Ignite Creation Date:
2024-05-06 @ 6:52 PM
Last Modification Date:
2024-10-26 @ 2:56 PM
Study NCT ID:
NCT05816538
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-04-18
First Post:
2023-01-16
Brief Title:
The Immune Response of Breast Cancer Patients Treated With Levobupivacaine Using Paravertebral or Superficial Chest Blocks
Sponsor:
University of Rijeka
Organization:
University of Rijeka
Study Overview
Official Title:
The Immune Response of Breast Cancer Patients Treated With Levobupivacaine Using Paravertebral or Superficial Chest Blocks
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 andor 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 05 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 bodys 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 299 kgm2
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 Brauns 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 40 Retrieved May 20 2021 from http www randomizerorg 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 03mlkg 05 levobupivacaine total divided into levels In Group 2 the investigators will apply PECS 2 block with 10 ml of 05 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 - 25 mgkg 10 mgml Fresenius sufentanil Sufentanil Altamedics 02 μg kg rocuronium Zemuron Schering - Plow 08 mgkg 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 mlkg 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 mgml Fresenius 25 - 150 mcgkgmin and rocuronium Zemuron Schering - Plow 001 mgkgmin 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 mgml 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 iv in 100 ml of saline for 15min If pain with VAS 6 is present a combination of diclofenac sodium Voltaren Pliva 75 mg iv 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 01 mgkg 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 manufacturers 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 manufacturers instructions
Statistics
The group size was obtained by power analysis Using Fishers 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 005 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 1903 MedCalc Software Ostend Belgium httpswwwmedcalcorg 2019 and G Power for Windows version 3192
IBM SPSS Statistics version 210 wwwspsscom 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 andor non-parametric statistical methods will be applied Quantitative data will be presented through ranges arithmetic means and standard deviations ie 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 ie 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 Fishers exact test An appropriate regression model will assess the effect of selected clinical variables on differences between study groups All P values less than 005 will be considered significant
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 bodys 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 299 kgm2
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 Brauns 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 40 Retrieved May 20 2021 from http www randomizerorg 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 03mlkg 05 levobupivacaine total divided into levels In Group 2 the investigators will apply PECS 2 block with 10 ml of 05 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 - 25 mgkg 10 mgml Fresenius sufentanil Sufentanil Altamedics 02 μg kg rocuronium Zemuron Schering - Plow 08 mgkg 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 mlkg 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 mgml Fresenius 25 - 150 mcgkgmin and rocuronium Zemuron Schering - Plow 001 mgkgmin 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 mgml 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 iv in 100 ml of saline for 15min If pain with VAS 6 is present a combination of diclofenac sodium Voltaren Pliva 75 mg iv 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 01 mgkg 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 manufacturers 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 manufacturers instructions
Statistics
The group size was obtained by power analysis Using Fishers 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 005 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 1903 MedCalc Software Ostend Belgium httpswwwmedcalcorg 2019 and G Power for Windows version 3192
IBM SPSS Statistics version 210 wwwspsscom 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 andor non-parametric statistical methods will be applied Quantitative data will be presented through ranges arithmetic means and standard deviations ie 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 ie 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 Fishers exact test An appropriate regression model will assess the effect of selected clinical variables on differences between study groups All P values less than 005 will be considered significant
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None