Argipressin's Influence on Blood Loss During Hepatic Resection

Study Overview
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Brief Summary
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Infusion of Argipressin during hepatic resection surgery may reduce blood loss. It may also reduce transfusion requirements, and mitigate the perioperative inflammatory response compared to placebo. Subjects will be randomized to infusion of Argipressin or placebo during surgery. Blood loss, transfusion requirements, surgical data including length of stay in hsopital, inflammatory markers and markers of renal- intestinal- and cardiac injury will be assessed.

Detailed Description
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Hepatic resection is a major surgical intervention with high risk of substantial blood loss. The surgical means to reduce blood loss may impair perfusion and induce intestinal congestion. If blood flow to the liver can be influenced by pharmacological means, blood loss and transfusion requirements may be reduced. Moreover, the inflammatory system is involved in cancer development, and the anti-inflammatory properties of Argipressin may decrease the inflammatory response after hepatic surgery. Argipressin is an endogenous substance, and part of the body's response to stress and trauma. Argipressin affects V1-receptors to produce vasoconstriction. It is also involved in inflammatory reactions and affects platelets. Patients will be stratified according to planned type of surgery (open/laparoscopic) and planned extent of resection, and randomized to etiher infusion of Argipressin or placebo (normal saline) during surgery. In all other aspects, the participants will be treated according to the institution protocol for hepatic resection. The study drug will be started as soon as the central line is placed, and discontinued at the end of surgery. Hemodynamic data will be collected during surgery, and blood and urine-samples will be obtained during and after surgery for analysis of inflammatory markers and markers of organ injury.

Official Title
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Influence of Argipressin on Blood Loss During Hepatic Resection; a Double-blinded, Randomized Placebo-controlled Trial (ARG-01)

Conditions
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Colon Cancer Liver Metastasis, Inflammatory Response, Vasopressin Causing Adverse Effects in Therapeutic Use

Intervention / Treatment
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* Drug: Argipressin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant planned for hepatic resection (open or laparoscopic, regardless of indication for surgery). Age ≥18 years. ASA class I-III. Signed informed consent form Exclusion Criteria: Participant does not understand the given information, and/ or cannot give written informed consent. Simultaneous operation of tumor with other localization, or surgery for superficial single hepatic tumor less than 2 cm, expected to be of short duration and with minimal blood loss. Terminal kidney failure (estimated preoperative GFR< 15 ml/min) Pregnancy or lactation. Known allergy to Empressin®. Patient included in other interventional study, interacting with the endpoints in the present study, or previous randomization in this study. Hyponatremia (S-Na < 130 mmol/L) Patient considered ineligible for other surgical or medical reason. Present infection. Patients with systemic inflammatory disease, inflammatory bowel disease or preoperative corticosteroid treatment will not be eligible for the subgroups where cytokines and interleukins are investigated.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Singel center double-blinded, randomized, placebo-controlled trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Argipressin<br>Patients will be treated with Empressin® 0.8 U/ml, 0.056 ml/kg/h during surgery. | Drug: Argipressin<br>* Infusion of Argipressin 0.8 U/ml, 0.056 ml/kg/h will be started as soon as the central line is placed, and continued until the end of surgery in the treatment arm.<br>* Other names: Arg;|
| Placebo Comparator: Placebo<br>Patients will receive normal saline 0.056 ml/kg/h during surgery. | Drug: Placebo<br>* Infusion of Normal Saline 0.056 ml/kg/h will be started as soon as the central line is placed, and continued until the end of surgery in the placebo arm.<br>* Other names: control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood loss | Blood loss at the end of surgery, measured according to the investigator's instructions, by visual assessment of suction devises and gauze, and subtraction of ascites and irrigation fluids. | through surgery, an average of 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood transfusion | Blood transfusion (ml) at the end of surgery and at postoperative day 1 and 2 and 5 respectively. | At end of surgery and until postoperative day 2 or 5 respectively | 
| Inflammatory markers-regular | Levels of White Blood Cell count, C Reactive Protein, Platelet count and Albumin at the end of surgery and postoperative day 1-5 | Measured throughout the study until postoperative day 2 (laparoscopic resection) or postoperative day 5 (open resection) | 
| Inflammatory markers- extended | Levels of Interleukin (IL)-1 Beta, IL-6, IL-8, IL-10, Monocyte chemoattractant protein-1, Stromal Cell-Derived Factor-1 alpha, Intercellular Adhesion Molecule, Complement (C) 3a, C5b-9 at the end of surgery and postoperative day 1 and 2. | Measured at throughout the study until postoperative day 2. | 
| surgical data | duration of Pringles manouvre (min), duration of resection phase (min) and surgery (min) | at the end of surgery, approximately 5 hours after start of surgery | 
| Tranexamic Acid | use of tranexamic acid (mg) | at the end of surgery, approximately 5 hours after start of surgery | 
| CVP (anesthesiological data) | achievement of CVP (central venous pressure) goal (mmHg), as recorded on the Phillips monitor. | during surgery | 
| Noradrenaline use (anesthesiologigal data) | Total use of noradrenaline (micrograms/minutes of surgery/ bodyweight) | during surgery | 
| use of diuretics | Furosemide use (mg) | until postoperative day 1 | 
| urine output | urine output (ml) | until postoperative day 1 | 
| postoperative complications | Postoperative complications including death and radicality of resection at 30-day follow up. | 30 days after surgery | 
| Length of stay | Length of stay in hospital | From admission in hospital to discharge, expected time 2-5 days but will be followed until actual discharge, which may be several months. | 
| Plasma Creatinine (change in organ damage markers) | Change in plasma creatinine (micro-mole/L) | from baseline (before surgery) to postoperative day 2 and 5 respectively. | 
| Urine samples (change in organ damage markers) | Change in urine creatinine and urine [TIMP-2] x [IGFBP-7] (quota, no unit) | from baseline to end of surgery, approximately 5 hours | 
| Cardiac marker (change in organ damage markers) | Change in hs- TNI (ng/L) | from baseline to postoperative day 1 | 
| Lactate (change in organ damage markers) | change in plasma lactate | from baseline to postoperative day 1 | 
| I-FABP (change in organ damage markers) | Change in I-FABP (ng/L) | from baseline to postoperative day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatic surgery, vasopressin, liver surgery, colon cancer metastasis, transfusion, blood loss, inflammatory response