Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery

Warm Hepatic Ischemia-reperfusion Injury Clinical Trial

— RISE  

Official title:

Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01700660
• Other study ID #: 2012_238
• Secondary ID: NL41737.018.12
• Status: Completed
• Phase: N/A
• First received: October 3, 2012
• Last updated: January 25, 2016
• Start date: October 2012
• Est. completion date: December 2014

Study information

• Verified date: January 2016
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients scheduled to undergo a major liver resection for a benign or malignant hepatic tumor

• Signed informed consent obtained prior to any study-specific procedure

• ASA classification I-III

Exclusion Criteria:

• VIO <20 min

• ASA classification IV/V

• Emergency operations

• Pregnancy or breast feeding

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Reperfusion Injury
• Warm Hepatic Ischemia-reperfusion Injury

Locations

Country	Name	City	State
Netherlands	Academic Medical Center	Amsterdam	Noord Holland

Sponsors (1)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

van Golen RF, van Gulik TM, Heger M. The sterile immune response during hepatic ischemia/reperfusion. Cytokine Growth Factor Rev. 2012 Jun;23(3):69-84. doi: 10.1016/j.cytogfr.2012.04.006. Epub 2012 May 17. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DAMPs in systemic circulation	Plasma DAMP levels will be determined perioperatively.	8 hours	No
Secondary	Up regulation of acute inflammatory response genes	Up regulation of acute inflammatory response genes will be determined in liver biopsy tissue (acquired intraoperatively) by means of qPCR.	1 hour	No
Secondary	Parenchymal damage	Measured as plasma ALT and AST.	8 hours	No
Secondary	Liver function	Assessed by means of total bilirubin levels and prothrombin time.	8 hours	Yes