Liver DiseaseNCT01031550
Isoflurane Preconditioning for Liver Resections
A study testing isoflurane and propofol in people with Liver Disease, run by Rutgers, The State University of New Jersey at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Liver Disease
- What is being tested?
- isoflurane and propofol
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2010to Jun 2012
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- patients with liver tumors undergoing liver resection of > 1 segment liver resection must be performed with inflow occlusion > 30 min
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Isoflurane Induced Anesthetic Preconditioning in Elective Liver Resection
The objective is to examine the efficacy of isoflurane (inhaled anesthetic gas) to induce clinically effective preconditioning in patients undergoing elective hepatic surgery.
Read the 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
- Conditions
- Liver Disease
- Being tested
- isoflurane, propofol
- Keywords
- liver resection for liver disease
- Medical subject headings
- Liver Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
isofluraneDrug
isoflurane an anesthetic gas agent administered at specific times at a flow of 2 MAC
propofolDrug
Also called diprivan
standard of care
| Study group | Role | What they receive |
|---|---|---|
| standard anesthetic management | Active comparator | standard anesthetic management with propofol 100-150mcg/kg/min Receives: Drug: propofol |
| preconditioning with 2 MAC isoflurane group | Experimental | 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). Receives: Drug: isoflurane |
What is being measured
The primary outcome is the main question the study is designed to answer.
Post Operative Complications Grade IIIb or Greater According to Clavien's Classification Which is a Classification System Used to Grade Surgical Complications
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.
Measured: first 7 post operative days
Secondary outcomes (3)
Peak Postoperative AST, ALT and T Bili
Measured: first 7 post operative days
Length of ICU and Hospital Stay
Measured: first 7 post operative days
Decrease in Liver Lipid Peroxidation and Apoptosis
Measured: first 7 post operative days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Dec 2009 (estimated)
- Study startJan 2010
- Primary completionJan 2012
- Study completionJun 2012
Why it stopped: We no longer had an appropriate patient population.Study closed
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Liver DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rutgers, The State University of New Jersey
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Yuriy Gubenko, MD, Rutgers, The State University of New Jersey
- Investigators
- Yuriy Gubenko, MD, Principal investigator, Rutgers, The State University of New Jersey
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01031550
- Sponsor's protocol ID
- 0120090226
- Status last verified
- Feb 2017
- First submitted
- 10 Dec 2009
- Last updated
- 20 Mar 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Isoflurane Induced Anesthetic Preconditioning in Elective Liver Resection
- ClinicalTrials.gov ID
- NCT01031550
- Acronym / sponsor ID
- 0120090226
- Conditions
- Liver Disease
- Keywords
- liver resection for liver disease
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: We no longer had an appropriate patient population.Study closed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Rutgers, The State University of New JerseyUniversity, hospital or other
- Study start
- Jan 2010
- Primary completion
- Jan 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 14 Dec 2009 (estimated)
- Results
- Posted 12 Dec 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| standard anesthetic management | Active comparator | Drug: propofolstandard anesthetic management with propofol 100-150mcg/kg/min |
| preconditioning with 2 MAC isoflurane group | Experimental | Drug: isofluraneAfter 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- patients with liver tumors undergoing liver resection of > 1 segment liver resection must be performed with inflow occlusion > 30 min
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| isofluraneisoflurane an anesthetic gas agent administered at specific times at a flow of 2 MAC | Drug | preconditioning with 2 MAC isoflurane group |
| propofolAlso: diprivanstandard of care | Drug | standard anesthetic management |
Primary outcome
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.
3 secondary outcomes
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yuriy Gubenko, MD principal investigator
Rutgers, The State University of New Jersey
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing isoflurane and propofol in people with Liver Disease, run by Rutgers, The State University of New Jersey at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Mar 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Dec 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2017.