Abdominal Drainage in the Postoperative Period of Liver Transplantation (DRALIT): Multi-institutional Randomized Clinical Trial
Phase: NA
Conditions: Liver Transplant; Complications, Drainage
Sponsor: Hospital Universitario Virgen de la Arrixaca

PROTOCOL
TITLE:
Abdominal drainage in the postoperative period of liver transplantation (DRALIT):
multi-institutional randomized clinical trial
Drenaje abdominal en el postoperatorio del trasplante hepático (DRALIT): Ensayo Clínico
multicéntrico aleatorizado.
Protocol code:
Version: v.1
Date: 24/5/2022
EudraCT:
1

PROMOTER: Department of General Surgery and Digestive Diseases
PRINCIPAL RESEARCHER / COORDINATOR: Víctor López López / Álvaro Cerezuela
Fernández de Palencia
CONFIDENTIAL
This document contains confidential information that should not be disclosed or published
to other people other than clinical researchers, members of the Clinical Research Ethics
Committees of the participating hospital centers and Spanish Health Authorities.
2

ABSTRACT
Title:
Abdominal DRAinage in the postoperative period of LIver Transplantation (DRALIT):
multi-institutional randomized clinical trial
Promoter: Department of General Surgery and Digestive Diseases
Principal researchers:
Victor Lopez Lopez. FEA General and Digestive System Surgery Service. Virgen de la
Arrixaca University Clinical Hospital.
Álvaro Cerezuela. General Surgery and Digestive System Resident. Virgen de la Arrixaca
University Clinical Hospital.
Justification of the study: Classically, in the postoperative period of liver transplantation
(LT), abdominal drainage has been used as a way to make the early diagnosis of
hemorrhages, bile leaks and other postsurgical complications, as well as an evacuation
route for ascites. The use of it routinely is currently under discussion due to the morbidities
associated with its use.
Objectives: The objective of the clinical trial is to evaluate whether the routine use of
abdominal drainage in the postoperative period of LT is associated or not with an increase
in postoperative complications. Also evaluate the quality of life in relation to the presence or
not of abdominal drainage.
Trial design: After signing the informed consent of those patients who meet the inclusion
criteria, they will be randomized into two groups for placement of an abdominal drain or not.
On the third day, the abdominal drainage will be removed except for signs of bleeding,
postoperative infection or bile leakage, and abdominal postoperative complications will be
evaluated according to the Clavien-Dindo scale in the first 90 postoperative days.
Randomization: 2 groups of equal size, total n = 365 patients. Simple intraoperative
randomization prior to closure of the abdominal wall after fulfilling all the inclusion criteria
and none of the exclusion criteria.
Masking: no masking.
Study population: liver transplants for all etiologies.
Variables analyzed:
3

●
Recipient preoperative variables: gender, age, pre-transplant stay, BMI, ASA,
diabetes, HTN, dialysis, MELD, Child-Pugh, serology, albumin, bilirubin, INR, CRP,
creatinine, ascites, SBP, prothrombin time, encephalopathy, time from SSI to LT
(months), retransplantation, previous surgeries, cirrhosis etiology, indication for
transplantation, sarcopenia.
●
Donor characteristic variables: age, stay in ICU, vasoactive drugs, cultures,
antibiotics, CIT, WIT, type of donation (DBD / DCD), previous immunosuppression.
●
Intraoperative variables: placement or not of abdominal drainage, surgical time
(min), transfusions, blood loss, surgical technique, arterial anastomosis type, biliary
anastomosis type, donation with extended criteria, recipient with extended criteria,
clamping times.
●
Postoperative
variables:
ICU
stay,
hospital
stay,
abdominal
complications
(collection, bile leak, hematoma, hemorrhage, paralytic ileus, ascites, bleeding,
wound drainage complications, vascular anastomosis complications, mechanical
obstruction, hollow viscus perforations, wound complications surgery), graft function,
post-transplant antibiotic therapy, post-transplant immunosuppressive regimen,
number of post-LT HC, mortality at 90 days, global complications at 90 days.
●
SF-36: Physical function, physical role, body pain, general health, vitality, social
function, emotional role, mental health (on inclusion in the waiting list, one month
after surgery, 4 months after surgery).
4

●
INDEX ………………………………………………………………………… ... Page
○
Summary ……………………………………………………………………..… 3
○
Index …………………………………………………………………………..…5
○
List of acronyms and definition of terms ………………………………..……6
○
General Information ………………………… .. …………………………..…..7
○
Justification ………………………………………………………………..……10
○
Objective and purpose of the study …………………………………….….…11
○
Study design ………………………………………………………………..… .11
○
Study population …………………………………………………...……… .... 14
○
Treatment of subjects ……………………………………………………… ... 15
○
Study variables ………………………………………………….…………… ..17
○
Follow-up of subjects …………………………………………...…………… ..17
○
Safety assessment ……………………………………………….………… ... 17
○
Statistics …………………………………………………  …………………..... 18
○
Ethics ………………………………………………………………………. .… ..20
○
Informed Consent …………………………………………………………… ... 21
○
Direct access to source data / documents ……………………………..…… .21
○
Data management and record file..………………………………………..… ..21
○
Data protection ………………………………………………………….…… ... 22
○
Financing and insurance ………………………………………………….… ... 22
○
Publication policy ……………………………………………………………… ..22
○
Bibliography ……………………………………………………………………....23
○
Annexes …………………………………………………………………………. .25
5

LIST OF ACRONYMS AND DEFINITION OF TERMS
●
ASA: American Society of Anesthesiologists Classification
●
BMI: Body Mass Index
●
MELD: Model For End-Stage Liver Disease
●
INR: International normalized ratio
●
LT: liver transplantation
●
CRP: C-Reactive Protein
●
SBP: Spontaneous Bacterial Peritonitis
●
ILQ:: Inclusion in Surgical Waiting List
●
ICU: Intensive Care Unit
●
CIT: Cold Ischemia Time
●
WIT: Warm Ischemia Time
●
DBD: Donation after brainstem death
●
DCD: Donation after circulatory death
●
CH: Red blood cell concentrates
●
RETH: Spanish Registry of Hepatic Transplantation
●
ERASⓇ: Enhanced Recovery After Surgey
●
CRD: Data Collection Notebook
●
RCT: Randomized Clinical Trial
●
CEIC: Clinical Research Ethics Committee
6

●
GENERAL INFORMATION
○
Trial identification
Abdominal drainage in the postoperative period of liver transplantation: multi-institutional
randomized clinical trial.
Acronym (if applicable): DRALIT
Version: v.1
Date: 12/7/2021
Eudra CT number:
○
Type of clinical trial
Randomized without masking.
○
Promoter
General Surgery and Digestive System Service
○
Researchers.
Álvaro Cerezuela Fernández de Palencia. Resident Internal Physician of General Surgery
and the Digestive System. Virgen de la Arrixaca University Clinical Hospital
alvaro.cerezuela@gmail.com / +34 620047702
Victor Lopez Lopez. Area Specialist Facultative, General Surgery and Digestive System
Service. Virgen de la Arrixaca University Clinical Hospital
victorrelopez@gmail.com / +34 637519516
7

Pablo Ramírez Romero. Head of the Transplant, General Surgery and Digestive System
Unit Section, Hospital Clínico Universitario Virgen de la Arrixaca. Professor of Surgery,
University of Murcia.
pablo.ramirez@carm.es / +34 629380442
Ricardo Robles Campos. Head of Section of the Hepatobiliary Surgery, General Surgery
and Digestive System, Hospital Clínico Universitario Virgen de la Arrixaca. Professor of
Surgery, University of Murcia.
rirocam@um.es / +34 606404241
Francisco Sánchez Bueno. Head of Section of the Hepatobiliary Surgery, General Surgery
and Digestive System, Hospital Clínico Universitario Virgen de la Arrixaca. Professor of
Surgery, University of Murcia.
francisco.sanchez26@carm.es / +34 609473428
Jose Antonio Pons Miñano. Head of the Hepatology and Liver Transplant Unit Section,
Digestive System Medicine, Hospital Clínico Universitario Virgen de la Arrixaca. Professor
at the University of Murcia.
joseapons@yahoo.es / +34 670563101
Laura Martínez-Alarcón. Research Supervisor. Virgen de la Arrixaca University Clinical
Hospital. Professor at the University of Murcia.
lma5@um.es / +34627408245
○
Physicians responsible for medical decisions
Álvaro Cerezuela Fernández de Palencia. Resident Internal Physician of General Surgery
and the Digestive System. Virgen de la Arrixaca University Clinical Hospital
alvaro.cerezuela@gmail.com / +34 620047702
8

Victor Lopez Lopez. Area Specialist Facultative, General Surgery and Digestive System
Service. Virgen de la Arrixaca University Clinical Hospital
victorrelopez@gmail.com
Pablo Ramírez Romero. Head of the Transplant, General Surgery and Digestive System
Unit Section, Hospital Clínico Universitario Virgen de la Arrixaca. Professor of Surgery,
University of Murcia. Autonomous Transplant Coordinator, Region of Murcia.
pablo.ramirez@carm.es / +34 629380442
Ricardo Robles Campos. Head of Section of the Hepatobiliary Surgery, General Surgery
and Digestive System, Hospital Clínico Universitario Virgen de la Arrixaca. Professor of
Surgery, University of Murcia.
rirocam@um.es / +34 606404241
Francisco Sánchez Bueno. Head of Section of the Hepatobiliary Surgery, General Surgery
and Digestive System, Hospital Clínico Universitario Virgen de la Arrixaca. Professor of
Surgery, University of Murcia.
francisco.sanchez26@carm.es / +34 609473428
Jose Antonio Pons .. Head of the Hepatology and Liver Transplant Unit Section, Digestive
System Medicine, Hospital Clínico Universitario Virgen de la Arrixaca. Professor at the
University of Murcia.
joseapons@yahoo.es / +34 670563101
○
Name
and
addresses of clinical laboratories and medical or technical
departments or other institutions involved in the trial.
Progressively, different centers at the European level will join the clinical trial.
9

●
JUSTIFICATION
LT has become in recent years a procedure with an increasing number of indications
and with a greater number of donations given the social knowledge of the donation
process
and
donation
in
controlled
asystole.
The
Spanish
Registry
of
Liver
Transplantation (RETH) shows a total of 28,609 TH in the period 1986-2019, which
represents an average of 867 TH per year in Spain. These data place Spain among the
first countries in terms of HT.
In LT, abdominal drainage has historically been used prophylactically as a way to
identify early intra-abdominal postoperative complications such as hemorrhage, bile
leakage, and others.
In transplant patients, the use of post-surgical abdominal drains on a routine basis has
shown an increase in total protein losses in patients with refractory ascites, an increase
in ascending infections secondary to drainage, infection and pain at the insertion point
of the drain, as well as as, an increase in hospital stay. Nor can a higher rate of
postsurgical bleeding and bile leakage be ruled out in patients with abdominal
drainage.
Currently, in the few studies that there are in reference to the systematic use of
abdominal drains in lTH, the need for them prophylactically is being discussed as an
early diagnosis of postoperative intra-abdominal complications is not observed, but
complications are seen to increase secondary to drainage. Therefore, the need to use
it systematically in all patients is currently under discussion.
Currently, we are facing an increase in ERASⓇ(Enhanced Recovery After Surgey)
programs, which began in 2008 with colorectal surgery and are currently expanding to
other surgical procedures. These programs advocate reducing the number of drains
and even not using them in patients with a low risk of post-surgical complications.
In the current bibliography, the methodology of the studies is varied, with the majority
being non-randomized retrospective studies, which is why it is a subject that requires
studies with a better methodological design and a higher number of patients to obtain
10

conclusions of clinical relevance. that can set the direction in this area that is in
constant discussion.
Given the absence of any randomized non-inferiority clinical trial that studies the
routine use of abdominal drainage in the postoperative period of liver transplantation,
we consider that it is necessary to carry it out to increase the evidence.
The number of HT performed in each center is limited and variable annually, which is
why we consider that the best design for this clinical trial is a European multicenter.
●
OBJECTIVE AND PURPOSE OF THE TEST
The objective of our randomized clinical trial is to evaluate whether the prophylactic use of
intra-abdominal drains in LT patients reduces postoperative intra-abdominal complications,
compared to their routine use.
○
Main goal.
●
To assess whether the prophylactic use of abdominal drains in the postoperative
period
of
LT
increases
the
number
of abdominal complications in the 90
postoperative days (Clavien-Dindo)
○
Secondary objectives.
●
To evaluate the possible improvement in the quality of life of the transplanted patient
derived from the absence of postsurgical drainage (SF-36).
●
Evaluate the postoperative stay in both groups.
●
STUDY DESIGN
Unmasked European multicenter randomized clinical trial with two arms parallel to the
study.
Patients who meet the inclusion criteria will be offered to participate in this study by signing
an informed consent. An informed consent approved by the Research Ethics Committee of
the Virgen de la Arrixaca University Hospital will be used.
Patients who give their consent for the study will be randomized to the drainage group (D)
and the control group without drainage (ND) before the beginning of the abdominal wall
closure.
11

In the drainage group (D), it will be placed on the right flank / right iliac fossa. The drain will
be connected to a bag and fixed to the skin with a silk. Said drain will be placed at the level
of the surgical bed.
Regarding the control group, intraoperative drainage will not be placed, except when the
surgeon's discretion considers it necessary due to the high risk of bleeding, bile leakage or
any other process / complication in which it may benefit from intra-abdominal drainage.
All
patients,
regardless
of
the
randomization
group, will receive a quality of life
questionnaire (SF-36) prior to surgery that they must complete.
All patients will receive routine antibiotic prophylaxis 60 minutes before surgery, repeating
the number of doses that are required according to blood loss and surgical time. Antibiotic
prophylaxis will be adjusted according to the resistance protocols of each participating
center.
○
DATA COLLECT
The following variables will be collected for each patient:
●
Recipient preoperative variables: gender, age, pre-transplant stay, BMI, ASA,
diabetes, HTN, dialysis, MELD, Child-Pugh, serology, albumin, bilirubin, INR, CRP,
creatinine, ascites, SBP, prothrombin time, encephalopathy, time from SSI to HT
(months), retransplantation, previous surgeries, cirrhosis etiology, indication for
transplantation, sarcopenia.
●
Donor characteristic variables: age, stay in ICU, vasoactive drugs, cultures,
antibiotics, CIT, WIT, type of donation (DBD / DCD), previous immunosuppression.
●
Intraoperative variables: placement or not of abdominal drainage, surgical time
(min), transfusions, blood loss, surgical technique, arterial anastomosis type, biliary
anastomosis type, donation with extended criteria, recipient with extended criteria,
clamping times.
●
Postoperative
variables:
ICU
stay,
hospital
stay,
abdominal
complications
(collection, bile leak, hematoma, hemorrhage, paralytic ileus, ascites, bleeding,
wound drainage complications, vascular anastomosis complications, mechanical
12

obstruction, hollow viscus perforations, wound complications surgery), graft function,
post-transplant antibiotic therapy, post-transplant immunosuppressive regimen,
number of post-HT HC, mortality at 90 days, global complications at 90 days.
○
FOLLOW-UP
The drain output will be evaluated daily after the surgical procedure. The quantity will be
measured in milliliters and the appearance of the drainage will be categorized as serous,
hematic, biliary or purulent. Its removal will be assessed on the 3rd postoperative day
unless the patient shows signs of bleeding, bile leakage, intra-abdominal infection or any
other complication that contraindicates its removal. When any of these complications that
have delayed removal of the intra-abdominal drain are resolved, the drain should be
removed.
Patients will be followed up during the postoperative period on a daily basis and
complications will be observed at 90 days from discharge.
Calls will be made from discharge, the first 30 days every 15 days, from the month of
discharge the periodicity will be monthly until 90 days from the intervention. The last
follow-up call will be made on day 90. Subsequently, the follow-up protocol of each center
will be followed.
The SF-36 quality of life questionnaire will be performed preoperatively, at one month and
at 4 months after surgery.
○
Sampling methods and assignment of subjects to groups. Randomization.
Subjects will be recruited at the pre-liver transplant consultation and/or at the time of
inclusion on the transplant waiting list (Liver Transplant Committee - General Surgery
Sessions Room - 3rd Floor Hospital Clínico Universitario Virgen de la Arrixaca, Murcia -
Tuesday at 12h) among those patients who meet the criteria for participation in the study.
Once the individual has signed the informed consent document for the study and it has
been verified that they meet all the inclusion criteria and none of the exclusion criteria, they
will be considered eligible to be included in the study. In this first contact with the patient,
you will fill out a first SF-36 health questionnaire.
13

Each patient will be assigned a numerical code consecutively as they are included in the
trial. Randomization should be done in the operating room at the time prior to abdominal
wall closure (optimal time for drain placement). This moment is chosen for randomization to
avoid randomizing patients who ultimately require drainage due to intraoperative conditions
by decision of the surgeon and not by randomization. Randomization will be performed
using a spreadsheet with restricted access to participating centers through simple
randomization. In order to carry out the randomization, the sheet will require filling in the
initial data of the patient with which it will be verified that he meets the inclusion criteria in
the study and none of the exclusion criteria. Subsequently, he will proceed to randomization
and assign a number to the patient.
●
STUDY POPULATION
○
Definition of the study population
Patients will be recruited into the transplantation committee of the Hospital Clínico
Virgen de la Arrixaca University. 365 individuals will be selected from both sexes,
aged between 18 and 75 years, diagnosed with cirrhosis, liver disease, fulminant
hepatitis or other indications specific to HT.
○
Inclusion criteria.
-
Patients of both sexes aged between 18 and 75 years included in the waiting
list for HT by the committee of the Virgen de la Arrixaca University Hospital.
-
Sign Informed Consent.
○
Exclusion criteria.
-
Having been rejected for liver transplantation by said committee.
-
Age less than 18 years or greater than 75.
-
Any contraindication by the main surgeon that makes the placement of an
intra-abdominal drain necessary.
-
Not having signed the Informed Consent.
○
Abandonment and replacement of patients.
14

Subjects can withdraw at any time, with or without reason, and without prejudice to them.
The subject participating in the study may revoke his consent at any time, without
expression of cause and without thereby incurring responsibility or harm to the participating
subject. Individuals who drop out of the study will not undergo further follow-up or be
substituted. The investigator may withdraw a subject from the study if he considers that the
subject can no longer comply with all the requirements of the study or if any of the
procedures is considered possibly harmful to him. Data that has already been collected on
withdrawn subjects will be retained and used for analysis, but no new data will be collected
after withdrawal.
○
Withdrawal criteria
Those patients who meet any of these criteria will be withdrawn from the study:
●
Presence of adverse events that at the discretion of the investigator implies the
withdrawal of the patient.
●
Deviation from the protocol that affects the interpretation of the study results and
its scientific validity.
●
Optional decision.
●
Resignation of the individual to continue in the study.
●
Loss of follow-up.
●
TREATMENT OF SUBJECTS
○
Description of the intervention
In the intervention group, intra-abdominal drainage will be placed in the right flank / right
iliac fossa. This drain will be placed on the surgical bed and the extracorporeal end will
drain into a collection bag. Control of the amount drained and the appearance of the
content will be carried out on a daily basis. If the clinical situation of the patient allows it, the
drain should be removed on the 3rd postoperative day. If the clinical status or complications
do not allow its withdrawal, consider withdrawing it as soon as said contraindications allow
it.
The control group will not receive drainage. The evolution and the appearance of
complications will be monitored in the ICU and ward on a daily basis.
15

The subjects will be closely monitored through the daily visit to the ICU and ward.
Regarding
the
assessment
of
quality of life (SF-36), the patient will complete a
questionnaire at various points in the process:
-
Inclusion on the waiting list.
-
One month after surgery.
-
4 months after surgery.
○
Management of investigational medications / products.
Investigational products will be supplied by the hospital. Said product will be administered
intraoperatively and supplied to the surgical ward when its placement is confirmed
depending on the group assigned after randomization.
○
Previous and concomitant treatments.
Any pharmacological treatment carried out during the experimental period must be
registered in the CRD. The principal investigator of the study will judge the suitability of the
participant's continuity in the study.
The taking of drugs or other treatments that may modify the biological effects of the
products under investigation will not be explicitly allowed.
○
Rescue medication.
The use of rescue medication required by the patient is contemplated: analgesia,
antipyretics, albumin in abundant ascitic losses, ...
○
Compliance evaluation.
Following the randomization plan, all patients will be evaluated daily during their stay in the
ward.
All
files
must
be
available
for
review by the Promoter or the Promoter's
representative.
●
STUDY VARIABLES.
The following variables will be collected for each patient:
16

●
Recipient preoperative variables: gender, age, pre-transplant stay, BMI, ASA,
diabetes, HTN, dialysis, MELD, Child-Pugh, serology, albumin, bilirubin, INR, CRP,
creatinine, ascites, SBP, prothrombin time, encephalopathy, time from SSI to HT
(months), retransplantation, previous surgeries, cirrhosis etiology, indication for
transplantation, sarcopenia.
●
Donor characteristic variables: age, stay in ICU, vasoactive drugs, cultures,
antibiotics, CIT, WIT, type of donation (DBD / DCD), previous immunosuppression.
●
Intraoperative variables: placement or not of abdominal drainage, surgical time
(min), transfusions, blood loss, surgical technique, arterial anastomosis type, biliary
anastomosis type, donation with extended criteria, recipient with extended criteria,
clamping times.
●
Postoperative
variables:
ICU
stay,
hospital
stay,
abdominal
complications
(collection, bile leak, hematoma, hemorrhage, paralytic ileus, ascites, bleeding,
wound drainage complications, vascular anastomosis complications, mechanical
obstruction, hollow viscus perforations, wound complications surgery), graft function,
post-transplant antibiotic therapy, post-transplant immunosuppressive regimen,
number of post-HT HC, mortality at 90 days, global complications at 90 days.
●
SF-36: Physical function, physical role, body pain, general health, vitality, social
function, emotional role, mental health (on inclusion in the waiting list, one month
after surgery, 4 months after surgery).
●
SUBJECT FOLLOW-UP
As we have previously indicated, patients will be evaluated daily by the research staff
during their hospital stay. Those who were discharged before day 30 post-transplant will
continue to contact the researchers by phone and report any event related to the insertion
point of the drain.
Calls will be made from discharge, the first 30 days every 15 days, from the month of
discharge the periodicity will be monthly until 90 days from the intervention. The last
follow-up call will be made on day 90.
●
SAFETY
ASSESSMENT
(only
for
medicines,
food
or
other
therapeutic
procedures).
17

All patients assigned to the control group (DN) will be reevaluated intraoperatively. If, for
obvious clinical reasons, the placement of the drain is required, said patient will be
excluded from the study (randomization will not be carried out, so it would not be included
in the RCT) and the drain will be placed.
Patient safety was not impaired at any point in the study, with the intervention group (D)
being the routine procedure in LT and the control group (ND) re-evaluated intraoperatively.
●
STATISTICS
○
Data handling
The data collection will be carried out through a Data Collection Notebook, capturing all the
data in it legibly and in blue pen. Subsequently, said data will be dumped into a CRD
through a spreadsheet. This sheet allows online access for the different study participants,
to perform randomization and assign the patient code and to enter the data of each of the
included
patients.
Patients
will
be included without personal data or identification
documents, only an identification code that will be assigned to each one at the time of
randomization. Once the trial is finished, all the data collected in the database will be
evaluated for the writing of the final report.
All the documentation related to the study will remain stored in the Investigator's File, in the
participating center, under the custody of the Principal Investigator until the end of the
study. Once the study is finished, the documentation will be indexed and transferred to the
general file of the center, complying with the recommendations established with respect to
the Good Clinical Practice Standards.
The Principal Investigator will ensure that subject identification codes are kept for at least
fifteen years after the trial has been completed or discontinued.
The data of all the CRDs will be entered into a database created for this purpose and
equipped with safety margins and internal coherence standards. This database will be
equipped with a double entry system and filters that prevent and detect any type of
inconsistency or error in it. The information will be validated through internal consistency
controls, studying the missing values. The data will be verified and corrected until the
18

database is fully validated. Once the database is purged, the variables will be recoded
generating new variables (regrouping, sums, etc.).
○
Sample size.
The hypothesis of this study was that the risk of postoperative complications at 90 days in
the ND group would not be higher than in group D. A non-inferiority configuration was
selected because the omission of drain placement is advantageous in terms of relieving to
patients from discomfort and a decrease in medical cost. In calculating the sample size, the
risk of an early postoperative complication related to LT was assumed to be 9% in the drain
group and 6% in the no-drain group according to the literature review performed. Under a
4% non-inferiority margin, an alpha error of 0.05, and a statistical power of 80%, the sample
was calculated as 174 patients in each arm. Assuming a 5% dropout rate, a total of 365
patients will be recruited into this study.
○
Statistic analysis
The subsequent statistical analysis will be performed with the SPSS v.25 software.
●
Descriptive analysis.
The demographic data and other baseline characteristics of the trial subjects will be
described using descriptive statistical indices, for the overall number of patients and for
each of the groups of patients under study. Continuous variables will be described using
measures of central tendency (mean) and measures of dispersion (standard deviation).
While the categorical variables will be described through absolute and relative frequency
tables. The baseline characteristics shown by the groups of participants included in the
study will be compared. Statistical tests will be performed depending on the nature of the
variables. To study the relationships between variables, standard chi-square tests have
been used in the case of qualitative variables and Pearson's correlation in the case of
quantitative variables. In each situation, any association in which the p-value was less than
0.05 was considered statistically significant. The magnitude of the association between
qualitative variables will be made by calculating the relative risk, and between quantitative
19

variables using Pearson's correlation coefficient. In this multivariate analysis, the odds
ratios will be obtained with a 95% confidence interval.
●
Analysis of the main variable
The
primary
efficacy
criterion
is
the comparison of the incidence of postsurgical
complications according to the Clavien-Dindo classification.
●
Secondary variables analysis
The univariate and multivariate study of all the included variables will be carried out.
●
ETHICS
This study will be carried out in European hospitals in accordance with current European
legislation that regulates the performance of clinical trials, for which this protocol is
established as a reference document for review by the Ethics Committees, as well as for
the taking of practical decisions in the management of included patients by participating
investigators. The study will only begin after obtaining written authorization from the Clinical
Research Ethics Committee.
With the exception of those emergency situations, no protocol changes or deviations will be
allowed without documented approval. The CEIC must be informed of the possible changes
and will approve in writing any change or deviation that may increase the risks of the
subject and / or may adversely affect the rights of the volunteer or the validity of the
research. This stipulation does not apply to those changes that are made to reduce
inconvenience or avoid risks to the subjects and to changes that affect the administrative
aspects of the study. Carrying out this study will respect at all times the rules of Good
Clinical Practice and the regulations and recommendations that appear in the Declaration of
Helsinki and that are included in the current legislation on the practice of clinical trials.
●
INFORMED CONSENT
Before any specific test or study procedure is carried out, patients (or witnesses or legal
representatives) who meet the participation criteria will be asked to sign the informed
consent document approved by the Ethics Committee. Sufficient time should be given to
them to review the informed consent document and to have their questions answered
20

before signing. Each individual will be informed orally and in writing of the study
methodology,
as
well
as
the possible undesirable effects that may appear as a
consequence of the different determinations that will be made. In the same way, they will be
informed of the voluntary nature of the study both in terms of their participation and in terms
of abandonment at any time during the study. Likewise, everyone will be aware of the
possible undesirable effects that may appear during the study, regardless of the assigned
group. All of them will sign an informed consent to participate in the project.
●
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS
Source documents are all original documents, data and records. All the data collected to
carry out the study, both for the preparation of the subject's Clinical History, and for the rest
of the study documents, will be archived in the participating centers, on paper or in digital
format, in accordance with the procedures of each center. The data collected for the study
will be identified by a numerical code and only the principal investigator / collaborators will
be able to relate said data with the patient and with their medical history.
Access to the information of the participating subjects will be restricted to the study doctor
and authorized collaborating team members. The researcher and the center will guarantee
direct access to the data or source documents to the personnel authorized by the promoter
(monitor, auditor), to the health authorities (Spanish Agency for Medicines and Health
Products), and to the Ethical Committee for Clinical Research, when need it.
●
DATA MANAGEMENT AND RECORDS FILE
Patient data will be collected in a CRD. The principal investigator or a sub-investigator of
the center must ensure the accuracy and completeness of the data recorded and put their
signature on the corresponding CRDs. These data will be exported to REDCap, which will
be the platform on which all the data from the centers participating in the trial will be shared.
When the database has been considered complete and accurate, it will be closed by
locking the database. The filing of all relevant documents in relation to the study will be
21

carried out according to the requirements of the ICH-GCP, Commission directive 2005/28 /
EC of April 8, 2005, and according to the pertinent national laws.
●
DATA PROTECTION
The data will be included in a database that must comply with Regulation 679/2016, of April
27, General Data Protection Regulation and Organic Law 3/2018, of December 5, on the
Protection of Personal Data and guarantee of digital rights. Likewise, the transmission of
said data will be done with the appropriate security measures in compliance with said
regulation. During documentation and analysis, patients will only be identified by their
individual patient code, while all subject names will be kept secret by the investigator.
●
FINANCING AND INSURANCE
No extraordinary financing is necessary, since we will use available resources in daily
clinical and surgical activity. This study would be exempt from the need to take out
insurance since the patients will undergo two surgical techniques performed in routine
clinical practice and do not pose an additional risk to the patient.
●
PUBLICATION POLICY
Each researcher is free to publish data from their center. However, the collected data will be
presented and published by the appropriate author according to the criteria established by
the International Committee of Medical Journal Editors (ICJME). Data will be published
regardless of trial results.
●
BIBLIOGRAPHY
1.
Hobeika C, Cauchy F, Weiss E, Chopinet S, Sepulveda A, Dondero F, et al.
Practical model to identify liver transplant recipients at low risk of
postoperative haemorrhage, bile leakage and ascites. BJS Open [Internet].
2021;5(1). Disponible en:
https://academic.oup.com/bjsopen/article-lookup/doi/10.1093/bjsopen/zraa03
1
22

2.
Schwarz C, Soliman T, Györi G, Silberhumer G, Schoppmann SF, Mühlbacher
F, et al. Abdominal drainage after liver transplantation from deceased donors.
Langenbecks Arch Surg. 2015;400(7):813–9.
3.
Rodríguez-Laiz GP, Melgar-Requena P, Alcázar-López CF, Franco-Campello
M, Villodre-Tudela C, Pascual-Bartolomé S, et al. Fast-track liver
transplantation: Six-year prospective cohort study with an enhanced recovery
after surgery (ERAS) protocol. World J Surg. 2021;45(5):1262–71.
4.
Gurusamy KS, Naik P, Davidson BR. Routine drainage for orthotopic liver
transplantation. Cochrane Database Syst Rev. 2011;(6):CD008399.
5.
Arita J, Sakamaki K, Saiura A, Konishi M, Sakamoto Y, Hashimoto M, et al.
Drain placement after uncomplicated hepatic resection increases severe
postoperative complication rate: A Japanese multi-institutional randomized
controlled trial (ND-trial). Ann Surg. 2021;273(2):224–31.
6.
Weiss S, Messner F, Huth M, Weissenbacher A, Denecke C, Aigner F, et al.
Impact of abdominal drainage systems on postoperative complication rates
following liver transplantation. Eur J Med Res. 2015;20(1):66.
7.
Brustia R, Monsel A, Skurzak S, Schiffer E, Carrier FM, Patrono D, et al.
Guidelines for perioperative care for liver transplantation: Enhanced recovery
after surgery (ERAS) society recommendations. Transplantation [Internet].
2021;Publish Ahead of Print. Disponible en:
https://pubmed.ncbi.nlm.nih.gov/33966024/
8.
Tang R, Yu L-H, Han J-W, Lin J-Y, An J-J, Lu Q. Abdominal drainage systems
in modified piggyback orthotopic liver transplantation. Hepatobiliary Pancreat
Dis Int. 2021;20(1):99–102.
9.
Fernandez-Aguilar JL, Suarez Muñoz MA, Santoyo Santoyo J,
Sanchez-Perez B, Perez-Daga JA, Aranda Narvaez JM, et al. Is liver
transplantation without abdominal drainage safe? Transplant Proc.
2010;42(2):647–8.
10.
Fernandez-Aguilar JL, Suarez-Muñoz MA, Sanchez-Perez B, Gamez
Cordoba E, Pulido Roa Y, Aranda Narvaez J, et al. Liver transplantation
without abdominal drainage. Transplant Proc. 2012;44(9):2542–4.
11.
Liu C-L, Fan S-T, Lo C-M, Wong Y, Ng IO-L, Lam C-M, et al. Abdominal
drainage after hepatic resection is contraindicated in patients with chronic
liver diseases. Ann Surg. 2004;239(2):194–201.
12.
Dindo D, Demartines N, Clavien P-A. Classification of surgical complications:
A new proposal with evaluation in a cohort of 6336 patients and results of a
survey. Ann Surg. 2004;240(2):205–13.
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13.
Petrowsky H, Demartines N, Rousson V, Clavien P-A. Evidence-based value
of prophylactic drainage in gastrointestinal surgery: A systematic review and
meta-analyses. Ann Surg. 2004;240(6):1074–85.
14.
de Rougemont O, Dutkowski P, Weber M, Clavien P-A. Abdominal drains in
liver transplantation: useful tool or useless dogma? A matched case-control
study. Liver Transpl. 2009;15(1):96–101.
15.
Sanada Y, Mizuta K, Urahashi T, Umehara M, Wakiya T, Okada N, et al.
Management of intra-abdominal drain after living donor liver transplantation.
Transplant Proc. 2010;42(10):4555–9.
16.
Baldini E, Gugenheim J, Ouzan D, Katkhouda N, Mouiel J. Orthotopic liver
transplantation with and without peritoneal drainage: a comparative study.
Transplant Proc. 1999;31(1–2):556–7.
17.
Hampe T, Dogan A, Encke J, Mehrabi A, Schemmer P, Schmidt J, et al.
Biliary complications after liver transplantation. Clin Transplant. 2006;20
Suppl 17(s17):93–6.
18.
Thethy S, Thomson BN, Pleass H, Wigmore SJ, Madhavan K, Akyol M, et al.
Management of biliary tract complications after orthotopic liver
transplantation. Clin Transplant. 2004;18(6):647–53.
19.
Cavallari A, Vivarelli M, Bellusci R, Jovine E, Mazziotti A, Rossi C. Treatment
of vascular complications following liver transplantation: multidisciplinary
approach. Hepatogastroenterology. 2001;48(37):179–83.
20.
Gurusamy KS, Nagendran M, Davidson BR. Methods of preventing bacterial
sepsis and wound complications after liver transplantation. Cochrane
Database Syst Rev. 2014;(3):CD006660
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●
ANNEXES
ANNEX 1. Clavien-Dindo Classification
(GRAVITY - POSTOPERATIVE COMPLICATION)
I.
Any deviation from the normal postoperative period that does not require
surgical or endoscopic reintervention. Includes additional use of
electrolyte
solutions,
antiemetics,
antipyretics,
analgesics,
and
physical therapies. Includes superficial infection
II.
Pharmacological treatment different from the previous ones. Blood
transfusions or blood products and parenteral nutrition
III.
Requires surgical, endoscopic or radiological reintervention:
a.
Without general anesthesia
b.
With general anesthesia
IV.
Complications that threaten the life of the patient and require treatment in
intermediate or intensive care:
a.
Organ dysfunction (includes hemodialysis)
b.
Multiple organ dysfunction
V.
Death of the patient
Dindo D, Demartines N, Clavien PA. Classification of surgical complications, a
new proposal with evaluation in a cohort of 6336 patients and results of a survey.
Ann Surg. 2004; 240(2):205-213
25

ANNEX 2. CLASSIFICATION AMERICAN SOCIETY OF ANESTHESIOLOGIST
(ASA)
I: No systemic disease.
II: Mild systemic disease.
III: Systemic disease that affects the activity of the patient.
IV: Serious disease, but not dying patient.
V: Dying patient, unexpected survival.
Saklad M. Grading of patients for surgical procedures. Anesthesiology 1941;
2:281–4. Dripps RD. New classification of physical status. Anesthesiology 1963;
24:111.
26

ANNEX 3. INFORMED CONSENT
27

28

ANNEX 4. PATIENT INFORMATION SHEET
29

30

31

ANNEX 5. QUESTIONNAIRE SF-36
32

33

34

35

36

37