Warm Hepatic Ischemia-reperfusion Injury Clinical Trial
Official title:
Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery
Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow
in order to prevent excessive blood loss. However, this predisposes the liver to a
detrimental inflammatory response once the circulation is restored. Altogether, the effects
that result from this temporary withdrawal of blood are known as ischemia and reperfusion
(I/R) injury, and the extent to which this occurs determines the functional outcome of the
liver after surgery.
Recently, it has become clear that (over)activation of the immune system forms the mainstay
of I/R injury in the liver. More importantly, it has been shown in animal models that
self-antigens, which are normal cellular constituents that become immunogenic mediators
following their release from dying cells, are involved in the earliest stages of I/R injury
of the liver. Clinical data on the release self-antigens in I/R injury are however scarce to
date. Therefore, the aim of this study is to investigate the release of self-antigens in
patients that undergo a major liver resection with or without withdrawal of the liver's
blood flow. Also, the results will be correlated to genes involved in the inflammatory
response as well as clinical parameters for liver damage and function.
Rationale
Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow
in order to prevent excessive blood loss. Vascular inflow occlusion (VIO) however
predisposes the liver to a detrimental inflammatory response once the circulation is
restored. Altogether, the ramifications that result from this temporary withdrawal of oxygen
supply are known as ischemia and reperfusion (I/R) injury, and the extent to which this
occurs determines the functional outcome of the liver after surgery. Recently, it has become
clear that (over)activation of the immune system forms the mainstay of hepatic I/R injury.
More importantly, it has been shown in animal models that endogenous self-antigens, known as
damage-associated molecular patterns (DAMPs), are released from stressed liver cells in the
earliest stages of reperfusion and, as such, form the most proximal triggers of hepatic I/R
injury. Clinical data on DAMP release following hepatic I/R are however scarce to date.
Therefore, the aim of this study is to investigate DAMP release in patients that undergo a
major liver resection with or without VIO and to correlate the results to the expression of
acute- phase inflammatory response genes and routine clinical parameters for hepatocellular
damage.
Objective
To investigate the release of damage-associated molecular patterns (DAMPs) following major
hepatic resection with or without VIO and to correlate the outcomes to the acute
inflammatory response and clinical parameters for hepatocellular damage.
Study design
The study is designed as an observational study. Because the decision to apply VIO is often
made during surgery, patients will be allocated to a group postoperatively. Therefore, the
inclusion of subjects in this study will continue until the calculated sample size of 15
patients has been reached in each group.
Study population
Eligible patients for participation in this study are those diagnosed with a malignant or
benign hepatic tumor that are scheduled to undergo major hepatectomy (resection of ≥3
segments).
Main study parameters/endpoints
The primary endpoint of this study is defined as the effect of I/R on the release of DAMPs,
measured in the systemic circulation. Secondary parameters constitute the expression of
acute inflammatory response genes, AST, ALT, total bilirubin, and INR.
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Observational Model: Case Control, Time Perspective: Prospective