<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/NCT03248908</url>
  </required_header>
  <id_info>
    <org_study_id>17/28/319</org_study_id>
    <nct_id>NCT03248908</nct_id>
  </id_info>
  <brief_title>Pupillary Dilation Reflex Assessment for Intraoperative Analgesic Titration.</brief_title>
  <acronym>PUP-AIT</acronym>
  <official_title>Pupillary Dilation Reflex Assessment for Intraoperative Analgesic Titration [PUP-AIT]. A Double Blinded Randomized Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Antwerp</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Universiteit Antwerpen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Antwerp</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this double blinded randomized controlled study, the pupillary dilation reflex is used for&#xD;
      as a nociceptive indicator for opioid administration during elective surgery under general&#xD;
      anesthesia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      An infrared camera of the video pupillometer measures the pupillary dilation reflex (PDR) in&#xD;
      response of a nociceptive stimulus. This autonomic reflex, parasympathetic mediated in&#xD;
      sedated patients, can be generated by various pain stimuli (built in standardized protocol,&#xD;
      surgical incision, …) The PDR is a robust reflex, even in patients under general anesthesia,&#xD;
      and provides a potential evaluation of the autonomous circuit within the nociceptive&#xD;
      evaluation based on pupil dilation upon A-delta and C fibers in both electrical or mechanic&#xD;
      stimulation. This double blind randomized controlled trial involving American Society of&#xD;
      Anesthesiologists (ASA) classification I-III patients undergoing elective surgery under&#xD;
      general anesthesia are recruited. Enrolled patients are randomized in four groups: (1)&#xD;
      remifentanil administration depending on PDR results, (2) remifentanil administration&#xD;
      depending on decision attending anesthesiologist, (3) sufentanil administration depending on&#xD;
      PDR results, (4) sufentanil administration depending on decision attending anesthesiologist.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 12, 2017</start_date>
  <completion_date type="Actual">January 31, 2022</completion_date>
  <primary_completion_date type="Actual">September 6, 2021</primary_completion_date>
  <phase>N/A</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>Double blinded randomized controlled trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
    <masking_description>The patient, the performer of the pupillary reflex measurement, and the postoperative health care provider are masked for the study arms.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Postoperative pain</measure>
    <time_frame>From patient extubation until postoperative day 5</time_frame>
    <description>Numeric rating scale (NRS) pain assessment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Postoperative analgesia</measure>
    <time_frame>From patient extubation until postoperative day 5</time_frame>
    <description>Analgetic consumption</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Stimulation intensity to elicit PDR</measure>
    <time_frame>From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours</time_frame>
    <description>Necessary stimulation intensity generated by the pupillometer to elicit a PDR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline pupil diameter</measure>
    <time_frame>From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours</time_frame>
    <description>Pupil size before stimulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pupillary dilation reflex amplitude</measure>
    <time_frame>From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours</time_frame>
    <description>The amplitude of the pupil enlargement after nociceptive stimulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pupillary pain index (PPI)</measure>
    <time_frame>From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours</time_frame>
    <description>Generated PPI score by the pupillometer in accordance to given stimulation and pupillary dilation reflex amplitude</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Opioid usage during surgery</measure>
    <time_frame>From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours</time_frame>
    <description>Total dose remifentanil or sufentanil administrated during surgery, in microgram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Extubation time</measure>
    <time_frame>From the day of surgery at the termination of propofol infusion until patient extubation, assessed up to 2 hours</time_frame>
    <description>The time between stop of propofol administration and patient extubation, in minutes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative nausea and vomiting</measure>
    <time_frame>From patient extubation until postoperative day 5</time_frame>
    <description>Frequency of nausea or vomiting after surgery, in numbers of events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay at the postanesthesia care unit</measure>
    <time_frame>From admission at the postanesthesia care unit until discharge to the nursing ward, assessed up to 24 hours</time_frame>
    <description>Hours of admission at the postanesthesia care unit after surgery until discharge to the nursing ward, in minutes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay</measure>
    <time_frame>From the day of the planned surgery until hospital discharge, assessed up to 5 days</time_frame>
    <description>Length of hospital stay, in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative health status</measure>
    <time_frame>From extubation until 1 month after surgery</time_frame>
    <description>Assessed by 5-level EQ-5D version (EQ-5D-5L), quality of life and health status questionnaire</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Pain, Acute</condition>
  <condition>Anesthesia</condition>
  <arm_group>
    <arm_group_label>Intervention 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pupillary dilation reflex based perioperative intravenous remifentanil administration. Starting dose 5 ng/ml by continous infusion, dosage adjustments are made after pupillary dilation reflex assessment every 10 minutes. When PPI score is 1, the dosage is decreased with 0.2 ng/ml. When PPI score is greater than 1, the dosage is increased with 0.2 ng/ml.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intervention 2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Anesthesiologist based perioperative intravenous remifentanil administration (daily practice, standard of care). Starting dose 5 ng/ml, dosage adjustments are made when deemed necessary by attending anesthesiologist.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intervention 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pupillary dilation reflex based perioperative intravenous sufentanil administration. Starting dose 0.1 mcg/kg bolus, dosage adjustments are made after pupillary dilation reflex assessment every 10 minutes. When PPI score is 1, no supplementary administration is executed. When PPI score is greater than 1, a supplementary bolus of 0.1 mcg/kg is given.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intervention 4</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Anesthesiologist based perioperative intravenous sufentanil administration (daily practice, standard of care). Starting dose 0.1 mcg/kg bolus, dosage adjustments are made when deemed necessary by attending anesthesiologist.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Pupillary dilation reflex</intervention_name>
    <description>Perioperative pupillary dilation reflex assessment is executed every 10 minutes from start sedation until extubation in patients allocated to study arm Intervention 1 and Intervention 3</description>
    <arm_group_label>Intervention 1</arm_group_label>
    <arm_group_label>Intervention 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of care</intervention_name>
    <description>Perioperative opioid administration based on the attending anesthesiologist decision (mainly including assessment of heart rate, blood pressure, and limb movement)</description>
    <arm_group_label>Intervention 2</arm_group_label>
    <arm_group_label>Intervention 4</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  &gt; 18 jaar&#xD;
&#xD;
          -  Elective abdominal or gynaecological operation&#xD;
&#xD;
          -  ASA (American Society of Anesthesiologists classification): I - II - III&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of invasive ophthalmological surgery&#xD;
&#xD;
          -  Known bilateral eye disease&#xD;
&#xD;
          -  Known optical of oculomotor nerve deficit&#xD;
&#xD;
          -  Active psychiatrical disease&#xD;
&#xD;
          -  Proven active pheochromocytoma&#xD;
&#xD;
          -  Opioid usage &gt; 7 days preoperative&#xD;
&#xD;
          -  Ongoing oncological treatment with chemotherapeutic agents&#xD;
&#xD;
          -  Usage of A-1 adrenergic of beta-blocking agents&#xD;
&#xD;
          -  Preoperative usage of benzodiazepines&#xD;
&#xD;
          -  Topical atropine or phenylephrine (eye droplets)&#xD;
&#xD;
          -  Planned perioperative usage of dopamine antagonists&#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_official>
    <last_name>Davina Wildemeersch, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Antwerp</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University hospital Antwerp</name>
      <address>
        <city>Edegem</city>
        <state>Antwerp</state>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 15, 2017</study_first_posted>
  <last_update_submitted>May 12, 2023</last_update_submitted>
  <last_update_submitted_qc>May 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Antwerp</investigator_affiliation>
    <investigator_full_name>Davina Wildemeersch</investigator_full_name>
    <investigator_title>Principle investigator</investigator_title>
  </responsible_party>
  <keyword>pupillary reflex</keyword>
  <keyword>nociception</keyword>
  <keyword>heart rate</keyword>
  <keyword>intraoperative monitoring</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mydriasis</mesh_term>
    <mesh_term>Acute Pain</mesh_term>
  </condition_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/NCT03248908
org study id: 17/28/319
nct id: NCT03248908
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
In this double blinded randomized controlled study, the pupillary dilation reflex is used for
      as a nociceptive indicator for opioid administration during elective surgery under general
      anesthesia.
An infrared camera of the video pupillometer measures the pupillary dilation reflex (PDR) in
      response of a nociceptive stimulus. This autonomic reflex, parasympathetic mediated in
      sedated patients, can be generated by various pain stimuli (built in standardized protocol,
      surgical incision, …) The PDR is a robust reflex, even in patients under general anesthesia,
      and provides a potential evaluation of the autonomous circuit within the nociceptive
      evaluation based on pupil dilation upon A-delta and C fibers in both electrical or mechanic
      stimulation. This double blind randomized controlled trial involving American Society of
      Anesthesiologists (ASA) classification I-III patients undergoing elective surgery under
      general anesthesia are recruited. Enrolled patients are randomized in four groups: (1)
      remifentanil administration depending on PDR results, (2) remifentanil administration
      depending on decision attending anesthesiologist, (3) sufentanil administration depending on
      PDR results, (4) sufentanil administration depending on decision attending anesthesiologist.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Double blinded randomized controlled trial
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Outcomes Assessor)
masking description: The patient, the performer of the pupillary reflex measurement, and the postoperative health care provider are masked for the study arms.
measure: Postoperative pain
time frame: From patient extubation until postoperative day 5
description: Numeric rating scale (NRS) pain assessment
measure: Postoperative analgesia
time frame: From patient extubation until postoperative day 5
description: Analgetic consumption
measure: Stimulation intensity to elicit PDR
time frame: From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours
description: Necessary stimulation intensity generated by the pupillometer to elicit a PDR
measure: Baseline pupil diameter
time frame: From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours
description: Pupil size before stimulation
measure: Pupillary dilation reflex amplitude
time frame: From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours
description: The amplitude of the pupil enlargement after nociceptive stimulation
measure: Pupillary pain index (PPI)
time frame: From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours
description: Generated PPI score by the pupillometer in accordance to given stimulation and pupillary dilation reflex amplitude
measure: Opioid usage during surgery
time frame: From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours
description: Total dose remifentanil or sufentanil administrated during surgery, in microgram
measure: Extubation time
time frame: From the day of surgery at the termination of propofol infusion until patient extubation, assessed up to 2 hours
description: The time between stop of propofol administration and patient extubation, in minutes
measure: Postoperative nausea and vomiting
time frame: From patient extubation until postoperative day 5
description: Frequency of nausea or vomiting after surgery, in numbers of events
measure: Length of stay at the postanesthesia care unit
time frame: From admission at the postanesthesia care unit until discharge to the nursing ward, assessed up to 24 hours
description: Hours of admission at the postanesthesia care unit after surgery until discharge to the nursing ward, in minutes
measure: Length of hospital stay
time frame: From the day of the planned surgery until hospital discharge, assessed up to 5 days
description: Length of hospital stay, in days
measure: Postoperative health status
time frame: From extubation until 1 month after surgery
description: Assessed by 5-level EQ-5D version (EQ-5D-5L), quality of life and health status questionnaire
arm group label: Intervention 1
arm group type: Experimental
description: Pupillary dilation reflex based perioperative intravenous remifentanil administration. Starting dose 5 ng/ml by continous infusion, dosage adjustments are made after pupillary dilation reflex assessment every 10 minutes. When PPI score is 1, the dosage is decreased with 0.2 ng/ml. When PPI score is greater than 1, the dosage is increased with 0.2 ng/ml.
arm group label: Intervention 2
arm group type: Active Comparator
description: Anesthesiologist based perioperative intravenous remifentanil administration (daily practice, standard of care). Starting dose 5 ng/ml, dosage adjustments are made when deemed necessary by attending anesthesiologist.
arm group label: Intervention 3
arm group type: Experimental
description: Pupillary dilation reflex based perioperative intravenous sufentanil administration. Starting dose 0.1 mcg/kg bolus, dosage adjustments are made after pupillary dilation reflex assessment every 10 minutes. When PPI score is 1, no supplementary administration is executed. When PPI score is greater than 1, a supplementary bolus of 0.1 mcg/kg is given.
arm group label: Intervention 4
arm group type: Active Comparator
description: Anesthesiologist based perioperative intravenous sufentanil administration (daily practice, standard of care). Starting dose 0.1 mcg/kg bolus, dosage adjustments are made when deemed necessary by attending anesthesiologist.
intervention type: Diagnostic Test
intervention name: Pupillary dilation reflex
description: Perioperative pupillary dilation reflex assessment is executed every 10 minutes from start sedation until extubation in patients allocated to study arm Intervention 1 and Intervention 3
arm group label: Intervention 1
arm group label: Intervention 3
intervention type: Other
intervention name: Standard of care
description: Perioperative opioid administration based on the attending anesthesiologist decision (mainly including assessment of heart rate, blood pressure, and limb movement)
arm group label: Intervention 2
arm group label: Intervention 4
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Davina Wildemeersch, MD
role: Principal Investigator
affiliation: University Hospital, Antwerp
facility: 
country: Belgium
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Antwerp
investigator full name: Davina Wildemeersch
investigator title: Principle investigator
mesh term: Mydriasis
mesh term: Acute Pain
sharing ipd: Undecided