Comparison of BQ123, Epoprostenol, and Verapamil as Vasodilators During Normothermic Ex Vivo Liver Machine Perfusion

Background The optimal vasodilator to avoid hepatic artery (HA) vasospasm during normothermic ex vivo liver perfusion (NEVLP) is yet to be determined. We compared safety and efficacy of BQ123 (endothelin1 antagonist), Epoprostenol (prostacyclin analogue), and Verapamil (calcium channel antagonist). Methods Livers from porcine heart beating donors were perfused for 3 hours and transplanted into recipient pigs. Four groups were compared: Group 1: livers perfused with a dose of 1.25 mg of BQ123 at baseline and at 2 hours of perfusion, Group 2: Epoprostenol at a continuous infusion of 4mg/hr, Group 3: Verapamil 2.5mg at baseline and at 2 hours of perfusion, Group 4: No vasodilator used during ex vivo perfusion. Liver injury and function were assessed during perfusion, and daily post transplantation until postoperative day 3. All groups were compared to a cold storage group for post operative graft function. Results Hepatic artery flow during NEVLP was significantly higher in BQ123 compared to Verapamil, Epopostenol, and no vasodilator treated livers. AST levels were significantly lower with BQ123 and Verapamil compared to Epoprostenol and control group during perfusion. Peak AST levels were lower in pigs receiving BQ123 and Verapamil perfused grafts compared to Epoprostenol and control group. INR, alkaline phosphatase, and total bilirubin levels were lower in the BQ123 and Verapamil groups compared to Epoprostenol group. Cold storage group had increased markers of ischemia reperfusion injury and slower graft function recovery compared to machine perfused grafts. Conclusion The use of BQ123, Epoprostenol, and Verapamil during NEVLP is safe. Livers perfused with BQ123 and Verapamil have higher HA flow and reduced hepatocyte injury during perfusion compared to Epoprostenol. Hepatic artery flow is significantly reduced in the absence of vasodilators during NEVLP. Authors Contributions. Juan Echeverri: Conception and design of the study, completion of experiments, acquisition of data, data analysis and interpretation, drafted manuscript, final approval for publication, and agreement to be accountable for all aspects of the work. Nicolas Goldaracena: Completion of experiments, acquisition of data, data analysis and interpretation, revised manuscript critically for important intellectual content, final approval for publication, and agreement to be accountable for all aspects of the work. Johan Moritz Kaths: Completion of experiments, acquisition of data, data analysis and interpretation, revised manuscript critically for important intellectual content, final approval for publication, and agreement to be accountable for all aspects of the work. Ivan Linares: Completion of experiments, acquisition of data, data analysis and interpretation final approval for publication, and agreement to be accountable for all aspects of the work. Roizar Rosales: Completion of experiments, acquisition of data, data analysis and interpretation final approval for publication, and agreement to be accountable for all aspects of the work. Dagmar Kollmann: Completion of experiments, acquisition of data, data analysis and interpretation final approval for publication, and agreement to be accountable for all aspects of the work. Matyas Hamar: Acquisition of data, data analysis and interpretation final approval for publication, and agreement to be accountable for all aspects of the work. Peter Urbanellis: Analysis and interpretation of data, revised manuscript critically for important intellectual content, final approval for publication, and agreement to be accountable for all aspects of the work. Sujani Ganesh: Acquisition of data, analysis and interpretation of data, revised manuscript critically for important intellectual content, final approval for publication, and agreement to be accountable for all aspects of the work. Oyedele Adeyi: Analysis and interpretation of data, revised manuscript critically for important intellectual content, final approval for publication, and agreement to be accountable for all aspects of the work. Mahmood Tazari: Statistical analysis and interpretation of data, revised manuscript critically, final approval for publication, and agreement to be accountable for all aspects of the work. Markus Selzner: Conception and design of the study, completion of experiments, acquisition of data, data analysis and interpretation, drafted manuscript, final approval for publication, and agreement to be accountable for all aspects of the work. Nazia Selzner: Conception and design of the study, acquisition of data, data analysis and interpretation, drafted manuscript, final approval for publication, and agreement to be accountable for all aspects of the work. Disclosure: The authors declare no conflicts of interest. Correspondence: Nazia Selzner, MD, PhD, Toronto General Hospital, NCSB 11C-1244, 585 University Avenue, Toronto, ON M5G2N2, Phone: 1-416-340-5230, Fax: 1-416-340-5242, e-mail: nazia.selzner@uhn Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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