Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans

Objective To determine whether ischemic preconditioning protects the human liver agai nst a subsequent period of ischemia in patients undergoing hemihepatectomy, and to identify possible underlying protective mechanisms of ischemic prec onditioning, such as inhibition of hepatocellular apoptosis. Summary Background Data Ischemic preconditioning is a short period of ischemia followed by a brief period of reperfusion before a sustained ischemic insult. Recent studies in rodents suggest that ischemic preconditioning is a simple and powerful pro tective modality against ischemic injury of the liver. The underlying mecha nisms are thought to be related to downregulation of the apoptotic pathway. Methods Twenty-four patients undergoing hemihepatectomy for various reasons alterna tively received ischemic preconditioning (10 minutes of ischemia and 10 min utes of reperfusion) before transection of the liver performed under inflow occlusion for exactly 30 minutes. Liver wedge and Tru-cut biopsy samples w ere obtained at the opening of the abdomen and 30 minutes after the end of the hepatectomy. Serum levels of aspartate transferase, alanine transferase , bilirubin and prothrombin time were determined daily until discharge. Hep atocellular apoptosis was evaluated by in situ terminal deoxynucleotidyl tr ansferase mediated d-UTP nick end-labeling (TUNEL) assay and electron micro scopy. Caspase 3 and 8 activities were measured in tissue using specific fl uorometric assays. Results Serum levels of aspartate transferase and alanine transferase were reduced by more than twofold in patients subjected to ischemic preconditioning vers us controls. The analysis of a subgroup of patients with mild to moderate s teatosis indicated possible increased protective effects of ischemic precon ditioning. In situ TUNEL staining demonstrated a dramatic reduction in the number of apoptotic sinusoidal lining cells in the ischemic preconditioning group. Electron microscopy confirmed features of apoptosis present in cont rol but not in ischemic preconditioning patients. There was no significant difference in caspase 3 and 8 activity when patients with ischemic precondi tioning were compared with controls. Conclusions Ischemic preconditioning is a simple and effective modality protecting the liver against subsequent prolonged periods of ischemia. This strategy may b e a more attractive technique than intermittent inflow occlusion, which is associated with increased blood loss during each period of reperfusion.