Restrictive Fluid Management In Liver Transplantation (REFIL)

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Liver Transplantation

Intervention / Treatment
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* Procedure: Low splanchnic blood volume restrictive fluid management strategy
* Procedure: Optimized cardiac output liberal fluid management strategy
* Procedure: Phlebotomy


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be allocated to either group in a 1:1 ratio. A research assistant will randomize the patient once a viable graft is confirmed, and then share allocation with the anesthesiology team.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Restrictive group: Low splanchnic blood volume Restrictive fluid management strategy<br>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<br>* Hemodynamic goal-directed restrictive fluid management strategy.<br>* Other names: Restrictive arm;Procedure: Phlebotomy<br>* Retrieval of blood in a blood donation bag performed prior to dissection and transfused back after graft reperfusion<br>|
| Active Comparator: Liberal group: Optimized cardiac output liberal fluid management strategy<br>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<br>* Permissive intraoperative hemodynamic goal-directed fluid management strategy that optimizes cardiac output throughout surgery<br>* Other names: Liberal arm;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemodynamic management, Fluid management, Transfusions, Phlebotomy