Isoflurane Preconditioning for Liver Resections

• Sponsor: Rutgers, The State University of New Jersey (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01031550
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arms: 2
• Duration (Months): 29
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Liver Disease	Drug: isoflurane; Drug: propofol	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Isoflurane Induced Anesthetic Preconditioning in Elective Liver Resection
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: standard anesthetic management standard anesthetic management with propofol 100-150mcg/kg/min	Drug: propofol; standard of care; Other Names: diprivan
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).	Drug: isoflurane; isoflurane an anesthetic gas agent administered at specific times at a flow of 2 MAC

Outcome Measures

Primary Outcome Measures

1. Post Operative Complications Grade IIIb or Greater According to Clavien's Classification Which is a Classification System Used to Grade Surgical Complications [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.

Secondary Outcome Measures

1. Peak Postoperative AST, ALT and T Bili [first 7 post operative days]

2. Length of ICU and Hospital Stay [first 7 post operative days]

3. Decrease in Liver Lipid Peroxidation and Apoptosis [first 7 post operative days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UMDNJ-University Hospital	Newark	New Jersey	United States	07101

Sponsors and Collaborators

• Rutgers, The State University of New Jersey

Investigators

• Principal Investigator: Yuriy Gubenko, MD, Rutgers, The State University of New Jersey

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Yuriy Gubenko, MD, Investigator Intiated Dept of Anesthesia, Rutgers, The State University of New Jersey
• ClinicalTrials.gov Identifier: NCT01031550
• Other Study ID Numbers: 0120090226
• First Posted: Dec 14, 2009
• Last Update Posted: Mar 20, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Yuriy Gubenko, MD, Investigator Intiated Dept of Anesthesia, Rutgers, The State University of New Jersey: liver resection for liver disease
• Additional relevant MeSH terms: Liver Diseases; Propofol; Isoflurane

Study Results

Participant Flow

Recruitment Details	Subjects will be randomized in two strata, those with and without preexisting liver disease. Subjects will be screened in pre admission testing
Pre-assignment Detail	Subjects may withdraw consent

Arm/Group Title	Standard Anesthetic Management	Preconditioning With 2 MAC Isoflurane Group
Arm/Group Description	standard anesthetic management propofol 100-150mcg/kg/min	preconditioning with isoflurane, anesthesia will be maintained with 1MAC 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).
Period Title: Overall Study
STARTED	5	3
COMPLETED	5	3
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Standard Anesthetic Management	Preconditioning With 2 MAC Isoflurane Group	Total
Arm/Group Description	standard anesthetic management with propofol 100-150mcg/kg/min	preconditioning with isoflurane anesthesia will be maintained with 1MAC 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).	Total of all reporting groups
Overall Participants	5	3	8
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 80%	3 100%	7 87.5%
>=65 years	1 20%	0 0%	1 12.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40 (10)	38 (8)	39 (9)
Sex: Female, Male (Count of Participants)
Female	2 40%	1 33.3%	3 37.5%
Male	3 60%	2 66.7%	5 62.5%
Region of Enrollment (participants) [Number]
United States	5 100%	3 100%	8 100%

Outcome Measures

1. Primary Outcome

Title	Post Operative Complications Grade IIIb or Greater According to Clavien's Classification Which is a Classification System Used to Grade Surgical Complications
Description	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.
Time Frame	first 7 post operative days

Outcome Measure Data

Analysis Population Description

Due to termination of the study no data analysis was performed.

Arm/Group Title	Standard Anesthetic Management	Preconditioning With 2 MAC Isoflurane Group
Arm/Group Description	standard anesthetic management with propofol 100-150mcg/kg/min	preconditioning with isoflurane , anesthesia will be maintained with 1MAC 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).
Measure Participants	0	0

2. Secondary Outcome

Title	Peak Postoperative AST, ALT and T Bili
Time Frame	first 7 post operative days

Outcome Measure Data

Analysis Population Description

Due to termination of the study no data analysis was performed.

Arm/Group Title	Standard Anesthetic Management	Preconditioning With 2 MAC Isoflurane Group
Arm/Group Description	standard anesthetic management	preconditioning with isoflurane
Measure Participants	0	0

3. Secondary Outcome

Title	Length of ICU and Hospital Stay
Time Frame	first 7 post operative days

Outcome Measure Data

Analysis Population Description

Due to termination of the study no data analysis was performed.

Arm/Group Title	Standard Anesthetic Management	Preconditioning With 2 MAC Isoflurane Group
Arm/Group Description	standard anesthetic management	preconditioning with isoflurane
Measure Participants	0	0

4. Secondary Outcome

Title	Decrease in Liver Lipid Peroxidation and Apoptosis
Time Frame	first 7 post operative days

Outcome Measure Data

Analysis Population Description

Due to termination of the study no data analysis was performed.

Arm/Group Title	Standard Anesthetic Management	Preconditioning With 2 MAC Isoflurane Group
Arm/Group Description	standard anesthetic management	preconditioning with isoflurane
Measure Participants	0	0

Adverse Events

Time Frame	Day of surgery and 7 days later
Arm/Group Title	Standard Anesthetic Management		Preconditioning With 2 MAC Isoflurane Group
Arm/Group Description	standard anesthetic management with propofol 100-150mcg/kg/min		preconditioning with isoflurane , anesthesia will be maintained with 1MAC 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).
All Cause Mortality
	Standard Anesthetic Management		Preconditioning With 2 MAC Isoflurane Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Standard Anesthetic Management		Preconditioning With 2 MAC Isoflurane Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Standard Anesthetic Management		Preconditioning With 2 MAC Isoflurane Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/3 (0%)

Limitations/Caveats

Due to termination of the study no data analysis was performed.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.