Isoflurane Preconditioning for Liver Resections

Tracking Information
First Submitted Date ICMJE	December 10, 2009
First Posted Date ICMJE	December 14, 2009
Results First Submitted Date	September 16, 2013
Results First Posted Date	December 12, 2013
Last Update Posted Date	March 20, 2017
Study Start Date ICMJE	January 2010
Actual Primary Completion Date	January 2012 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: September 30, 2016)	Post Operative Complications Grade IIIb or Greater According to Clavien's Classification Which is a Classification System Used to Grade Surgical Complications [ Time Frame: first 7 post operative days ]; Post operative complications grade IIIB or greater according to Clavien's classification: IIIb=complication necessitating an intervention under general anesthesia; Grade IV=Life threatening complications requiring ICU management, IV a =single organ dysfunction, IVb=multi-organ dysfunction; V=death Suffix d(disability)=subject suffers from complication at time of discharge. This label indicates the need for a follow up to fully evaluate the complication.
Original Primary Outcome Measures ICMJE; (submitted: December 11, 2009)	Post Operative Complications Grade IIIb or Greater According to Clavien's Classification [ Time Frame: first 7 post operative days ]
Change History	Complete list of historical versions of study NCT01031550 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: December 11, 2013)	Peak Postoperative AST, ALT and T Bili [ Time Frame: first 7 post operative days ]; Length of ICU and Hospital Stay [ Time Frame: first 7 post operative days ]; Decrease in Liver Lipid Peroxidation and Apoptosis [ Time Frame: first 7 post operative days ]
Original Secondary Outcome Measures ICMJE; (submitted: December 11, 2009)	peak postoperative AST, ALT and T Bili, length of ICU and Hosp[ital stay, decrease in liver lipid peroxidation and apoptosis. [ Time Frame: first 7 post operative days ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Isoflurane Preconditioning for Liver Resections
Official Title ICMJE	Isoflurane Induced Anesthetic Preconditioning in Elective Liver Resection
Brief Summary	The objective is to examine the efficacy of isoflurane (inhaled anesthetic gas) to induce clinically effective preconditioning in patients undergoing elective hepatic surgery.
Detailed 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
Study Type ICMJE	Interventional
Study Phase	Not Applicable
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Liver Disease
Intervention ICMJE	Drug: isoflurane isoflurane an anesthetic gas agent administered at specific times at a flow of 2 MAC; Drug: propofol standard of care Other Name: diprivan
Study Arms	Active Comparator: standard anesthetic management standard anesthetic management with propofol 100-150mcg/kg/min Intervention: Drug: propofol; Experimental: preconditioning with 2 MAC isoflurane group After induction, anesthesia will be maintained with 1MAC (minimum alveolar concentration) of Isoflurane according to age and end-expiratory concentration. Thirty minutes before the anticipated inflow occlusion and commencement of liver transaction, Isoflurane concentration will be gradually increased to 2 MAC over a period of 5 minutes (induction) and maintained at 2 MAC for 10 minutes (preconditioning). Then the concentration of Isoflurane will be decreased to 1 MAC during next 15 minutes (washout). Intervention: Drug: isoflurane
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Terminated
Actual Enrollment ICMJE; (submitted: December 8, 2011)	8
Original Estimated Enrollment ICMJE; (submitted: December 11, 2009)	64
Actual Study Completion Date	June 2012
Actual Primary Completion Date	January 2012 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01031550
Other Study ID Numbers ICMJE	0120090226
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Plan to Share IPD: No
Responsible Party	Yuriy Gubenko, MD, Rutgers, The State University of New Jersey
Study Sponsor ICMJE	Rutgers, The State University of New Jersey
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Yuriy Gubenko, MD Rutgers, The State University of New Jersey
PRS Account	Rutgers, The State University of New Jersey
Verification Date	February 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP