Blood Loss, Hepatocellular Injury
Conditions
Keywords
liver surgery, pringle manoeuvre, hepatocellular damage, surgical complications, patients requiring liver surgery
Brief summary
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
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.
Interventions
PROCEDUREPringle manoeuvre 15 minutes
During parenchymal transection, the hepatoduodenal ligament will be clamped by a rubber band for 2-times 15 minutes with 5 minutes reperfusion
PROCEDUREPringle manoeuvre 30 minutes
During parenchymal transection, the hepatoduodenal ligament will be clamped by a rubber band for 30 minutes with 5 minutes reperfusion
Sponsors
Maastricht University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatocellular Damage Reflected by Liver Fatty-acid Binding Protein (L-FABP) Levels | L-FABP area under curve from start of surgery up until postoperative day 3 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-resectional Complications | within 90-days after initial liver surgery | 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. |
| Amount of Blood Loss | at the end of liver surgery, an average of 225 minutes | amount of blood in the suction container (and, if applicable, in the weighted gauzes) |
| Hepatocellular Damage Reflected by Alanine Aminotransferase (ALAT) Levels | ALAT area under curve from start of surgery up until postoperative day 3 | 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. |
Countries
Netherlands
Participant flow
Recruitment details
Inclusion of participants: Oct 2007 - Jul 2009 Location: Department of Surgery, Maastricht University Medical Centre
Participants by arm
| Arm | Count |
|---|---|
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion 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.
Pringle manoeuvre using 15 minutes ischemic interval: During parenchymal transection, the hepatoduodenal ligament will be clamped by a rubber band for 2-times 15 minutes with 5 minutes reperfusion | 10 |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion 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
Pringle Manoeuvre using 30 minutes ischemic interval: During parenchymal transection, the hepatoduodenal ligament will be clamped by a rubber band for 30 minutes with 5 minutes reperfusion | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Total |
|---|---|---|---|
| Age, Continuous | 64 years | 62 years | 62 years |
| American Society of Anesthesiologists (ASA) classification ASA 1 | 0 participants | 2 participants | 2 participants |
| American Society of Anesthesiologists (ASA) classification ASA 2 | 8 participants | 5 participants | 13 participants |
| American Society of Anesthesiologists (ASA) classification ASA 3 | 2 participants | 3 participants | 5 participants |
| Indication for resection benign disease | 0 participants | 1 participants | 1 participants |
| Indication for resection malignant disease | 10 participants | 9 participants | 19 participants |
| Region of Enrollment Netherlands | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
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).
Time frame: L-FABP area under curve from start of surgery up until postoperative day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Hepatocellular Damage Reflected by Liver Fatty-acid Binding Protein (L-FABP) Levels | 9097 ng*h/mL | Standard Error 1781 |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Hepatocellular Damage Reflected by Liver Fatty-acid Binding Protein (L-FABP) Levels | 11,688 ng*h/mL | Standard Error 2247 |
Secondary
Amount of Blood Loss
amount of blood in the suction container (and, if applicable, in the weighted gauzes)
Time frame: at the end of liver surgery, an average of 225 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Amount of Blood Loss | 575 mL |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Amount of Blood Loss | 450 mL |
Secondary
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.
Time frame: ALAT area under curve from start of surgery up until postoperative day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Hepatocellular Damage Reflected by Alanine Aminotransferase (ALAT) Levels | 3196 IU*h/L | Standard Error 797 |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Hepatocellular Damage Reflected by Alanine Aminotransferase (ALAT) Levels | 3609 IU*h/L | Standard Error 812 |
Secondary
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.
Time frame: within 90-days after initial liver surgery
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Post-resectional Complications | bile leakage | 4 participants |
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Post-resectional Complications | sepsis | 1 participants |
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Post-resectional Complications | intra-abdominal hemorrhage | 0 participants |
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Post-resectional Complications | post-resectional liver failure | 2 participants |
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Post-resectional Complications | ascites | 1 participants |
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Post-resectional Complications | 30-day mortality | 1 participants |
| Pringle Manoeuvre Using 15 Minutes Inflow Occlusion | Post-resectional Complications | intra-abdominal abscess | 3 participants |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Post-resectional Complications | 30-day mortality | 1 participants |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Post-resectional Complications | intra-abdominal abscess | 2 participants |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Post-resectional Complications | intra-abdominal hemorrhage | 1 participants |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Post-resectional Complications | bile leakage | 1 participants |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Post-resectional Complications | ascites | 0 participants |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Post-resectional Complications | sepsis | 2 participants |
| Pringle Manoeuvre Using 30 Minutes Inflow Occlusion | Post-resectional Complications | post-resectional liver failure | 1 participants |