A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning

Abstract

Objective: To evaluate the protective effects of ischemic preconditioning in a prospective randomized study involving a large population of unselected patients and to identify factors affecting the protective effects.

Summary background data: Ischemic preconditioning is an effective protective strategy in several animal models. Protection has also been suggested in a small series of patients undergoing a hemihepatectomy with 30 minutes of inflow occlusion. Whether preconditioning confers protection in other types of liver resection and longer periods of ischemia is unknown. Therefore, we conducted a prospective randomized study to evaluate the impact of ischemic preconditioning in liver surgery.

Methods: A total of 100 unselected patients undergoing major liver resection (> bisegmentectomy) under inflow occlusion for at least 30 minutes were randomized during surgery to either receive or not receive an ischemic preconditioning protocol (10 minutes of ischemia followed by 10 minutes of reperfusion). Univariate and multivariate analyses were performed to identify independent factors affecting the protective effects of ischemic preconditioning. ATP contents in liver were measured as a possible mechanism of protection.

Results: Both groups (n = 50 in each) were comparable regarding age, gender, duration of inflow occlusion, and resected liver volumes. Postoperative serum transaminase levels were significantly lower in preconditioned than in control patients (median peak AST 364 U/L vs. 520 U/L, P = 0.028; ALT 406 vs. 519 U/L, P = 0.049). Regression multivariate analysis revealed an increased benefit of ischemic preconditioning in younger patients, in patients with longer duration of inflow occlusion (up to 60 minutes), and in cases of lower resected liver volume (<50%). Patients with steatosis were also particularly protected by ischemic preconditioning. ATP content in liver tissue was preserved by ischemic preconditioning in young but not older patients.

Conclusions: This study establishes ischemic preconditioning as a protective strategy against hepatic ischemia in humans. The strategy is particularly effective in young patients requiring a prolonged period of inflow occlusion, and in the presence of steatosis, and is possibly related to preservation of ATP content in liver tissue. Other strategies are needed in older patients.

Figures

FIGURE 1. Treatment protocol of the preconditioning and the control groups. Preconditioning patients received 10 minutes of ischemia and 10 minutes of reperfusion (ischemic preconditioning) prior to the prolonged ischemic insult.

FIGURE 2. Peak AST levels of the preconditioning and the control groups after liver resection. Ischemic preconditioning resulted in decreased AST levels when compared with the control (n = 50 in each group, P = 0.028).

FIGURE 3. The impact of age on postoperative transaminase levels was evaluated in a match pair analysis. Each dot represents a pair of patients, one without preconditioning (control) and one from the preconditioning group. Both patients were matched for age, Pringle time, and resected volume. The y-axis represents the difference in peak AST levels in each pair (delta AST = peak-ASTcontrol – peak-ASTpreconditioning). Higher delta AST values indicate protection from ischemic preconditioning. Younger patients are maximally protected, whereas patients older than 70 years appear to have negative effects.

FIGURE 4. Ischemic preconditioning in patients younger than 60 years versus patients 60 years of age or older. Preconditioning resulted in a significantly reduced AST level in young patients. In contrast, older patients were not protected by ischemic preconditioning with similar AST values when compared with the control.

FIGURE 5. Ischemic preconditioning was particularly effective in patients receiving liver resections of <50% liver volume. In contrast, no statistical difference was detected between the preconditioning and the control group if >50% liver volume were resected.

FIGURE 6. Effects of ischemia time on ischemic preconditioning. Ischemic preconditioning resulted in a 50% decrease in AST levels when >40 minutes inflow occlusion was used during liver resection. If the inflow occlusion were <40 minutes, only a moderate decrease of AST levels was achieved by preconditioning.

FIGURE 7. Ischemic preconditioning was particularly effective in steatotic livers with a 40% decrease of postoperative peak AST levels. In contrast, a smaller AST reduction was achieved by preconditioning in nonsteatotic livers when compared with the control.

FIGURE 8. ATP levels were determined in the liver tissue from old (≥60 years) and young (<60 years) patients with or without preconditioning. Patients were matched for age, ischemia time, and resected liver volume in the young and old patient group. The results are expressed as ATP content in the post-reperfusion biopsy (Rp) minus the baseline biopsy (BL) per milligram of protein. In the young group, control patients decreased the intrahepatic ATP levels during ischemia and reperfusion, while ischemic preconditioning resulted in an increased intrahepatic ATP content. In the old group, control patients also decreased the ATP level during ischemia and reperfusion. Ischemic preconditioning in old patients resulted in a further decline of post-reperfusion ATP values.