<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/NCT02225041</url>
  </required_header>
  <id_info>
    <org_study_id>1R01HD074757-01A1</org_study_id>
    <secondary_id>1R01HD074757-01A1</secondary_id>
    <nct_id>NCT02225041</nct_id>
  </id_info>
  <brief_title>Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood</brief_title>
  <acronym>RESTORE-cog</acronym>
  <official_title>Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the relationships between sedative exposure during&#xD;
      pediatric critical illness and long-term neurocognitive outcomes. We will test for drug- and&#xD;
      dose-dependent relationships between sedative exposure and neurocognitive outcomes along the&#xD;
      early developmental spectrum and will control for baseline and environmental factors, as well&#xD;
      as the severity and course of illness.&#xD;
&#xD;
      Hypotheses:&#xD;
&#xD;
        1. Greater exposure to benzodiazepines and/or ketamine will be associated with lower IQ&#xD;
           even when controlling for severity of illness, hospital course, and baseline factors. In&#xD;
           addition, benzodiazepines and/or ketamine will negatively affect other aspects of&#xD;
           neurocognitive function.&#xD;
&#xD;
        2. Younger children exposed to benzodiazepines and/or ketamine will have worse&#xD;
           neurocognitive outcomes than older children with similar sedative exposure and severity&#xD;
           of illness.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ensuring the safety and comfort of the more than 100,000 critically ill infants and young&#xD;
      children supported on mechanical ventilation in the US each year is integral to the practice&#xD;
      of pediatric critical care. Humane care of these young patients requires the use of sedating&#xD;
      medications, most commonly combinations of opioids and benzodiazepines. Unfortunately,&#xD;
      sedative use also carries risk. Animal studies found that even transient administration of&#xD;
      benzodiazepines and other sedatives during periods of developmental synaptogenesis caused&#xD;
      widespread neuronal apoptosis and residual learning and memory deficits. Sedation is&#xD;
      administered for days to weeks in &gt;90% of acutely-ill, ventilated infants and children. Thus,&#xD;
      a commonly used treatment in critically ill young children may itself have detrimental,&#xD;
      age-dependent long-term effects.&#xD;
&#xD;
      An opportunity to increase the understanding of the long-term cognitive effects of sedation&#xD;
      during critical illness in children has been provided by the cluster randomized, controlled&#xD;
      trial of a sedation protocol, Randomized Evaluation of Sedation Titration for Respiratory&#xD;
      Failure (RESTORE), U01 HL086622, PI Curley, 31 sites, n=2,816. This trial determined whether&#xD;
      the trial's sedation protocol used at intervention sites decreased the duration of mechanical&#xD;
      ventilation and sedative exposure among children with acute respiratory failure due to a&#xD;
      primary pulmonary process. Control sites continued usual sedation practice. We collected&#xD;
      detailed data on doses and durations of sedative medications, in-hospital course, and&#xD;
      post-discharge quality of life.&#xD;
&#xD;
      The purpose of RESTORE-cognition is to determine the relationships between sedative exposure&#xD;
      during pediatric critical illness and long-term neurocognitive outcomes. We will assess&#xD;
      multiple domains of neurocognitive function 2.5-5 years post-discharge in 500 RESTORE&#xD;
      subjects with normal baseline cognitive function aged 2 weeks to 8 years at pediatric&#xD;
      intensive care unit admission. In addition, we will study 310 matched, healthy siblings of&#xD;
      RESTORE subjects to provide data on an unexposed group with similar baseline biological&#xD;
      characteristics and environment. Our goal is to increase our understanding of the&#xD;
      relationships between sedative exposure, critical illness, and long-term neurocognitive&#xD;
      outcomes in infants and young children.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 2014</start_date>
  <completion_date type="Actual">December 2018</completion_date>
  <primary_completion_date type="Actual">December 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Neurocognitive function at 2.5 years post-ICU discharge, as assessed using standardized tests of attention, processing speed, learning and memory, visual-spatial skills, motor skills, language, executive function, IQ, and behavior</measure>
    <time_frame>2.5 to 5 years post-discharge</time_frame>
  </primary_outcome>
  <enrollment type="Actual">360</enrollment>
  <condition>Intellectual Disability</condition>
  <condition>Perceptual Disorders</condition>
  <condition>Memory Disorders</condition>
  <eligibility>
    <study_pop>
      <textblock>
        RESTORE subjects who consented for 6-month follow-up with normal baseline cognitive&#xD;
        function aged 2 weeks to 8 years at PICU admission. In addition, we will study matched,&#xD;
        healthy siblings of these subjects to provide data on an unexposed group with similar&#xD;
        baseline biological characteristics and environment. If more than one sibling meets&#xD;
        enrollment criteria, the one closest in age will be selected.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        RESTORE subjects&#xD;
&#xD;
          -  Age ≤8 years and PCPC=1 at RESTORE PICU admission&#xD;
&#xD;
          -  PCPC ≤3 at RESTORE hospital discharge Sibling control subjects&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          -  Age 4 to 17 years at time of testing&#xD;
&#xD;
          -  PCPC=1&#xD;
&#xD;
          -  Same biological parents as primary subject&#xD;
&#xD;
          -  Lives with the primary subject&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        RESTORE subjects&#xD;
&#xD;
          -  Hospital readmission that includes MV and sedation&#xD;
&#xD;
          -  History of cardiac arrest, traumatic brain injury (TBI) with loss of consciousness,&#xD;
             genetic disorder, premature birth &lt;32 weeks gestational age, or birth weight &lt;2500 g&#xD;
             Sibling control subjects&#xD;
&#xD;
          -  Adopted or step siblings&#xD;
&#xD;
          -  History of MV and sedation, receipt of general anesthesia, cardiac arrest, TBI with&#xD;
             loss of consciousness, genetic disorder, premature birth &lt;32 weeks gestational age, or&#xD;
             birth weight &lt;2500 gm.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Months</minimum_age>
    <maximum_age>13 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Martha AQ Curley, RN, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pennsylvania</affiliation>
  </overall_official>
  <overall_official>
    <last_name>R. Scott Watson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Seattle Childrens Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center, The University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85724</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital and Research Center at Oakland</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94609-1809</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Orange County</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lucile Salter Packard Children's Hospital at Stanford</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304-0126</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California Davis Medical Center</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital at University of California San Francisco Medical Center</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Connecticut Children's Medical Center</name>
      <address>
        <city>Hartford</city>
        <state>Connecticut</state>
        <zip>06106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale-New Haven Children's Hospital</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520-8064</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nemours/Alfred I. duPont Hospital for Children</name>
      <address>
        <city>Wilmington</city>
        <state>Delaware</state>
        <zip>19803</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Holtz Children's Hospital</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Florida Hospital for Children</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32803</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Memorial Hospital, Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60614-3363</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Advocate Hope Children's Hospital</name>
      <address>
        <city>Oak Lawn</city>
        <state>Illinois</state>
        <zip>60453</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Maryland Hospital for Children</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21201-1595</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins Children's Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Massachusetts Memorial Children's Medical Center</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01655</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C. S. Mott Children's Hospital of the University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109-0243</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Mercy Hospital, Kansas City</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>84108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Louis Children's Hospital</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dartmouth-Hitchcock Medical Center</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03756-0001</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Children's Hospital at Montefiore</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10467</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cohen Children's Medical Center of New York</name>
      <address>
        <city>New Hyde Park</city>
        <state>New York</state>
        <zip>11040</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke Children's Hospital and Health Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Doernbecher Children's Hospital</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Monroe Carell, Jr. Children's Hospital at Vanderbilt</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232-9075</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical City Children's Hospital</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Medical Center Dallas</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75235</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Primary Children's Medical Center</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84113</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>July 25, 2014</study_first_submitted>
  <study_first_submitted_qc>August 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 25, 2014</study_first_posted>
  <last_update_submitted>June 17, 2019</last_update_submitted>
  <last_update_submitted_qc>June 17, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>intensive care</keyword>
  <keyword>critical care</keyword>
  <keyword>child</keyword>
  <keyword>family</keyword>
  <keyword>survivors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Intellectual Disability</mesh_term>
    <mesh_term>Memory Disorders</mesh_term>
    <mesh_term>Perceptual Disorders</mesh_term>
    <mesh_term>Critical Illness</mesh_term>
  </condition_browse>
  <!-- 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/NCT02225041
org study id: 1R01HD074757-01A1
secondary id: 1R01HD074757-01A1
nct id: NCT02225041
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
The purpose of this study is to determine the relationships between sedative exposure during
      pediatric critical illness and long-term neurocognitive outcomes. We will test for drug- and
      dose-dependent relationships between sedative exposure and neurocognitive outcomes along the
      early developmental spectrum and will control for baseline and environmental factors, as well
      as the severity and course of illness.

      Hypotheses:

        1. Greater exposure to benzodiazepines and/or ketamine will be associated with lower IQ
           even when controlling for severity of illness, hospital course, and baseline factors. In
           addition, benzodiazepines and/or ketamine will negatively affect other aspects of
           neurocognitive function.

        2. Younger children exposed to benzodiazepines and/or ketamine will have worse
           neurocognitive outcomes than older children with similar sedative exposure and severity
           of illness.
Ensuring the safety and comfort of the more than 100,000 critically ill infants and young
      children supported on mechanical ventilation in the US each year is integral to the practice
      of pediatric critical care. Humane care of these young patients requires the use of sedating
      medications, most commonly combinations of opioids and benzodiazepines. Unfortunately,
      sedative use also carries risk. Animal studies found that even transient administration of
      benzodiazepines and other sedatives during periods of developmental synaptogenesis caused
      widespread neuronal apoptosis and residual learning and memory deficits. Sedation is
      administered for days to weeks in >90% of acutely-ill, ventilated infants and children. Thus,
      a commonly used treatment in critically ill young children may itself have detrimental,
      age-dependent long-term effects.

      An opportunity to increase the understanding of the long-term cognitive effects of sedation
      during critical illness in children has been provided by the cluster randomized, controlled
      trial of a sedation protocol, Randomized Evaluation of Sedation Titration for Respiratory
      Failure (RESTORE), U01 HL086622, PI Curley, 31 sites, n=2,816. This trial determined whether
      the trial's sedation protocol used at intervention sites decreased the duration of mechanical
      ventilation and sedative exposure among children with acute respiratory failure due to a
      primary pulmonary process. Control sites continued usual sedation practice. We collected
      detailed data on doses and durations of sedative medications, in-hospital course, and
      post-discharge quality of life.

      The purpose of RESTORE-cognition is to determine the relationships between sedative exposure
      during pediatric critical illness and long-term neurocognitive outcomes. We will assess
      multiple domains of neurocognitive function 2.5-5 years post-discharge in 500 RESTORE
      subjects with normal baseline cognitive function aged 2 weeks to 8 years at pediatric
      intensive care unit admission. In addition, we will study 310 matched, healthy siblings of
      RESTORE subjects to provide data on an unexposed group with similar baseline biological
      characteristics and environment. Our goal is to increase our understanding of the
      relationships between sedative exposure, critical illness, and long-term neurocognitive
      outcomes in infants and young children.
observational model: Case-Control
time perspective: Cross-Sectional
measure: Neurocognitive function at 2.5 years post-ICU discharge, as assessed using standardized tests of attention, processing speed, learning and memory, visual-spatial skills, motor skills, language, executive function, IQ, and behavior
time frame: 2.5 to 5 years post-discharge
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 30 Months
maximum age: 13 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Martha AQ Curley, RN, PhD
role: Principal Investigator
affiliation: University of Pennsylvania
last name: R. Scott Watson, MD
role: Principal Investigator
affiliation: Seattle Childrens Hospital
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country: United States
responsible party type: Sponsor
mesh term: Intellectual Disability
mesh term: Memory Disorders
mesh term: Perceptual Disorders
mesh term: Critical Illness