The Effect of Remote Ischemic Preconditioning in Living Donor Hepatectomy

Liver Transplantation Clinical Trial

Official title:

The Effect of Remote Ischemic Preconditioning on the Postoperative Liver Function in Living Donor Hepatectomy: a Randomized Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03386435
• Other study ID #: RIPC_donor
• Status: Completed
• Phase: N/A
• Start date: August 22, 2016
• Est. completion date: October 30, 2017

Study information

• Verified date: August 2019
• Source: Asan Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Liver transplantation is the gold standard treatment for patients with end-stage liver disease. Despite its outstanding success, liver transplantation still entails certain complications including ischemia-reperfusion injury. Remote ischemic preconditioning is a novel and simple therapeutic method to lessen the harmful effects of ischemia-reperfusion injury, however, the majority of remote ischemic preconditioning studies on hepatic ischemia-reperfusion injury have been animal studies. Therefore, our aim was to assess the effects of remote ischemic preconditioning on postoperative liver function in living donor hepatectomy.

Description:

Liver transplantation(LT) is the gold standard treatment for patients with end-stage liver disease. In light of advancements in surgical techniques, immunosuppressive agents, and perioperative critical care, the overall 3-year survival of patients undergoing LT has exceeded 80%. Despite its outstanding success, LT still entails certain complications including ischemia-reperfusion injury (IRI).

IRI occurs when the blood supply to an organ or tissue is temporarily cut-off and then restored, and it is well-known as an underlying cause of primary non-function, biliary complications, and eventual graft loss after LT. Despite many attempts to ameliorate hepatic IRI, no definitive therapies have been established. In addition, the mechanisms of IRI remain largely unclear.

Remote ischemic preconditioning (RIPC) is a novel and simple therapeutic method to lessen the harmful effects of IRI. RIPC indicate that brief episodes of ischemia with intermittent reperfusion are introduced at a remote site, leading to systemic protection against subsequent insults as evinced on kidney, heart, liver, and other tissues. While RIPC has been shown to reduce hepatic IRI in several small animal studies, the beneficial effects of RIPC in hepatic IRI have been inconsistent. By far, the majority of RIPC studies on hepatic IRI have been animal studies; hence, there are limitations relating to the lack of human clinical trials.

Therefore, our aim was to assess the effects of RIPC on postoperative liver function in living donor hepatectomy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: October 30, 2017
• Est. primary completion date: August 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Donors who plan to have living right hepatectomy for liver transplantation.

• age : between 18 to 60 years.

Exclusion Criteria:

• donors who plan to donate left lobe

• donors who plan to have laparoscopic right hepatectomy

• donors who cannot proceed remote ischemic preconditioning

Related Conditions & MeSH terms

• Ischemia
• Ischemia Reperfusion Injury
• Liver Transplantation
• Reperfusion Injury
• Tissue Donors

Intervention

Procedure:
• remote ischemic preconditioning
Remote ischemic preconditioning was performed following anesthesia induction in donors. The protocol involves 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mm Hg to one upper arm, followed by 5-minute reperfusion with the cuff deflated

Locations

Country	Name	City	State
Korea, Republic of	Asan medical center	Seoul	Songpa-gu

Sponsors (1)

Lead Sponsor	Collaborator
Asan Medical Center

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (24)

Abu-Amara M, Yang SY, Quaglia A, Rowley P, de Mel A, Tapuria N, Seifalian A, Davidson B, Fuller B. Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury. Clin Sci (Lond). 2011 Sep;121(6):257-66. doi: 10.1042/CS20100598. — View Citation

Abu-Amara M, Yang SY, Quaglia A, Rowley P, Tapuria N, Seifalian AM, Fuller BJ, Davidson BR. Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model. Liver Transpl. 2011 Jan;17(1):70-82. doi: 10.1002/lt.22204. — View Citation

Amador A, Grande L, Martí J, Deulofeu R, Miquel R, Solá A, Rodriguez-Laiz G, Ferrer J, Fondevila C, Charco R, Fuster J, Hotter G, García-Valdecasas JC. Ischemic pre-conditioning in deceased donor liver transplantation: a prospective randomized clinical trial. Am J Transplant. 2007 Sep;7(9):2180-9. — View Citation

Björnsson B, Winbladh A, Bojmar L, Sundqvist T, Gullstrand P, Sandström P. Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion. World J Gastroenterol. 2014 Jul 28;20(28):9506-12. doi: 10.3748/wjg.v20.i28.9506. — View Citation

Charlton MR. Improving long-term outcomes after liver transplantation. Clin Liver Dis. 2014 Aug;18(3):717-30. doi: 10.1016/j.cld.2014.05.011. Review. — View Citation

Foley DP, Fernandez LA, Leverson G, Chin LT, Krieger N, Cooper JT, Shames BD, Becker YT, Odorico JS, Knechtle SJ, Sollinger HW, Kalayoglu M, D'Alessandro AM. Donation after cardiac death: the University of Wisconsin experience with liver transplantation. Ann Surg. 2005 Nov;242(5):724-31. — View Citation

Franchello A, Gilbo N, David E, Ricchiuti A, Romagnoli R, Cerutti E, Salizzoni M. Ischemic preconditioning (IP) of the liver as a safe and protective technique against ischemia/reperfusion injury (IRI). Am J Transplant. 2009 Jul;9(7):1629-39. doi: 10.1111/j.1600-6143.2009.02680.x. Epub 2009 Jun 10. — View Citation

Gill R, Kuriakose R, Gertz ZM, Salloum FN, Xi L, Kukreja RC. Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance. Mol Cell Biochem. 2015 Apr;402(1-2):41-9. doi: 10.1007/s11010-014-2312-z. Epub 2015 Jan 1. Review. — View Citation

Halladin NL. Oxidative and inflammatory biomarkers of ischemia and reperfusion injuries. Dan Med J. 2015 Apr;62(4):B5054. Review. — View Citation

Hausenloy DJ, Erik Bøtker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, Lecour S, van Laake LW, Madonna R, Ruiz-Meana M, Schulz R, Sluijter JP, Yellon DM, Ovize M. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res. 2013 Apr 1;98(1):7-27. doi: 10.1093/cvr/cvt004. Epub 2013 Jan 19. Review. — View Citation

Hwang S, Lee SG, Lee YJ, Sung KB, Park KM, Kim KH, Ahn CS, Moon DB, Hwang GS, Kim KM, Ha TY, Kim DS, Jung JP, Song GW. Lessons learned from 1,000 living donor liver transplantations in a single center: how to make living donations safe. Liver Transpl. 2006 Jun;12(6):920-7. — View Citation

Imamura H, Kokudo N, Sugawara Y, Sano K, Kaneko J, Takayama T, Makuuchi M. Pringle's maneuver and selective inflow occlusion in living donor liver hepatectomy. Liver Transpl. 2004 Jun;10(6):771-8. — View Citation

Jung KW, Kim WJ, Jeong HW, Kwon HM, Moon YJ, Jun IG, Song JG, Hwang GS. Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy: A Propensity Score-Matched Analysis. Anesth Analg. 2018 Mar;126(3):796-804. doi: 10.1213/ANE.0000000000002756. — View Citation

Kanoria S, Jalan R, Seifalian AM, Williams R, Davidson BR. Protocols and mechanisms for remote ischemic preconditioning: a novel method for reducing ischemia reperfusion injury. Transplantation. 2007 Aug 27;84(4):445-58. Review. — View Citation

Kanoria S, Robertson FP, Mehta NN, Fusai G, Sharma D, Davidson BR. Effect of Remote Ischaemic Preconditioning on Liver Injury in Patients Undergoing Major Hepatectomy for Colorectal Liver Metastasis: A Pilot Randomised Controlled Feasibility Trial. World J Surg. 2017 May;41(5):1322-1330. doi: 10.1007/s00268-016-3823-4. — View Citation

Karp SJ, Johnson S, Evenson A, Curry MP, Manning D, Malik R, Lake-Bakaar G, Lai M, Hanto D. Minimising cold ischaemic time is essential in cardiac death donor-associated liver transplantation. HPB (Oxford). 2011 Jun;13(6):411-6. doi: 10.1111/j.1477-2574.2011.00307.x. Epub 2011 Apr 4. Review. — View Citation

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Kim YK, Shin WJ, Song JG, Jun IG, Kim HY, Seong SH, Huh IY, Hwang GS. Effect of right ventricular dysfunction on dynamic preload indices to predict a decrease in cardiac output after inferior vena cava clamping during liver transplantation. Transplant Proc. 2010 Sep;42(7):2585-9. doi: 10.1016/j.transproceed.2010.04.041. — View Citation

Man K, Fan ST, Ng IO, Lo CM, Liu CL, Yu WC, Wong J. Tolerance of the liver to intermittent pringle maneuver in hepatectomy for liver tumors. Arch Surg. 1999 May;134(5):533-9. — View Citation

Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993 Mar;87(3):893-9. — View Citation

Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, Koch M, Makuuchi M, Dematteo RP, Christophi C, Banting S, Usatoff V, Nagino M, Maddern G, Hugh TJ, Vauthey JN, Greig P, Rees M, Yokoyama Y, Fan ST, Nimura Y, Figueras J, Capussotti L, Büchler MW, Weitz J. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011 May;149(5):713-24. doi: 10.1016/j.surg.2010.10.001. Epub 2011 Jan 14. — View Citation

Robertson FP, Fuller BJ, Davidson BR. An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation. J Clin Med. 2017 Jul 14;6(7). pii: E69. doi: 10.3390/jcm6070069. Review. — View Citation

Robertson FP, Magill LJ, Wright GP, Fuller B, Davidson BR. A systematic review and meta-analysis of donor ischaemic preconditioning in liver transplantation. Transpl Int. 2016 Nov;29(11):1147-1154. doi: 10.1111/tri.12849. Epub 2016 Sep 20. Review. — View Citation

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postopera The Maximal Aspartate Aminotransferase Level Within 7 Postoperative Days	The serial assessments of routine laboratory values were used as early markers for postoperative liver function. The maximal aspartate aminotransferase level within 7 postoperative days were assessed following RIPC in living donor hepatectomy.	within 7 days after operation
Primary	The Maximal Alanine Aminotransferase Level Within 7 Postoperative Days	The serial assessments of routine laboratory values were used as early markers for postoperative liver function. The maximal alanine aminotransferase level within 7 postoperative days were assessed following RIPC in living donor hepatectomy	within 7 days after operation
Secondary	Number of Participants With Delayed Recovery of Liver Function	The incidence of delayed recovery of hepatic function (DRHF) were used as surrogate parameters indicating the possible benefits of RIPC. DRHF was defined based on a proposal by the International Study Group of Liver Surgery, as follows: an impaired ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased PT INR and concomitant hyperbilirubinemia (considering the normal limits of the local laboratory) on or after postoperative day 5. The normal upper limits of PT and bilirubin in our institutional laboratory were 1.30 INR and 1.2 mg/dL, respectively. If either the PT INR or serum bilirubin concentration was preoperatively elevated, DRHF was defined by an increasing PT INR and increasing serum bilirubin concentration on or after postoperative day 5 (compared with the values of the previous day).	postoperative 7 days
Secondary	Postoperative Liver Regeneration	The postoperative liver regeneration index (LRI) at postoperative 1 month ) was used as surrogate parameters indicating the possible benefits of RIPC. The LRI was defined as [(VLR - VFLR)/VFLR)] × 100, where VLR is the volume of the liver remnant and VFLR is the volume of the future liver remnant. Liver volume was calculated by CT volumetry using 3-mm-thick dynamic CT images. The graft weight was subtracted from the total liver volume to define the future liver remnant.	1 month