TRANSPLANTATION OF HEPATOCYTES FOR PREVENTION OF INTRACRANIAL HYPERTENSION IN PIGS WITH ISCHEMIC LIVER-FAILURE

Intracranial hypertension leading to brain stem herniation is a major cause of death in fulminant hepatic failure (FHF). Mannitol, barbitura tes, and hyperventilation have been used to treat brain swelling, but most patients are either refractory to medical management or cannot be treated because of concurrent medical problems or side effects. In th is study, we examined whether allogeneic hepatocellular transplantatio n may prevent development of intracranial hypertension in pigs with ex perimentally induced liver failure. Of the two preparations tested-tot al hepatectomy (n = 47), and liver devascularization (n = 16)-only pig s with liver ischemia developed brain edema provided, however, that an imals were maintained normothermic throughout the postoperative period . This model was then used in transplantation studies, in which six pi gs received intrasplenic injection of allogeneic hepatocytes (2.5 x 10 (9) cells/pig) and 3 days later acute liver failure was induced. In bo th models (anhepatic state, liver devascularization), pigs allowed to become hypothermic had significantly longer survival compared to those maintained normothermic. Normothermic pigs with liver ischemia had, a t all time points studied, ICP greater than 20 mmHg, Pigs that receive d hepatocellular transplants had ICP below 15 mmHg until death; at the same time, cerebral perfusion pressure (CPP) in transplanted pigs was consistently higher than in controls (45 +/- 11 mmHg vs. 16 +/- 18 mm Hg; p < 0.05). Spleens of transplanted pigs contained clusters of viab le hepatocytes (hematoxylin-eosin, CAM 5.2), It was concluded that rem oval of the liver does not result in intracranial hypertension; hypoth ermia prolongs survival time in both anhepatic pigs and pigs with live r devascularization, and intrasplenic transplantation of allogeneic he patocytes prevents development of intracranial hypertension in pigs wi th acute ischemic liver failure. (C) 1998 Elsevier Science Inc.