Effect of Intermittent Pedicle Clamping on Hepatocellular Injury During Liver Surgery

Study Overview
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Brief Summary
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In order to prevent excessive blood loss during liver surgery, an intermittent Pringle manoeuvre (IPM) can be applied. This implies a temporary clamping of the portal vein and hepatic artery in the hepatoduodenal ligament in order to occlude hepatic inflow. The optimal duration of the IPM is unknown. This randomized controlled trial aimed to analyse differences in hepatocellular damage after 15 minutes or 30 minutes IPM during liver surgery for primary or secondary liver tumours.

Detailed Description
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Surgical procedure Patients were anaesthetized using isoflurane and propofol. They routinely had an epidural catheter, urinary catheter, two peripheral venous catheters and indwelling catheters in a jugular vein and radial artery. Body temperature was maintained using a Bair Hugger system (Arizant Healthcare Inc. Eden Prairie, Minnesota). The surgical procedure was performed using a subcostal bilateral incision and Olivier retractors to improve exposure. After dissection of the teres hepatis ligament, the liver was mobilized. Thereafter, an intra-operative ultrasound was performed to define the position of the tumour in relation to vascular and biliary structures. As IPM was not routinely applied, a patient was randomized for 15 minted IPM (15IPM) or 30 minutes IPM (30IPM) only after the surgeon had decided a complete Pringle manoeuvre would be required. During 15IPM or 30IPM, the complete portal triad was clamped using a rubber sling. The time of inflow occlusion was adapted to the need according to the randomization protocol. Occasionally, the left or right pedicle was ligated after protocolled IPM. Five minutes reperfusion intervals were applied during which transection was stopped and cut surfaces were gently compressed to ensure hemostasis. A Cavitron Ultrasonic Surgical Aspirator (CUSA system 200 macrodissector, Cavitron Surgical Systems, Stamford, Connecticut) and Argon beam coagulation (Force GSU System, Valleylab, Boulder, Colorado) were used for liver transection. A stapler device or clamps were used for transection of the hepatic veins. Central venous pressure was maintained below 5 centimetre of water (cm H2O) during transection to reduce venous back-bleeding. After surgery, the weight of the resection specimen was recorded. Perioperative care was protocolled, as described earlier.

Official Title
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Randomized Controlled Trial on the Effect of Intermittent Pedicle Clamping Using 15 or 30 Minutes Ischemic Intervals During Liver Surgery

Conditions
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Hepatocellular Injury, Blood Loss

Intervention / Treatment
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* Procedure: Pringle manoeuvre 15 minutes
* Procedure: Pringle manoeuvre 30 minutes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients > 18 years of age and < 100 years of age primary or secondary liver tumours requiring liver surgery Exclusion Criteria: pre-existent liver disease (e.g. inflammatory liver disease, cirrhosis, inborn errors of metabolism) cholangiocarcinoma requiring biliary tract reconstruction during surgery steroid hormone medication tumours deemed irresectable during liver surgery laparoscopic liver surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pringle manoeuvre 15 minutes<br>When intermittent pedicle occlusion during parenchymal transection is necessary, 2 cycles of 15 minutes of hepatic inflow occlusion will be applied each followed by 5 minutes of reperfusion. During inflow occlusion, the complete portal triad was clamped using a rubber sling. | Procedure: Pringle manoeuvre 15 minutes<br>* During parenchymal transection, the hepatoduodenal ligament will be clamped by a rubber band for 2-times 15 minutes with 5 minutes reperfusion<br>|
| Experimental: Pringle manoeuvre 30 minutes<br>When intermittent pedicle occlusion during parenchymal transection is necessary, 1 cycle of 30 minutes of hepatic inflow occlusion will be applied followed by 5 minutes of reperfusion. During inflow occlusion, the complete portal triad was clamped using a rubber sling. | Procedure: Pringle manoeuvre 30 minutes<br>* During parenchymal transection, the hepatoduodenal ligament will be clamped by a rubber band for 30 minutes with 5 minutes reperfusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatocellular Damage Reflected by Liver Fatty-acid Binding Protein (L-FABP) Levels | At specific time points before, during and after liver surgery, plasma samples will be obtained to analyse the amount of hepatocellular damage reflected by L-FABP) level. These timepoints include: baseline (before operation), just before intermittent pedicle clamping, just before end of 15 or 30 minutes pedicle clamping, end of 5 minutes reperfusion, end of liver surgery, 8 hours after start liver surgery, postoperative day 1, 2 and 3. This continuous variable with repeated measurements was summarized as area under the curve (AUC) from baseline to postoperative day 3 (as described in Matthews JN, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical research. Bmj 1990;300:230-5). | L-FABP area under curve from start of surgery up until postoperative day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-resectional Complications | morbidity and mortality occuring after liver surgery graded according to Clavien-Dindo's grading system. In short, any deviation from the postoperative course without the need for pharmacological, radiological or surgical intervention was classified as Clavien-Dindo grade 1; complications requiring pharmacological treatment were graded as grade 2; complications requiring surgical or radiological intervention not under general anesthesia as grade 3a and under general anesthesia as grade 3b; grade 4 complications were life-threatening complications requiring intensive care unit care because of single organ dysfunction (grade 4a) or multiple organ dysfunction (grade 4b); mortality was classed as grade 5. | within 90-days after initial liver surgery | 
| Amount of Blood Loss | amount of blood in the suction container (and, if applicable, in the weighted gauzes) | at the end of liver surgery, an average of 225 minutes | 
| Hepatocellular Damage Reflected by Alanine Aminotransferase (ALAT) Levels | At specific time points before, during and after liver surgery, plasma samples will be obtained to analyse the amount of hepatocellular damage reflected by ALAT level. These timepoints include: baseline (before operation), just before intermittent pedicle clamping, just before end of 15 or 30 minutes pedicle clamping, end of 5 minutes reperfusion, end of liver surgery, 8 hours after start liver surgery, postoperative day 1, 2 and 3. | ALAT area under curve from start of surgery up until postoperative day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver surgery, pringle manoeuvre, hepatocellular damage, surgical complications, patients requiring liver surgery