Pharmacological interventions show potential for a protective role against ischaemia-reperfusion injury in liver resections

Elective liver surgery undertaken for a variety of reasons may require occlusion of the blood supply to the liver in order to reduce bleeding from the cut liver surface. This temporary blood supply interruption can cause liver damage for a variety of reasons. In experimental studies many drugs have shown some promise in decreasing liver damage caused by the occluded blood supply. We identified a total of 15 randomised trials evaluating 11 different pharmacological interventions (methylprednisolone, multivitamin antioxidant infusion, vitamin E infusion, amrinone, prostaglandin E1, pentoxifylline, mannitol, trimetazidine, dextrose, allopurinol, and OKY 046). All trials had risk of bias ('systematic errors') and risk of play of chance ('random errors'). There was no significant difference between the groups in mortality, liver failure, or post-operative complications. The trimetazidine group had a significantly shorter hospital stay, and the vitamin E group had a significantly shorter intensive therapy unit stay than the respective controls. There was no significant difference in any of the clinically relevant outcomes in the remaining comparisons. Methylprednisolone improved the enzyme markers of liver function and trimetazidine, methylprednisolone, and dextrose reduced the enzyme markers of liver injury compared to controls. However, there is a high risk of type I (erroneously concluding that an intervention is beneficial when it is actually not beneficial) and type II errors (erroneously concluding that an intervention is not beneficial when it is actually beneficial) because of the few trials included, the small sample size in each trial, and the risks of bias. Three pharmacological drugs - trimetazidine, methylprednisolone, and dextrose - have potential for a protective role against liver injury in elective liver surgery involving blood supply occlusion. However, based on the current evidence it is recommended that the use of these agents should be restricted to well-designed trials in patients undergoing resection.

Authors' conclusions: 

Trimetazidine, methylprednisolone, and dextrose may protect against ischaemia reperfusion injury in elective liver resections performed under vascular occlusion, but this is shown in trials with small sample sizes and high risk of bias. The use of these drugs should be restricted to well-designed randomised clinical trials before implementing them in clinical practice.

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Background: 

Vascular occlusion to reduce blood loss is used during elective liver resection but results in significant ischaemia reperfusion injury. This, in turn, might lead to significant postoperative liver dysfunction and morbidity. Various pharmacological drugs have been used with an intention to ameliorate the ischaemia reperfusion injury in liver resections.

Objectives: 

To assess the benefits and harms of different pharmacological agents versus no pharmacological interventions to decrease ischaemia reperfusion injury during liver resections where vascular occlusion was performed during the surgery.

Search strategy: 

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until January 2009.

Selection criteria: 

We included randomised clinical trials, irrespective of language or publication status, comparing any pharmacological agent versus placebo or no pharmacological agent during elective liver resections with vascular occlusion.

Data collection and analysis: 

Two authors independently identified trials for inclusion and independently extracted the data. We analysed the data with both the fixed-effect and the random-effects models using RevMan Analysis. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis or available case analysis.

Main results: 

We identified a total of 15 randomised trials evaluating 11 different pharmacological interventions (methylprednisolone, multivitamin antioxidant infusion, vitamin E infusion, amrinone, prostaglandin E1, pentoxifylline, mannitol, trimetazidine, dextrose, allopurinol, and OKY 046 (a thromboxane A2 synthetase inhibitor)). All trials had high risk of bias. There were no significant differences between the groups in mortality, liver failure, or perioperative morbidity. The trimetazidine group had a significantly shorter hospital stay than control (MD -3.00 days; 95% CI -3.57 to -2.43). There were no significant differences in any of the clinically relevant outcomes in the remaining comparisons. Methylprednisolone improved the enzyme markers of liver function and trimetazidine, methylprednisolone, and dextrose reduced the enzyme markers of liver injury compared with controls. However, there is a high risk of type I and type II errors because of the few trials included, the small sample size in each trial, and the risk of bias.

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