End-stage Liver Disease (ESLD), Liver Transplantation (LT)
Conditions
Keywords
Liver Transplantation, Phlebotomy, Hemodynamic Management, Fluid Management, Transfusions, Liver Diseases
Brief 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 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.
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).
Interventions
Hemodynamic goal-directed restrictive fluid management strategy
PROCEDUREPhlebotomy
Blood drawn in a blood donation bag prior to dissection and transfused back after graft reperfusion
Permissive hemodynamic goal-directed fluid management strategy that optimizes cardiac output throughout surgery
Sponsors
Centre hospitalier de l'Université de Montréal (CHUM)
Canadian Institutes of Health Research (CIHR)
Canadian Donation and Transplantation Research Program (CDTRP)
Canadian Perioperative Anesthesia Clinical Trial (PACT) Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Only the anesthesiology team will know which group the participant is assigned to, since they are responsible for implementing the intervention. They receive the allocated intervention by text message or email. Patients, surgeons, non-anesthesia health professionals, and research staff involved in the study procedures and data collection will not know this information. The primary outcome will be adjudicated by blinded adjudicators.
Intervention model description
Participants are allocated to either group in a 1:1 ratio. Participants are only randomized once a viable graft is available.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult ≥ 18 years old 2. Undergoing liver transplantation (LT) 3. End-stage liver disease (ESLD) (with or without hepatocellular carcinoma) as the indication for transplantation.
Exclusion criteria
1. 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) 2. Undergoing combined solid organ transplantations 3. 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) 4. Physician refusal to enroll the patient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with at least one severe complication | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of participants who were transfused at least one unit of red blood cells (RBC) during the perioperative period of surgery | 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 |
| Number of participants who were transfused at least one unit of red blood cells (RBC) during surgery | Intraoperative (from entrance in the operating room to exit of the operating room) | Incidence of at least one RBC transfusion during surgery |
| Intraoperative blood loss | Intraoperative (from entrance in the operating room to exit of the operating room) | Blood loss as estimated by clinicians |
| 7-day quality of recovery | 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. |
| Number of participants with a 7-day graft dysfunction | One time point: 7 days after surgery (transplantation) | Incidence of graft dysfunction (as per Olthoff's definition) |
| Number of participants with a 7-day acute kidney injury (AKI) | 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 |
| Number of participants who were transfused at least one unit of red blood cells (RBC) up to hospital discharge | 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 |
| Number of participants who were transfused at least one unit of any labile blood product up to hospital discharge | 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 |
| Number of participants with at least one postoperative hemorrhagic complication up to hospital discharge | 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. |
| Number of participants with postoperative acute kidney injury (AKI) up to hospital discharge | 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 |
| Number of participants requiring renal replacement therapy (RRT) up to hospital discharge | 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 |
| Number of participants with at least one postoperative graft complication up to hospital discharge | 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 |
| Number of participants with at least one postoperative infectious complication up to hospital discharge | 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 |
| Number of patients with a postoperative wound dehiscence up to hospital discharge | 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 |
| Number of patients with at least one postoperative pulmonary complication up to hospital discharge | 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 |
| Number of participants with at least one postoperative thromboembolic complication up to hospital discharge | 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 |
| Number of participants with a postoperative ICU readmission up to hospital discharge | 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 |
| Number of days not in an intensive care unit (ICU) at 30 days after surgery (30-day ICU-free days over 30 days) | 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. |
| Number of days without organ support at 30 days after surgery (30-day organ support free days) | 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. |
| Hospital length of stay | From surgery to hospital discharge (up to 12 months after surgery) | Length of hospital stay (days) |
| Quality of life score | 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). |
| Rate of hospital readmissions | From hospital discharge after surgery to 12 months after surgery | Number of postoperative hospital readmissions over 12 months after surgery |
| Rate of 1-year graft complications | From surgery to 12 months after surgery | Time to any graft complication (vascular or biliary) to 1 year after surgery |
| Rate of 1-year graft survival | 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. |
| Rate of 1-year recipient survival | 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. |
| Costs of the intervention | Up to 12 months post-transplantation | Complication-related costs (total and subcomponent costs including complications, ressource utilization and hospital readmissions) |
Countries
Canada
Contacts
CONTACTManuela Mbacfou, MSc
CONTACTFrançois Martin Carrier, MD
PRINCIPAL_INVESTIGATORFrançois Martin Carrier, MD
Centre hospitalier de l'Université de Montréal (CHUM)
Outcome results
None listed