Isoflurane Preconditioning for Liver Resections

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