In Situ Hypothermic Perfusion During Right Hemihepatectomy
Currently, surgical resection is often the only curative treatment for primary or secondary
hepatic malignancies. Also, liver resection is frequently performed in patients with benign
liver tumors to prevent malignant transformation and/or alleviate symptoms. Liver resections
are nowadays performed with low mortality and acceptable morbidity. As result of that, an
increasing number of patients is currently under consideration for resection of more complex
or large tumors, thus requiring extensive resection procedures. Application of vascular
exclusion (i.e., clamping of the portal vein and hepatic artery) during such procedures
reduces blood loss, which is one of the most important factors affecting peri-operative
outcomes. However, vascular exclusion causes ischemia-reperfusion (I/R) injury of the liver
parenchyma as an inevitable side-effect, which adversely impacts postoperative liver
function and regeneration. Additional cooling of the liver by means of hypothermic perfusion
is expected to further reduce intraoperative blood loss, as well as to protect the liver
from I/R injury. Therefore, the aim of this pilot study is to cool the future remnant liver
(FRL) in situ during right hemihepatectomy under vascular exclusion. Consequently, we expect
an improvement in postoperative outcomes, due to a decrease in intraoperative blood loss and
less parenchymal damage, as well as a better ability of the liver remnant to regenerate.
This pilot study encompasses 3 main objectives:
- To assess the technical feasibility of R-IHP in patients undergoing right
- To investigate the effect of R-IHP versus that of intermittent vascular occlusion (IVO)
on I/R injury, manifested as a decrease in parenchymal damage parameters.
- To investigate whether R-IHP reduces intraoperative blood loss compared to IVO.
The study is designed as a prospective randomized pilot study in 18 patients.
- Intervention group. 9 patients with a malignant or benign hepatic tumor who are
scheduled for right hemihepatectomy (i.e., resection of segments 5-8) under vascular
inflow occlusion and who are not diagnosed with any hepatic co- morbidity that might
influence postoperative outcomes, that is cirrhosis, cholestasis, severe steatosis,
and/or hepatitis B/C infection.
- Control group. 9 patients that meet the criteria as stated above, but who will not
However, prior to randomized allocation, 4 patients (as described above) are included to
undergo R-IHP with the aim of assessment of its feasibility. Due to the existence of a
learning curve, these 4 patients will no be included in the study group's statistical
analysis and are therefore mentioned separately.
Consequently, a total of 22 patients will be included in this study.
Main study parameter/endpoint
The primary endpoint of this study is defined as the effect of R-IHP versus that of IVO on
the resilience of the FRL against I/R injury, measured as a decrease in postoperative
biochemical parameters for hepatocellular damage (i.e., AST and ALT).
Secondary study parameters/endpoints
- Intraoperative blood loss
- Intra- and postoperative (5 days) transfusion requirements (whole blood and blood
- Postoperative morbidity and complications
- Regeneration of liver function (measured via hepatobiliary scintigraphy) and -volume
(determined by CT-volumetry)
- Biochemical parameters for liver function (total/conjugated bilirubin, INR)
- Inflammatory parameters (IL-6, IL-8, C5a, MPO, LTB4, GSH/GSSG ratio, syndecan-1,8-OHG,
8-OHdG, MDA, 4-HNE, PCC, and 3-nitrotyrosine)
- Parenchymal energy (ATP/ADP) levels, determined in biopsy tissue
- Up-regulation of acute phase oxidative stress response genes, determined in biopsy
Tertiary study parameters/endpoints
- Duration of vascular occlusion
- Cumulative operating time
- Intraoperative liver core temperature
- Intraoperative body temperature
- Hospital stay (expressed as days until release)
Additional study parameters
- Indication for surgery (primary or secondary hepatic tumor, tumor type)
- Neoadjuvant chemotherapy (duration, drug type)
- Patient demographics (age, gender, BMI)
- Compromised livers (steatosis, cholestasis, or cirrhosis) according to
histopathological assessment of the resected specimen
- Perfusate volume
Prior to definitive participation in the study, several hepatic co-morbidities need to be
excluded. Therefore, the following diagnostics will be employed:
- Transient ultrasound elastography (Fibroscan). Fibroscan is a relatively new but
validated and non-invasive method for the assessment of liver stiffness as a measure
for fibrosis/cirrhosis. An increased stiffness value (expressed in kPa) represents more
fibrotic parenchymal tissue. To exclude cirrhosis, a cutoff value of 9.2 kPa will be
used. Therefore, patients showing a liver stiffness of ≥ 9.2 kPa will be considered
cirrhotic and will thus be excluded from participating in the study.
- Unenhanced CT imaging. CT scanning is a reliable method for the detection and
quantification of hepatic fatty infiltration ≥ 30%, expressed by a liver-spleen
attenuation < 42 HU. This method will be employed to detect patients that suffer from
- Blood tests. Laboratory determination of bilirubin (total/conjugated) will be employed
for determination of cholestasis (cutoff points: total bilirubin ≥ 30 μmol/L and
conjugated bilirubin ≥ 15 μmol/L). The presence of hepatitis B/C infection will be
determined by serology (HBeAg and anti-HCV).
Investigational treatments; intervention group
During hemihepatectomy, the FRLs of subjects allocated to the intervention group of this
study will be perfused with a chilled perfusion solution (4°C lactated Ringer's solution) in
order to reduce parenchymal blood loss and enhance the livers resilience against I/R injury.
Investigational treatments; control group
The control subjects will undergo IVO, in which the portal vein and hepatic artery are
clamped and released intermittently (20 minutes ischemia, followed by 10 minutes
reperfusion). This comprises the standard method for vascular inflow occlusion in our
Investigational treatments; both groups
All patients included in the study will undergo the following investigational procedures:
- Biopsies. Biopsies are taken from the FRL for assessment of hepatocellular energy
(ATP/ADP) status and up-regulation of acute phase oxidative stress response genes.
Specimens will be taken prior to vascular inflow occlusion and after 30 minutes
- Hepatobiliary scintigraphy. Dynamic 99mTc-mebrofenin hepatobiliary scintigraphy
combined with singe photon emission computed tomography (SPECT) is a validated modality
that is able to measure the total liver function, as well as that of the FRL in
specific. Liver function will be determined pre- and postoperatively (3 days).
- CT-volumetry. Liver volume will be assessed pre- and postoperatively (3 days) by means
- Biochemical parameters. Blood will be drawn one day preoperatively and at various
postoperative time-points (1, 3, and 5 days). The samples will be analyzed for AST,
ALT, total/conjugated bilirubin, and INR via routine clinical chemistry.
- Inflammatory parameters. In addition to the biochemical parameters stated above, an
additional set of inflammatory parameters (IL-6, IL-8, C5a, MPO, LTB4, GSH/GSSG ratio,
syndecan-1, 8-OHG, 8-OHdG, MDA, 4-HNE, PCC, and 3- nitrotyrosine) will be assessed. To
this end, blood will be drawn preoperatively, as well as 1, 6, and 12 hours
postoperatively. Subsequently, samples will be analyzed in our laboratory.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Postoperative hepatocellular damage
Hepatocellular damage expressed as an postoperative increase in transaminases (i.e., AST and ALT).
5 days postoperatively
Prof. Thomas M. van Gulik, MD, PhD
Academic Medical Center, Amsterdam
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)