Desflurane Preconditioning in Hepatectomies

Pharmacological Preconditioning With Desflurane in Liver Surgery

Hepatectomies are considered as operations of high bleeding risk. The history of massive hemorrhage in liver surgery led to the emergence of techniques to control excessive blood loss. These techniques temporarily occlude the blood vessels that supply liver (the Pringle Maneuver) limiting subsequent losses. However, this leads to the ischemia - reperfusion injury impairing liver function. Research points to methods targeting on tempering reperfusion pathophysiology. Volatile anesthetics have been used for pharmacological preconditioning and proved to protect against organ damage. The aim of this study was to investigate the potential beneficial effect of desflurane on ischemia-reperfusion injury of the liver. Patients presenting for elective hepatectomy were randomized equally into two groups. The Control Group received no pharmacological preconditioning and the Desflurane Group received pharmacological preconditioning with Desflurane before induction of ischemia.

Study Overview

• Status: Completed
• Conditions: Ischemia Reperfusion Injury
• Intervention / Treatment: Drug: Desflurane

Detailed Description

Hepatectomies are characterized by an elevated risk of severe hemorrhage. The high vascular supply of the liver has historically troubled surgeons who resolved to techniques to control excessive blood loss. The Pringle Maneuver commonly employed in liver surgery is a temporary method to occlude the vascular supply of the liver. As a result, ischemia is developed and a pathophysiologic cascade is initiated. Upon the resolution of ischemia, reperfusion occurs which is linked to further damage and the ischemia-reperfusion injury is developed. Ischemia and reperfusion lead to activation of the innate immune response, which interacts with the adaptive immune response. Result of this interaction is the production of inflammatory cytokines, chemokines, complement products, and the recruitment of neutrophils to the site of injury. Previous studies have shown that animal's livers suffered from ischemia-reperfusion injury had increased neutrophil infiltration and pharmacological agents attenuating neutrophil's activity improved hepatic Ischemia-Reperfusion Injury (IRI). Preconditioning refers to the exposure of an organ to short intervals of ischemia which has been shown to mitigate the aforementioned ischemia-reperfusion injury. Preconditioning can be pharmacological and volatile anesthetics have been successfully used in preconditioning models. Sevoflurane have been proved beneficial for a series of hepatectomies in limiting transaminase levels postoperatively. However, sevoflurane by virtue can be hepatotoxic through Compound A production, elevated free calcium and reactive oxide species activation. On the other hand, desflurane undergoes minimum liver metabolism. In liver ischemia-reperfusion models, desflurane preconditioning led to decreased cell death and inflammatory cytokines inhibition.

The goal of the investigator's study was to investigate the effect of desflurane preconditioning in patients undergoing elective hepatectomy of at least two segments. Patients were randomized 1:1 to receive pharmacological preconditioning (Desflurane Group, Group D) or not (Control Group, Group C). The surgeon and the Intensive Care Unit were blinded as to the intervention. Anesthetic management was the same for all patients. For GroupD thirty minutes before the initiation of ischemia desflurane was delivered and propofol was stopped for the same interval.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• hepatectomy of at least two segments

Exclusion Criteria:

• Hepatitis B, C or HIV infection
• liver cirrhosis
• autoimmune disease, inflammatory bowel disease
• pregnancy
• prior additional ablation therapies (cryosurgery or radiofrequency)
• liver resections without inflow occlusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Desflurane Group; Thirty minutes before initiation of ischemia the surgeon was instructed to notify the anesthesiologist. At this single time point, propofol infusion was stopped and substituted with the volatile anesthetic desflurane to achieve a Minimum Alveolar Concentration of 1. The procedure included a 5-minute induction of desflurane, a 20-minute preconditioning and a 5-minute washout period when propofol was reintroduced and desflurane stopped.	Drug: Desflurane
NO_INTERVENTION: Control Group; No pharmacological preconditioning was implemented

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Matrix Metalloproteinases (MMPs) 2 and 9 level	The levels of Matrix Metalloproteinase 2 and Matrix Metalloproteinase 9 as evaluated by the relative gene expression using RT-PCR. The comparative CT method also referred to as the 2-ΔΔCT method was used to calculate the fold change and then convert it to percentage. Their presence has been linked to hepatic cellular injury so increased levels represent worse injury.	Sample 1: At surgery, before initiation of the procedure , Sample 2: Thirty minutes after reperfusion
Tissue Inhibitor Metalloproteinase (TIMPs) 1and 2	The levels of Tissue Inhibitor Metalloproteinase 1 and Tissue Inhibitor Metalloproteinase 2 as evaluated by the relative gene expression using RT-PCR. The comparative CT method also referred to as the 2-ΔΔCT method was used to calculate the fold change and then convert it to percentage. Their inhibitory effect on Matrix Metalloproteinases has been associated with a limitation of cellular injury. Thus, the higher the levels of Tissue Inhibitor Metalloproteinases the greater their protective activity.	Sample 1: At surgery, before initiation of the procedure , Sample 2: Thirty minutes after reperfusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histological findings of hepatic parenchyma	Hematoxylin Eosin, Gomori and Μasson staining were used. With Hematoxylin Eosin staining the degree of steatosis was assessed while Gomori and Masson staining was used to determine the level of fibrosis. Steatosis was characterized (x100 magnification) as mild (10%-30%), moderate (30%-60%), severe (>60%) according to the presence of fat droplets in hepatic cells. Fibrosis was also graded based on the METAVIR score as absent - F0, portal fibrosis without septa - F1, portal fibrosis with rare septa - F2, numerous septa - F3 and cirrhosis - F4.	Sample 1: Upon surgical dissection of the liver, before inflow occlusion, Sample: thirty minutes after reperfusion

Collaborators and Investigators

• Sponsor: Aristotle University Of Thessaloniki
• Investigators: Principal Investigator: Eleni Koraki, Dr, Aristotle University of Thessaloniki

Publications and helpful links

General Publications

• Rosen HR, Martin P, Goss J, Donovan J, Melinek J, Rudich S, Imagawa DK, Kinkhabwala M, Seu P, Busuttil RW, Shackleton CR. Significance of early aminotransferase elevation after liver transplantation. Transplantation. 1998 Jan 15;65(1):68-72. doi: 10.1097/00007890-199801150-00013.
• Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Kato A, Yoshitomi H, Nozawa S, Furukawa K, Mitsuhashi N, Sawada S, Takeuchi D, Ambiru S, Miyazaki M. Circulating cytokines, chemokines, and stress hormones are increased in patients with organ dysfunction following liver resection. J Surg Res. 2006 Jun 15;133(2):102-12. doi: 10.1016/j.jss.2005.10.025. Epub 2006 Jan 4.
• Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant. 2006 Apr;6(4):652-8. doi: 10.1111/j.1600-6143.2005.01228.x.
• Beck-Schimmer B, Breitenstein S, Urech S, De Conno E, Wittlinger M, Puhan M, Jochum W, Spahn DR, Graf R, Clavien PA. A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ann Surg. 2008 Dec;248(6):909-18. doi: 10.1097/SLA.0b013e31818f3dda.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2016
• Primary Completion (ACTUAL): June 30, 2018
• Study Completion (ACTUAL): June 30, 2018

Study Registration Dates

• First Submitted: January 29, 2019
• First Submitted That Met QC Criteria: February 19, 2019
• First Posted (ACTUAL): February 21, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 21, 2019
• Last Update Submitted That Met QC Criteria: February 19, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: preconditioning; ischemia reperfusion injury; hepatectomy
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Ischemia; Reperfusion Injury; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, General; Anesthetics; Anesthetics, Inhalation; Desflurane
• Other Study ID Numbers: 3779

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No