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NCT Number: NCT07695363

Restrictive Fluid Management In Liver Transplantation (REFIL)

The goal of the REFIL-2 study is to evaluate the effectiveness of a low splanchnic blood volume restrictive fluid management strategy (a strategy that involves limiting fluid administration and prioritizing the use of medications that raise blood pressure during surgery, combined with phlebotomy) in improving patients' recovery after surgery. The study compares the low splanchnic blood volume restrictive fluid management strategy to an optimized cardiac-output liberal fluid management strategy (which involves administering more fluids to raise blood pressure with less reliance on medications). Outcomes important to patients will be measured.

This study (REFIL-2) had a vanguard phase (internal pilot) that included 138 patients (NCT05647733). The patients included in the vanguard pilot phase were not compared between groups but only analyzed descriptively using aggregated data. Only feasibility metrics were compared (see NCT05647733). These 138 patients were thus rolled into the REFIL-2 trial and included in the final sample size reported herein.

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Key information

Conditions

Liver Transplantation (LT) Digestive System Diseases End Stage Liver Disease End-stage Liver Disease (ESLD) Hepatic Insufficiency Liver Diseases Liver Failure

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Vancouver General Hospital (VGH), Vancouver, British Columbia, Canada

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About this study

People with advanced liver disease have poor blood circulation, and too much blood accumulates in the abdomen (a condition known as high intra-abdominal blood volume). However, liver transplantation (LT) is a complex surgery during which the patient can lose a significant amount of blood and blood pressure can fluctuate widely. Therefore, restricting fluids and using medications to raise blood pressure is a strategy that could reduce blood loss and potentially also certain complications after surgery. Furthermore, phlebotomy appears to reduce intra-abdominal blood volume, blood loss, drops in blood pressure, and the need for red blood cell transfusions, potentially improving recovery after surgery. This study therefore aims to determine the best way to manage fluids during a liver transplantation by comparing these two care strategies. Another goal of the study is to measure the cost-effectiveness of the proposed intervention.

Hypothesis: An intraoperative low splanchnic blood volume restrictive fluid management strategy is superior to an optimized cardiac-output liberal fluid management strategy in reducing postoperative severe complications after liver transplantation

Design: Multicenter blinded parallel arm randomized controlled trial

Study population: Adult patients undergoing a liver transplantation for end-stage liver disease (ESLD)

All participants will be followed during their index hospitalization up to post-transplantation Day 30 (whichever comes first), and for 12 months post-transplantation to assess some clinical outcomes, quality of life (QoL), and survival (being alive beyond the index hospitalization).

Participation in this study lasts 12 months.

The results of this study will help determine whether or not to recommend a low splanchnic blood volume restrictive fluid management strategy for people who undergo a liver transplantation.

This study is conducted in two phases: a pilot phase, which demonstrated feasibility across Canada, followed by the current larger-scale phase (REFIL-2).

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Adult ≥ 18 years old
  • Undergoing liver transplantation (LT)
  • End-stage liver disease (ESLD) (with or without hepatocellular carcinoma) as the indication for transplantation.

Exclusion criteria

  • Undergoing LT for an indication other than ESLD (e.g., acute liver failure, primary liver cancer without ESLD, retransplantation, amyloid neuropathy, polycystic liver disease, or any other indication not associated with ESLD)
  • Undergoing combined solid organ transplantations
  • Any of the following conditions:
  • severe chronic renal failure (GFR < 15 ml/minute/1.73 m2 [CKD-EPI equation] or already on renal replacement therapy (RRT))
  • severe anemia (hemoglobin level < 80 g/L)
  • hemodynamic instability (norepinephrine equivalent > 10 ug/min)
  • Physician refusal to enroll the patient.

Treatment and study plan

Low splanchnic blood volume restrictive fluid management strategy

Procedure

Hemodynamic goal-directed restrictive fluid management strategy

Other names: Restrictive

Phlebotomy

Procedure

Blood drawn in a blood donation bag prior to dissection and transfused back after graft reperfusion

Optimized cardiac output liberal fluid management strategy

Procedure

Permissive hemodynamic goal-directed fluid management strategy that optimizes cardiac output throughout surgery

Other names: Liberal

Primary outcomes

  1. Number of participants with at least one severe complication

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of at least one severe complications defined as a complication of grade ≥ 3 according to the Dindo-Clavien scale (grade 1 to 5)

Secondary outcomes

  1. Number of participants who were transfused at least one unit of red blood cells (RBC) during the perioperative period of surgery

    Time frame: During surgery (from entrance in the operating to exit of the operating room) and up to 48 hours after surgery (from exit of the operating room to 48 hours after exit of the operating room)

    Incidence of participants transfused at least 1 unit of RBC during the perioperative period of surgery

  2. Number of participants who were transfused at least one unit of red blood cells (RBC) during surgery

    Time frame: Intraoperative (from entrance in the operating room to exit of the operating room)

    Incidence of at least one RBC transfusion during surgery

  3. Intraoperative blood loss

    Time frame: Intraoperative (from entrance in the operating room to exit of the operating room)

    Blood loss as estimated by clinicians

  4. 7-day quality of recovery

    Time frame: One time point: 7 days after surgery (transplantation)

    Quality of recovery measured using the 15-item Quality of Recovery (QoR-15) score. Each item is scored on an 11-point numerical rating scale (0-10) for a total between 0 and 150, 0 being the worst possible recovery and 150 being a perfect recovery.

  5. Number of participants with a 7-day graft dysfunction

    Time frame: One time point: 7 days after surgery (transplantation)

    Incidence of graft dysfunction (as per Olthoff's definition)

  6. Number of participants with a 7-day acute kidney injury (AKI)

    Time frame: Over 7 days after surgery (criteria met at any day from surgery to day 7 after surgery)

    Acute kidney injury (AKI) of KDIGO grade 2 or 3

  7. Number of participants who were transfused at least one unit of red blood cells (RBC) up to hospital discharge

    Time frame: From surgery to hospital discharge (from entrance in the operating room to hospital discharge) or 30 days, whichever comes first

    Incidence of at least one RBC transfusion from surgery to hospital discharge

  8. Number of participants who were transfused at least one unit of any labile blood product up to hospital discharge

    Time frame: From surgery to hospital discharge (from entrance in the operating room to hospital discharge) or 30 days, whichever comes first

    Incidence of at least one labile blood product transfused from surgery up to hospital discharge

  9. Number of participants with at least one postoperative hemorrhagic complication up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of at least one postoperative hemorrhagic complication, defined as any bleeding episode associated with a drop of hemoglobin of 20 g/L within 24 hours of bleeding, requiring 2 blood units within 24 hours of bleeding, a surgical hemostasis or an angioembolization.

  10. Number of participants with postoperative acute kidney injury (AKI) up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of any postoperative acute kidney injury (AKI) (any grade as per KDIGO criteria) up to hospital discharge

  11. Number of participants requiring renal replacement therapy (RRT) up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of postoperative requirement for renal replacement therapy (RRT) [hemodialysis or hemofiltration] up to hospital discharge

  12. Number of participants with at least one postoperative graft complication up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of at least one postoperative graft complication (primary non-function, vascular, biliary) or retransplantation up to hospital discharge

  13. Number of participants with at least one postoperative infectious complication up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of any postoperative infectious complication (other than pneumonia) up to hospital discharge

  14. Number of patients with a postoperative wound dehiscence up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of postoperative wound dehiscence or evisceration up to hospital discharge

  15. Number of patients with at least one postoperative pulmonary complication up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of any postoperative pulmonary complications (atelectasis, pneumonia, pulmonary oedema) up to hospital discharge

  16. Number of participants with at least one postoperative thromboembolic complication up to hospital discharge

    Time frame: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first

    Incidence of at least one thromboembolic complication (deep vein thrombosis, pulmonary embolism, myocardial infraction, stroke, mesenteric ischemia) up to hospital discharge

  17. Number of participants with a postoperative ICU readmission up to hospital discharge

    Time frame: From initial ICU discharge (planned postoperative ICU or step-down unit admission) to hospital discharge or 30 days, whichever comes first

    Incidence of ICU readmissions after initial discharge (from the planned postoperative ICU or step-down unit admission) to hospital discharge

  18. Number of days not in an intensive care unit (ICU) at 30 days after surgery (30-day ICU-free days over 30 days)

    Time frame: From surgery to 30 days after surgery

    Number of days alive and not hospitalized in an ICU.

    0 means 30 consecutive days in the ICU or death within 30 days without any day without being in an ICU from surgery to death.

    30 means no days hospitalized in an ICU from surgery to the 30-day time point.

  19. Number of days without organ support at 30 days after surgery (30-day organ support free days)

    Time frame: From surgery to 30 days after surgery

    Number of days alive without renal replacement therapy, mechanical ventilation or vasopressor 30 days after surgery.

    0 means 30 consecutive days with any organ support or death within 30 days without any day without organ support from surgery to death.

    30 means no days with organ support from surgery to the 30-day time point.

  20. Hospital length of stay

    Time frame: From surgery to hospital discharge (up to 12 months after surgery)

    Length of hospital stay (days)

  21. Quality of life score

    Time frame: Two time points: 6 and 12 months after surgery

    Quality of life (QoL) score using the 36-item Short Form health survey questionnaire (SF-36). Score ranges from 0 (worst possible health) to 100 (best possible health).

  22. Rate of hospital readmissions

    Time frame: From hospital discharge after surgery to 12 months after surgery

    Number of postoperative hospital readmissions over 12 months after surgery

  23. Rate of 1-year graft complications

    Time frame: From surgery to 12 months after surgery

    Time to any graft complication (vascular or biliary) to 1 year after surgery

  24. Rate of 1-year graft survival

    Time frame: From surgery to 12 months after surgery

    Time to graft lost (death of retransplantation) up to 1 year after surgery.

    Censoring will occur if lost to follow-up or 1 year after surgery.

  25. Rate of 1-year recipient survival

    Time frame: From surgery to 12 months after surgery.

    Time to death up to 1 year after surgery.

    Censoring will occur if lost to follow-up or at 12 months after surgery.

  26. Costs of the intervention

    Time frame: Up to 12 months post-transplantation

    Complication-related costs (total and subcomponent costs including complications, ressource utilization and hospital readmissions)

Study contacts

Contact information is provided by the study sponsor or research team.

François Martin Carrier, MD

CONTACT

[email protected]

514-890-8000

Manuela Mbacfou, MSc

CONTACT

[email protected]

514-890-8000 ext. 31576

Sponsors and collaborators

Lead sponsor

Centre hospitalier de l'Université de Montréal (CHUM)

Other

Collaborators

  • Canadian Donation and Transplantation Research Program (CDTRP)
  • Canadian Institutes of Health Research (CIHR)
  • Canadian Perioperative Anesthesia Clinical Trial (PACT) Group

Registry information

Official study title

Effects of an Intraoperative Low-splanchnic Blood Volume Restrictive Fluid Management Strategy Compared to a Cardiac Output Optimized Liberal Fluid Management Strategy on Postoperative Outcomes in Liver Transplantation: A Multicenter Randomized Controlled Trial (REFIL-2)

Acronym: REFIL-2

Important dates

Study start
2026
Primary completion
2030
Study completion
2031
First posted
Jul 10, 2026
Registry last updated
Jul 10, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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