Evaluation Of The Influence Of Anesthetic Interventions On The Evolution Of Hepatic Neoplastic Processes

NCT07207304 | Completed DMC

• 1 other identifier: DEP45/22.11.2021
• Study Type: interventional
• Target: 153
• Locations: 1 country
• Sites: 1

Brief Summary

Evaluation Of The Influence Of Anesthetic Interventions On The Evolution Of Hepatic Neoplastic Processes The goal of this clinical trial is to evaluate of the involvement of Neutrophil extracellular traps in the evolution of hepatocellular cancer. The main questions it aims to answer are:

• How does the type of anesthesia used in hepatobiliary oncological surgery influence postoperative evolution and the immune response?
• How does the type of anesthesia, TIVA versus inhalational influence the generation of neutrophil extracellular traps (NETs)? Researchers will compare the evolution of the patients assigned to 4 study groups depending on the anesthetic intervention performed. Participants will:
• will be evaluated pre and postanesthesia, blood samples will be collected for analysis of the inflammatory response
• will be followed up one year for establishing the outcome

Conditions

Hepato-cellular Carcinoma; Neutrophil Extracellular Trap Formation; Anesthesia; Lidocaine Infusion

Keywords

Anesthesia; Lidocaine infusion; Neutrophil Extracellular traps; Hepatocellular carcinoma

Outcome Measures

Primary Outcomes (2)

• Survival outcomes after hepatocellular carcinoma resection.

  Patients will be followed for a period of one year to assess overall survival and progression-free survival. Follow-up will be conducted via direct contact, telephone, or e-mail. Information will be collected regarding the patient's general health status, disease progression, the presence and timing of tumor recurrence, as well as any hospitalizations occurring postoperatively, including the reason for medical consultation. Additionally, results from relevant investigations-such as computed tomography (CT), ultrasound, and blood tests-recommended by the treating surgeon or oncologist will be requested and reviewed.

  one year postoperatively

• NETosis quantification

  For each patient, 10 mL of blood will be collected from a peripheral vein both preoperatively and 6 hours postoperatively to determine the concentrations of MPO-DNA (myeloperoxidase-DNA complexes), H3Cit (citrullinated histone H3), and cfDNA (cell-free DNA). These biomarkers are closely associated with the formation of neutrophil extracellular traps (NETs). We aim to analyze the potential relationship between the dynamics of NETosis formation, the duration of anesthesia, and postoperative patient outcomes.

  Preoperatively and after 6 hours postoperatively

Secondary Outcomes (3)

• Quantification of the inflammatory response

  Preoperatively and at 6, 12, and 24 hours postoperatively

• Opioid use

  In the first 24 hours postoperatively

• Length of hospital stay

  From the immediate postoperative period until discharge

Study Arms (4)

Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

ACTIVE COMPARATOR

Patients will receive total intravenous anesthesia (TIVA) with 1% propofol, administered using the Schneider pharmacokinetic model. The initial target effect-site concentration will be 4 µg/mL, titrated intraoperatively to maintain a BIS value between 40 and 59.

Procedure: Anesthesia; Procedure: Anesthesia induction with TCI; Drug: Intraoperative analgesia; Drug: Non-opioid analgesics; Drug: Morphine (+); Device: Bispectral Index (BIS); Procedure: Intraoperative mechanical ventilation; Procedure: Blood sampling

HCC resection performed under sevoflurane anesthesia

ACTIVE COMPARATOR

Patients will receive volatile anesthesia with sevoflurane, maintained at an end-tidal concentration (EtSevo) corresponding to 1.0-1.5 MAC. The concentration will be adjusted in increments or decrements of 0.25-0.5 MAC to maintain a BIS value between 40 and 59.

Procedure: Anesthesia; Procedure: sevoflurane anesthesia; Drug: Intraoperative analgesia; Drug: Non-opioid analgesics; Drug: Morphine (+); Device: Bispectral Index (BIS); Procedure: Intraoperative mechanical ventilation; Procedure: Blood sampling

HCC resection performed under TIVA + Lidocaine infusion

ACTIVE COMPARATOR

Patients in this group will receive TIVA with 1% propofol administered via TCI using the Schneider pharmacokinetic model. A 1.5 mg/kg intravenous bolus of 1% lidocaine will be administered at induction. Following intubation, a continuous infusion of 1% lidocaine at 2 mg/kg/hour will be maintained until emergence from anesthesia, not exceeding a maximum dose of 200 mg/hour.

Procedure: Anesthesia; Procedure: Anesthesia induction with TCI; Drug: Lidocaine Infusion; Drug: Intraoperative analgesia; Drug: Non-opioid analgesics; Drug: Morphine (+); Device: Bispectral Index (BIS); Procedure: Intraoperative mechanical ventilation; Procedure: Blood sampling

HCC resection performed under sevoflurane anesthesia + Lidocaine infusion

ACTIVE COMPARATOR

Patients in this group will receive sevoflurane-based general anesthesia. Anesthesia will be maintained with sevoflurane at an end-tidal concentration of 1.0-1.5 MAC, titrated in increments or decrements of 0.25-0.5 MAC based on BIS monitoring (target range 40-59). A 1.5 mg/kg intravenous bolus of 1% lidocaine will be administered at induction, followed by a continuous intravenous infusion of 1% lidocaine at 2 mg/kg/hour, not exceeding 200 mg/hour, until emergence from anesthesia.

Procedure: Anesthesia; Procedure: sevoflurane anesthesia; Drug: Lidocaine Infusion; Drug: Intraoperative analgesia; Drug: Non-opioid analgesics; Drug: Morphine (+); Device: Bispectral Index (BIS); Procedure: Intraoperative mechanical ventilation; Procedure: Blood sampling

Interventions

Anesthesia PROCEDURE

Patients diagnosed with hepatocellular carcinoma will be randomly assigned to one of four groups. They will receive standard anesthesia with maintenance based on either sevoflurane or propofol. Two of the groups will additionally receive intravenous lidocaine, administered from induction until the end of surgery. Blood samples will be collected preoperatively and six hours postoperatively to measure citrullinated histone H3 (H3Cit), a reliable biomarker of NETosis. Additional inflammatory markers will also be analyzed. All patients will be followed for a period of one year

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

Anesthesia induction with TCI PROCEDURE

During induction, patients will receive fentanyl (2-3 µg/kg), propofol (1-1.5 mg/kg) as a bolus or via TCI, and rocuronium (0.5-0.6 mg/kg) to facilitate anesthesia induction and ensure adequate neuromuscular relaxation for endotracheal intubation. Anesthesia will be maintained using TIVA with 1% propofol administered via TCI, guided by the Schneider pharmacokinetic model. The initial target effect-site concentration will be 4 µg/mL and will be titrated intraoperatively to maintain a BIS value between 40 and 59.

HCC resection performed under TIVA + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

sevoflurane anesthesia PROCEDURE

During induction, patients will receive fentanyl (2-3 µg/kg), propofol (1-1.5 mg/kg), and rocuronium (0.5-0.6 mg/kg) to facilitate anesthesia induction and ensure adequate neuromuscular relaxation for endotracheal intubation. For patients in the inhalation anesthesia group, maintenance will be performed using sevoflurane. The end-tidal concentration of sevoflurane (EtSevo) will be maintained between 1.0 and 1.5 MAC, with adjustments in increments or decrements of 0.25-0.5 MAC, depending on the BIS value, which will be maintained between 40 and 59.

HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion

Lidocaine Infusion DRUG

During induction, a 1.5 mg/kg intravenous bolus of 1% lidocaine will also be administered. In the maintenance phase of anesthesia, a continuous infusion of 1% lidocaine at 2 mg/kg/hour-up to a maximum of 200 mg/hour-will be administered, starting after endotracheal intubation and continued until emergence from anesthesia.

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion

Intraoperative analgesia DRUG

Intraoperative analgesia will be ensured by administering fentanyl 0.5-1 µg/kg as needed, based on clinical signs of inadequate analgesia (e.g., an increase in blood pressure or heart rate exceeding 20% of baseline, mydriasis, lacrimation, or diaphoresis)

Also known as: Fentanyl

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

Non-opioid analgesics DRUG

Thirty minutes before the end of surgery, nefopam 40 mg, paracetamol 1 g, and ketoprofen 100 mg will be administered intravenously, depending on the patient's comorbidities, surgical particularities, extent of resection, and residual liver volume.

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

Morphine (+) DRUG

Postoperative analgesia will be provided with morphine at a dose of 0.1-0.2 mg/kg, administered 30 minutes before emergence from anesthesia. The administration will be performed intravenously, with the dose adjusted based on patient weight and clinical condition. Additional bolus doses may be given in the post-anesthesia care unit (PACU), guided by the patient's reported pain intensity using the Visual Analog Scale (VAS). In the PACU, morphine will be titrated starting with 2-5 mg IV given slowly over 4-5 minutes, with repeated doses every 5-10 minutes if needed, while closely monitoring respiratory rate, level of consciousness, and hemodynamic stability. For ongoing pain management, intermittent IV bolus dosing (typically 0.05-0.1 mg/kg every 4 hours as required) may be used, taking into account factors such as patient comorbidities, type of surgery, and residual hepatic function.

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

Bispectral Index (BIS) DEVICE

Bispectral index (BIS) monitoring will be used to guide the depth of anesthesia. The target BIS value will be maintained between 40 and 59 throughout the procedure to ensure adequate hypnosis while avoiding excessive anesthetic depth. BIS values will be continuously recorded and adjustments to anesthetic agents will be made accordingly.

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

Intraoperative mechanical ventilation PROCEDURE

Intraoperative mechanical ventilation will be performed using a lung-protective strategy. Patients will be ventilated with a volume-controlled mode, using a tidal volume of 6-8 mL/kg of predicted body weight, a respiratory rate adjusted to maintain end-tidal CO₂ (EtCO₂) between 35-45 mmHg, and a positive end-expiratory pressure (PEEP) of minimum 6 cmH₂O. Fraction of inspired oxygen (FiO₂) will be set to maintain peripheral oxygen saturation (SpO₂) above 94%. Recruitment maneuvers may be applied periodically or as clinically indicated.

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

Blood sampling PROCEDURE

A total of 10 mL of peripheral venous blood will be collected from each patient at two time points: preoperatively (baseline) and 6 hours after surgery. These samples will be used to quantify the concentration of neutrophil extracellular trap (NET)-associated biomarkers, including myeloperoxidase-DNA complexes (MPO-DNA) and cell-free DNA (cfDNA), which are closely associated with NET formation. Following collection, samples will be centrifuged at 1000 rpm, and the resulting plasma will be aliquoted and stored at -80 °C for later analysis. In parallel, additional inflammatory and metabolic markers will be measured, including C-reactive protein (CRP), total leukocyte count, blood glucose, procalcitonin, and interleukin levels (IL-6, IL-8, IL-10, and IL-17) in selected patients. All participants will be monitored for a period of one year to assess the incidence of postoperative complications and cancer recurrence, including metastasis.

HCC resection performed under TIVA + Lidocaine infusion; HCC resection performed under sevoflurane anesthesia; HCC resection performed under sevoflurane anesthesia + Lidocaine infusion; Hepatocellular carcinoma (HCC) resection performed under total intravenous anesthesia (TIVA)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosed with: hepatocellular carcinoma, or hepatic metastases
• Scheduled for elective liver surgery:

You may not qualify if:

• Undergoing emergency surgery
• Receiving chronic immunosuppressive therapy
• Having contraindications to any of the study medications
• Diagnosed with psychiatric disorders, such as: depression, bipolar disorder, schizophrenia, having autoimmune diseases
• Suffering from corticosteroid-dependent bronchial asthma
• Diagnosed with congenital or acquired coagulation disorders

Sponsors & Collaborators

• Iuliu Hatieganu University of Medicine and Pharmacy: lead

Study Sites (1)

Regional Institute of Gastroenterology and Hepatology Octavian Fodor

Cluj-Napoca, Cluj, 400162, Romania

Location

Related Publications (7)

• Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, Wang Y, Simmons RL, Huang H, Tsung A. Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress. Cancer Res. 2016 Mar 15;76(6):1367-80. doi: 10.1158/0008-5472.CAN-15-1591. Epub 2016 Jan 12.

  PMID: 26759232 BACKGROUND

• Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, Li Y. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021 Jul 12;6(1):263. doi: 10.1038/s41392-021-00658-5.

  PMID: 34248142 BACKGROUND

• Zhang W, Liu J, Li X, Bai Z, Sun Y, Chen X. Lidocaine effects on neutrophil extracellular trapping and angiogenesis biomarkers in postoperative breast cancer patients with different anesthesia methods: a prospective, randomized trial. BMC Anesthesiol. 2024 Apr 27;24(1):162. doi: 10.1186/s12871-024-02540-7.

  PMID: 38678209 BACKGROUND

• Cata JP, Sood AK, Eltzschig HK. Anesthetic Drugs and Cancer Progression. Anesthesiology. 2020 Oct 1;133(4):698-699. doi: 10.1097/ALN.0000000000003510. No abstract available.

  PMID: 32833387 BACKGROUND

• Ramirez MF, Cata JP. Anesthetic care influences long-term outcomes: What is the evidence? Best Pract Res Clin Anaesthesiol. 2021 Dec;35(4):491-505. doi: 10.1016/j.bpa.2021.01.004. Epub 2021 Feb 3.

  PMID: 34801212 BACKGROUND

• Allaire M, Goumard C, Lim C, Le Cleach A, Wagner M, Scatton O. New frontiers in liver resection for hepatocellular carcinoma. JHEP Rep. 2020 Jun 4;2(4):100134. doi: 10.1016/j.jhepr.2020.100134. eCollection 2020 Aug.

  PMID: 32695968 BACKGROUND

• Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019 Jan;70(1):151-171. doi: 10.1016/j.jhep.2018.09.014. Epub 2018 Sep 26.

  PMID: 30266282 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Anesthesia; Transcobalamins; Fentanyl; Analgesics, Non-Narcotic; Morphine; Consciousness Monitors; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Anesthesia and Analgesia; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Carrier Proteins; Globulins; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Central Nervous System Agents; Therapeutic Uses; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Surgical Equipment; Equipment and Supplies; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: The laboratory physician who processed the samples was blinded to the group assignment of each sample.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant professor

Model Details: Formation of four study groups, each around of 50 patients diagnosed with hepatocellular carcinoma or hepatic metastases, according to the type of anesthesia administered during surgery: Group 1 - TIVA (propofol) + lidocaine Group 2 - TIVA (propofol) + placebo Group 3 - Sevoflurane + lidocaine Group 4 - Sevoflurane + placebo

Study Record Dates

• First Submitted: July 7, 2025
• First Posted: October 3, 2025
• Study Start: February 3, 2022
• Primary Completion: March 23, 2023
• Study Completion: June 3, 2024
• Last Updated: October 3, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

RO (1)