The Impact of Intravenous Anaesthesia on Angiogenesis in Patients With Breast Cancer (TIVA/TCI-BC)

NCT ID: NCT02839668

Last Updated: 2019-10-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-31
• Study Completion Date: 2019-09-30

Brief Summary

Because neoplastic disease is one of the leading causes of death worldwide and breast cancer is one of the most frequent neoplasia among women, the possibility of influencing the evolution of patients starting from the moment of surgical intervention using a perianesthesic intervention is a scientific topic of high interest. The study will compare two anesthetic techniques and their efficiency in lowering the factors that can favorize the dissemination of neoplasia and their role in the prevention of postoperative pain. The serum level of vascular endothelial growth factor A (VEGF-A) will be determined before and after the surgical intervention after using two different types of anesthesia (inhalational and intravenous), and the immunohistochemical expression of vascular endothelial growth factor receptors (VEGFR) will be determined on the excised tissue. For the two different types of anesthesia a continuous infusion of lidocaine 1% will be associated. The study will compare the short-term and long term-outcome of the patients assigned the two different types of anesthesia and their immediate postoperative evolution .

Detailed Description

The study will enroll patients with ages between 18 and 80 years old, diagnosed with breast cancer but without proof of disease dissemination on medical imaging. After obtaining an informed consent the patients will be computer randomized to 4 groups. Each group will benefit from a certain type of anesthesia. The first group will be assigned general anesthesia using Sevoflurane for maintenance of hypnosis, the second group will be assigned general anesthesia with Sevoflurane and a continuous infusion of lidocaine 1%. The thrid group will be assigned total intravenous anesthesia using propofol for maintenance of hypnosis and the fourth group will be assigned to total intravenous anesthesia with propofol and a continuous infusion of lidocaine 1%. Before the surgical procedure a blood sample will be drawn from each patient for the measurement of serum vascular endothelial growth factor A ( VEGF-A). All the patients will receive pre-medication a night before the intervention with low molecular weight heparin (LMWH) and midazolam 5mg the morning of the intervention. For the first two groups the anesthetic induction will be conducted using propofol 1,5-2 mg/kg, fentanyl 1-3 microg/kg, atracurium 0,5 mg/kg.For the maintenance of anesthesia Sevoflurane will be used at a alveolar concentration of 1-1,5 MAC, as to maintain a BIS between 45-55. Intraoperative anesthesia will be ensured by using fentanyl boluses of 100 microg and the muscular relaxation needed for mechanical ventilation will be maintained using boluses of 10 mg of atracurium. At the end of the surgery the neuromuscular blockade will be antagonized with neostigmine 0.05 mg/kg and atropine 0.2 mg/kg. For the second group at the induction of anesthesia the patient will be administered a bolus of lidocaine 1% of 1.5 mg/kg and a continuous infusion of lidocaine 1% 2 mg/kg/h will be associated throughout the procedure and 1mg/kg/h,24 h postoperative. The postoperative analgesia will be assured by administering acetaminophen 1 g each 8 h and tramadol 25-50 mg each 4-6 h as needed. For the third and fourth groups the induction of aneshesia will be made using propofol administered by target controlled infusion (TCI) technique with a target plasma concentration of 4 microg/ml . Throughout the intervention the plasma concentration of propofol will be adjusted with increments of 0.2 microg/ml as to maintain a BIS between 45-55. To attenuate the response to laryngoscopy the patient will receive a bolus of fentanyl 1-3 microg/ml. During the intervention fentanyl will be administered in boluses of 100microg as needed. Muscular relaxation necessary for intubation will be provided using atracurium 0.5 mg/kg at induction of anesthesia and 10 mg boluses during the surgery as needed. At the end of the surgery the neuromuscular blockade will be antagonized with neostigmine 0.05 mg/kg and atropine 0.2 mg/kg. For the fourth group at the induction of anesthesia the patient will be administered a bolus of lidocaine 1% of 1.5 mg/kg and a continuous infusion of lidocaine 1% 2 mg/kg/h will be associated throughout the procedure and 1mg/kg/h, 24 h postoperative.Postoperative analgesia will be assured by administering acetaminophen 1 g each 8 h and tramadol 25-50 mg each 4-6 h as needed. Throughout the surgical intervention the patients will be monitored accordingly to the American Society of Anesthesiologists (ASA) standards (electrocardiogram-ECG, heart rate- HR, peripheral capillary oxygen saturation- SpO2, non-invasive blood pressure- NIBP, capnography and for the 3rd and 4th groups the bispectral index - BIS will be monitored). In the postoperative period non-invasive blood pressure -NIBP, heart rate- HR,peripheral capillary oxygen saturation SpO2, intensity of pain at 24 and 48 h will be monitored.Vascular endothelial growth factor- VEGF levels will be monitored at 24 h postoperative using ELISA technique. Vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2) will be determined using immunohistochemical staining.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Sevoflurane

The patients enrolled in this arm will receive general anesthesia in which the hypnosis will be maintained with Sevoflurane. Postoperative analgesia will be assured by the administration of tramadol and acetaminophen.A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery.A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine.The bispectral index- BIS will be monitored throughout the anesthesia

Group Type: EXPERIMENTAL

Sevoflurane

Intervention Type: DRUG

maintenance of hypnosis during anaesthesia with sevoflurane

Acetaminophen

Intervention Type: DRUG

administration of 1 g acetaminophen for postoperative analgesia

Tramadol

Intervention Type: DRUG

administration of tramadol for postoperative analgesia

Neostigmine

Intervention Type: DRUG

A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery.

Atropine

Intervention Type: DRUG

A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine

BIS

Intervention Type: DEVICE

For the groups receveing TIVA-TCI anesthesia the bispectral index will be monitored

Sevoflurane+Lidocaine

The patients enrolled in this group will receive general anesthesia in which the hypnosis will be maintained with Sevoflurane. At the induction of anesthesia the patients will receive a bolus of lidocaine 1% 1.5 mg/kg. A continuous infusion of lidocaine 1% of 2 mg/kg/h will be associated throughout the surgical procedure and 1mg/kg/h until 24 h postoperative. Postoperative analgesia will be assured by the administration of tramadol and acetaminophen.A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery. A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine.The bispectral index- BIS will be monitored throughout the anesthesia

Group Type: ACTIVE_COMPARATOR

Lidocaine

Intervention Type: DRUG

Continuous infusion of lidocaine

Sevoflurane

Intervention Type: DRUG

maintenance of hypnosis during anaesthesia with sevoflurane

Acetaminophen

Intervention Type: DRUG

administration of 1 g acetaminophen for postoperative analgesia

Tramadol

Intervention Type: DRUG

administration of tramadol for postoperative analgesia

Neostigmine

Intervention Type: DRUG

A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery.

Atropine

Intervention Type: DRUG

A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine

BIS

Intervention Type: DEVICE

For the groups receveing TIVA-TCI anesthesia the bispectral index will be monitored

TIVA-TCI

The patients enrolled in this group will receive total intravenous anesthesia with propofol using a target controlled infusion technique for the maintenance of hypnosis throughout the surgery. Postoperative analgesia will be assured by the administration of tramadol and acetaminophen.A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery.A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine. The bispectral index- BIS will be monitored throughout the anesthesia.

Group Type: EXPERIMENTAL

TIVA-TCI

Intervention Type: DRUG

maintenance of hypnosis during anaesthesia with sevoflurane

Acetaminophen

Intervention Type: DRUG

administration of 1 g acetaminophen for postoperative analgesia

Tramadol

Intervention Type: DRUG

administration of tramadol for postoperative analgesia

Neostigmine

Intervention Type: DRUG

A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery.

Atropine

Intervention Type: DRUG

A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine

BIS

Intervention Type: DEVICE

For the groups receveing TIVA-TCI anesthesia the bispectral index will be monitored

TIVA-TCI+lidocaine

The patients enrolled in this group will receive total intravenous anesthesia with propofol using a target controlled infusion technique for the maintenance of hypnosis throughout the surgery. At the induction of anesthesia the patients will receive a bolus of lidocaine 1% 1.5 mg/kg. A continuous infusion of lidocaine 1% of 2 mg/kg/h will be associated throughout the surgical procedure and 1mg/kg/h until 24 h postoperative. Postoperative analgesia will be assured by the administration of tramadol and acetaminophen.A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery. A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine.The bispectral index- BIS will be monitored throughout the anesthesia.

Group Type: ACTIVE_COMPARATOR

Lidocaine

Intervention Type: DRUG

Continuous infusion of lidocaine

TIVA-TCI

Intervention Type: DRUG

maintenance of hypnosis during anaesthesia with sevoflurane

Acetaminophen

Intervention Type: DRUG

administration of 1 g acetaminophen for postoperative analgesia

Tramadol

Intervention Type: DRUG

administration of tramadol for postoperative analgesia

Neostigmine

Intervention Type: DRUG

A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery.

Atropine

Intervention Type: DRUG

A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine

BIS

Intervention Type: DEVICE

For the groups receveing TIVA-TCI anesthesia the bispectral index will be monitored

Interventions

Lidocaine

Continuous infusion of lidocaine

Intervention Type: DRUG

Sevoflurane

maintenance of hypnosis during anaesthesia with sevoflurane

Intervention Type: DRUG

TIVA-TCI

maintenance of hypnosis during anaesthesia with sevoflurane

Intervention Type: DRUG

Acetaminophen

administration of 1 g acetaminophen for postoperative analgesia

Intervention Type: DRUG

Tramadol

administration of tramadol for postoperative analgesia

Intervention Type: DRUG

Neostigmine

A 0.05 mg/kg dose of neostigmine will be administered to antagonize the neuromuscular block at the end of surgery.

Intervention Type: DRUG

Atropine

A 0.2 mg/kg dose of atropine will be administered at the end of surgery to attenuate the parasymatomimetic effects of neostigmine

Intervention Type: DRUG

BIS

For the groups receveing TIVA-TCI anesthesia the bispectral index will be monitored

Intervention Type: DEVICE

Other Intervention Names

lidocaine 1%, lignocaine; Diprivan; paracetamol; Tramal; Prostigmin, vagostigmin; atropine sulfate; bispectral index monitor

Eligibility Criteria

Inclusion Criteria

• diagnosis of breast cancer
• ASA risk class I-III
• no metastatic disease

Exclusion Criteria

• hepatic, pulmonary metastasis
• type I and II diabetes
• rheumatoid arthritis
• osteoarthritis
• ischemic cardiovascular disease (history of myocardial infarction, angina)
• peripheral vascular disease
• endometriosis
• allergies to lidocaine, fentanyl, propofol, sevoflurane, atracurium, midazolam, acetaminophen, tramadol
• neuropsychiatric disorders
• incapacity of understanding the study
• refusal of participation

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Prof. Dr. I. Chiricuta Institute of Oncology

OTHER

Sponsor Role: collaborator

Iuliu Hatieganu University of Medicine and Pharmacy

OTHER

Sponsor Role: lead

Responsible Party

Dr.Draghiciu Elena

Universitary Assistant

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

IOCN Prof Dr I chiricuta

Cluj-Napoca, , Romania

Countries

Romania

References

Mao L, Lin S, Lin J. The effects of anesthetics on tumor progression. Int J Physiol Pathophysiol Pharmacol. 2013;5(1):1-10. Epub 2013 Mar 8.

Reference Type: BACKGROUND

PMID: 23525301 (View on PubMed)

Byrne K, Levins KJ, Buggy DJ. Can anesthetic-analgesic technique during primary cancer surgery affect recurrence or metastasis? Can J Anaesth. 2016 Feb;63(2):184-92. doi: 10.1007/s12630-015-0523-8.

Reference Type: BACKGROUND

PMID: 26497721 (View on PubMed)

Chang YC, Liu CL, Chen MJ, Hsu YW, Chen SN, Lin CH, Chen CM, Yang FM, Hu MC. Local anesthetics induce apoptosis in human breast tumor cells. Anesth Analg. 2014 Jan;118(1):116-24. doi: 10.1213/ANE.0b013e3182a94479.

Reference Type: RESULT

PMID: 24247230 (View on PubMed)

Terkawi AS, Sharma S, Durieux ME, Thammishetti S, Brenin D, Tiouririne M. Perioperative lidocaine infusion reduces the incidence of post-mastectomy chronic pain: a double-blind, placebo-controlled randomized trial. Pain Physician. 2015 Mar-Apr;18(2):E139-46.

Reference Type: RESULT

PMID: 25794212 (View on PubMed)

Galos EV, Tat TF, Popa R, Efrimescu CI, Finnerty D, Buggy DJ, Ionescu DC, Mihu CM. Neutrophil extracellular trapping and angiogenesis biomarkers after intravenous or inhalation anaesthesia with or without intravenous lidocaine for breast cancer surgery: a prospective, randomised trial. Br J Anaesth. 2020 Nov;125(5):712-721. doi: 10.1016/j.bja.2020.05.003. Epub 2020 Jun 29.

Reference Type: DERIVED

PMID: 32616309 (View on PubMed)

Other Identifiers

IuliuHatieganu Cluj-Napoca

Identifier Type: -

Identifier Source: org_study_id