Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04732689 |
| Other study ID # |
20.353 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 16, 2021 |
| Est. completion date |
July 31, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
Centre hospitalier de l'Université de Montréal (CHUM) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
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.
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.
