size of the organ. The donors were 10 months to 43 years old. These livers were initially flushed with 500 to 1,300 ml of lactated Ringer’s solution and subsequently with 400 to 800 ml of Collins solution (Table 2). The final flushing of the organ with lactated Ringer’s solution during implantation was the same as that with the dog. Transplantation was by previously reported techniques (10–12).
There was minimal acute ischemic damage of the grafts in control animals that had immediate transplantation of cooled livers (Fig. 1). Rejection supervened within a few days. Five of the control animals lived for at least 7 days.
With preservation for 9 hr, the survival and behavior of the animals were similar to those of the controls. Furthermore, there were no differences by the criteria of postoperative behavior and mortality with lactated Ringer’s, Collins, or plasma solutions. Nevertheless, biochemical evidence of ischemic damage was less with Collins solution than with lactated Ringer’s or plasma solutions (Fig. 1).
One animal survived with no immunosuppression and is alive 3 months later.
Recipients of three livers preserved with lactated Ringer’s solution died within 1 day. With plasma and Collins solutions, about one-half of the recipients survived the immediate postoperative period, in spite of the fact that moderate to severe ischemic injury was always present (Fig. 2). In terms of both survival and liver function, there seemed to be a slight advantage with Collins solution compared with the plasma (Fig. 2).
Six of the seven cadaveric livers functioned well after 6 hr, 45 min to 10 hr of preservation, with prompt relief of jaundice and generation of good clotting factors. The serum glutamic-oxaloacetic transaminase always rose (Fig. 3), but the increase was to above 1,000 in only two of the six patients, and in these recipients there was a return to normal within 3 to 10 days. Five of these six patients are still alive from 3 weeks to 8 months post-transplant. The patient who died had normal liver function but developed lethal cardiopulmonary complications.
The seventh patient was 30 years old. At operation, the liver could not be completely revascularized because of thrombosis of the recipient’s portal vein. The graft functioned poorly, and there was an increase of serum glutamic-oxaloacetic transaminase to more than 3,000 IU (normal <50).
Eleven days later, another donor became available. Retransplantation was performed but the second homograft that was transplanted with the usual cooling (10, 11), without prolonged preservation, behaved the same as the first and the patient died 2 days later. The histopathological changes were much the same in the first and second organs, including wide spread ischemic changes.
The intravascular infusion of cold electrolyte solution was the first effective technique of liver preservation (11), and it was not surprising that the same general method immediately became the standard for the quick cooling of kidney (9) and other organs.
However, in the early experience with canine liver transplantation, it was found that delay of more than 2 hr after this kind of cooling was not compatible with survival. From our present results, it is obvious that the time of 2 hr was a gross underestimate of what can be expected after simple infusion, providing other aspects of the operation and care are of high caliber. Even after 9 hr the results with lactated Ringer’s solution alone were almost equal to those achieved with the complex solutions. Thus, the most important ingredient of success, no matter what the solution, was organ hypothermia.
In our experiments, the extra value of special solutions became clear only with longer preservation times. At 18 hr, both the plasma solution of Shalm et al. (8) modified by Wall et al. (13) and the Collins solution yielded better results than lactated Ringer’s. Lambotte et al. (7) have previously shown the supplementary value of Collins solution for liver preservation.
If Collins solution is used, or for that matter the plasma solution preferred by Calne et al. (3), the safe time for liver preservation is extended to at least 9 hr and probably considerably beyond this. With this much time, the shipping of livers between most major American cities has become a real possibility. The implications of such a development were emphasized by Calne et al. (3) in their efforts at liver procurement in Europe.
The precaution of final flushing with lactated Ringer’s solution should be scrupulously taken if the Collins solution is used. In one of our patients, this step was omitted. When the organ was revascularized, the serum potassium abruptly rose to 6.5 mEq/p 1,000 ml, followed by cardiac arrest from which resuscitation fortunately was possible. The sudden efflux of the potassium-rich intrahepatic fluid with revascularization of the unflushed graft was undoubtedly responsible.
The organ procurement was organized and carried out by Shawney Fine, Natalie Nankin, Barbara Schulman, and Roger Smith, coordinators of the Terasaki Organ Procurement Program. Paul D. Taylor, Senior Instructor in Surgery, at the University of Colorado Medical Center arranged and carried out the organ transfer to Denver, Colorado.
1The work was supported by Research Grants MRIS 8118-01 and 7227-01 from the Veterans Administration, by Grants AM-17260 and AM-07772 from the National Institutes of Health, and by Grants RR-00051 and RR-00069 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Presented at the Third Annual Meeting of the American Society of Transplant Surgeons, June 2 to 3, 1977, Chicago, Illinois.