<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/NCT03022240</url>
  </required_header>
  <id_info>
    <org_study_id>REB16-0104</org_study_id>
    <nct_id>NCT03022240</nct_id>
  </id_info>
  <brief_title>Neurobiological and Cognitive Changes Following Exposure to Either Sevoflurane- or Propofol-based Anesthesia in Children</brief_title>
  <official_title>Neurobiological, Cognitive-affective and Behavioral Changes Following Exposure to Either Sevoflurane- or Propofol-based Anesthesia in Children Undergoing MRI</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Calgary</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Calgary</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The demand for magnetic resonance imaging (MRI) in pediatric patients is increasing due to&#xD;
      its use in medical diagnosis and surveillance. Pediatric patients often require general&#xD;
      anesthesia (GA) for MRI due to the need for prolonged immobility during the scanning process&#xD;
      to obtain high quality images. Two widely used anesthetic techniques for pediatric MRIs are&#xD;
      volatile-based anesthesia using sevoflurane and total intravenous anesthesia (TIVA) using&#xD;
      propofol. Concerns have been raised regarding the potential neurotoxic effects of anesthetics&#xD;
      on the developing brain. Within the animal literature, there is emerging evidence to suggest&#xD;
      that both sevoflurane and propofol may cause inflammation, impacting brain cell survival and&#xD;
      connections, thereby contributing to possible cognitive dysfunction. However, given the&#xD;
      challenges in extrapolating the animal data to humans, and the relatively limited human&#xD;
      cohort studies examining the long-term effects of anesthesia exposure, there is inadequate&#xD;
      information available to make informed clinical decisions regarding the choice of optimal&#xD;
      anesthetic agents for MRI in children. Therefore, this study will uniquely examine the&#xD;
      mechanisms of two widely used anesthetics and their short and long-term impact on&#xD;
      developmental outcomes in healthy children.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>January 2017</start_date>
  <completion_date type="Actual">September 2019</completion_date>
  <primary_completion_date type="Actual">September 2019</primary_completion_date>
  <phase>Phase 3</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>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV)</measure>
    <time_frame>12-15 weeks from date of randomization</time_frame>
    <description>The WPPSI - IV is designed for children aged 2.5 to 7.5 years, and is used to assess general intelligence.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The Child Behavior Checklist (CBCL) 1.5 to 5 years</measure>
    <time_frame>Change from baseline at 12-13 weeks after randomization</time_frame>
    <description>The CBCL is widely used for identifying problem behaviors in children ages 1.5 to 5 years</description>
  </secondary_outcome>
  <other_outcome>
    <measure>The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)</measure>
    <time_frame>Change from baseline within 1 week after randomization</time_frame>
    <description>The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).</description>
  </other_outcome>
  <other_outcome>
    <measure>The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)</measure>
    <time_frame>Change from baseline within 2-3 weeks after randomization</time_frame>
    <description>The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).</description>
  </other_outcome>
  <other_outcome>
    <measure>The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)</measure>
    <time_frame>Change from baseline within 12-13 weeks after randomization</time_frame>
    <description>The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).</description>
  </other_outcome>
  <other_outcome>
    <measure>The Post Hospital Behavior Questionnaire (PHBQ)</measure>
    <time_frame>Within 1 week after randomization</time_frame>
    <description>The PHBQ asks parents to rate their child's behavior on 27 items concerning sleep, eating, internalizing and externalizing behaviors. For each item parents must compare their child's current behavior with their behavior one week prior to hospitalization.</description>
  </other_outcome>
  <other_outcome>
    <measure>The Post Hospital Behavior Questionnaire (PHBQ)</measure>
    <time_frame>Within 2-3 weeks after randomization</time_frame>
    <description>The PHBQ asks parents to rate their child's behavior on 27 items concerning sleep, eating, internalizing and externalizing behaviors. For each item parents must compare their child's current behavior with their behavior one week prior to hospitalization.</description>
  </other_outcome>
  <other_outcome>
    <measure>The Modified Yale Preoperative Anxiety Scale (mYPAS)</measure>
    <time_frame>On the day of randomization, obtained just prior to the intervention</time_frame>
    <description>The mYPAS is the current &quot;gold standard&quot; for assessing anxiety during induction of anesthesia for children ages 2-16 years.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pediatric Anesthesia Emergence Delirium (PAED) Scale</measure>
    <time_frame>On the day or randomization, obtained immediately after the intervention</time_frame>
    <description>Validated tool to measure emergence delirium in children.</description>
  </other_outcome>
  <other_outcome>
    <measure>Nuclear Magnetic Resonance Spectroscopy (NMRS)</measure>
    <time_frame>On the day of randomization, obtained during the intervention</time_frame>
    <description>Glucose, lactate, choline and NAA values will be obtained from the parietal cortex</description>
  </other_outcome>
  <other_outcome>
    <measure>Resting State Functional Magnetic Resonance Imaging (rfMRI)</measure>
    <time_frame>On the day of randomization, obtained during the intervention</time_frame>
    <description>Resting functional brain networks will be identified and compared between groups</description>
  </other_outcome>
  <other_outcome>
    <measure>Inflammatory Markers</measure>
    <time_frame>On the day of randomization, change from baseline, obtained immediately after the intervention</time_frame>
    <description>Concentrations of plasma IL-1b, TNF-a, IL-6, IL-10 will be quantified</description>
  </other_outcome>
  <other_outcome>
    <measure>Blood metabolites</measure>
    <time_frame>On the day of randomization, change from baseline, obtained immediately after the intervention</time_frame>
    <description>Concentrations of plasma proteins, peptides and metabolites will be quantified</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Cognitive Change</condition>
  <condition>Behavior</condition>
  <arm_group>
    <arm_group_label>Inhalational Technique</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to induction. After inhalation induction of anesthesia with sevoflurane (in 100% O2), an IV will be obtained. Anesthesia will be maintained with sevoflurane (in a mixture of air:oxygen) with a minimum alveolar concentration of 1.0-1.3, titrated to effect. No long acting opioids or nitrous oxide will be used. Airway management will be at the discretion of the anesthesiologist. Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Total Intravenous Anesthetic Technique</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to IV insertion. Once an IV is established, patients will receive an IV bolus of propofol (2-6mg/kg). Anesthesia will be maintained with a propofol infusion starting at 250 mcg/kg/min and titrated to effect. Airway management will be at the discretion of the anesthesiologist. Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propofol</intervention_name>
    <description>The child will be randomized via a block design to receive either a volatile anesthetic (induction: sevoflurane), or total intravenous anesthetic technique (induction: propofol)</description>
    <arm_group_label>Total Intravenous Anesthetic Technique</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sevoflurane</intervention_name>
    <description>The child will be randomized via a block design to receive either a volatile anesthetic (induction: sevoflurane), or total intravenous anesthetic technique (induction: propofol)</description>
    <arm_group_label>Inhalational Technique</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ametop</intervention_name>
    <description>Each patient will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to induction.</description>
    <arm_group_label>Inhalational Technique</arm_group_label>
    <arm_group_label>Total Intravenous Anesthetic Technique</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ondansetron</intervention_name>
    <description>Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.</description>
    <arm_group_label>Inhalational Technique</arm_group_label>
    <arm_group_label>Total Intravenous Anesthetic Technique</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Those between the ages 2 to 5 years who require general anesthesia for MRI Brain and have&#xD;
        an American Society of Anesthesiologists' physical status of I to II&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Emergency cases&#xD;
&#xD;
          -  Intubated prior to MRI&#xD;
&#xD;
          -  Allergies/contraindication to anesthetics&#xD;
&#xD;
          -  Requirement of a painful procedure with MRI&#xD;
&#xD;
          -  Significant developmental delay&#xD;
&#xD;
          -  Autism or suspected autism&#xD;
&#xD;
          -  History of extreme prematurity &lt;28 wks gestational age&#xD;
&#xD;
          -  Sedation or general anesthesia in the last 14 days&#xD;
&#xD;
          -  Receiving chemotherapy or radiation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>5 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tiffany Rice, PhD, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Calgary</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Calgary</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T2N 1N4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>March 24, 2020</last_update_submitted>
  <last_update_submitted_qc>March 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ondansetron</mesh_term>
    <mesh_term>Propofol</mesh_term>
    <mesh_term>Sevoflurane</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03022240
org study id: REB16-0104
nct id: NCT03022240
lead sponsor: 
has dmc: Yes
The demand for magnetic resonance imaging (MRI) in pediatric patients is increasing due to
      its use in medical diagnosis and surveillance. Pediatric patients often require general
      anesthesia (GA) for MRI due to the need for prolonged immobility during the scanning process
      to obtain high quality images. Two widely used anesthetic techniques for pediatric MRIs are
      volatile-based anesthesia using sevoflurane and total intravenous anesthesia (TIVA) using
      propofol. Concerns have been raised regarding the potential neurotoxic effects of anesthetics
      on the developing brain. Within the animal literature, there is emerging evidence to suggest
      that both sevoflurane and propofol may cause inflammation, impacting brain cell survival and
      connections, thereby contributing to possible cognitive dysfunction. However, given the
      challenges in extrapolating the animal data to humans, and the relatively limited human
      cohort studies examining the long-term effects of anesthesia exposure, there is inadequate
      information available to make informed clinical decisions regarding the choice of optimal
      anesthetic agents for MRI in children. Therefore, this study will uniquely examine the
      mechanisms of two widely used anesthetics and their short and long-term impact on
      developmental outcomes in healthy children.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: None (Open Label)
measure: Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV)
time frame: 12-15 weeks from date of randomization
description: The WPPSI - IV is designed for children aged 2.5 to 7.5 years, and is used to assess general intelligence.
measure: The Child Behavior Checklist (CBCL) 1.5 to 5 years
time frame: Change from baseline at 12-13 weeks after randomization
description: The CBCL is widely used for identifying problem behaviors in children ages 1.5 to 5 years
measure: The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)
time frame: Change from baseline within 1 week after randomization
description: The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).
measure: The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)
time frame: Change from baseline within 2-3 weeks after randomization
description: The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).
measure: The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)
time frame: Change from baseline within 12-13 weeks after randomization
description: The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).
measure: The Post Hospital Behavior Questionnaire (PHBQ)
time frame: Within 1 week after randomization
description: The PHBQ asks parents to rate their child's behavior on 27 items concerning sleep, eating, internalizing and externalizing behaviors. For each item parents must compare their child's current behavior with their behavior one week prior to hospitalization.
measure: The Post Hospital Behavior Questionnaire (PHBQ)
time frame: Within 2-3 weeks after randomization
description: The PHBQ asks parents to rate their child's behavior on 27 items concerning sleep, eating, internalizing and externalizing behaviors. For each item parents must compare their child's current behavior with their behavior one week prior to hospitalization.
measure: The Modified Yale Preoperative Anxiety Scale (mYPAS)
time frame: On the day of randomization, obtained just prior to the intervention
description: The mYPAS is the current "gold standard" for assessing anxiety during induction of anesthesia for children ages 2-16 years.
measure: Pediatric Anesthesia Emergence Delirium (PAED) Scale
time frame: On the day or randomization, obtained immediately after the intervention
description: Validated tool to measure emergence delirium in children.
measure: Nuclear Magnetic Resonance Spectroscopy (NMRS)
time frame: On the day of randomization, obtained during the intervention
description: Glucose, lactate, choline and NAA values will be obtained from the parietal cortex
measure: Resting State Functional Magnetic Resonance Imaging (rfMRI)
time frame: On the day of randomization, obtained during the intervention
description: Resting functional brain networks will be identified and compared between groups
measure: Inflammatory Markers
time frame: On the day of randomization, change from baseline, obtained immediately after the intervention
description: Concentrations of plasma IL-1b, TNF-a, IL-6, IL-10 will be quantified
measure: Blood metabolites
time frame: On the day of randomization, change from baseline, obtained immediately after the intervention
description: Concentrations of plasma proteins, peptides and metabolites will be quantified
arm group label: Inhalational Technique
arm group type: Experimental
description: All patients will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to induction. After inhalation induction of anesthesia with sevoflurane (in 100% O2), an IV will be obtained. Anesthesia will be maintained with sevoflurane (in a mixture of air:oxygen) with a minimum alveolar concentration of 1.0-1.3, titrated to effect. No long acting opioids or nitrous oxide will be used. Airway management will be at the discretion of the anesthesiologist. Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.
arm group label: Total Intravenous Anesthetic Technique
arm group type: Experimental
description: All patients will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to IV insertion. Once an IV is established, patients will receive an IV bolus of propofol (2-6mg/kg). Anesthesia will be maintained with a propofol infusion starting at 250 mcg/kg/min and titrated to effect. Airway management will be at the discretion of the anesthesiologist. Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.
intervention type: Drug
intervention name: Propofol
description: The child will be randomized via a block design to receive either a volatile anesthetic (induction: sevoflurane), or total intravenous anesthetic technique (induction: propofol)
arm group label: Total Intravenous Anesthetic Technique
intervention type: Drug
intervention name: Sevoflurane
description: The child will be randomized via a block design to receive either a volatile anesthetic (induction: sevoflurane), or total intravenous anesthetic technique (induction: propofol)
arm group label: Inhalational Technique
intervention type: Drug
intervention name: Ametop
description: Each patient will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to induction.
arm group label: Inhalational Technique
arm group label: Total Intravenous Anesthetic Technique
intervention type: Drug
intervention name: Ondansetron
description: Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.
arm group label: Inhalational Technique
arm group label: Total Intravenous Anesthetic Technique
criteria: 
gender: All
minimum age: 2 Years
maximum age: 5 Years
healthy volunteers: No
last name: Tiffany Rice, PhD, MD
role: Principal Investigator
affiliation: University of Calgary
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Ondansetron
mesh term: Propofol
mesh term: Sevoflurane
sharing ipd: Undecided