<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03293472</url>
  </required_header>
  <id_info>
    <org_study_id>URzeszow</org_study_id>
    <nct_id>NCT03293472</nct_id>
  </id_info>
  <brief_title>Neurotoxicity of Spinal Anesthesia With Ropivacaine and Bupivacaine</brief_title>
  <acronym>BuRoNe</acronym>
  <official_title>Inflammatory Mediators, Neural Tissue Injury Markers and the Markers of Oxidative Stress in the CSF of Patients Undergoing Spinal Anesthesia With Ropivacaine and Bupivacaine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Rzeszow</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Department of Anesthesiology, Intensive Therapy, District Hospital No2 in Rzeszow</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Rzeszow</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Consenting patients, scheduled for orthopaedic surgery under spinal anesthesia will be&#xD;
      randomly assigned (1:1) to receive ropivacaine or bupivacaine as a single shot before the&#xD;
      start of surgery, followed by bolus doses of the same local anesthetic as required during the&#xD;
      surgery, and continuous infusion of the same local anesthetic for 24 hours postoperatively.&#xD;
&#xD;
      Primary Outcome Measures: Evaluation of changes in concentrations of glutamate in the&#xD;
      cerebrospinal fluid and in the blood. Secondary outcomes: : Evaluation of changes in&#xD;
      concentrations of selected mediators of inflammatory response (IL-1β, IL-6, TNF and others)&#xD;
      and selected chemokines as markers of the glia damage.&#xD;
&#xD;
      Hemodynamic stability during the surgery, and efficacy of postoperative analgesia will be&#xD;
      also evaluated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      With the approval from the Bioethical Committee of the University of Rzeszow, informed&#xD;
      written consent will be obtained from all patients.&#xD;
&#xD;
      A sample size of 60 patients was calculated to obtain at least 25% reduction of glutamate&#xD;
      concentration in the cerebrospinal fluid in the ropivacaine group with 0,05 significance and&#xD;
      power of 0,8.&#xD;
&#xD;
      Consenting patients, scheduled for orthopaedic surgery under spinal anesthesia will be&#xD;
      randomly (1:1) assigned using closed envelopes to receive intrathecally ropivacaine or&#xD;
      bupivacaine as a single shot before the start of surgery, followed by bolus doses of the same&#xD;
      local anesthetic as required during the surgery, and continuous infusion of the same local&#xD;
      anesthetic for 24 h for postoperative pain relief. All block will be performed in the sitting&#xD;
      position, and the drug will be administered in supine position through the catheter in the&#xD;
      intrathecal space. Blood and cerebrospinal fluid samples will be drawn at predetermined time&#xD;
      intervals centrifuged as required and frosen in -70deg C until analysis.&#xD;
&#xD;
      Eligibility Ages eligible for study 18 years and older (Adult, Senior) Sexes Eligible for the&#xD;
      Study: All Accepts Healthy Volunteers: No&#xD;
&#xD;
      Inclusion Criteria:&#xD;
&#xD;
      Orthopedic procedures in the lower limbs Written informed consent Exclusion criteria&#xD;
      Patients' refusal Known allergies to study medications Anatomic, posttraumatic and&#xD;
      postoperative deformations of the spinal column making placement of intrathecal catheter&#xD;
      impossible Neurological contraindications Any other contraindications for spinal anesthesia&#xD;
      (coagulations disorders, antiplatelet or anticoagulant treatment, infection at the puncture&#xD;
      site.&#xD;
&#xD;
      Inability to comprehend or participate in pain scoring scale&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2019</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Parallel study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Patient unaware of the local anesthetic used.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the cerebrospinal fluid of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.</measure>
    <time_frame>24 h</time_frame>
    <description>Evaluation of changes in concentrations of&#xD;
• glutamate in the cerebrospinal fluid and in the blood of patients undergoing orthopaedic surgery under spinal anesthesia with either ropivacaine or bupivacaine</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the cerebrospinal fluid of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.</measure>
    <time_frame>24 h</time_frame>
    <description>Evaluation of changes in concentrations of selected mediators of inflammatory response (IL-1β, IL-6, tumor necrosis factor and others)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the cerebrospinal fluid of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.</measure>
    <time_frame>24 h</time_frame>
    <description>Evaluation of changes in concentrations of • selected chemokines as markers of the glia damage in the cerebrospinal fluid and in the blood of patients undergoing orthopaedic surgery under continuous spinal anesthesia with either ropivacaine or bupivacaine</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the CSF of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.</measure>
    <time_frame>24 h</time_frame>
    <description>Assessment of hemodynamic stability in patients anaesthetized with continuous epidural infusion of ropivacaine and bupivacaine</description>
  </other_outcome>
  <other_outcome>
    <measure>Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the CSF of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.</measure>
    <time_frame>24h</time_frame>
    <description>Postoperative pain severity in Numerical Rating Scale (NRS) in the first 24 hours after surgery [Time Frame: 24 h] NRS range from 0 for no pain to 10 for worst pain imaginable</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Anesthesia; Adverse Effect, Spinal and Epidural</condition>
  <condition>Anaesthetic Complication Neurological</condition>
  <arm_group>
    <arm_group_label>Ropivacaine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental: 0.5% ropivacaine (isobaric) 4.5 ml for the patients &lt; 160 cm tall, 5.0 ml for 161-170 cm tall, 5.5 ml for 171-180 cm tall, and 6.0 ml &gt; 180 cm.&#xD;
supplementary bolus doses of ropivacaine as required, followed by 0.2% ropivacaine, 1 ml/h for the postoperative period</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bupivacaine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>0.5% v Bupivacaine mg (isobaric) loading dose of 0.5% bupivacaine, 3.0 ml for the patients &lt; 160 cm tall, 3.3 ml for 161-170 cm tall, 3.6 ml for 171-180 cm tall, and 4.0 ml &gt; 180 cm.&#xD;
and supplementary bupivacaine bolus dose as required, followed by 0,12% bupivacaine 1 ml/h for the postoperative period</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ropivacaine</intervention_name>
    <description>Procedure: Continuous Epidural Anesthesia Local anesthetic injection to the cerebrospinal fluid (subarachnoid space) at the L3-L4 or L4-L5 level Drug: ropivacaine Other name: Ropimol 0.5% ropivacaine (isobaric) 4.5 ml for the patients &lt; 160 cm tall, 5.0 ml for 161-170 cm tall, 5.5 ml for 171-180 cm tall, and 6.0 ml &gt; 180 cm, supplementary ropivacaine bolus doses as required, followed by 0.2% ropivacaine, 1 ml/h for the postoperative period Device : The Wiley Spinal Catheter-Over-Needle System for Continuous Spinal Anesthesia 4-6&quot; 23-gauge intrathecal cannula over a 27-gauge pencil-point spinal needle</description>
    <arm_group_label>Ropivacaine</arm_group_label>
    <other_name>Ropimol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupivacaine</intervention_name>
    <description>Procedure: Continuous Epidural Anesthesia Local anesthetic injection to the subarachnoid space at the L3-L4 or L4-L5 level Drug: bupivacaine Loading dose of bupivacaine followed by 0.12% bupivacaine, 1 ml/h Other name: bupivacaine&#xD;
Device:&#xD;
The Wiley Spinal Catheter-Over-Needle System for Continuous Spinal Anesthesia 4-6&quot; 23-gauge intrathecal cannula over a 27-gauge pencil-point spinal needle</description>
    <arm_group_label>Bupivacaine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - Orthopedic procedures in the lower limbs Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients' refusal Known allergies to study medications Inability to comprehend or&#xD;
             participate in pain scoring scale Anatomic, posttraumatic and postoperative&#xD;
             deformations of the spinal column making placement of intrathecal catheter impossible&#xD;
             Neurological contraindications Any other contraindications for spinal anesthesia&#xD;
             (coagulations disorders, antiplatelet or anticoagulant treatment, infection at the&#xD;
             puncture site.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Marek Wojtaszek, M.D., Ph.D.</last_name>
    <phone>+48-17-872-1195</phone>
    <email>wojtaaszek@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Bogumila Woloszczuk-Gebicka, M.D., Ph.D.</last_name>
    <phone>+48-17-872-1195</phone>
    <email>gebicka@hotmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Rzeszow</name>
      <address>
        <city>Rzeszów</city>
        <zip>35310</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marek Wojtaszek, M.D.</last_name>
      <phone>+48-17-872-1195</phone>
      <email>wojtaaszek@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Bogumila Woloszczuk-Gebicka, M.D., Ph.D.</last_name>
      <phone>+48-17-872-1195</phone>
      <email>gebicka@hotmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <results_reference>
    <citation>Wille M. Intrathecal use of ropivacaine: a review. Acta Anaesthesiol Belg. 2004;55(3):251-9.</citation>
    <PMID>15515303</PMID>
  </results_reference>
  <results_reference>
    <citation>Kuthiala G, Chaudhary G. Ropivacaine: A review of its pharmacology and clinical use. Indian J Anaesth. 2011 Mar;55(2):104-10. doi: 10.4103/0019-5049.79875.</citation>
    <PMID>21712863</PMID>
  </results_reference>
  <results_reference>
    <citation>Sung CM, Hah YS, Kim JS, Nam JB, Kim RJ, Lee SJ, Park HB. Cytotoxic effects of ropivacaine, bupivacaine, and lidocaine on rotator cuff tenofibroblasts. Am J Sports Med. 2014 Dec;42(12):2888-96. doi: 10.1177/0363546514550991. Epub 2014 Oct 8.</citation>
    <PMID>25296645</PMID>
  </results_reference>
  <verification_date>December 2017</verification_date>
  <study_first_submitted>September 21, 2017</study_first_submitted>
  <study_first_submitted_qc>September 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 26, 2017</study_first_posted>
  <last_update_submitted>December 14, 2017</last_update_submitted>
  <last_update_submitted_qc>December 14, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">December 18, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Rzeszow</investigator_affiliation>
    <investigator_full_name>Marek Wojtaszek</investigator_full_name>
    <investigator_title>M.D., Ph.D.</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bupivacaine</mesh_term>
    <mesh_term>Ropivacaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03293472
org study id: URzeszow
nct id: NCT03293472
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Consenting patients, scheduled for orthopaedic surgery under spinal anesthesia will be
      randomly assigned (1:1) to receive ropivacaine or bupivacaine as a single shot before the
      start of surgery, followed by bolus doses of the same local anesthetic as required during the
      surgery, and continuous infusion of the same local anesthetic for 24 hours postoperatively.

      Primary Outcome Measures: Evaluation of changes in concentrations of glutamate in the
      cerebrospinal fluid and in the blood. Secondary outcomes: : Evaluation of changes in
      concentrations of selected mediators of inflammatory response (IL-1β, IL-6, TNF and others)
      and selected chemokines as markers of the glia damage.

      Hemodynamic stability during the surgery, and efficacy of postoperative analgesia will be
      also evaluated.
With the approval from the Bioethical Committee of the University of Rzeszow, informed
      written consent will be obtained from all patients.

      A sample size of 60 patients was calculated to obtain at least 25% reduction of glutamate
      concentration in the cerebrospinal fluid in the ropivacaine group with 0,05 significance and
      power of 0,8.

      Consenting patients, scheduled for orthopaedic surgery under spinal anesthesia will be
      randomly (1:1) assigned using closed envelopes to receive intrathecally ropivacaine or
      bupivacaine as a single shot before the start of surgery, followed by bolus doses of the same
      local anesthetic as required during the surgery, and continuous infusion of the same local
      anesthetic for 24 h for postoperative pain relief. All block will be performed in the sitting
      position, and the drug will be administered in supine position through the catheter in the
      intrathecal space. Blood and cerebrospinal fluid samples will be drawn at predetermined time
      intervals centrifuged as required and frosen in -70deg C until analysis.

      Eligibility Ages eligible for study 18 years and older (Adult, Senior) Sexes Eligible for the
      Study: All Accepts Healthy Volunteers: No

      Inclusion Criteria:

      Orthopedic procedures in the lower limbs Written informed consent Exclusion criteria
      Patients' refusal Known allergies to study medications Anatomic, posttraumatic and
      postoperative deformations of the spinal column making placement of intrathecal catheter
      impossible Neurological contraindications Any other contraindications for spinal anesthesia
      (coagulations disorders, antiplatelet or anticoagulant treatment, infection at the puncture
      site.

      Inability to comprehend or participate in pain scoring scale
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Parallel study
primary purpose: Treatment
masking: Single (Participant)
masking description: Patient unaware of the local anesthetic used.
measure: Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the cerebrospinal fluid of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.
time frame: 24 h
description: Evaluation of changes in concentrations of
• glutamate in the cerebrospinal fluid and in the blood of patients undergoing orthopaedic surgery under spinal anesthesia with either ropivacaine or bupivacaine
measure: Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the cerebrospinal fluid of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.
time frame: 24 h
description: Evaluation of changes in concentrations of selected mediators of inflammatory response (IL-1β, IL-6, tumor necrosis factor and others)
measure: Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the cerebrospinal fluid of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.
time frame: 24 h
description: Evaluation of changes in concentrations of • selected chemokines as markers of the glia damage in the cerebrospinal fluid and in the blood of patients undergoing orthopaedic surgery under continuous spinal anesthesia with either ropivacaine or bupivacaine
measure: Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the CSF of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.
time frame: 24 h
description: Assessment of hemodynamic stability in patients anaesthetized with continuous epidural infusion of ropivacaine and bupivacaine
measure: Inflammatory mediators, neural tissue injury markers and the markers of oxidative stress in the CSF of patients undergoing spinal anesthesia with ropivacaine and bupivacaine.
time frame: 24h
description: Postoperative pain severity in Numerical Rating Scale (NRS) in the first 24 hours after surgery [Time Frame: 24 h] NRS range from 0 for no pain to 10 for worst pain imaginable
arm group label: Ropivacaine
arm group type: Experimental
description: Experimental: 0.5% ropivacaine (isobaric) 4.5 ml for the patients < 160 cm tall, 5.0 ml for 161-170 cm tall, 5.5 ml for 171-180 cm tall, and 6.0 ml > 180 cm.
supplementary bolus doses of ropivacaine as required, followed by 0.2% ropivacaine, 1 ml/h for the postoperative period
arm group label: Bupivacaine
arm group type: Active Comparator
description: 0.5% v Bupivacaine mg (isobaric) loading dose of 0.5% bupivacaine, 3.0 ml for the patients < 160 cm tall, 3.3 ml for 161-170 cm tall, 3.6 ml for 171-180 cm tall, and 4.0 ml > 180 cm.
and supplementary bupivacaine bolus dose as required, followed by 0,12% bupivacaine 1 ml/h for the postoperative period
intervention type: Drug
intervention name: Ropivacaine
description: Procedure: Continuous Epidural Anesthesia Local anesthetic injection to the cerebrospinal fluid (subarachnoid space) at the L3-L4 or L4-L5 level Drug: ropivacaine Other name: Ropimol 0.5% ropivacaine (isobaric) 4.5 ml for the patients < 160 cm tall, 5.0 ml for 161-170 cm tall, 5.5 ml for 171-180 cm tall, and 6.0 ml > 180 cm, supplementary ropivacaine bolus doses as required, followed by 0.2% ropivacaine, 1 ml/h for the postoperative period Device : The Wiley Spinal Catheter-Over-Needle System for Continuous Spinal Anesthesia 4-6" 23-gauge intrathecal cannula over a 27-gauge pencil-point spinal needle
arm group label: Ropivacaine
other name: Ropimol
intervention type: Drug
intervention name: Bupivacaine
description: Procedure: Continuous Epidural Anesthesia Local anesthetic injection to the subarachnoid space at the L3-L4 or L4-L5 level Drug: bupivacaine Loading dose of bupivacaine followed by 0.12% bupivacaine, 1 ml/h Other name: bupivacaine
Device:
The Wiley Spinal Catheter-Over-Needle System for Continuous Spinal Anesthesia 4-6" 23-gauge intrathecal cannula over a 27-gauge pencil-point spinal needle
arm group label: Bupivacaine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marek Wojtaszek, M.D., Ph.D.
phone: +48-17-872-1195
email: wojtaaszek@gmail.com
last name: Bogumila Woloszczuk-Gebicka, M.D., Ph.D.
phone: +48-17-872-1195
email: gebicka@hotmail.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Poland
citation: Wille M. Intrathecal use of ropivacaine: a review. Acta Anaesthesiol Belg. 2004;55(3):251-9.
PMID: 15515303
citation: Kuthiala G, Chaudhary G. Ropivacaine: A review of its pharmacology and clinical use. Indian J Anaesth. 2011 Mar;55(2):104-10. doi: 10.4103/0019-5049.79875.
PMID: 21712863
citation: Sung CM, Hah YS, Kim JS, Nam JB, Kim RJ, Lee SJ, Park HB. Cytotoxic effects of ropivacaine, bupivacaine, and lidocaine on rotator cuff tenofibroblasts. Am J Sports Med. 2014 Dec;42(12):2888-96. doi: 10.1177/0363546514550991. Epub 2014 Oct 8.
PMID: 25296645
responsible party type: Principal Investigator
investigator affiliation: University of Rzeszow
investigator full name: Marek Wojtaszek
investigator title: M.D., Ph.D.
mesh term: Bupivacaine
mesh term: Ropivacaine
sharing ipd: No