Argipressin's Influence on Blood Loss During Hepatic Resection (ARG-01)

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

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. Two sub-studies has been added; one for evaluation of coagulation function, and one for assessment of pain scores and morphine consumption.

Study Overview

• Status: Completed
• Conditions: Inflammatory Response; Colon Cancer Liver Metastasis; Vasopressin Causing Adverse Effects in Therapeutic Use
• Intervention / Treatment: Drug: Argipressin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 248
• Phase: Phase 4

Contacts and Locations

Study Locations

• Sweden
  • Gothenburg, Sweden, 41345
    • Sahlgrenska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participant planned for hepatic resection (open or laparoscopic, regardless of indication for surgery).
2. Age ≥18 years.
3. ASA class I-III.
4. Signed informed consent form

Exclusion Criteria:

1. Participant does not understand the given information, and/ or cannot give written informed consent.
2. 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.
3. Terminal kidney failure (estimated preoperative GFR< 15 ml/min)
4. Pregnancy or lactation.
5. Known allergy to Empressin®.
6. Patient included in other interventional study, interacting with the endpoints in the present study, or previous randomization in this study.
7. Hyponatremia (S-Na < 130 mmol/L)
8. Patient considered ineligible for other surgical or medical reason.
9. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Argipressin; Patients will be treated with Empressin® 0.8 U/ml, 0.056 ml/kg/h during surgery.	Drug: Argipressin; 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.; Other Names: Arg
Placebo Comparator: Placebo; Patients will receive normal saline 0.056 ml/kg/h during surgery.	Drug: Placebo; 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.; Other Names: control

What is the study measuring?

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
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.
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
postoperative complications	Postoperative complications including death and radicality of resection at 30-day follow up.	30 days after surgery
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
oral morphine eqivalents	total opioid consumption converted to oral morphine eqivalents (mg)	from day of surgery, postoperative day 1,2 and at discharge from hospital (but no longer than post operative day 5)
Numeric Rating Scale (NRS)	pain assement by Numeric Rating Scale 0-10 (0= no pain, 10= worst pain imaginable), at rest and at activity	Once daily at day of surgery, postoperative day 1 and 2
Clotting Time (CT)	Clotting Time (CT) measured by ROTEM (Thrombelastometry) in Extem, Intem, Fibtem, Heptem channels	before anesthesia, at end of surgery (assessed up to one hour after closing of the abdomen) and postoperative day 1
Clot Formation time (CFT)	Clot Formation time (CFT) measured by ROTEM (Thrombelastometry) in Extem, Intem, Fibtem, Heptem channels	before anesthesia, at end of surgery (assessed up to one hour after closing of the abdomen) and postoperative day 1
Amplitude at 10 minutes (A10)	Amplitude at 10 minutes (A10) measured by ROTEM (Thrombelastometry) in Extem, Intem, Fibtem, Heptem channels	before anesthesia, at end of surgery (assessed up to one hour after closing of the abdomen) and postoperative day 1
Maximum Clot Firmness (MCF)	Maximum Clot Firmness (MCF) measured by ROTEM (Thrombelastometry) in Extem, Intem, Fibtem, Heptem channels	before anesthesia, at end of surgery (assessed up to one hour after closing of the abdomen) and postoperative day 1
vWf	von Willebrand factor (vWf)	before anesthesia, at end of surgery (assessed up to one hour after closing of the abdomen) and postoperative day 1
fVIII	factor VIII	before anesthesia, at end of surgery (assessed up to one hour after closing of the abdomen) and postoperative day 1

Collaborators and Investigators

• Sponsor: Kristina Svennerholm
• Investigators: Principal Investigator: kristina svennerholm, MD PhD, Senior Consultant Anesthesia and Intensive Care, Sahlgrenska University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2022
• Primary Completion (Actual): December 6, 2024
• Study Completion (Actual): February 17, 2025

Study Registration Dates

• First Submitted: November 15, 2021
• First Submitted That Met QC Criteria: March 14, 2022
• First Posted (Actual): March 24, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 3, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: pain; blood loss; transfusion; coagulation; vasopressin; inflammatory response; liver surgery; hepatic surgery; colon cancer metastasis
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Neoplastic Processes; Colonic Neoplasms; Neoplasm Metastasis; Hemorrhage; Physiological Effects of Drugs; Hemostatics; Coagulants; Natriuretic Agents; Vasoconstrictor Agents; Antidiuretic Agents; Arginine Vasopressin
• Other Study ID Numbers: ARG-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Metadata will be shared by the Swedish National Data Service (SND, https://snd.gu.se/en) and selected psedonymised data will be made available on reasonable request, after proper confidentiality and ethics assessment. The extent of data made available will be decided after study closure, and also the time span for availability.
• IPD Sharing Time Frame: 12 months after study closure, and maximum 25 years
• IPD Sharing Access Criteria: Confidentiality and ethics assessment.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No