Hypothesis: A Canadian multicentre clinical trial is feasible. Study Design: Multicenter internal pilot parallel arm randomized controlled trial.

Study population: Patients with end-stage liver disease (ESLD) undergoing a liver transplantation, not meeting any exclusion criteria.

Primary feasibility endpoint: An overall recruitment rate ≥ 4 patients/month across all four participating sites.

Secondary feasibility endpoints: A protocol adherence > 90%, a 30-day (or hospital discharge) and 6-month outcome measurement > 90%, and a mean difference in total intraoperative volume received (crystalloids and colloids combined) > 1000 ml between groups.

Study intervention: Low splanchnic blood volume restrictive fluid management strategy (intervention). A phlebotomy, performed prior to dissection and transfused back after graft reperfusion, combined with a hemodynamic goal-directed restrictive fluid management strategy.

Optimized cardiac-output liberal fluid management strategy (control) A hemodynamic goal-directed liberal fluid management strategy that optimizes cardiac output throughout surgery.

MAIN OBJECTIVE The main objective of the REFIL-1 pilot study is to establish the feasibility (recruitment, adherence, outcome measurement) of conducting a Canadian multicentre randomized controlled trial comparing an intraoperative low-splanchnic blood volume restrictive fluid management strategy to a cardiac output optimised liberal fluid management strategy in adult liver transplantation (LT) for ESLD. The hypothesis is that a Canadian multicentre clinical trial is feasible.

SECONDARY OBJECTIVES The overarching objective of the REFIL (Restrictive Fluid management In Liver transplantation) research program, which will be answered in a future large-scale trial, regards the efficacy of the proposed interventional strategy to improve postoperative outcomes in LT.

TERTIARY OBJECTIVES Our tertiary objective is to measure the cost-effectiveness of the proposed intervention based on the composite outcome of any severe postoperative complications and graft loss.

DESIGN AND STUDY POPULATION This study is a multicentre internal pilot parallel arm randomized trial comparing two intraoperative hemodynamic and splanchnic blood volume management strategies in LT recipients.

This study is conducted in two phases: a pilot phase, which demonstrated feasibility across Canada, followed by a larger-scale phase (the efficacy phase).

Inclusion Criteria:

• Any adult patient ≥ 18 years of age undergoing liver transplantation for ESLD.

Exclusion Criteria:

• Patients undergoing LT for an indication other than ESLD such as acute liver failure, liver cancer without ESLD, retransplantation, amyloid neuropathy or any other indication not associated with ESLD.
• Patients undergoing a combined liver and lung or liver and heart transplantation.
• Patients with any of the following conditions:
• severe chronic renal failure (GFR < 15 ml/minute/1.73 m2 [CKD-EPI equation] or already on RRT);
• severe anemia (hemoglobin level < 80 g/L);76,93,109
• hemodynamic instability (norepinephrine equivalent > 10 ug/min).

End-of-grant KT modalities will be used to reach other important stakeholders, researchers and members of the anesthesia and transplantation community: scientific meetings, publication in an open-access journal, and public presentations with patient partners. Knowledge diffusion on potential difficulties of conducting such trials (and solutions) will be transferred to the research community through the Canadian Perioperative Anesthesia Clinical Trial group (PACT), the Canadian Donation and Transplantation Research Program (CDTRP) and the International Liver Transplantation Society (ILTS) meetings.

Only the anesthesiology team will know the allocation received, as they must implement the intervention, thereby limiting differential outcome classification bias because they will not assess outcomes. Patients, surgeons, and non-anesthesia health professionals will be blinded to the allocation.