Hypothermic Perfusion During Hemihepatectomy

In Situ Hypothermic Perfusion During Right Hemihepatectomy

Rationale

Currently, hepatic resection is often the only curative treatment for primary or secondary hepatic malignancies and is also frequently performed in patients with benign liver tumors to prevent malignant transformation and/or alleviate symptoms. Liver resections are nowadays associated 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 leads to ischemia-reperfusion (I/R) injury 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, an overall improvement in postoperative outcomes is expected due to a decrease in intraoperative blood loss, reduced parenchymal damage, and a better ability of the liver remnant to regenerate.

Objective

To reduce intraoperative blood loss and enhance tolerance of the FRL to I/R injury during right hemihepatectomy under vascular exclusion by means of in situ hypothermic perfusion with retrograde outflow (R-IHP) of the FRL.

Study design

The study is designed as a prospective randomized pilot study in 18 patients (9 interventions and 9 controls) to assess the effects of the proposed intervention. Additionally, 4 patients will be included separately for assessment of the intervention's feasibility prior to randomized inclusion.

Study population

Eligible patients for participation in this study are those planned to undergo right hemihepatectomy under vascular inflow occlusion because of a malignant or benign liver tumor, and who do not suffer from any hepatic co-morbidity that might influence postoperative outcomes (i.e., severe steatosis, cholestasis, cirrhosis, or hepatitis B/C infection).

Intervention

During right hemihepatectomy, the FRL of patients allocated to the intervention group will be perfused with a chilled perfusion solution (i.e., lactated Ringer's solution).

Study Overview

• Status: Completed
• Conditions: Hepatic Ischemia-reperfusion Injury
• Intervention / Treatment: Procedure: In situ hypothermic perfusion

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
      • Academic Medical Center (AMC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients scheduled for right hemihepatectomy under vascular inflow occlusion for a malignant or benign hepatic tumor

• Diagnostic exclusion of hepatic co-morbidity, that is:

  • Cirrhosis,
  • Severe steatosis (≥ 30%),
  • Cholestasis, and
  • Hepatitis B/C infection
• Age ≥ 18 years
• Signed informed consent obtained prior to any study-specific procedure
• ASA classification I-III

Exclusion Criteria:

• Patients diagnosed with any of the hepatic co-morbidities listed under point 2 of the inclusion criteria
• Age < 18 years
• BMI > 35 kg/m2
• ASA classification IV/V
• Patient is scheduled for a combined surgical procedure (e.g., bile duct resection, gastrointestinal procedures)
• Patient underwent liver resection ≤ 1 year prior to scheduled surgery
• Emergency operations
• Pregnancy or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Vascular inflow occlusion; Patients that will receive intermittent vascular inflow occlusion, the standard method for vascular occlusion at our institution, during liver resection.
Experimental: Hypothermic perfusion; Patients will receive in situ hypothermic perfusion of the future remnant liver during liver resection.	Procedure: In situ hypothermic perfusion; In situ perfusion of the future remnant liver with chilled lactated Ringer's solution during liver resection.; Other Names: In situ hypothermic preservation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative hepatocellular damage	Hepatocellular damage expressed as an postoperative increase in transaminases (i.e., AST and ALT).	5 days postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative blood loss	Blood loss during surgery	2-3 hours
Postoperative complications	Incidence of surgery-related complications	5 days postoperatively
Regeneration of liver function and volume	Regeneration of liver function (measured via hepatobiliary scintigraphy) and -volume (measured via CT volumetry).	3 days

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Study Chair: Prof. Thomas M. van Gulik, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: Rowan F. van Golen, MSc, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Azoulay D, Eshkenazy R, Andreani P, Castaing D, Adam R, Ichai P, Naili S, Vinet E, Saliba F, Lemoine A, Gillon MC, Bismuth H. In situ hypothermic perfusion of the liver versus standard total vascular exclusion for complex liver resection. Ann Surg. 2005 Feb;241(2):277-85. doi: 10.1097/01.sla.0000152017.62778.2f.
• Dinant S, van Veen SQ, Roseboom HJ, van Vliet AK, van Gulik TM. Liver protection by hypothermic perfusion at different temperatures during total vascular exclusion. Liver Int. 2006 May;26(4):486-93. doi: 10.1111/j.1478-3231.2006.01248.x.
• Verhoef C, de Wilt JH, Brunstein F, Marinelli AW, van Etten B, Vermaas M, Guetens G, de Boeck G, de Bruijn EA, Eggermont AM. Isolated hypoxic hepatic perfusion with retrograde outflow in patients with irresectable liver metastases; a new simplified technique in isolated hepatic perfusion. Ann Surg Oncol. 2008 May;15(5):1367-74. doi: 10.1245/s10434-007-9714-z. Epub 2008 Feb 1.
• Reiniers MJ, van Golen RF, Heger M, Mearadji B, Bennink RJ, Verheij J, van Gulik TM. In situ hypothermic perfusion with retrograde outflow during right hemihepatectomy: first experiences with a new technique. J Am Coll Surg. 2014 Jan;218(1):e7-16. doi: 10.1016/j.jamcollsurg.2013.09.013. Epub 2013 Nov 6. No abstract available.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: December 20, 2011
• First Submitted That Met QC Criteria: December 23, 2011
• First Posted (Estimate): December 26, 2011

Study Record Updates

• Last Update Posted (Estimate): January 26, 2016
• Last Update Submitted That Met QC Criteria: January 25, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Ischemia-reperfusion injury; In situ hypothermic perfusion; In situ hypothermic preservation
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Body Temperature Changes; Ischemia; Reperfusion Injury; Hypothermia
• Other Study ID Numbers: 2011_214; NL37241.018.11 (Other Identifier: Centrale Commissie Mensgebonden Onderzoek (CCMO))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No