Intraoperative Hemodynamic Management and Postoperative Outcomes in Liver Transplantation — ELIPTO-2  

Surgery Clinical Trial

Official title: Intraoperative Hemodynamic Management and Postoperative Outcomes in Liver Transplantation: a Multicenter Prospective Cohort Study

Status Completed

Clinical Trial Summary

The overarching objective of the research program entitled ELIPTO (Enhancing Liver Insufficiency and Postoperative Transplantation Outcomes) (www.elipto.ca) is to improve the perioperative care of liver transplant recipients. One of this program's purposes is to better define the effects of intraoperative hemodynamic management on postoperative outcomes in adult liver transplant recipients. In this study, the incidence of postoperative complications within this population will be defined in Canada and France and the association between intraoperative hemodynamics and postoperative outcomes will be measured.

Liver transplantation improves the survival of patients with end-stage liver disease (ESLD). It is the second most transplanted organ with a continuously increasing annual number of transplantations, an observation partly explained by an endemic ESLD etiology in the United States, the obesity-related non-alcoholic steatohepatitis (NASH) cirrhosis. In recent decades, although sicker patients are prioritized, survival has improved possibly through an overall improvement in the quality of care. However, postoperative complications have concomitantly increased. On average, liver transplant recipients suffer from more than three postoperative complications, mainly infectious, pulmonary, renal or graft-related, two thirds of them being severe. In a low-risk patients cohort, close to 60% of all patients suffered from at least one severe complication up to 6 months after surgery. Such complications increase mortality, readmissions and cost of care. Organs available for transplantation are a scarce resource; up to 10% of grafts are no longer functional after one year. Interventions that improve patients' postoperative and graft outcomes are needed and few perioperative ones are supported by high-quality evidence.

Clinical Trial Description

OBJECTIVES:

The main objective of this study is to describe and measure the effects of intraoperative hemodynamic management on postoperative outcomes in liver transplantation in Canada and France.

The specific objectives are:

1. To describe the overall incidence of postoperative complications and graft outcomes in adult liver transplant recipients in Canada and France and across different recipients' characteristics.

2. To measure the effects of fluid balance, within an overall hemodynamic instability and management strategy, on the postoperative outcomes of liver transplant recipients in Canada and France.

The central hypotheses of this study are that an intraoperative hemodynamic management based on a restrictive fluid administration may improve postoperative outcomes in this population.

EXPOSURE VARIABLES:

The exposures of interest will be the intraoperative fluid balance and the intraoperative doses and types of vasopressors used. Fluid balance will be defined as the sum of the volume of administered crystalloids, colloids and blood product transfusions minus drained ascites, intraoperative diuresis and bleeding. Doses of administered vasopressors will be converted into a time-weighted total norepinephrine equivalent dose calculated as the total equipotent units of norepinephrine administered as an infusion divided by the number of hours the infusion was given during the period between entrance in the operating room and end of surgery. Types of vasopressors used will also be collected. Since a restrictive fluid management strategy is associated with a higher use of vasopressors and vice versa, both variables may covary together. However, more difficult surgeries will be associated with higher blood loss, higher volume of administered fluid and higher doses of vasopressors. The combination of these two variables will help estimate the intraoperative hemodynamic management strategy used and delineate the effects of each component.

OTHER DESCRIPTIVE VARIABLES:

Other patients' characteristics and perioperative practices variables will be captured for descriptive purposes. Recipients' demographic characteristics (age, sex), anthropometric variables (body mass index (BMI)), the presence of any previous abdominal surgery, presence of hepatic encephalopathy, need for preoperative organ support or any preoperative hospital admission will be collected as well. Data on the perioperative use of invasive cardiac output monitoring (thermodilution catheter, transoesophageal echocardiography, etc.), as well as coagulation management (use of thromboelastometry, tranexamic acid, transfusion thresholds, etc.) will be collected. Other donor and graft variables, such as donor sex, donor's BMI, the type of vascular and biliary anastomoses, the use of extended-criteria donor graft, the use of ex vivo perfusion, ischemia time, the practice of donation after circulatory death (donor characteristics, heparin usage, etc.) and the perioperative use of liver biopsies will also be collected.

DESCRIPTIVE AND STATISTICAL ANALYSIS:

Missing data The investigators will train all sites regarding quality of data collection and will emphasize the importance of complete data collection. In case a complete case analysis would exclude more than 5% of the observations, the investigators will use multiple imputations by chained equations using 5 to 20 imputated datasets assuming MAR (missingness at random) on the covariables and the outcomes. In case of any missing outcome, the investigators will not include imputated outcomes in the analyses.

Descriptive analyses and complications incidences across centers:

The cumulative incidences of different complications will be described. The main descriptive analysis will be to report these incidences overall as well as across denominated centers. For each complication, the investigators will first compute a chi-square test for each complication to test if the variation across centre is statistically significant. Secondly, investigators will estimate multivariable determination models for each complication by fitting generalized mixed effect models using a logit link adjusted for age, sex, disease severity (MELD) and the DRI with an estimated random-effect for clustering within centres. The investigators will then compute intra-class correlation (ICC) coefficients to better define the variability of complications across centres (heterogeneity). However, investigators will fit a Cox regression with a frailty factor for biliary complications.Finally, the investigators will fit a generalized mixed effect model using a log link and quasi-Poisson distribution for the total number of complications up to 30 days per patient with an estimated random effect for clustering within centres The secondary exploratory analyses will be to report the cumulative incidence of each complications according to age categories (< 50, 50-60, >60), sex, nature and severity of liver disease (chronic liver disease (CLF), acute liver failure (ALF), retransplantation and MELD categories among CLD patients (< 20, 20-30, >30). Such incidences per subgroups will be reported with 95% confidence intervals. The investigators will also report survival up to 6 months over and across centres by fitting a Cox regression with a frailty factor.

Association between hemodynamic management and postoperative complications:

The primary association analysis will be the association between fluid balance and primary graft dysfunction by 7 days after transplantation using a multivariable mixed-effect model using a logistic link and random intercepts to estimate inter-centre variability and intra-cluster correlation, adjusted for the time-weighted dose of vasopressors and the aforementioned confounders, and estimated using residualized penalized quasi-likelihood. The investigators will consider any patient needing a retransplantation within 7 days after the index transplantation as having a primary graft dysfunction.

The secondary main analysis will be the association between fluid balance and time to biliary non-anastomotic strictures using a multivariable Fine and Gray model, adjusted for the same confounders, with retransplantation and death (not caused by the biliary non-anastomotic strictures) considered as competing risks. The intra-cluster correlation will be addressed using a frailty factor. The second transplantation of any patient performed during the observation period will have been excluded by design to avoid intra-patient correlation.

The other secondary analyses will be the association between fluid balance and other outcomes, including the total number of complications up to 30 days, using similar adjusted survival models (with frailty factors) or generalized mixed effect models (with random intercepts). Statistical interaction will be explored between fluid balance and the vasopressors dose variable. Risk proportionality over time will be explored using the Harrel and Lee test and a visual inspection of the Schoenfeld residuals.

Sensitivity analyses For the primary outcome, the main secondary outcome and the total number of complications at 30 days, the investigators will first conduct a sensitivity analysis using a generalized propensity score for fluid balance (based on probability density) that will include all confounders and the vasopressor exposure and estimate a marginal effect of fluid balance using an inverse probability of treatment weighting with stabilized weights. The investigators will evaluate the confounding effect of hypotension by removing it from the models as well as by a sensitivity analysis restricted in the subgroup of patients without significant residual hypotension (< 150 min*Hg). The investigators will conduct influential analyzes to explore the robustness of their findings by alternatively excluding patients transplanted for acute liver failure, those who received a living donor graft or cadaveric donor graft after cardiocirculatory arrest, and those with severe chronic renal failure (glomerular filtration rate < 15 mL/hour/1.73 m2 or on dialysis).

Finally, the investigators will conduct all analyses by adding data from the French centres to explore the variation in the estimates created by adding non-Canadian centres.

Economic analysis:

An economic analysis to evaluate hospital costs associated with the observed incidences of postoperative complications will be conducted. The costs associated with our fluid balance exposure effect will be analyzed. Costs will be those associated with the actual procedures, as determined by every hospital using its account systems, and include both fixed and variable components previously identified as major cost drivers (mechanical ventilation days, LOS, reoperation and ICU readmission).

SAMPLE SIZE

Based on clinical trials in major surgery, a relative difference of 25% for all complications was considered minimally clinically significant. If investigators assume an overall 7-day proportion (cumulative) incidence of primary graft dysfunction of 25% at the mean of fluid balance and a relative increase of 25% of this complication (absolute increase of 6.25%) by increasing the fluid balance by 1 standard deviation, a sample of 475 will be necessary (power = 90%, R2 of the covariables on the main exposure = 0,1).Since random effects have a minimal impact on the sample size when the intervention is not cluster randomized, the investigators did not take it into account in the sample size calculation. To prevent potential seasonal variability in organ procurement, have more power in case of missing data or a slightly lower than expected incidence of the primary outcome, the investigators planned to enroll all eligible patients over a 1-year period. The investigators anticipated being able to enroll 500 consecutive liver transplant recipients over such period according to the annual volume in each centre (CHUM: 65, MUHC: 45, TGH: 200, LHSC: 60, UAH: 100, QEIIHSC: 30). Sample size calculation was conducted using G-Power software using the recommended Demidenko procedure. ;

Related Conditions & MeSH terms

• Liver Diseases
• Liver Failure
• Surgery
• Surgery--Complications
• Transplant; Failure, Liver

• NCT number: NCT04732689
• Study type: Observational
• Source: Centre hospitalier de l'Université de Montréal (CHUM)
• Status: Completed
• Start date: June 16, 2021
• Completion date: July 31, 2023