Remote ischaemic preconditioning in orthotopic liver transplantation (RIPCOLT trial): a pilot randomized controlled feasibility study

Abstract

Abstract:Ischaemia Reperfusion (IR) injury is a major cause of post-operative morbidity, mortality and graft loss following Orthotopic Liver Trasnplantation (OLT). There is no current accepted treatment for IR injury. The recent drive to implant more marginal grafts, which are more susceptible to IR injury makes this clinical problem a key research goal. Remote Ischaemic Preconditioning (RIPC) has been shown to ameliorate hepatic IR injury in small animal models. Whether recipient RIPC can reduce IR injury in human liver transplant recipients has not previously been investigated. Methods:Forty patients with end stage liver disease undergoing liver transplantation were randomized to RIPC or a sham control group. RIPC was induced through three 5 minute cycles of alternate ischaemia and reperfusion using an orthopaedic tourniquet to the left lower limb under general anaesthesia prior to commencement of the abdominal procedure. The aim of the study was to determine the safety and feasibility of limb RIPC in patients with end stage cirrhosis. Data on clinical outcomes was collected prospectively (minimum 3 month follow up) and the function of the graft was also evaluated. Plasma cytokine levels were measured at baseline, 2 hours post reperfusion and at 24 hours post-operatively. Results:45 of 51 patients approached (88%) were willing to enroll in the study. 5 patients were then excluded and 40 patients were randomized of which 20 underwent RIPC.RIPC was able to be performed in all patients randomized to the RIPC group. There was no evidence of localized complications following RIPC. One patient died in the control group and 1 further graft was lost in the control group due to a non-IR related 3 issue. Median AST levels on the third post-operative day showed a slightly higher trend in the RIPC group than in the control group (221iU vs 149iU, p=1.00) but this was not statistically significant. Conclusions:RIPC is acceptable and can be carried out safely in patients with advanced liver disease. This pilot feasibility study has not demonstrated evidence of a reduction in IR injury or clinical benefit. A longer follow up, a larger study or an altered preconditioning protocol may be required. 4Liver transplantation is the treatment of choice for both acute and chronic end stage liver disease. As outcomes following transplantation have improved, the indications for liver transplantation have been widened and a shortage of suitable organ donors has developed. This has resulted in an increased use of grafts from marginal donors such as the elderly and those with a fatty liver from obesity (extended criteria donors) and especially the use of grafts from donors following cardiac death (DCD). The use of liver DCD grafts in the UK has increased from 6.9% in 2005 1 to 19.1% of grafts implanted in 2013 2 .Ischaemia Reperfusion (IR) injury is the damage that happens to an organ when its blood supply is interrupted and reconstituted. It is a major cause of morbidity and mortality following liver transplantation and is believed to acc...

Novel Benefits of Remote Ischemic Preconditioning Through VEGF-dependent Protection From Resection-induced Liver Failure in the Mouse

“…RIPC is a recent preconditioning method, and its clinical efficacy is being evaluated. 21,22 We have initiated a clinical trial assessing the impact of RIPC on postoperative complications associated with major surgical procedures including hepatectomies (NCT02375269). Meanwhile, experimental data can give hints to estimate the advantages that may be expected from RIPC.…”

Impact of three methods of ischemic preconditioning on ischemia-reperfusion injury in a pig model of liver transplantation

“…For RIPC, the most widely used technique is clamping one limb of a patient 25 or animal. 26 However, for our project we chose a different target territory, i.e.…”

“…26 On the other hand, our results are consistent with those from human studies in which direct and remote IPC increased AST and ALT values 24h after reperfusion. 25,30 We made a refinement in this current investigation, by adding some molecular analyses that could show some beneficial effects of IPC. In the liver tissue, the combined IPC approach resulted in marked positive changes in gene expression.…”

Ischemic Preconditioning Directly or Remotely Applied on the Liver to Reduce Ischemia-Reperfusion Injury in Resections and Transplantation

“…This was repeated twice and completed prior to the transplant procedure. Authors demonstrated that RIPC is feasible, acceptable to patients and safe in this group of patients but clinical benefits within the first 3 months post transplantation were not detected [75]. Authors suggest that 5 min cycles are insufficient to create localized ischemia in the limb [75].…”

“…The first trial to investigate the feasibility of RIPC in liver transplant recipients was addressing by Robertson et al [75]. The trial involved randomization of adult recipients undergoing deceased donor liver transplantation.…”