<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/NCT01712477</url>
  </required_header>
  <id_info>
    <org_study_id>r039226</org_study_id>
    <secondary_id>IRRC#1201M</secondary_id>
    <nct_id>NCT01712477</nct_id>
  </id_info>
  <brief_title>A Comparison of Propofol Versus Midazolam to Sedate Critically Brain Injury; Measurement of Cytokine Response and Assessment of Function</brief_title>
  <official_title>Propofol Versus Midazolam for Sedation in Mechanically Ventilated Critically Ill Patients Who Presented With Traumatic Brain Injury: Cytokine Response and Neuropsychological Assessment (IRRC#1201M)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Michigan State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Michigan State University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective randomized controlled pilot study in traumatic brain injury (TBI)&#xD;
      patients who are sedated with either propofol or midazolam to compare the cytokine response&#xD;
      and neuropsychological outcomes with and without elevated blood alcohol levels.&#xD;
&#xD;
      Sedation is part of the standard treatment in patients with a TBI and has been proposed as a&#xD;
      neuroprotective intervention in head-injured patients. Sedative regimens, such as midazolam&#xD;
      and propofol, are not standardized and it is unclear whether sedation has a significant&#xD;
      impact on recovery and outcome. A review of propofol versus midazolam in mechanically&#xD;
      ventilated patients shows evidence that both provide effective sedation but there is lack of&#xD;
      data to support one sedative over the other.&#xD;
&#xD;
      Cytokines are released in response to tissue injury and act to generate a variety of&#xD;
      physiologic responses. The cytokine elevation has been correlated with the extent of tissue&#xD;
      injury. This study will compare the cytokine distribution patterns at specific posttraumatic&#xD;
      time points in patients with a TBI sedated with either propofol or midazolam. Additional&#xD;
      analysis will compare the cytokine response in patients whom had elevated blood alcohol&#xD;
      levels with those with normal levels. Neuropsychological testing will also be performed to&#xD;
      determine the extent of brain injury and recovery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this research is to compare the effectiveness, length of time from cessation&#xD;
      of sedation till extubation, recovery time, duration of admission to the ICU, recovery of&#xD;
      brain function, cytokine response, and complication rate of propofol versus midazolam when&#xD;
      used for sedation in patients with traumatic brain injury (TBI) with or without elevated&#xD;
      blood alcohol levels. Since this type of trauma patient will require significant medical care&#xD;
      upon admission to the emergency room (ER) and the family will be concerned about the&#xD;
      injuries, the patient and/or family will not be approached about the research study during&#xD;
      this time. At the earliest possible time following neurointensive (NICU) or intensive care&#xD;
      (ICU) admission, an informed consent will be obtained from the patient. Depending on the&#xD;
      severity of the head injury, the patients may not be able to sign an informed consent. In&#xD;
      this case, the consent will be obtained from next-of-kin or a legal guardian. No&#xD;
      interventions or study research will be conducted on the patient until the consent is&#xD;
      obtained.&#xD;
&#xD;
      Standard blood panels are drawn for every trauma patient regardless of whether or not the&#xD;
      patient is a participant of the research protocol, including blood alcohol levels. During the&#xD;
      trauma workup in ER, it is standard of care to draw an extra vial in case additional lab&#xD;
      tests are needed. After consent is obtained, the research team will obtain the extra vial&#xD;
      from the Sparrow Lab to perform cytokine and blood cell phenotype measurements for the&#xD;
      research study. Typically 0.5-1.0 ml of whole blood is needed for these measurements and that&#xD;
      can be taken from the standardized EDTA tube that is drawn on admission. This small amount of&#xD;
      blood sample would otherwise be discarded. Plasma cytokines and cell phenobype IL-1, IL-3,&#xD;
      IL-6, IL-8, IL-10, IL-17, TNF-¦Á, TGF-¦Â, G-CSF, GM-CSF, SCF, FGF, and IGF-II will be&#xD;
      performed by Luminex-based mutiplex assay and ELISA. In addition to the ER analysis, left&#xD;
      over blood will be used from the EDTA tubes at 24 hours, day 3 and day 7 after admission.&#xD;
      These additional measurements will be taken from the routine morning laboratory blood draws&#xD;
      which are done on all intubated patients to evaluate electrolytes. No additional blood will&#xD;
      be drawn for the research and the study will only be using left over blood already drawn for&#xD;
      standard of care labs that are done on all intubated patients.&#xD;
&#xD;
      Once consented, the patients will be randomized to treatment group by random allocation&#xD;
      process using Research Randomizer (Urbaniak, G. C., &amp; Plous, S. Version 3.0 Computer&#xD;
      software]. The patient and family will be blinded to which sedation is given. Nurses and&#xD;
      physicians will not be blinded as they will be administering the sedatives. Although the&#xD;
      patients will receive randomized sedation, these patients would be administered either&#xD;
      propofol or midazolam even if they were not included in this research. The only modification&#xD;
      for research purposes is the randomization of sedation medication by the randomizer rather&#xD;
      than the physician. Currently, the providers in the research team do not have a preference of&#xD;
      one type of sedation medication over the other.&#xD;
&#xD;
      Once randomized, patients allocated to the propofol group will be initiated with a 0.5-1&#xD;
      mg/kg i.v. bolus followed by repeated 10-20 mg doses at variable intervals (approximately 15&#xD;
      s, at the discretion of the physician/nurse) until an appropriate level of sedation will be&#xD;
      achieved (NICU protocol), which will be subsequently titrated to achieve a target Richmond&#xD;
      Agitation-Sedation Scale (+4 = combative to -5 = unarousable) (Sessler et al. The Richmond&#xD;
      Agitation-Sedation Scale.Am J Respir Crit Care Med 2002; 166:1338-1344). Nurses will note&#xD;
      pre-sedation levels based on the Richmond Agitation-Sedation Scale. While undergoing&#xD;
      sedation, target sedation will be defined when the Richmond Agitation-Sedation Scale meets a&#xD;
      score of -4 to -5. Patients randomized to the midazolam group will be initiated with 0.5-1.0&#xD;
      mg with incremental dosing at intervals of approximately 1-3 min until a level of sedation&#xD;
      will be achieved at a target Richmond Agitation-Sedation scale sedation score (per NICU&#xD;
      protocol).&#xD;
&#xD;
      Management of all trauma patients include a careful history taking for alcoholism with&#xD;
      referral for further evaluation or treatment when indicated, and determination whether other&#xD;
      drugs are also being used. All patients with an elevated alcohol level require a medical&#xD;
      social service consultation and all patients with a TBI require a neuropsychology&#xD;
      consultation, both consultations are standard of care. The neuropsychological testing&#xD;
      conducted after extubation is also standard of care. The neuropsychological evaluations will&#xD;
      be measured based on the following assessments: intellectual functioning, language&#xD;
      processing, visuospatial processing, attention, concentration, verbal learning, memory,&#xD;
      executive functioning, sensory, perception, motor, strength, and personal assessment. The&#xD;
      level of impairment will be based on a scale from zero to seven. Data will be collected until&#xD;
      the patient is discharged from the hospital. The clinical records from the neuropsychologist&#xD;
      will be reviewed to analyze the progression of the patient's outcome. Similar to all trauma&#xD;
      patients, the patients enrolled in this study will be offered continued care with&#xD;
      neuropsychology as well as the option to withdrawal all care if competent to make independent&#xD;
      decisions.&#xD;
&#xD;
      Throughout the study consciousness will be measured using the Glasgow Coma Score (GCS) from&#xD;
      the time of presentation to the ER and two times each day until the patient is discharged&#xD;
      from the NICU or ICU (routinely done on TBI patients). The Injury severity scores (ISS) will&#xD;
      be recorded from admission (done on all trauma patients). Recovery of consciousness will be&#xD;
      determined by measurement of the acute physiology and chronic health evaluation (APACHE) III&#xD;
      modification of the Glasgow coma score to allow for scoring of the verbal component in&#xD;
      intubated patients. Patients will be judged to be awake when the Glasgow coma score was &gt; or&#xD;
      = 12.&#xD;
&#xD;
      The following will be recorded from the Sparrow medical record for each patient: gender, age,&#xD;
      sex, weight, primary diagnosis, significant co morbidities, blood alcohol level at admission,&#xD;
      intracranial pressure measurements (standard of care for TBI patients), time of starting and&#xD;
      finishing of the sedation, total amount of medications given, any restraint required,&#xD;
      additional oxygen required, resuscitative measures required, time of transfer out of the&#xD;
      unit, and time of discharge.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Difficulty in recruiting&#xD;
  </why_stopped>
  <start_date>November 2011</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">November 2014</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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Neuropsychgologic outcome</measure>
    <time_frame>30 days</time_frame>
    <description>Extent of functional deficits from underlying traumatic brain injury</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>cytokine levels correlating to extent of injury</measure>
    <time_frame>30 days</time_frame>
    <description>cytokine levels will be measured to see if there is meaningful correlation between groups</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Intravenous sedation with propofol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Traumatic brain injured patient, already requiring sedation. Intervention is sedation with intravenous propofol during mechanical ventilation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intravenous sedation with midazolam</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with traumatic brain injury requiring mechinical ventilation. Intervention is intravenous midazolam for sedation at variable doses to achieve adequite sedation levels</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intravenous sedation using propofol</intervention_name>
    <description>Patients will be given intravenous sedation for treatment of traumatic brain injury requiring mechanical ventilation</description>
    <arm_group_label>Intravenous sedation with propofol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intravenous sedation with midazolam</intervention_name>
    <description>patients with severe traumatic brain injury requiring mechanical ventilation and sedation will be sedated with midazolam</description>
    <arm_group_label>Intravenous sedation with midazolam</arm_group_label>
    <other_name>Versed</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ages 18 Years or older&#xD;
&#xD;
          -  Males or Females&#xD;
&#xD;
          -  Primary diagnosis of TBI, subarachnoid hemmorhage (SAH), intracranial hemmorhage&#xD;
             (ICH), stroke&#xD;
&#xD;
          -  Requires mechanical ventilation&#xD;
&#xD;
          -  Requires or is receiving continuous IV sedation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Glascow Coma Score (GCS) of 3 persisting from the scene with bilaterally fixed dilated&#xD;
             pupils with no appreciable chance of survival&#xD;
&#xD;
          -  The inability to identify a next of kin or guardian to give consent if patient unable&#xD;
             to consent&#xD;
&#xD;
          -  Pregnant&#xD;
&#xD;
          -  Allergy or contraindication to propofol&#xD;
&#xD;
          -  Allergy to contraindication to midalozam&#xD;
&#xD;
          -  Status epilepticus&#xD;
&#xD;
          -  Current neuromuscular blockade&#xD;
&#xD;
          -  Patient with a known hypersensitivity to propofol or midalozam&#xD;
&#xD;
          -  Allergies to eggs, egg products, soybeans or soy products&#xD;
&#xD;
          -  Acute narrow-angle glaucoma&#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>Chet A Morrison, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Michigan State University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sparrow Health System</name>
      <address>
        <city>Lansing</city>
        <state>Michigan</state>
        <zip>48912</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>October 19, 2012</study_first_submitted>
  <study_first_submitted_qc>October 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 23, 2012</study_first_posted>
  <last_update_submitted>May 22, 2018</last_update_submitted>
  <last_update_submitted_qc>May 22, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 24, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Michigan State University</investigator_affiliation>
    <investigator_full_name>Chet Morrison</investigator_full_name>
    <investigator_title>Assistant Professor of Surgery</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Propofol</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>September 10, 2020</submitted>
    <returned>October 1, 2020</returned>
  </pending_results>
  <!-- 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/NCT01712477
org study id: r039226
secondary id: IRRC#1201M
nct id: NCT01712477
lead sponsor: 
has dmc: No
This is a prospective randomized controlled pilot study in traumatic brain injury (TBI)
      patients who are sedated with either propofol or midazolam to compare the cytokine response
      and neuropsychological outcomes with and without elevated blood alcohol levels.

      Sedation is part of the standard treatment in patients with a TBI and has been proposed as a
      neuroprotective intervention in head-injured patients. Sedative regimens, such as midazolam
      and propofol, are not standardized and it is unclear whether sedation has a significant
      impact on recovery and outcome. A review of propofol versus midazolam in mechanically
      ventilated patients shows evidence that both provide effective sedation but there is lack of
      data to support one sedative over the other.

      Cytokines are released in response to tissue injury and act to generate a variety of
      physiologic responses. The cytokine elevation has been correlated with the extent of tissue
      injury. This study will compare the cytokine distribution patterns at specific posttraumatic
      time points in patients with a TBI sedated with either propofol or midazolam. Additional
      analysis will compare the cytokine response in patients whom had elevated blood alcohol
      levels with those with normal levels. Neuropsychological testing will also be performed to
      determine the extent of brain injury and recovery.
The purpose of this research is to compare the effectiveness, length of time from cessation
      of sedation till extubation, recovery time, duration of admission to the ICU, recovery of
      brain function, cytokine response, and complication rate of propofol versus midazolam when
      used for sedation in patients with traumatic brain injury (TBI) with or without elevated
      blood alcohol levels. Since this type of trauma patient will require significant medical care
      upon admission to the emergency room (ER) and the family will be concerned about the
      injuries, the patient and/or family will not be approached about the research study during
      this time. At the earliest possible time following neurointensive (NICU) or intensive care
      (ICU) admission, an informed consent will be obtained from the patient. Depending on the
      severity of the head injury, the patients may not be able to sign an informed consent. In
      this case, the consent will be obtained from next-of-kin or a legal guardian. No
      interventions or study research will be conducted on the patient until the consent is
      obtained.

      Standard blood panels are drawn for every trauma patient regardless of whether or not the
      patient is a participant of the research protocol, including blood alcohol levels. During the
      trauma workup in ER, it is standard of care to draw an extra vial in case additional lab
      tests are needed. After consent is obtained, the research team will obtain the extra vial
      from the Sparrow Lab to perform cytokine and blood cell phenotype measurements for the
      research study. Typically 0.5-1.0 ml of whole blood is needed for these measurements and that
      can be taken from the standardized EDTA tube that is drawn on admission. This small amount of
      blood sample would otherwise be discarded. Plasma cytokines and cell phenobype IL-1, IL-3,
      IL-6, IL-8, IL-10, IL-17, TNF-¦Á, TGF-¦Â, G-CSF, GM-CSF, SCF, FGF, and IGF-II will be
      performed by Luminex-based mutiplex assay and ELISA. In addition to the ER analysis, left
      over blood will be used from the EDTA tubes at 24 hours, day 3 and day 7 after admission.
      These additional measurements will be taken from the routine morning laboratory blood draws
      which are done on all intubated patients to evaluate electrolytes. No additional blood will
      be drawn for the research and the study will only be using left over blood already drawn for
      standard of care labs that are done on all intubated patients.

      Once consented, the patients will be randomized to treatment group by random allocation
      process using Research Randomizer (Urbaniak, G. C., & Plous, S. Version 3.0 Computer
      software]. The patient and family will be blinded to which sedation is given. Nurses and
      physicians will not be blinded as they will be administering the sedatives. Although the
      patients will receive randomized sedation, these patients would be administered either
      propofol or midazolam even if they were not included in this research. The only modification
      for research purposes is the randomization of sedation medication by the randomizer rather
      than the physician. Currently, the providers in the research team do not have a preference of
      one type of sedation medication over the other.

      Once randomized, patients allocated to the propofol group will be initiated with a 0.5-1
      mg/kg i.v. bolus followed by repeated 10-20 mg doses at variable intervals (approximately 15
      s, at the discretion of the physician/nurse) until an appropriate level of sedation will be
      achieved (NICU protocol), which will be subsequently titrated to achieve a target Richmond
      Agitation-Sedation Scale (+4 = combative to -5 = unarousable) (Sessler et al. The Richmond
      Agitation-Sedation Scale.Am J Respir Crit Care Med 2002; 166:1338-1344). Nurses will note
      pre-sedation levels based on the Richmond Agitation-Sedation Scale. While undergoing
      sedation, target sedation will be defined when the Richmond Agitation-Sedation Scale meets a
      score of -4 to -5. Patients randomized to the midazolam group will be initiated with 0.5-1.0
      mg with incremental dosing at intervals of approximately 1-3 min until a level of sedation
      will be achieved at a target Richmond Agitation-Sedation scale sedation score (per NICU
      protocol).

      Management of all trauma patients include a careful history taking for alcoholism with
      referral for further evaluation or treatment when indicated, and determination whether other
      drugs are also being used. All patients with an elevated alcohol level require a medical
      social service consultation and all patients with a TBI require a neuropsychology
      consultation, both consultations are standard of care. The neuropsychological testing
      conducted after extubation is also standard of care. The neuropsychological evaluations will
      be measured based on the following assessments: intellectual functioning, language
      processing, visuospatial processing, attention, concentration, verbal learning, memory,
      executive functioning, sensory, perception, motor, strength, and personal assessment. The
      level of impairment will be based on a scale from zero to seven. Data will be collected until
      the patient is discharged from the hospital. The clinical records from the neuropsychologist
      will be reviewed to analyze the progression of the patient's outcome. Similar to all trauma
      patients, the patients enrolled in this study will be offered continued care with
      neuropsychology as well as the option to withdrawal all care if competent to make independent
      decisions.

      Throughout the study consciousness will be measured using the Glasgow Coma Score (GCS) from
      the time of presentation to the ER and two times each day until the patient is discharged
      from the NICU or ICU (routinely done on TBI patients). The Injury severity scores (ISS) will
      be recorded from admission (done on all trauma patients). Recovery of consciousness will be
      determined by measurement of the acute physiology and chronic health evaluation (APACHE) III
      modification of the Glasgow coma score to allow for scoring of the verbal component in
      intubated patients. Patients will be judged to be awake when the Glasgow coma score was > or
      = 12.

      The following will be recorded from the Sparrow medical record for each patient: gender, age,
      sex, weight, primary diagnosis, significant co morbidities, blood alcohol level at admission,
      intracranial pressure measurements (standard of care for TBI patients), time of starting and
      finishing of the sedation, total amount of medications given, any restraint required,
      additional oxygen required, resuscitative measures required, time of transfer out of the
      unit, and time of discharge.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Neuropsychgologic outcome
time frame: 30 days
description: Extent of functional deficits from underlying traumatic brain injury
measure: cytokine levels correlating to extent of injury
time frame: 30 days
description: cytokine levels will be measured to see if there is meaningful correlation between groups
arm group label: Intravenous sedation with propofol
arm group type: Active Comparator
description: Traumatic brain injured patient, already requiring sedation. Intervention is sedation with intravenous propofol during mechanical ventilation
arm group label: Intravenous sedation with midazolam
arm group type: Active Comparator
description: Patients with traumatic brain injury requiring mechinical ventilation. Intervention is intravenous midazolam for sedation at variable doses to achieve adequite sedation levels
intervention type: Drug
intervention name: Intravenous sedation using propofol
description: Patients will be given intravenous sedation for treatment of traumatic brain injury requiring mechanical ventilation
arm group label: Intravenous sedation with propofol
intervention type: Drug
intervention name: Intravenous sedation with midazolam
description: patients with severe traumatic brain injury requiring mechanical ventilation and sedation will be sedated with midazolam
arm group label: Intravenous sedation with midazolam
other name: Versed
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Chet A Morrison, M.D.
role: Principal Investigator
affiliation: Michigan State University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Michigan State University
investigator full name: Chet Morrison
investigator title: Assistant Professor of Surgery
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Wounds and Injuries
mesh term: Midazolam
mesh term: Propofol
submitted: September 10, 2020
returned: October 1, 2020