Restrictive Fluid Management In Liver Transplantation (REFIL) (REFIL)

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

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 undergoing a liver transplantation not meeting any exclusion criteria.

Primary endpoint: The primary feasibility endpoint is an overall recruitment rate ≥ 4 patients/month across all three participating sites.

Secondary endpoint: The secondary feasibility endpoints are 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

Study Overview

• Status: Recruiting
• Conditions: Liver Transplantation
• Intervention / Treatment: Procedure: Low splanchnic blood volume restrictive fluid management strategy; Procedure: Phlebotomy; Procedure: Optimized cardiac output liberal fluid management strategy

Detailed Description

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 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 a multicentre internal pilot parallel arm randomized trial comparing two intraoperative hemodynamic and splanchnic blood volume management strategies in LT recipients.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: François-Martin Carrier, MD; Phone Number: 514-890-8000; Email: francois.martin.carrier.med@ssss.gouv.qc.ca
• Study Contact Backup: Name: Martine Lebrasseur, RN; Phone Number: 514-890-8000; Email: martine.lebrasseur.chum@ssss.gouv.qc.ca

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6G 2V4
      • Not yet recruiting
      • London Health Sciences Centre
      • Contact: Nelson Javier Gonzalez Valencia, MD; Phone Number: (519) 661-2111; Email: nelson.gonzalezvalencia@lhsc.on.ca
      • Principal Investigator: Nelson Javier Gonzalez Valencia, MD
  • Quebec
    • Montréal, Quebec, Canada, H2X 0C1
      • Recruiting
      • Centre Hospitalier de l'Universite de Montreal (CHUM)
      • Contact: François-Martin Carrier, MD; Phone Number: 514-890-8000; Email: francois.martin.carrier.med@ssss.gouv.qc.ca
      • Principal Investigator: François-Martin Carrier, MD
      • Sub-Investigator: Michael Chassé, MD
    • Montréal, Quebec, Canada, H4A 3J1
      • Not yet recruiting
      • McGill University Health Centre
      • Contact: Stanislas Kandelman, MD; Phone Number: (514)934-1934; Email: stanislas.kandelman.med@ssss.gouv.qc.ca
      • Principal Investigator: Stanilas Kandelman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Restrictive group: Low splanchnic blood volume Restrictive fluid management strategy; The intervention group is targeted at lowering splanchnic blood volume using a phlebotomy and restricting fluid infusion, individualized to the physiological needs of this population and the distinct LT surgical phases. The strategy will first consist of performing a phlebotomy without fluid replacement at the start of surgery.We will combine it with fluid restriction to prevent excessive fluid administration and its effect on splanchnic blood volume and blood loss, combined with the effect of the phlebotomy, as well as to limit fluid overload, as previously reported. Fluid will be administered to compensate blood loss and treat severe hemodynamic instability.The phlebotomy will be transfused back at the beginning of the reperfusion phase where fluid management will be based on a goal-directed therapy (GDT) using either PPV or SV, as in the control group.	Procedure: Low splanchnic blood volume restrictive fluid management strategy; Hemodynamic goal-directed restrictive fluid management strategy.; Other Names: Restrictive arm; Procedure: Phlebotomy; Retrieval of blood in a blood donation bag performed prior to dissection and transfused back after graft reperfusion
Active Comparator: Liberal group: Optimized cardiac output liberal fluid management strategy; The control group will receive a liberal intraoperative fluid management strategy optimizing cardiac output throughout the surgery. It will consist of administering 250 mL fluid boluses until SV stops to increase by more than 10% or until PPV is below 12%, a dynamic indicator of fluid responsiveness validated in many surgical populations, including ESLD patients undergoing a LT.This strategy is informed by data from recent clinical trials on benefits of GDT in major surgery, data on strategies used in major surgery, liver resection or LT and our survey on current practice.	Procedure: Optimized cardiac output liberal fluid management strategy; Permissive intraoperative hemodynamic goal-directed fluid management strategy that optimizes cardiac output throughout surgery; Other Names: Liberal arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Overall recruitment rate ≥ 4 patients/month (across all sites)	18 months (at study level)
Adherence	Protocol adherence > 90%, defined using a questionnaire	At time of surgery
Hospital outcome measurement completeness	A 30 days or hospital discharge outcome measurement > 90%	At 30 days (or hospital discharge) after surgery
6-month outcome measurement completeness	6-month outcome measurement > 90%	6 months after surgery
Mean difference in total volume received	A mean difference in total volume received (crystalloids and colloids combined) > 1000 ml between groups.	At time of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe complications and graft lost	Composite incidence of severe complication (Dindo-Clavien III or more) or graft lost (retransplantation or death)	Up to 30 days or hospital discharge
Intraoperative blood loss	Intraoperative blood loss in mL	End of surgery
Intraoperative and perioperative blood product transfusions	Total number of transfused units of labile and non-labile blood products (red blood cells, plasma, platelets, cryoprecipitates, fibrinogen, prothrombin complex concentrates)	From randomization up to 30 days or hospital discharge, whichever comes first
7-day quality of recovery	7-day quality of recovery measured using the QoR-15 (Quality of Recovery) tool	7 days after surgery
7-day graft dysfunction	7-day graft dysfunction (definition as reported by Olthoff et al.)	7 days after surgery
7-day AKI (grade 2 or 3)	7-day AKI grade 2 or 3 using the KDIGO (Kidney Disease: Improving Global Outcomes) definition	7 days after surgery
Any complication	Any of the following complications, graded according to the Dindo-Clavien classification system: hemorrhagic, graft related, pulmonary, infectious or thromboembolic.	From randomization up to 30 days or hospital discharge, whichever comes first
Any other severe complication	Any other severe complication (Dindo-Clavien III or more)	From randomization up to 30 days or hospital discharge, whichever comes first
Organ dysfunction and support	30-day organ support free days, using a recognized definition (as reported by Heyland et al.)	30 days
Intensive care unit (ICU) length of stay	Total duration of stay (days) in the intensive care unit (ICU)	From randomization up to hospital discharge (ascertained up to end of follow-up at 1 year)
Hospital length of stay	Total duration of stay (days) in the hospital	From randomization up to hospital discharge (ascertained up to end of follow-up at 1 year)
Quality of life (QoL)	Quality of life (QoL) using the SF-36 tool	6 & 12 months after surgery
Hospital readmissions	Hospital readmissions	From randomization up to 1 year after surgery
Graft complications	Graft complications	From randomization up to 1 year after surgery
Survival	Survival	From randomization up to 1 year after surgery

Collaborators and Investigators

• Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Donation and Transplantation Research Program (CDTRP); Canadian Perioperative Anesthesia Clinical Trial (PACT) Group
• Investigators: Principal Investigator: Francois-Martin Carrier, MD, Centre Hospitalier Universite de Montreal

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2023
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: November 30, 2022
• First Submitted That Met QC Criteria: December 8, 2022
• First Posted (Actual): December 12, 2022

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Phlebotomy; Fluid management; Transfusions; Hemodynamic management
• Other Study ID Numbers: 2023-11173

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No