Restrictive Fluid Management for Liver Transplant Patients

(REFIL Trial)

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Francois-Martin Carrier, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)

Disqualifiers: Acute liver failure, Severe renal failure, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing a method of carefully managing fluids during liver transplant surgery for patients with severe liver disease. The goal is to see if this approach can reduce complications and improve recovery by keeping blood volume in the abdominal organs low. This method has been shown to reduce complications following various major surgeries.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the restrictive fluid management treatment for liver transplant patients?

Research suggests that using a restrictive fluid management strategy during liver transplants can reduce complications like acute kidney injury (AKI) and surgical bleeding compared to more liberal fluid approaches. This is because it helps maintain better blood flow balance and reduces the risk of fluid overload, which can harm kidney function and increase bleeding risk. ^{1 2 3 4 5}

Is restrictive fluid management safe for liver transplant patients?

Restrictive fluid management strategies have been studied in liver transplant patients and are generally considered safe. They may reduce the need for blood transfusions and shorten hospital stays without negatively affecting kidney or liver function. ^{1 2 3 4 6}

How is the restrictive fluid management strategy unique for liver transplant patients?

The restrictive fluid management strategy for liver transplant patients is unique because it focuses on maintaining low splanchnic blood volume to reduce complications like bleeding and acute kidney injury, unlike traditional approaches that use liberal fluid administration which can worsen surgical bleeding and affect kidney function. ^{2 3 4 7 8}

Research Team

Francois-Martin Carrier, MD

Principal Investigator

Centre hospitalier université de Montréal

Eligibility Criteria

The REFIL trial is for adults over 18 years old who need a liver transplant due to end-stage liver disease (ESLD). It's not for those with acute liver failure, cancer without ESLD, retransplantation, amyloid neuropathy, severe kidney failure (GFR < 15), severe anemia (hemoglobin < 80 g/L), or hemodynamic instability.

Inclusion Criteria

I am 18 or older and getting a liver transplant for end-stage liver disease.

Exclusion Criteria

Patients with severe anemia (hemoglobin level < 80 g/L)

I have severe kidney failure or am on dialysis.

I require high doses of medication to maintain my blood pressure.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Intraoperative Treatment

Participants undergo liver transplantation with either a restrictive or liberal fluid management strategy

During surgery

Postoperative Follow-up

Participants are monitored for postoperative outcomes, including complications and graft function

30 days

Regular monitoring until hospital discharge

Extended Follow-up

Participants are monitored for long-term outcomes, including survival and quality of life

Up to 1 year

Treatment Details

Interventions

• Low splanchnic blood volume Restrictive fluid management strategy (Procedure)
• Optimized cardiac output liberal fluid management strategy (Procedure)

Trial Overview This study compares two fluid management strategies during liver transplantation. One group receives a restrictive strategy with phlebotomy and limited fluids; the other gets a liberal strategy aiming to optimize cardiac output. The goal is to see which method leads to better outcomes.

Participant Groups

Group I: Restrictive group: Low splanchnic blood volume Restrictive fluid management strategy Experimental Treatment 2 Interventions

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.

Group II: Liberal group: Optimized cardiac output liberal fluid management strategy Active Control 1 Intervention

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.

Low splanchnic blood volume Restrictive fluid management strategy is already approved in Canada for the following indications:

Approved in Canada as Restrictive Fluid Management Strategy for:

• Liver Transplantation

Who Is Running the Clinical Trial?

Centre hospitalier de l'Université de Montréal (CHUM)

Lead Sponsor

Trials

389

Recruited

143,000+

Dr. Réjean Lapointe

Centre hospitalier de l'Université de Montréal (CHUM)

Chief Medical Officer since 2023

MD from Université de Montréal

Dr. Fabrice Brunet

Centre hospitalier de l'Université de Montréal (CHUM)

Chief Executive Officer since 2015

MD from Université de Montréal

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Dr. Paul C. Hébert

Canadian Institutes of Health Research (CIHR)

Chief Executive Officer

MD, University of Ottawa

Dr. Paul C. Hébert

Canadian Institutes of Health Research (CIHR)

Chief Medical Officer

MD, University of Ottawa

Canadian Donation and Transplantation Research Program (CDTRP)

Collaborator

Trials

1

Recruited

70+

Canadian Perioperative Anesthesia Clinical Trial (PACT) Group

Collaborator

Trials

1

Recruited

70+

Findings from Research

A low central venous pressure (CVP) fluid management strategy during liver transplantation resulted in increased rates of postoperative renal failure and higher 30-day mortality compared to a normal CVP strategy.

While the low CVP approach reduced blood transfusion requirements, it is not recommended for liver transplantation patients due to the associated risks of renal complications and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative fluid management during orthotopic liver transplantation. Schroeder, RA., Collins, BH., Tuttle-Newhall, E., et al.[2019]

Restrictive fluid management strategies during liver transplant surgery did not show any significant impact on the incidence of acute kidney injury (AKI) or mortality, based on a systematic review of 7 randomized controlled trials and 29 observational studies.

However, these strategies were associated with reduced pulmonary complications, shorter duration of mechanical ventilation, and less blood loss, suggesting potential benefits in other postoperative outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restrictive fluid management strategies and outcomes in liver transplantation: a systematic review. Carrier, FM., Chassé, M., Wang, HT., et al.[2021]

In patients with liver cirrhosis undergoing liver transplantation, traditional volume loading methods may be ineffective and could worsen surgical bleeding due to splanchnic vasodilatation that diverts blood away from the systemic circulation.

Alternative volume therapy strategies, such as volume restriction or using vasoconstrictors, may be more effective in maintaining hemodynamic stability during surgery, although the optimal central venous pressure to avoid graft congestion post-reperfusion remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Splanchnic and systemic circulation cross talks: Implications for hemodynamic management of liver transplant recipients. Mukhtar, A., Lotfy, A., Hussein, A., et al.[2021]

In a study of 532 adult liver transplant recipients, the use of vasopressors did not increase the risk of acute kidney injury (AKI) within 48 hours or 7 days post-surgery, suggesting they may be safe in this context.

However, higher fluid balance was linked to increased need for renal replacement therapy and lower survival rates in patients not receiving vasopressors, indicating that vasopressor use may alter the negative effects of fluid management on postoperative outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of intraoperative hemodynamic management on postoperative acute kidney injury in liver transplantation: An observational cohort study. Carrier, FM., Sylvestre, MP., Massicotte, L., et al.[2020]

In a study of 121 liver transplant patients, a cumulative positive fluid balance (FB) of over 10 liters in the first 4 days post-surgery was found to significantly increase the risk of acute kidney injury (AKI) and the need for renal replacement therapy (RRT).

While fluid overload did not directly affect mortality rates, other factors like liver function markers and the severity of the patient's condition were more closely linked to survival outcomes after liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cumulative positive fluid balance is a risk factor for acute kidney injury and requirement for renal replacement therapy after liver transplantation. Codes, L., de Souza, YG., D'Oliveira, RAC., et al.[2020]

A restrictive fluid management strategy combined with acute normovolemic intraoperative hemodilution (ANIH) was found to be a safe technique for living donors undergoing liver transplantation, with no significant differences in postoperative renal and liver functions.

This approach led to a shorter hospital stay for patients (8.2 days vs. 10.1 days) and showed a trend towards reduced blood transfusion requirements, suggesting it may enhance recovery after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of restrictive fluid management and acute normovolemic intraoperative hemodilution on transfusion requirements during living donor hepatectomy. Balci, ST., Pirat, A., Torgay, A., et al.[2008]

This systematic review aims to evaluate the impact of restrictive versus liberal perioperative fluid management strategies on postoperative outcomes in liver transplant recipients, focusing on acute renal failure as the primary outcome and other complications and mortality as secondary outcomes.

The review will include randomized controlled trials and comparative studies, analyzing data from major medical databases to provide high-quality evidence that could inform future clinical practices and improve survival rates for liver transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of perioperative fluid management on postoperative outcomes in liver transplantation: a systematic review protocol. Carrier, FM., Chassé, M., Wang, HT., et al.[2019]

In a study of liver transplant recipients, fluid management guided by stroke volume variation (SVV) resulted in similar outcomes to traditional central venous pressure (CVP) monitoring, with no significant differences in blood loss, acute kidney injury (AKI), or survival rates at 30 days and 1 year.

The use of SVV as a decision-making tool for fluid management in liver transplant patients appears to be as effective as CVP, suggesting that both methods can be used interchangeably in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluid management guided by stroke volume variation failed to decrease the incidence of acute kidney injury, 30-day mortality, and 1-year survival in living donor liver transplant recipients. Wang, SC., Teng, WN., Chang, KY., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Intraoperative fluid management during orthotopic liver transplantation. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Restrictive fluid management strategies and outcomes in liver transplantation: a systematic review. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Splanchnic and systemic circulation cross talks: Implications for hemodynamic management of liver transplant recipients. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Effects of intraoperative hemodynamic management on postoperative acute kidney injury in liver transplantation: An observational cohort study. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Cumulative positive fluid balance is a risk factor for acute kidney injury and requirement for renal replacement therapy after liver transplantation. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Effect of restrictive fluid management and acute normovolemic intraoperative hemodilution on transfusion requirements during living donor hepatectomy. [2008]

7. England pubmed.ncbi.nlm.nih.gov

Effects of perioperative fluid management on postoperative outcomes in liver transplantation: a systematic review protocol. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Fluid management guided by stroke volume variation failed to decrease the incidence of acute kidney injury, 30-day mortality, and 1-year survival in living donor liver transplant recipients. [2019]