Liver Transplantation (LT)REFIL-2NCT07695363
Restrictive Fluid Management In Liver Transplantation (REFIL)
A study testing Low splanchnic blood volume restrictive fluid management strategy, Phlebotomy and Optimized cardiac output liberal fluid management strategy in people with Liver Transplantation (LT) and End-stage Liver Disease (ESLD), run by Centre hospitalier de l'Université de Montréal (CHUM) at 4 sites in Canada.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Liver Transplantation (LT), End-stage Liver Disease (ESLD)
- What is being tested?
- Low splanchnic blood volume restrictive fluid management strategy, Phlebotomy and Optimized cardiac output liberal fluid management strategy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 866 participants
- Where
- 4 sitesCanada
- Study dates
- 15 Feb 2026to Nov 2031
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult ≥ 18 years old
- Undergoing liver transplantation (LT)
- End-stage liver disease (ESLD) (with or without hepatocellular carcinoma) as the indication for transplantation.
Who cannot join
- 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.
Trial locations and contacts
4 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Canada4 sites, 4 recruiting
- Recruiting
London Health Sciences Centre (LHSC)
London, Ontario, N6G 2V4
Nelson Javier Gonzalez Valencia, MD, 519-661-2111, nelson.gonzalezvalencia@lhsc.on.ca
Nelson Javier Gonzalez Valencia, MD
- Recruiting
Centre hospitalier de l'Université de Montréal (CHUM)
Montreal, Quebec, H2X 0C1
Manuela Mbacfou, MSc, 514-890-8000 ext. 31576, manuela.mbacfou.temgoua.chum@ssss.gouv.qc.ca
François Martin Carrier, MD
- Recruiting
McGill University Health Centre (MUHC)
Montreal, Quebec, H4A 3J1
Stanislas Kandelman, MD, 514-934-1934, stanislas.kandelman.med@ssss.gouv.qc.ca
Stanislas Kandelman, MD
- Recruiting
Vancouver General Hospital (VGH)
Vancouver, British Columbia, V5Z 1M9
JeiEung Park, MD, 604-875-4111, jeieung.park@vch.ca
JeiEung Park, MD
About this study
Official 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)
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.
Read the detailed description
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).
- Being tested
- Low splanchnic blood volume restrictive fluid management strategy, Phlebotomy, Optimized cardiac output liberal fluid management strategy
- Keywords
- Liver Transplantation, Phlebotomy, Hemodynamic Management, Fluid Management, Transfusions, Liver Diseases
- Medical subject headings
- End Stage Liver Disease, Liver Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low splanchnic blood volume restrictive fluid management strategyProcedure or surgery
Also called Restrictive
Hemodynamic goal-directed restrictive fluid management strategy
PhlebotomyProcedure or surgery
Blood drawn in a blood donation bag prior to dissection and transfused back after graft reperfusion
Optimized cardiac output liberal fluid management strategyProcedure or surgery
Also called Liberal
Permissive hemodynamic goal-directed fluid management strategy that optimizes cardiac output throughout surgery
| Study group | Role | What they receive |
|---|---|---|
| Restrictive group - Low splanchnic blood volume restrictive fluid management strategy | Experimental | A phlebotomy (a procedure where the patient's blood is drawn, similar to a blood donation, without fluid replacement) at the start of the surgery combined with fluid restriction (use of vasopressor preferentially to treat hemodynamic instability with tolerance to relative hypovolemia defined as a Pulse Pressure Variation (PPV) or Stroke Volume (SVV) up to 18%). Fluids will be administered to compensate for blood loss and/or treat severe hemodynamic instability.
Blood collected by phlebotomy will always be transfused back at the beginning of the reperfusion phase, during which fluid management will be based on goal-directed therapy (GDT) using either PPV or SV, as in the control group. Receives: Procedure: Low splanchnic blood volume restrictive fluid management strategy; Procedure: Phlebotomy |
| Liberal group - Optimized cardiac output liberal fluid management strategy | Active comparator | Goal-directed therapy (GDT): Patients will receive 250 ml fluid boluses until SV stops increasing by more than 10% or until PPV is below 12%. Fluids will thus be used preferentially to treat hemodynamic instability. Fluids will also be administered to compensate for blood loss and/or treat severe hemodynamic instability. Receives: Procedure: Optimized cardiac output liberal fluid management strategy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with at least one severe complication
Incidence of at least one severe complications defined as a complication of grade ≥ 3 according to the Dindo-Clavien scale (grade 1 to 5)
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Secondary outcomes (26)
Number of participants who were transfused at least one unit of red blood cells (RBC) during the perioperative period of surgery
Incidence of participants transfused at least 1 unit of RBC during the perioperative period of surgery
Measured: 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)
Number of participants who were transfused at least one unit of red blood cells (RBC) during surgery
Incidence of at least one RBC transfusion during surgery
Measured: Intraoperative (from entrance in the operating room to exit of the operating room)
Intraoperative blood loss
Blood loss as estimated by clinicians
Measured: Intraoperative (from entrance in the operating room to exit of the operating room)
7-day quality of recovery
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.
Measured: One time point: 7 days after surgery (transplantation)
Number of participants with a 7-day graft dysfunction
Incidence of graft dysfunction (as per Olthoff's definition)
Measured: One time point: 7 days after surgery (transplantation)
Number of participants with a 7-day acute kidney injury (AKI)
Acute kidney injury (AKI) of KDIGO grade 2 or 3
Measured: Over 7 days after surgery (criteria met at any day from surgery to day 7 after surgery)
Number of participants who were transfused at least one unit of red blood cells (RBC) up to hospital discharge
Incidence of at least one RBC transfusion from surgery to hospital discharge
Measured: From surgery to hospital discharge (from entrance in the operating room to hospital discharge) or 30 days, whichever comes first
Number of participants who were transfused at least one unit of any labile blood product up to hospital discharge
Incidence of at least one labile blood product transfused from surgery up to hospital discharge
Measured: From surgery to hospital discharge (from entrance in the operating room to hospital discharge) or 30 days, whichever comes first
Number of participants with at least one postoperative hemorrhagic complication up to hospital discharge
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.
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of participants with postoperative acute kidney injury (AKI) up to hospital discharge
Incidence of any postoperative acute kidney injury (AKI) (any grade as per KDIGO criteria) up to hospital discharge
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of participants requiring renal replacement therapy (RRT) up to hospital discharge
Incidence of postoperative requirement for renal replacement therapy (RRT) [hemodialysis or hemofiltration] up to hospital discharge
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of participants with at least one postoperative graft complication up to hospital discharge
Incidence of at least one postoperative graft complication (primary non-function, vascular, biliary) or retransplantation up to hospital discharge
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of participants with at least one postoperative infectious complication up to hospital discharge
Incidence of any postoperative infectious complication (other than pneumonia) up to hospital discharge
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of patients with a postoperative wound dehiscence up to hospital discharge
Incidence of postoperative wound dehiscence or evisceration up to hospital discharge
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of patients with at least one postoperative pulmonary complication up to hospital discharge
Incidence of any postoperative pulmonary complications (atelectasis, pneumonia, pulmonary oedema) up to hospital discharge
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of participants with at least one postoperative thromboembolic complication up to hospital discharge
Incidence of at least one thromboembolic complication (deep vein thrombosis, pulmonary embolism, myocardial infraction, stroke, mesenteric ischemia) up to hospital discharge
Measured: Up to hospital discharge (from surgery to hospital discharge) or 30 days, whichever comes first
Number of participants with a postoperative ICU readmission up to hospital discharge
Incidence of ICU readmissions after initial discharge (from the planned postoperative ICU or step-down unit admission) to hospital discharge
Measured: From initial ICU discharge (planned postoperative ICU or step-down unit admission) to hospital discharge or 30 days, whichever comes first
Number of days not in an intensive care unit (ICU) at 30 days after surgery (30-day ICU-free days over 30 days)
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.
Measured: From surgery to 30 days after surgery
Number of days without organ support at 30 days after surgery (30-day organ support free days)
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.
Measured: From surgery to 30 days after surgery
Hospital length of stay
Length of hospital stay (days)
Measured: From surgery to hospital discharge (up to 12 months after surgery)
Quality of life score
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).
Measured: Two time points: 6 and 12 months after surgery
Rate of hospital readmissions
Number of postoperative hospital readmissions over 12 months after surgery
Measured: From hospital discharge after surgery to 12 months after surgery
Rate of 1-year graft complications
Time to any graft complication (vascular or biliary) to 1 year after surgery
Measured: From surgery to 12 months after surgery
Rate of 1-year graft survival
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.
Measured: From surgery to 12 months after surgery
Rate of 1-year recipient survival
Time to death up to 1 year after surgery.
Censoring will occur if lost to follow-up or at 12 months after surgery.
Measured: From surgery to 12 months after surgery.
Costs of the intervention
Complication-related costs (total and subcomponent costs including complications, ressource utilization and hospital readmissions)
Measured: Up to 12 months post-transplantation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jul 2026
- Study start15 Feb 2026
- Primary completionNov 2030 (estimated)
- Study completionNov 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Liver Transplantation (LT)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants are allocated to either group in a 1:1 ratio. Participants are only randomized once a viable graft is available.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 866 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre hospitalier de l'Université de Montréal (CHUM)
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR), Canadian Donation and Transplantation Research Program (CDTRP), Canadian Perioperative Anesthesia Clinical Trial (PACT) Group
- Responsible party
- Sponsor
- Investigators
- François Martin Carrier, MD, Principal investigator, Centre hospitalier de l'Université de Montréal (CHUM)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07695363
- Sponsor's protocol ID
- 22.206
- Acronym
- REFIL-2
- Status last verified
- Jun 2026
- First submitted
- 15 Jun 2026
- Last updated
- 10 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: End-of-study knowledge translation (KT) planned
Publications
Carrier FM, Chasse M, Wang HT, Aslanian P, Iorio S, Bilodeau M, Turgeon AF. Restrictive fluid management strategies and outcomes in liver transplantation: a systematic review. Can J Anaesth. 2020 Jan;67(1):109-127. doi: 10.1007/s12630-019-01480-y. Epub 2019 Sep 25.
PubMed 31556006Thacker JK, Mountford WK, Ernst FR, Krukas MR, Mythen MM. Perioperative Fluid Utilization Variability and Association With Outcomes: Considerations for Enhanced Recovery Efforts in Sample US Surgical Populations. Ann Surg. 2016 Mar;263(3):502-10. doi: 10.1097/SLA.0000000000001402.
PubMed 26565138Shin CH, Long DR, McLean D, Grabitz SD, Ladha K, Timm FP, Thevathasan T, Pieretti A, Ferrone C, Hoeft A, Scheeren TWL, Thompson BT, Kurth T, Eikermann M. Effects of Intraoperative Fluid Management on Postoperative Outcomes: A Hospital Registry Study. Ann Surg. 2018 Jun;267(6):1084-1092. doi: 10.1097/SLA.0000000000002220.
PubMed 28288059Parikh A, Washburn KW, Matsuoka L, Pandit U, Kim JE, Almeda J, Mora-Esteves C, Halff G, Genyk Y, Holland B, Wilson DJ, Sher L, Koneru B. A multicenter study of 30 days complications after deceased donor liver transplantation in the model for end-stage liver disease score era. Liver Transpl. 2015 Sep;21(9):1160-8. doi: 10.1002/lt.24181.
PubMed 25991395