Ischemic preconditioning: application in clinical liver transplantation.

I schemic preconditioning (IPC) was first described as a situation in which a brief episode of ischemia slows the rate of adenosine triphosphate depletion during subsequent ischemic episodes. This was later correlated with enhanced viability and organ function.1 First described in hearts, this phenomenon has been extended to brain, lung, kidney, skeletal muscle, intestine, and liver. The significance of this finding is highlighted by the overwhelming consistency of ameliorating ischemic injury in these experimental systems using IPC. However, the mechanism(s) of IPC protection against subsequent ischemia and reperfusion has not been clearly elucidated. A variety of mechanisms have been postulated, from mitochondrial adenosine triphosphate–sensitive potassium channels2 to suppression of such leukocyte adhesion molecules as P-selectin3 to induction of heat-shock proteins4 and possibly augmenting adenosine release.5 Whatever the mechanism(s) of IPC, this response may be an inherent method of organ and tissue protection against a variety of insults. Other conditions can mimic the changes associated with IPC; for instance, dipyridamole increases adenosine bioavailability, which is believed to be important in attenuating leukocyte endothelial cell adhesion. Administration of dipyridamole before an ischemic insult significantly reduces injury during reperfusion.6 Adenosine-A2 (but not A1) receptor agonists also have been able to protect liver endothelial cells from ischemia.7 Inhibitors of nitric oxide synthase, such as NG-monomethyl-L-arginine, worsen ischemia-reperfusion injury, most likely through enhancement of P-selectin expression.8 It has been shown that P-selectin mediates reperfusion injury through adherence of neutrophils and platelets to damaged endothelium.9 Even such physical stress as heat shock (at temperatures as low as 42°C) can protect livers from subsequent ischemia.10 The concept of IPC recently has been applied to experimental models of organ preservation. In animal models, IPC has enhanced donor heart preservation, and this protection is additive to the benefit associated with hypothermia and preservation solutions.11,12 Garcia-Valdecasas et al13 reported that livers from pigs that sustained brief periods of cardiac arrest followed by normothermic recirculation had significantly improved survival compared with donors that experienced cardiac arrest without reperfusion. In the current study by Arai et al,14 they confirmed other studies showing that vascular inflow occlusion for a brief period extends the time that a liver can tolerate subsequent ischemic injury, as well as to increase survival of animals that were subjected to IPC before prolonged preservation injury. In addition, they showed that the benefits of IPC appear to be reflected primarily in the nonparenchymal cell population, particularly sinusoidal endothelial cells and Kuppfer cells. It previously has been shown that the primary target of preservation-reperfusion injury is endothelial cells.15 IPC appears to mitigate endothelial cell injury. The interesting finding in this study is that IPC of 1 portion of the liver also preconditions the nonparenchymal cell population to further ischemia in the contralateral portion, termed heterologous preconditioning. Although there are no prospectively designed studies of IPC for clinical liver transplantation, several pieces of evidence support the validity of this concept to clinical applications. For example, Totsuka et al16 showed that livers procured from human donors who sustained cardiopulmonary arrest and were resuscitated had no effect on graft survival or function. Postperfusion liver injury, measured by the peak levels of transaminases, was significantly less in the livers from donors who sustained prior cardiac arrest. These data clearly refute the older practice of disregarding donors with a recent history of cardiac arrest. In addition, during liver resections, it is commonplace for liver surgeons to either clamp the entire hepatoduodenal ligament for brief periods (i.e., Pringle manuever) or more selectively clamp lobar inflow vessels to delineate the lines of demarcation for From Transplantation Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. Address reprint requests to John J. Fung, MD, PhD, Transplantation Surgery, University of Pittsburgh Medical Center, 3601 Fifth Ave, 4 Falk Clinic, Pittsburgh, PA 15213. Telephone: 412-647-9576; FAX: 412647-5480; E-mail: fungjf@msx.upmc.edu Copyright © 2001 by the American Association for the Study of Liver Diseases 1527-6465/01/0704-0018$35.00/0 doi:10.1053/jlts.2001.22457