A Multicenter Randomized Controlled Trial to Compare the Efficacy of End-ischemic Dual Hypothermic Oxygenated Perfusion with Standard Static Cold Storage of Liver Grafts Donated after Circulatory Death in Preventing Non-anastomotic Biliary Strictures after Transplantation

Recent publications report good results of controlled donation after
circulatory death (DCD) Maastricht category III liver transplantation when
strict donor-recipient matching is applied and ischemia times are kept to a
minimum. However a major concern remains the high rate of biliary complications
after transplantation of DCD livers. Non-anastomotic biliary strictures (NAS)
occur in 29% of patients receiving a DCD graft whereas the incidence of NAS in
recipients of donation after brain death (DBD) liver grafts is 11%. NAS are
associated with higher morbidity and increased cost of liver transplantation.
Injury to the biliary epithelium and the peribiliary vascular plexus occurring
during donor warm ischemia and static cold storage (SCS) has been identified as
a major risk factor for development of NAS. Machine perfusion has been proposed
as an alternative strategy for organ preservation, offering the opportunity to
improve the quality of the organ by providing oxygen to the graft. Experimental
studies have shown that end-ischemic hypothermic oxygenated machine perfusion
(DHOPE) helps liver grafts to recover from ischemia by restoring mitochondrial
function. Moreover, DHOPE has been shown to provide better preservation of
peribiliary vascular plexus of the bile ducts, which could be an important step
forward in reducing the incidence of NAS after transplantation.

To study the efficacy of end-ischemic DHOPE in reducing the incidence of NAS
within six months after controlled DCD (Maastricht category III) liver
transplantation.

An international, multicenter, prospective, randomized, controlled,
interventional, clinical trial with a two parallel arm approach
(treatment/control).

In the intervention group liver grafts will be subjected to two hours of
hypothermic, oxygenated perfusion at the end of SCS and before implantation. In
the control group donor liver grafts will be preserved in accordance to
standard practice by SCS only, without any further intervention.

Patients participating in this trial will experience minimal burden. There are
only three differences compared with the routine practice: livers undergo DHOPE
and patients undergo a MRCP at six months after transplantation and fill in a
questionnaire. The intervention, DHOPE, is associated with a non-significant
risk of injury of the isolated liver due to perfusion pressure or perfusion
failure. The perfusion pressures in this protocol are very low and are reported
to cause no harm to the organ. In case of perfusion failure, the liver can
easily and quickly (within minutes) be brought to the same conditions as in the
control group. In these bridging minutes the organ has a metabolism of 19%
instead of the 11%. This is non-significant especially because the organ is
saturated with oxygen before the possible event. There is a burden but there
are no risks related to MRCP, which is planned during a routine hospital visit.
When the intervention is effective in reducing the incidence of NAS, the
patients participating in this trial benefit substantially when they are
randomized to the intervention group. This study can only be performed in these
patients because they undergo a DCD liver transplantation. The questionnaire is
on health related quality of life and consists of six questions which take
about 5 minutes to fill in. The questionnaire is obtained before
transplantation and six months after transplantation.