An evaluation of the safety and preliminary efficacy of peri‐ and post‐operative treprostinil in preventing ischemia and reperfusion injury in adult orthotopic liver transplant recipients

Abstract

Background Orthotopic liver transplantation (OLT) is the only treatment option for various end‐stage liver diseases. Ischemia and reperfusion (I/R) injury is one of the unavoidable complications/conditions in OLT. In 2019, a total of 8896 livers were transplanted of which >94% organs were procured from deceased donors. An increase in the use of extended criteria donor (ECD) livers for transplantation further unraveled the role of hepatic I/R injury on short‐term and long‐term graft outcomes. Despite promising outcomes with the use of antioxidants, free radical scavengers, and vasodilators; I/R‐mediated liver injury persists and significantly influences the overall clinical outcomes. Treprostinil, a synthetic prostacyclin I2 (PGI2) analog, due to its vasodilatory property, antiplatelet activity, and its ability to downregulate pro‐inflammatory cytokines can potentially minimize I/R injury. Aim We investigated the safety and preliminary efficacy of continuous intravenous infusion of treprostinil in liver transplant recipients in a prospective, single‐center, non‐randomized, interventional study. Material and methods This was a dose escalation (3 + 3 design) phase 1/2 study. Deceased donor liver transplant recipients received 5 ng/kg/min for two days, or 2.5, 5, and 7.5 ng/min/kg for 5 days as a continuous infusion. Multiple blood samples were collected for biochemical parameter assessment and for measuring treprostinil levels. Indocyanine green plasma disappearance rate was used as a measure of hepatic functional capacity. Results Subjects tolerated continuous infusion of treprostinil up to 5 ng/kg/min for 120 h with no occurrence of primary graft non‐function (PNF), minimized need for ventilation support, reduced hospitalization time, 100% graft and patient survival, and improved hepatobiliary excretory function comparable to normal healthy adults. Discussion Treprostinil can be administered to liver transplant patients safely during the perioperative period. Conclusion Based on this phase 1/2 study, further efficacy studies of treprostinil in preventing I/R injury of liver should be conducted to potentially increase the number of livers available for transplantation.

Novel Targets and Therapeutic Strategies to Protect Against Hepatic Ischemia Reperfusion Injury

“…To examine the actual clinical effect of prostacyclin, early in 2000, a placebo controlled randomized clinical trial by Neumann et al ( 61 ) showed that treatment with prostacyclin tended to lower peak AST levels and induced a significant decrease in the difference between mixed venous oxygen content and hepatic venous oxygen content (delta O 2 ) after 24 and 48 h after reperfusion, which indicated an improvement of regional hepatic-splanchnic oxygenation. To our interest, recently, a prospective, single-center, non-randomized, interventional study was performed by Almazroo et al ( 30 ) to evaluate the safety and preliminary efficacy of perioperative treprostinil in preventing IRI in adult OLT recipients. In this study, subjects showed good tolerance to the continuous infusion of treprostinil without occurrence of primary graft non-function, which achieved 100% graft and recipient survival, minimized need for ventilation support, shortened hospitalization time, and improved hepatobiliary excretion comparable to normal healthy adults.…”

O-sialoglycoprotein Endopeptidase (OSGEP) Suppresses Hepatic Ischemia-Reperfusion Injury-Induced Ferroptosis Through Modulating the MEK/ERK Signaling Pathway

“…Ischemic reperfusion injury (IRI) is defined as the functional metabolic disorder and structural destruction caused by reperfusion based on ischemic injury after the blood supply of organs and tissues [1]. Hepatic ischemia-reperfusion injury (HIRI) is a serious and harmful surgical complication, typically appearing during hepatobiliary surgery [2], liver transplantation [3] traumatic shock, and severe infection in clinical practice [4]. To date, although tremendous efforts have been made to clarify the potential underlying mechanisms that contribute to HIRI insult, the cellular and molecular events, regulating cell damage after HIRI, have still remained elusive.…”

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog

“…However, no pharmacological options are currently approved for the prevention of hepatic ischemia-reperfusion injury following transplantation. A prospective, pilot, single-center, open-label, nonrandomized, dose-escalation phase I/II study in liver transplant patients investigated the efficacy of intravenous treprostinil administration in the prevention of hepatic ischemia-reperfusion with some encouraging results[ 118 ]. A small group of patients who underwent liver transplantation and received perioperative intravenous treprostinil at a dose of 5 ng/kg/min followed by postoperative contentious infusion at a dose of 2.5-5 ng/kg/min for approximately 5 d showed improved liver function and 100% graft and recipient survival at six months[ 118 ].…”

“…A prospective, pilot, single-center, open-label, nonrandomized, dose-escalation phase I/II study in liver transplant patients investigated the efficacy of intravenous treprostinil administration in the prevention of hepatic ischemia-reperfusion with some encouraging results[ 118 ]. A small group of patients who underwent liver transplantation and received perioperative intravenous treprostinil at a dose of 5 ng/kg/min followed by postoperative contentious infusion at a dose of 2.5-5 ng/kg/min for approximately 5 d showed improved liver function and 100% graft and recipient survival at six months[ 118 ]. Preliminary observations indicated a rapid reduction in transaminase plasma levels, improvement in hepatobiliary excretory function and prevention of the occurrence of acute kidney failure.…”

“…Although myocardial impairment is documented mostly as a subclinical event, the general clinical status of remote organ damage in the postreperfusion phase can directly affect overall survival rates. Additionally, while a hypothesis of myocardial injury in the setting of hepatic ischemia-reperfusion has already been reported, the consequences of the particular issue remain unclear[ 116 - 118 ].…”