Isoflurane Preconditioning for Liver Resections

Liver Disease Clinical Trial

Official title:

Isoflurane Induced Anesthetic Preconditioning in Elective Liver Resection

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01031550
• Other study ID #: 0120090226
• Status: Terminated
• Phase: N/A
• First received: December 10, 2009
• Last updated: December 11, 2013
• Start date: January 2010
• Est. completion date: June 2012

Study information

• Verified date: December 2013
• Source: Rutgers, The State University of New Jersey
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The objective is to examine the efficacy of isoflurane (inhaled anesthetic gas) to induce clinically effective preconditioning in patients undergoing elective hepatic surgery.

Description:

Elective liver resection is performed primarily for the treatment of benign and malignant liver tumors1. In addition, with the increasing use of living donor liver transplantation to supplement the inadequate pool of cadaveric organs available, liver resection is performed also in live liver donors2.

Postoperative complications are common following liver resections. Occurrence of complications increases ICU and hospital stay, and resource utilization. The most serious postoperative complication after a liver resection is post-resectional liver failure (PLF)3. Risk factors for the development of PLF are preexisting liver disease, especially cirrhosis, excessive blood loss during liver resection, and liver ischemia and reperfusion injury4-5. Several strategies have been developed to combat excessive intra-operative blood loss including: lowering the central venous pressure6, hypoventilation7, and hepatic inflow occlusion using an atraumatic clamp8 (Pringle's maneuver)9; While inflow occlusion is the most important of these steps, hepatic ischemia and reperfusion is an important sequel to the inflow occlusion. Therefore, interventions which decrease hepatic ischemia reperfusion injury to the liver have the potential to improve outcomes following liver resection.

A strategy that directly modulates the hepatic response to ischemia is ischemic preconditioning (IPC). Classically, IPC has been induced by exposing an organ to brief periods of ischemia and reperfusion before exposing the organ to a more prolonged ischemic insult. In patients undergoing liver resection, IPC decreases postoperative aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels15. IPC is also associated with decreased histological evidence of apoptosis as well as immunohistochemical evidence of increased protective gene expression16 in the liver.

The primary disadvantage of IPC is the direct stress to the target organ as well as the mechanical trauma to major vasculature.

More recently, it has been found that inhaled volatile anesthetics such as Desflurane, Sevoflurane and Isoflurane induce similar preconditioning effects19 without causing any significant direct organ damage. While several animal studies exist, which demonstrate the hepatoprotective effect of volatile anesthetics on the liver23, there is only limited clinical data examining their effect in humans. One recent small clinical study, examining the preconditioning effect of volatile anesthetic on patients undergoing liver surgery, showed that anesthetic pre conditioning (APC) using Sevoflurane significantly decreased the several measures of liver dysfunction postoperatively24.

However, Sevoflurane is partially metabolized by the liver and may increase plasma fluoride concentration. Also, it may react with CO2 absorbent and can produce Compound-A, which in turn has been linked to nephrotoxicity. On the other hand, isoflurane, another inhalational anesthetic agent commonly used during liver surgery also has been shown to have a preconditioning effect in experimental animals, and does not carry the potential side effects of sevoflurane.

Therefore, the primary objective of this study is to examine the efficacy of isoflurane to induce clinically effective preconditioning in patients undergoing elective hepatic surgery.

Study Design:

In this prospective study, patients undergoing elective liver resection with inflow occlusion (Pringle maneuver) at UH, Newark will be randomized (1:1) to either standard anesthetic management with Propofol (No APC group) or anesthetic preconditioning with 2 minimum alveolar concentration (MAC) of isoflurane (APC group). Because preexisting liver disease, especially cirrhosis, is an important determinant of post operative outcomes, and to balance the randomization of subjects regarding this important variable randomization will be stratified into those with and without preexisting liver disease. The primary endpoint is the occurrence of postoperative complications grade IIIb or greater (Clavien's classification). The secondary endpoints are peak postoperative aspartate and alanine aminotransferase (AST and ALT) and total bilirubin (T Bili), length of ICU and hospital stay, and a decrease in liver lipid peroxidation and apoptosis

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 8
• Est. completion date: June 2012
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• patients with liver tumors undergoing liver resection of > 1 segment liver resection must be performed with inflow occlusion > 30 min

Exclusion Criteria:

• patients undergoing liver resection of one segment or less

• patients undergoing laparoscopic liver resection

• patients in whom the liver resection is performed with no inflow occlusion or inflow occlusion of < 30 min

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Liver Disease
• Liver Diseases

Intervention

Drug:
• isoflurane
isoflurane an anesthetic gas agent administered at specific times at a flow of 2 MAC

Other:
• standard of care
standard of care

Locations

Country	Name	City	State
United States	UMDNJ-University Hospital	Newark	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Rutgers, The State University of New Jersey

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Post Operative Complications Grade IIIb or Greater According to Clavien's Classification	Post operative complications grade IIIB or greater according to Clavien's classification	first 7 post operative days	No
Secondary	Peak Postoperative AST, ALT and T Bili		first 7 post operative days	No
Secondary	Length of ICU and Hospital Stay		first 7 post operative days	No
Secondary	Decrease in Liver Lipid Peroxidation and Apoptosis		first 7 post operative days	No