Trial Title:
The Immune Response of Breast Cancer Patients Treated With Levobupivacaine Using Paravertebral or Superficial Chest Blocks
NCT ID:
NCT05816538
Condition:
Paravertebral Block
Pectoralis and Serratus Plane Nerve Blocks
Breast Cancer
Immunologic Suppression
Levobupivacaine
Conditions: Official terms:
Breast Neoplasms
Anesthetics
Levobupivacaine
Conditions: Keywords:
Breast Cancer
Levobupivacaine
Immunologic Suppression
Paravertebral block
Pectoralis and Serratus Plane Nerve Blocks
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Basic Science
Masking:
Single (Care Provider)
Intervention:
Intervention type:
Procedure
Intervention name:
Paravertebral nerve block (PVB)
Description:
PVB is a regional anesthetic technique applied at the thoracic (Th) level of Th2, Th3,
and Th4 at a dose of 0.3ml/kg 0.5% levobupivacaine total, divided into levels. Block will
be performed with ultrasound-guided in-plane technique and neurostimulation.
Arm group label:
Group 1 PVB
Intervention type:
Procedure
Intervention name:
Pectoralis and Serratus Plane Nerve Blocks (PECS 2)
Description:
Pectoralis and Serratus Plane Nerve blocks (PECS 2) is a regional anesthetic technique
applied in the space between the large and small pectoral muscles (10 ml of 0.5%
levobupivacaine), and in the space between the small pectoralis muscle and the serratus
anterior muscle (with 15 ml of 0.5% levobupivacaine). Block will be performed with
ultrasound-guided in-plane technique and neurostimulation.
Arm group label:
Group 2 PECS
Intervention type:
Device
Intervention name:
Regional anesthetic technique with ultrasound guidance
Description:
The device that will be used is an ultrasound with an 8 Hz ultrasonic linear probe for
both regional anesthetic techniques.
Arm group label:
Group 1 PVB
Arm group label:
Group 2 PECS
Intervention type:
Device
Intervention name:
Regional anesthetic technique with peripheral nerve stimulation.
Description:
The 22G neurostimulator needle (Stimuplex D®, B. Braun Melsungen AG)], and
neurostimulator (Stimuplex HNS 12, B. Braun, Melsungen AG, Germany) will be used for both
regional anesthesias.
Arm group label:
Group 1 PVB
Arm group label:
Group 2 PECS
Intervention type:
Drug
Intervention name:
Levobupivacaine 0.5%
Description:
Local anesthetic levobupivacaine 0.5% will be used for regional anesthetic technique with
ultrasound guidance and peripheral nerve stimulation. For the paravertebral block at a
dose of 0.3ml/kg total, applied at the thoracic (Th) level of Th2, Th3, and Th4 and
divided into levels. For the PECS 2 block levobupivacaine 0.5% 10 ml will be applied in
the space between the large and small pectoral muscles and 15 ml in the space between the
small pectoralis muscle and the serratus anterior muscle.
Arm group label:
Group 1 PVB
Arm group label:
Group 2 PECS
Intervention type:
Procedure
Intervention name:
General anesthesia
Description:
In both groups for induction of general anesthesia we will use 1% propofol 2 - 2.5 mg/kg
(10 mg/ml, Fresenius), sufentanil (Sufentanil® Altamedics) 0.2 μg / kg, rocuronium
[Zemuron®, Schering - Plow] 0.8 mg/kg. We will use a laryngeal mask (I - gel supraglottic
airway) of appropriate sizes for airway maintenance. All subjects will be ventilated by
controlled mechanical ventilation with a volume of 8 ml/kg, a frequency of about 12
breaths per min with a mixture of oxygen and air in a 40: 60% ratio. Maintenance of
anesthesia and sedation in group 1 will be performed with continuous infusion of 1%
propofol (10 mg / ml, Fresenius) (25 - 150 mcg / kg / min.) and rocuronium [Zemuron®,
Schering - Plow] 0.01 mg / kg / min per perfusor.
Arm group label:
Group 1 PVB
Arm group label:
Group 2 PECS
Summary:
The use of regional anesthesia in breast surgery improves the postoperative outcome,
reduces the development of infection, and weakens the perioperative immunosuppressive
response associated with the response to surgical stress. The investigators hypothesize
that the use of propofol / paravertebral anesthesia and analgesia will be accompanied by
a decrease in serum proinflammatory cytokines and/or an increase in anti-inflammatory
cytokines compared to propofol / PECS 2 anesthesia and analgesia. The research will be on
100 respondents divided into two groups. 0.5% levobupivacaine will be administered to
both groups. Serum concentrations of pro- and anti-inflammatory cytokines, and lymphocyte
subpopulations 1h before, 24h, and 48h after surgery will be measured. The investigators
aim to compare the effect of propofol / paravertebral and propofol / PECS 2 anesthesia
and analgesia on serum perioperative values of pro-inflammatory and anti-inflammatory
cytokines to standardize protocols and apply the best method of perioperative analgesia
in breast cancer surgery.
Detailed description:
Introduction
The human immune system is extremely adaptable and complex. The immune response in the
body is often a defense against tumors or infection and maintenance of homeostasis. It
includes specific (acquired) and nonspecific (innate) immunity. The immune system is
known to be shaped by a complex network of cytokines; interleukins (IL), interferons
(IFN), tumor necrosis factor [Eng. Tumor necrosis factor (TNF)] etc. Tumor cells respond
differently to cytokines. Certain cytokines stimulate immune reactions and are called
pro-inflammatory, while others inhibit the immune system response and are called
anti-inflammatory. In previous studies, Il-1, Il-6, TNFα, and IL-10 are common indicators
of inflammatory changes in cancer. IL-6 is a potent proinflammatory cytokine with
multiple mechanisms of antitumor activity. TNFα stimulates the production of other
proinflammatory factors and proteases. IL-10 inhibits the production of pro-inflammatory
cytokines.
Surgery and anesthesia change the activity of the immune system quickly and through
various processes. Pain, fear, medications, inhalation anesthetics, opioids, tissue
injury, blood transfusions, increased stress, and infection activate the immune system
during the perioperative period by suppressing the adaptive immune response or enhancing
the immune response.
Breast cancer is the most common malignancy in women, second only to lung cancer in
mortality. Breast cancer surgery is the primary and most effective treatment, with
special emphasis on the minimal release of tumor cells into the vascular and lymphatic
systems. Whether the release of tumor cells will result in clinical metastases depends
primarily on the balance between antimetastatic immune activity and the ability of the
tumor to metastasize to other tissues.
Regional anesthesia is a technique in which the application of a local anesthetic near a
nerve or spinal cord inhibits the sensation, pain, and motor stimulation of one region of
the body. Applied local anesthetics thus prevent the endocrine-metabolic response to
stress. Many studies have shown that the use of neuraxial (spinal and epidural) and
perineuroaxial paravertebral block (PVB) regional anesthesia in breast surgery [(propofol
/ paravertebral block anesthesia - analgesia)] improve postoperative outcome and reduce
the development of perioperative immunosuppressive response associated with surgical
stress.
A paravertebral block is applied to the wedge-shaped anatomical space located bilaterally
paravertebral, between the parietal pleura anteriorly; vertebrae, and intervertebral
discs medially; and the upper transverse rib ligament posteriorly. Pectoralis and
serratus plane nerve blocks 1 and 2 (PECS 1 and 2) are newer regional anesthesia
techniques in which a local anesthetic is administered between the pectoral muscle
sheets. Recent research has shown that the use of PECS 2 in breast cancer surgery has the
same perioperative analgesic effect as a paravertebral block, with fewer side effects.
Although it has been proven that it is the blocks of these nerves that achieve
satisfactory analgesia in breast surgery, their influence on the perioperative immune
response has not yet been proven, nor has a comparison of the body's immune response to
surgical stimulation with PECS 2 and PVB.
Participants
In the prospective, randomized, monocentric study, the investigators will perform a study
on 100 participants, divided into two groups, or 50 participants per group. In Group 1
propofol / paravertebral anesthesia and analgesia will be used; in Group 2 the
investigators will use propofol / PECS 2 anesthesia and analgesia. The investigators will
include women scheduled for quadrantectomy with equilateral axillary lymphadenectomy,
anesthesia preoperative status (American Society of Anesthesiologists (ASA)) 1 and 2,
aged 18 to 65 years. Exclusive criteria are patient rejection, ASA> 3, contraindication
for local anesthetic, contraindications for planned regional anesthesia and analgesia,
immunosuppressive therapy including corticosteroids, acute infection, history of chronic
opioid use, presence of autoimmune disease, obesity (defined as body mass index BMI
greater than 29.9 kg/m2).
Research plan
The research will be conducted at the Clinical Hospital Center Rijeka, Department of
Anesthesiology, Reanimation and Intensive Medicine, the Surgery Department, and the
Department of Physiology, Immunology, and Pathophysiology at the Faculty of Medicine,
University of Rijeka. The devices that will be used are ultrasound (8 Hz ultrasonic
linear probe), neurostimulator needle [22G (Stimuplex D®, B. Braun Melsungen AG)],
neurostimulator (Stimuplex HNS 12, B. Braun, Melsungen AG, Germany), a bispectral index
monitoring device (BIS A-2000 BIS monitor, Aspect Medical Systems, Newton, MA, USA),
perfusor (B. Braun's Perfusor®), enzyme-linked immunosorbent assay (ELISA), flow
cytometry device (FACSCalibur, Becton Dickinson, San Jose, CA, USA).
The randomization schedule will be implemented by a computer-free randomization service
(Urbaniak, GC, & Plous, S. (2013) Research Randomizer (Version 4.0)). Retrieved May 20,
2021, from http: // www. randomizer.org. Standard preoperative preparation and
supervision will be performed in the ward and the pre-and post-anesthesia units. The
first blood sample will be taken to all participants 1 hour before surgery on arrival at
the above unit. In Group 1 the investigators will apply PVB at the thoracic (Th) level of
Th2, Th3, and Th4 at a dose of 0.3ml/kg 0.5% levobupivacaine total, divided into levels.
In Group 2 the investigators will apply PECS 2 block with 10 ml of 0.5% levobupivacaine
in the space between the large and small pectoral muscles, and 15 ml in the space between
the small pectoralis muscle and the serratus anterior muscle. Both blocks will be
performed with ultrasound-guided in-plane technique and neurostimulation, as described in
the literature. In both groups for induction of general anesthesia, the investigators
will use 1% propofol 2 - 2.5 mg/kg (10 mg/ml, Fresenius), sufentanil (Sufentanil®
Altamedics) 0.2 μg / kg, rocuronium [Zemuron®, Schering - Plow] 0.8 mg/kg. The
investigators will use a laryngeal mask (I - gel supraglottic airway) of appropriate
sizes for airway maintenance. All subjects will be ventilated by controlled mechanical
ventilation with a volume of 8 ml/kg, a frequency of about 12 breaths per min with a
mixture of oxygen and air in a 40: 60% ratio. Maintenance of anesthesia and sedation in
group 1 will be performed with continuous infusion of 1% propofol (10 mg/ml, Fresenius)
(25 - 150 mcg/kg/min) and rocuronium [Zemuron®, Schering - Plow] 0.01 mg/kg/min via
perfusor. After induction, mean arterial pressure, heart rate, oxygen saturation, and BIS
values will be recorded every five minutes for the duration of the operation. Continuous
infusion of 1% propofol (10 mg/ml, Fresenius) will be adjusted according to the target
values of BIS devices in the range of 45 to 55.
At the end of the operation, the investigators will wake up the participants from
anesthesia. Postoperatively, participants will be monitored in a post-anesthesia care
unit (PACU) room where vital parameters (ECG, non-invasive blood pressure measurement,
and saturation) and visual analgesic scale (VAS) [from 0 (no pain) to 10 (worst
imaginable pain) according to Rawal will be notified. If pain with VAS> 3 is present,
participants will receive diclofenac sodium (Voltaren®, Pliva) 75 mg i.v. in 100 ml of
saline for 15min. If pain with VAS ≥ 6 is present, a combination of diclofenac sodium
(Voltaren®, Pliva) 75 mg i.v. and tramal (Tramal® Stada) 100 mg in 500 ml saline will be
obtained. In case of nausea and vomiting as assessed on a three-point scale (0 = no
nausea and vomiting; 1 = nausea, no vomiting; 2 = vomiting with or without nausea)
thietylperazine (Torecan®, Krka) will be administered in a dose of 0.1 mg/kg on a scale
≥1. If all vital parameters are satisfactory and there are no complications, the
participants will be referred to the department after two hours postoperatively. There,
non-invasive hemodynamic monitoring (pressure, ECG, heart rate, saturation) will be
performed until the block resolution. During the first 24 hours, the recovery of patients
will be monitored and VAS will be assessed every 3 hours. Appropriate analgesic measures
(non-steroidal anti-inflammatory drugs or opioid analgesics) will be performed based on
VAS values.
Venous blood samples will be collected 24 and 48 hours after surgery. All samples will be
delivered to the laboratory on the same day where they will be processed and stored at
-20 Cs until analysis. According to the manufacturer's instructions, serum concentrations
of pro-inflammatory cytokines Il-1, Il-6, TNFα, and anti-inflammatory cytokine IL-10 will
be analyzed using an ELISA test. Subpopulations of T lymphocytes (helper and cytotoxic),
B lymphocytes, NK, and NKT cells will be analyzed and determined from the samples by flow
cytometry. Serum subpopulations of Treg (FITC-CD4, APC-CD25, and PE-Foxp3 positive) in
serum will also be determined according to the manufacturer's instructions.
Statistics
The group size was obtained by power analysis. Using Fisher's exact test, according to
the paper by Deegan CA, Murray D, Doran P, et al. Anesthetic technique and the cytokine
and matrix metalloproteinase response to primary breast cancer surgery. Reg Anesth. Pain
Med. 2010; 35: 490-5; the expected difference in the share of interleukin level increase
of at least 25% (expected increase in group 1 of 30% and group 2 of 5%) is assumed. For a
test power of 85%, a significance level of α = 0.05, and an equal number of subjects in
groups, at least 45 subjects per group should be included in the study. Power analysis
was performed using MedCalcStatistical Software version 19.0.3 (MedCalc Software, Ostend,
Belgium; https://www.medcalc.org; 2019) and G * Power for Windows version 3.1.9.2.
IBM SPSS Statistics, version 21.0 (www.spss.com) will be used in the data analysis.
The data will be presented in tables and graphs. An analysis of the normality of data
distribution (Kolmogorov-Smirnov test) will be made, and according to the obtained
results, appropriate data display methods and parametric and/or non-parametric
statistical methods will be applied. Quantitative data will be presented through ranges,
arithmetic means, and standard deviations i.e., median and interquartile ranges in cases
of nonparametric distribution. Category data will be presented through absolute
frequencies and associated shares.
Differences between individual measurements will be analyzed by observing the variance
for repeated measurements, i.e. the Friedman test. Differences in individual measurement
times will be analyzed by the independent t-test or the Mann-Whitney U test. Differences
in categorical values will be analyzed by Fisher's exact test. An appropriate regression
model will assess the effect of selected clinical variables on differences between study
groups. All P values less than 0.05 will be considered significant.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- quadrantectomy with equilateral axillary lymphadenectomy
- anesthesia preoperative status (American Society of Anesthesiologists (ASA)) 1 and 2
Exclusion Criteria:
- patient rejection
- ASA> 3
- contraindication for local anesthetic
- contraindications for planned regional anesthesia and analgesia
- immunosuppressive therapy including corticosteroids
- acute infection
- history of chronic opioid use
- presence of autoimmune disease
- obese definite body mass index BMI) greater than 29.9 kg/m2
Gender:
Female
Minimum age:
18 Years
Maximum age:
65 Years
Healthy volunteers:
No
Start date:
April 2023
Completion date:
December 2025
Lead sponsor:
Agency:
University of Rijeka
Agency class:
Other
Source:
University of Rijeka
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05816538
