1 Primary Objective To investigate the effects of 15* liver ischemia versus 30* liver ischemia on liver injury and liver function.To investigate the effect of liver manipulation during mobilisation for a right hemihepatectomy, that can be used as a…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Hepatobiliary neoplasms malignant and unspecified
- Hepatobiliary therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
As the primary endpoint, we will look at plasma levels of novel markers of
liver damage, such as ophthalmic acid and Liver - Fatty Acid Binding Protein
(L-FABP), as well as more traditional markers such as ASAT, ALAT.
We will compare the alanin aminotransferase (ALAT) and aspartate
aminotransferase (ASAT) plasma levels between the three groups. ASAT and ALAT
are commonly used and accepted as parameters for liver cell injury and will be
used as the gold standard in this study. However ASAT and ALAT are crude
estimates of liver cell injury because they are gradually and slowly released
from injured cells and remain in the circulation for a long period. Esaki (5)
et al concluded that there was no clinically relevant difference in the
bilirubin ratio and ASAT/ ALAT levels on the second post operative day between
two groups of patients that underwent a period of 15* or 30* minutes liver
ischemia. In this study the aim is to investigate the effects of 15* liver
ischemia versus 30* liver ischemia using more sophisticated markers of liver
injury and liver function such as L-FABP and Ophthalmic acid.
L-FABP plasma levels are currently arising as more sensitive and specific
plasma markers for hepatic injury. L-FABP*s are small and cystolic proteins
which after leakage from injured cells have a short plasma half-life. The
L-FABP plasma level is a good liver injury marker because it possesses liver
tissue-specificity and its molecular weight is low by which it can be released
from injured liver cells in an early stage and in significant amounts.
During liver surgery (resection, transplantation) the liver is exposed to
oxidative stress during the phase of temporary clamping of the portal vein and
hepatic artery. Ischemia is typically characterized by ATP depletion and
necrotic cell death. Upon reperfusion a multifactorial process leading to
apoptotic cell death is initiated that further aggravates cell injury already
initiated by plain ischemia. An important factor in this process is the
formation of large quantities of reactive oxygen species (ROS) immediately
after reperfusion. This so-called oxidative burst may induce per-oxidation of
membrane phospholipids and intracellular proteins, triggering a cascade leading
to caspase activation and apoptotic cell death. Oxidative injury can be limited
by one of the most important intracellular anti-oxidants in human cells in
quantitative terms, the antioxidant gluthathione. Glutathione (GSH γ-
glutamyl-cysteinyl-glycine) is a tripeptide, which is synthesized from
glutamate, glycine, and cysteine. GSH contains a sulfhydryl group which can
reduce ROS upon oxidation to glutathione disulfide (GSSG). Information about
the glutathione synthesis rate and capacity in the perioperative phase is very
important in order to protect a patient against ischemia reperfusion damage
(which can also occur during e. g. aorta surgery). In vivo measurements of
glutathion synthesis in human are complex and attempts to use stable isotopes
in order to clarify this, also our group, have led to data that are difficult
to interpret and not easy to reproduce. Recently it has been suggested that
tissue and plasma ophthalmic acid can be an *alternative read-out* for hepatic
glutathione synthesis. Ophthalmate is an analog of GSH and has the same pathway
of synthesis as GSH. However when GSH levels are decreased during conditions of
higher oxidative stress because of a persistent oxidative load which leads to
an acceleration of hepatic depletion that is not matched by an equal increase
of GSH synthesis, the ophthalmic acid level increases (reciproke *read out* see
figure 2). Ophthalmate is not an antioxidant, can not conjugate with free
radicals and will be effluxed to the circulation.
Recently Soga et al (8) found that in mice with acetaminophen-induced
hepatotoxicity, activation of the ophthalmic acid biosynthesis pathway occurs.
The first step is that 2-aminobutyrate is linked to glutamate which is
catalyzed by GCS, then glycine is linked to this dipeptide via GS. The only
difference between glutathione and ophthalmic acid is that 2-aminobutyraat is
replaced by cystein. Glutathione has a normally negative feedback on GCS. In a
situation of ischemia (for example acetaminophen-induced hepatotoxicity) this
negative feedback mechanism disappears and because all the cystein is depleted
by oxidation, the alternative pathway will be activated leading to excessive
generation of ophthalmic acid via the same pathway. The increase of the
ophthalmic acid is just as high as the decrease of gluthathion is. See figure 2.
The focus of this study will be to asses the effects of different ischemia
times on the ophthalmic acid plasma levels. By measuring Ophthalmate
concentration in hepatic serum several times in both groups we are able to
compare the level of hepatic GSH depletion and thus oxidative stress in order
to make an accurate estimation of possible differences in liver function and
injury.
Secondary outcome
Concentrations of different inflammatory and intestinal damage markers will be
measured in blood.
Inflammatory markers
- Soluble TNF-receptor (n75/ n55)
- IL-6
- IL-8
- Interferon-γ
- MPO
- IL-10
Intestinal damage markers:
- Intestinal Fatty Acid Binding Protein (I-FABP)
- Ileal Lipid Binding Protein (I-LBP)
Background summary
Colorectal cancer is the second commonest malignancy in Europe. Approximately
50 % of all patients diagnosed with CRC will develop liver metastases at some
stage of their disease. For these patients the only potentially curative
treatment option is an operation in which the part of the liver that contains
metastases is removed. Patients that have undergone a liver resection can
develop postoperative complications due to extensive intraoperative blood loss
(1, 2). To make an attempt to avoid blood loss during transection a Pringle
manoeuvre can be performed. This implies a temporary clamping of the portal
vein and hepatic artery in order to reduce hepatic inflow (3). The advantage of
this manoeuvre is that surgery can be performed in a *blood free* liver. This
could reduce intraoperative blood loss and consequently the risk of
complications.
To prevent ischemic damage the Pringle manoeuvre is applied intermittently
which means that every 15 minutes the inflow to the liver is re-established by
releasing the clamp to allow reperfusion for a period of 5 minutes. However,
the transection of the liver takes in general longer than 15 minutes and
therefore several cycles of 15 minutes inflow occlusion and reperfusion are
necessary. The safe upper limit of cumulative hepatic ischemia in a normal
liver can be extended to 325 minutes (4). Unfortunately, during each
reperfusion phase a possibility exists of hemorrhage which is a significant
prognostic indicator for postoperative complications.
A possible solution for this problem could be prolonging the interval of
ischemia from 15 to 30 minutes. Fewer cycles of inflow occlusion and
reperfusion will be necessary, while the safe upper limit of cumulative hepatic
ischemia will not be exceeded. Because there are less phases of portal pedicle
declamping, cumulative blood loss will probably be reduced. Recent data show
that routine application of a prolonged period of 30 minutes will also reduce
operation time and even cumulative ischemia time, because the transection can
be performed more efficiently (5). A reduced operation time will lower the risk
of postoperative infection. A possible disadvantage of a period of 30 minutes
liver ischemia is that it might cause more ischemic damage to the functional
parenchyma of the remnant liver, than a period of 15 minutes. Recent literature
data suggest that a period of 30 minutes liver ischemia can be endured without
any clinically relevant effect on remnant liver function (5). However, in that
particular study only crude estimates of liver function were applied. Our aim
is to investigate the effects of 15* liver ischemia versus 30* liver ischemia
using more sophisticated markers of liver injury and liver function.
Our group recently showed that even during liver manipulation at the beginning
of surgery for colorectal liver metastases and before application of the
Pringle manoeuvre, plasma levels of markers for liver damage (ASAT, GSTα and
L-FABP) and inflammation (Il-6) increased significantly in humans. A possible
explanation might be that manipulation of the liver induces microcirculatory
derangements and oxidative stress followed by Kupffer cell activation and cell
death. This damage might even be aggravated in livers suffering from
pre-existent liver diseases like steatosis, chemotherapy-associated
hepatotoxicity or cirrhosis. After mobilisation of the liver, transection of
the extremely perfused liver parenchyma takes place.
The inflammatory response following surgery or trauma is essentially
favourable, as defense mechanisms are needed to trace and combat pathogens.
However, under circumstances the inflammatory response can derail, leading to
systemic inflammatory response syndrome (SIRS) and sepsis. Patients suffering
from these syndromes are prone to develop organ damage that can be lethal.
Our group has shown that high fat nutrition administered before hemorrhagic
shock reduces inflammation and preserves gut integrity. The presence of fat in
the proximal small intestine leads to release of neuropeptide cholecystokinin
(CCK) that activates the autonomous nervous system. Hence, activation of the
efferent vagus nerve inhibits the inflammatory actions of macrophages via
binding to nicotinic receptors (figure 1).6
In order to translate this protective mechanism to the human setting, the
optimal composition and volume of nutrition is determined in a separate
protocol (METC number 06-1-076) In protocol 07-4-016, parameters of
inflammation and tissue damage are determined in patients undergoing surgery of
the colon and femur fractures. In this study, inflammation and tissue damage
are determined during and after liver surgery.7 The results of this study will
be used for future intervention studies.
Study objective
1 Primary Objective
To investigate the effects of 15* liver ischemia versus 30* liver ischemia on
liver injury and liver function.
To investigate the effect of liver manipulation during mobilisation for a right
hemihepatectomy, that can be used as a standardized model in future studies.
To identify markers of inflammation and tissue damage during and after liver
surgery, that can be used in future intervention studies.
2 Secondary Objectives
To investigate mechanisms leading to cell injury, liver dysfunction and
cellular protective processes during ischemia of the liver in humans.
Study design
Groups:
A Pringle manoeuvre will be necessary in approximately 50% of the patients.
This necessity becomes clear not until during surgery. In that case
randomisation will take place between a continuous period of 15 (group A) or 30
min (group B) minutes liver ischemia. In 50% of all patients undergoing liver
surgery a Pringle manoeuvre is not necessary. This group C will be used as a
control group to study the relation between remnant liver volume and
postoperative liver function. For a schematic representation of al the time
schedule in each group see figure 1.
In all patients (group A, B and C) arterial and renal, portal and hepatic
venous blood will be sampled and liver biopsies will be taken according to the
schedules below. Blood samples will be taken from the artery line (routinely
placed by the anaesthetist) and also from the liver vein, portal vein and renal
vein by direct puncture. By measuring concentration differences between the
artery, portal vein and the liver vein, the uptake and production of substances
(e.g. proteins, cytokines) can be quantified. The measurement of concentration
differences between the renal vein and the artery are necessary to study renal
metabolism. Renal metabolism is worthwhile measuring because the kidney is able
to compensate important liver functions when the liver is failing, for example
clearance of ammonia and urea (1, 6). Markers of liver injury and liver
function will be measured and compared between group A and B in order to
investigate the effects of 15* liver ischemia versus 30* liver ischemia. In
group C the blood flow through the liver will be determined with the use of an
indocyanine green infusion. The post operative liver volume will be calculated
in group C with a specially developed computer method (7). Liver biopsies will
be taken from the part of the liver that will be removed. The methods applied
(intraabdominal blood sampling, liver biopsies, ICG infusion) have been used
before without any problems for the surgical procedure or the patient (MEC
02-045 and MEC 03-032).
Study burden and risks
There are no additional risks on top of the normal risks of undergoing liver
surgery. At present, it is unclear whether prolonging the interval of ischemia
from 15 to 30 minutes will cause more liver cell injury. The literature
indicates that this is probably not the case, or at least not clinically
relevant (5). This is in agreement with our own observations, when the interval
of ischemia is longer than 15 minutes as a consequence of the situation. The
chance that liver biopsies during surgery will cause an important bleeding is
very small because biopsies will be taken from the part of the liver that will
be removed. The amount of blood loss due to a biopsy or puncturing the liver,
portal and kidney vein is very small compared to the amount of blood loss due
to the liver resection (± 0.5-3 litre).The methods applied (intraabdominal
blood sampling, liver biopsies, ICG infusion) have been used before without any
problems for the surgical procedure or the patient (MEC 02-045 and MEC 03-032)
and have been published in peer reviewed journals (9, 10).
Postbus 616
6200 MD
Nederland
Postbus 616
6200 MD
Nederland
Listed location countries
Age
Inclusion criteria
Patients with resectable liver tumors (mostly colorectal cancer liver metastases) who undergo a liver resection at the University Hospital Maastricht. Patients should be older than 18 years and younger than 75 years.
Exclusion criteria
Parenchymal liver disease, inflammatory liver disease, inborn errors of metabolism (liver enzyme deficiencies), steroid hormone medication, n-acetyl cystein medication
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL13089.068.06 |