Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00908245 |
| Other study ID # |
AOR01010 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
May 22, 2009 |
| Last updated |
December 15, 2011 |
| Start date |
September 2003 |
| Est. completion date |
December 2008 |
Study information
| Verified date |
July 2011 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
France: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
To evaluate the accuracy of ischemic preconditioning (IPC) as a protective maneuver against
ischemia/reperfusion lesion in patients undergoing major liver resection with intermittent
portal triad Clamping (IPTC).
Summary Background Data: For sake of safety and to avoid excessive blood loss during
parenchymal transection, vascular inflow occlusion is an effective trick but may cause
ischemic damage to the remnant liver and can lead to liver failure in case of chronic liver
disease. IPTC has been proven to be superior to continuous hepatic pedicle clamping as it
preserve liver remnant from severe ischemia/reperfusion lesion, so does IPC. Yet, if IPC is
beneficial if liver resection is performed under IPTC has never been demonstrated in a
randomised controlled trial (RCT). The investigators designed a RCT to assess the impact of
IPC in patient undergoing major liver resection with intermittent vascular inflow occlusion.
Description:
This is a prospective controlled trial, conducted between January 2005 and December 2007.
Three centres specialized in hepatobiliary surgery (Cochin hospital (Paris, France), BEAUJON
hospital (Clichy, France) and PONTCHAILLOU Hospital (Rennes, France)) participated to this
study, which has been initiated by the department of hepatobiliary surgery and liver
transplantation of the Cochin hospital. The protocol was approved by ethics committees of
each participating centres and an informed consent was obtained from each patients before
they were enrolled. Eighty seven patients were randomized to either receive ischemic
preconditioning prior to liver resection under intermittent pedicular clamping or not.
Ischemic preconditioning was performed through a sequence of 10 minutes vascular inflow
occlusion and 10 minutes of reperfusion prior to intermittent pedicular clamping.
Intermittent pedicular clamping was conducted through a sequence of 15 minutes of vascular
inflow occlusion and 5 minutes of reperfusion. The randomization process which was
centralized was held in the operating room after inclusion criteria had been check and
exclusion criteria ruled out. Inclusion criteria were: patients' age (≥ 18 years old), liver
resection of 3 segments (as described by Couinaud) or more, posterior lesionectomy (segment
VI and VII), liver resection only or associated with a primary digestive or biliary tumor.
Exclusion criteria : Patients with cirrhosis, synchronous radiofrequency or cryotherapy
ablation, undergoing segmentectomy, left lateral lesionectomy or laparoscopic liver
resection were excluded from further analysis as well as pregnant women.
Anaesthetic protocol:
Patients' status was evaluated by the ASA (American Society of Anaesthesiology) scoring
system. Surgical procedure was conducted under low central venous pressure (5cm H2O) to
avoid excessive bleeding from suprahepatic veins backflow.13 Patients' anaesthesia was
performed using a single protocol that was common to all participating centres. Patients in
whom this protocol was contraindicated due to medical reasons were excluded. A standardized
general anesthesia using thiopental, sufentanil, atracurium and sevoflurane was applied
throughout the study period. Mechanical ventilation was carried out using 50 % oxygen in
nitrous oxide and was adjusted to keep end-tidal PCO2 between 4.7 and 6.0 kPA. Intra-venous
cefazolin (Cephazolin, PANPHARMA laboratory, FOUGERES, France) was administered for
antibioprophylaxy. An arterial line was inserted for arterial pressure monitoring and blood
sampling. Central venous pressure was not consistently maintained below a predetermined
level. Intraoperative Ringer lactate infusion was limited to the minimum, practically below
500 mL, until parenchymal resection was completed. Following liver resection, hydroxyethyl
starch 130 (Voluven, Fresenius laboratory, SEVRES, France), 20 mL/kg, was infused in one
hour. Thereafter, additional hydroxyethyl starch, fresh frozen plasma, red blood cell packs
were administered as indicated by urinary output, hemodynamics, and biological data.
Thresholds for blood transfusion were a hemoglobin level of 7g/dL for healthy patients 64
years of age or under, and 9 g/dL for patients 65 years of age or over and/or with
preexisting cardiopulmonary disease (1).
Surgical protocol:
All of the patients included in this study were operated in high volume centres by senior
surgeons specialized in hepatobiliary surgery. Major resection was defined as resection of 3
or more liver segment as described by Couinaud. Ischemic preconditioning was performed
through a sequence of 10 minutes vascular inflow occlusion and 10 minutes of reperfusion
prior to intermittent pedicular clamping. Intermittent pedicle clamping was conducted
through a sequence of 15 minutes of vascular inflow occlusion and 5 minutes of reperfusion.
Intermittent clamping was used during the whole parenchyma transection process. During
ischemic preconditioning the liver left in native position to avoid ischemic process due to
compression. Surgical liver biopsies were performed before after interruption of the
vascular inflow. The samples were all collected in the same centre (Cochin Hospital) for
histological and molecular biological analysis. The device used for clamping was left to the
surgeon's discretion (Tourniquet or vascular clamp) but had to be the same for both
preconditioning and clamping. The technique used for parenchymal liver transection was left
to the surgeon's discretion as well as haemostasis and BILIOSTASIS techniques which were
performed using bipolar forceps, metallic clips or ligation depending on vessels or bile
ducts size. Devices used for parenchymal transection and haemostasis/BILIOSTASIS techniques
were recorded in the preoperative data collection form. Postoperative drainage of the
abdominal cavity was left to the surgeon's discretion but was collected in the data sheet.
All complications occurring during surgery were collected as well as blood loss, blood
transfusion and fluid infusion.
Patient's follow-up and data collection:
Patients' follow-up was 3 months and was initiated the day before surgery (Di). Given that
primary hypothesis was a 50% reduction of transaminases (AST, ALT) level on postoperative
day 1 in the preconditioning group, blood samples were collected on all patients on Di and
POD1 for transaminases measurement. All of these samples were collected in a unique
biochemistry laboratory (Hospital Cochin) to avoid inter laboratory variations. Besides
these two samples, each centres conducted a regular biological follow-up of patients on a
previously established schedule which was common to all centres. Biological assessment was
performed on blood samples collected on Di and POD 1, 3, 5, 7, 14 and 28. Blood samples were
tested for liver biochemistry (AST, ALT, PAL, GGT, BT and BC), prothrombin time, factor V,
blood cells count (red blood cells, white blood cells and platelets) and albumine. Clinical
examination was performed every day by the senior surgeon in charge of the patients until
they were discharge from hospital, as well as on POD 15, POD 30 (5 days) and POD 90 (10
days). All impaired outcomes were noted in the data sheets. Surgical complications collected
were: Intra abdominal bleeding, biliary fistula, vascular complication, intra abdominal
abscess, wound infection and reintervention. Medical complication collected were: Infection
(urinary tract, lung, catheter) liver dysfunction, liver failure, ascitis, pleural fluid
effusion necessitating a drainage or not. Postoperative morbidity and mortality were defined
as any impaired surgical or medical outcome or death occurring within POD 90, respectively.
When hospital readmission was required patients where hospitalised in the surgical
department. Finally histological analysis of the liver samples collected at surgery was
reviewed by a single pathologist who was unaware of any clinical data.
Statistical analysis:
The analysis was performed in intention-to-treat. The sample size calculation was based on
the primary endpoint postoperative (POD1) aspartate aminotransferase (ALT). According to
previous data (ref 4-7,9,10 protocol), the sample size calculation was performed with the
expectation of a 50% difference in postoperative serum ALT level with a level of statistical
significance of 0.05 and a power of 0.80, using a two-tailed t-test. This calculation
indicated to include 38 patients in each group. Modification of ALT was also quantified as
the difference between Di and POD 1. Demographic data, baseline characteristics, and
surgical data are summarized by groups using descriptive statistic. Categorical variables
are expressed as numbers (percentages) and comparisons between groups were performed by the
chi-square test or Fisher exact test, when needed. Continuous variables are expressed as
mean (standard deviation of the mean (sd)) and were compared using two-tailed t-test.
Analyses were performed using SAS software, version 9.1, SAS institute inc, Cary, North
Carolina.
