<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/NCT01669642</url>
  </required_header>
  <id_info>
    <org_study_id>201112017</org_study_id>
    <nct_id>NCT01669642</nct_id>
  </id_info>
  <brief_title>Study to Find the Dose of Rapidly Administered Ketamine for Brief Painful Procedures in Children</brief_title>
  <official_title>Mean Effective Dose of Rapidly Administered Ketamine for Brief Pediatric Procedural Sedation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to find the dose of rapidly administered ketamine in 3 different&#xD;
      pediatric age groups (2-5, 6-11 and 12-17) for abscess drainage and fracture reduction.&#xD;
&#xD;
      Ketamine is the most common drug administered to children to facilitate painful procedures in&#xD;
      the emergency setting because it achieves potent sedation, pain relief and amnesia with&#xD;
      minimal adverse cardiopulmonary effects.(1-5) However, the 1-2 hour recovery period (1,6)&#xD;
      associated with standard ketamine administration guidelines(7) strains work flow because it&#xD;
      requires bedside one-on-one nurse monitoring in a treatment room, tying up these limited and&#xD;
      valuable resources. Consequently, a combination of two other drugs, propofol + fentanyl&#xD;
      (P/F), with recovery of 20-30 minutes, is rapidly gaining popularity for procedural sedation&#xD;
      despite more frequent respiratory depression, apnea and hypotension caused by this&#xD;
      technique.(2,4,8,9)&#xD;
&#xD;
      The investigators believe recovery associated with our novel method for administering&#xD;
      ketamine is significantly shorter than with the standard larger dose more slowly administered&#xD;
      ketamine technique(7). Through the investigators clinical experience, the investigators have&#xD;
      found rapid infusion of smaller than standard doses of ketamine safely achieves the drug's&#xD;
      sedative effect, with the benefit of more rapid recovery due to the use of a smaller dose.&#xD;
      However, this novel technique challenges published beliefs that time of recovery from&#xD;
      ketamine sedation does not differ significantly with the dose administered, within the usual&#xD;
      dose ranges, and that rapid infusion may cause respiratory depression, similar to that seen&#xD;
      with other classes of sedative-analgesic drugs.(7,10) the investigators believe the slow&#xD;
      infusion recommended by standard guidelines(7) requires a larger ketamine dose necessary to&#xD;
      achieve effective sedation, and, consequently, prolongs recovery. It is the prolonged&#xD;
      recovery that has prompted increased use of other less safe but briefer sedatives, such as&#xD;
      propofol/fentanyl. By demonstrating patients recover rapidly with new ketamine technique,&#xD;
      without increased adverse cardiopulmonary effects, the investigators will provide clinicians&#xD;
      with an important new method for ketamine procedural sedation. The investigators believe&#xD;
      clinicians will prefer more rapid recovery ketamine technique because it is safer and reduces&#xD;
      pain and distress better than the propofol/fentanyl combination for sedation.&#xD;
&#xD;
      The investigators complete proposal requires two steps. In Step One, this proposal, the&#xD;
      investigators will determine the minimum effective dose of rapidly infused ketamine that&#xD;
      achieves deep sedation for at least 5 minutes in 95% of children (ED95). Two groups of&#xD;
      patients will be studied: one group is patients undergoing abscess incision and drainage and&#xD;
      the other group is patients undergoing fracture reduction in our Emergency Department. The&#xD;
      investigators believe that the ED95 is different for both the groups as the severity of pain&#xD;
      is different. The investigators will compare the safety and recovery times to published&#xD;
      standard ketamine techniques. In the following study, Step Two, the investigators will&#xD;
      compare this novel technique, in a blinded randomized trial using the ED95 ketamine dose&#xD;
      determined in Step One to the standard ketamine technique to determine if the novel technique&#xD;
      results in significantly shorter recovery without an increase in the frequency of adverse&#xD;
      effects. The study the investigators are proposing in this submission is Step One only.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      During fracture reduction in children, the investigators found less distress using&#xD;
      ketamine+midazolam (K/M) sedation (P&lt;0.0001) and less hypoxia (5% vs. 25%) compared to&#xD;
      sedation with fentanyl+midazolam (F/M)(1). Others also found less hypoxia with K/M (4%)&#xD;
      compared to propofol+fentanyl (P/F) (18-31%)(2,4). Because of the greater safety and efficacy&#xD;
      determined in these and similar studies, ketamine is now the most common drug administered&#xD;
      for procedural sedation of children undergoing painful procedures in the ED.(7) For the past&#xD;
      15 years, the investigators have sedated about 2,500 children each year with ketamine in the&#xD;
      St. Louis Children's Emergency Department for setting broken bones, debriding burns, draining&#xD;
      abscesses, and other very painful procedures. Midazolam was co-administered with ketamine in&#xD;
      early studies to reduce dysphoria during recovery, but this practice has since been shown not&#xD;
      to be beneficial. For the past 5-10 years the investigators have used ketamine without&#xD;
      midazolam and have seen no change in how children wake up from ketamine sedation.(6,11)&#xD;
&#xD;
      Ketamine administration in the investigators previous studies (1,3) was similar to recent&#xD;
      recommendations (1.5-2 mg/kg I.V. infused over 30-60 sec)(7). Problematically, while most of&#xD;
      these ED procedures such as fracture reduction, burn debridement, or abscess incision and&#xD;
      drainage, require only 5-10 minutes of deep sedation, this standard ketamine technique&#xD;
      results in recovery periods of 60-120 minutes(1,3,6). During recovery, patients remain in&#xD;
      treatment rooms to be monitored one-on-one by nurses for respiratory depression, airway&#xD;
      obstruction, vomiting and other potentially life-threatening adverse events, thus tying up&#xD;
      these limited resources(10). This long recovery has led to increased use of propofol based&#xD;
      techniques which have more rapid recovery (20-30 minutes) but cause increased respiratory&#xD;
      depression and hypotension and less effective sedation(2-6,9). Because of ketamine's greater&#xD;
      safety and efficacy profile, the investigators have been interested in developing alternative&#xD;
      ketamine administration regimens that result in more rapid recovery, similar to propofol. If&#xD;
      successful in hastening recovery, the investigators believe that the relative lack of&#xD;
      respiratory depression and greater analgesia with ketamine will improve patient safety by&#xD;
      encouraging continued use of ketamine as the preferred technique for procedural sedation in&#xD;
      children undergoing painful procedures in the ED.&#xD;
&#xD;
      To explore new techniques for hastening recovery from sedation, the investigators took&#xD;
      advantage of the uniqueness of ketamine. Rapid administration of opioid and gabaergic drugs&#xD;
      such as fentanyl and propofol significantly augments the drugs' beneficial effects, but it&#xD;
      also markedly increases respiratory depression, apnea and hypotension.(13) Cautions that&#xD;
      rapid infusion of ketamine may cause brief respiratory depression stem from early anesthesia&#xD;
      trials using doses larger than those typically used for sedation.(7) Although not formally&#xD;
      studied, for the past 5 years the investigators have observed no adverse effects with rapid&#xD;
      administration of 0.5-1.5 mg/kg ketamine doses for brief painful procedures like fracture&#xD;
      reduction and abscess incision &amp; drainage in children in the Emergency Unit of St. Louis&#xD;
      Children's Hospital.&#xD;
&#xD;
      Lipophilic drugs used for procedural sedation-analgesia, such as ketamine, fentanyl, and&#xD;
      propofol rapidly diffuse from the bloodstream into the brain. A disproportionately high&#xD;
      percentage of the cardiac output goes to the brain, thus a large portion of a drug injected&#xD;
      intravenously initially goes into the brain's circulation on first pass through the heart and&#xD;
      exerts clinical effects within a single circulation time, usually &lt; 60 seconds. The drug&#xD;
      remaining in the bloodstream circulates throughout the body and diffuses into muscle, bone&#xD;
      and fat, causing the blood concentration to fall. The blood-brain concentration gradient then&#xD;
      favors drug diffusion out of the brain and the patient awakens.&#xD;
&#xD;
      Rapid infusion of sedative drugs increases central nervous system clinical effects by&#xD;
      directing a larger portion of the drug into the brain. A rapidly injected dose of drug&#xD;
      travels as a more concentrated bolus into the brain circulation than a slowly injected dose&#xD;
      that is diluted by the passing blood. With rapid injection, therefore, the initial&#xD;
      blood-brain concentration gradient is greater and a larger portion of the dose initially&#xD;
      enters the brain, causing deeper sedation. Smaller doses, rapidly injected, therefore can be&#xD;
      used to achieve deep sedation similar to that of larger doses injected more slowly. With the&#xD;
      smaller dose, the blood-brain concentration gradient subsequently reverses more rapidly and&#xD;
      &quot;wake up time&quot; is shorter. Because rapid increases in brain concentration of ketamine does&#xD;
      not cause respiratory depression, unlike that seen with fentanyl or propofol, this rapid&#xD;
      infusion technique can be used with ketamine.&#xD;
&#xD;
      The purpose of this research project is to determine formally the minimum dose of ketamine&#xD;
      that, when rapidly infused, achieves 5 minutes of deep sedation in 95% of patients (ED95).&#xD;
      The investigators will use the up and down method (15) which is a standard method in&#xD;
      anesthesiology to find the mean effective dose. Five minutes is typically enough time to&#xD;
      perform these brief painful procedures. The investigators anticipate the ED95 will be smaller&#xD;
      than the standard recommended ketamine dose and thus patients will wake up faster.&#xD;
&#xD;
      Of special note, determination of the &quot;standard dose and rate of administration of&#xD;
      ketamine&quot;(7) has been based upon our and others' studies in which the dose and rate of&#xD;
      infusion of ketamine were not carefully controlled and, in fact, varied widely(1,3,4,7).&#xD;
      Thus, the &quot;standard recommendation for administration of ketamine&quot; is somewhat anecdotal and&#xD;
      has not been precisely determined. Our proposed study will be the first to precisely&#xD;
      determine a minimum effective ketamine dose.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2012</start_date>
  <completion_date type="Actual">August 2014</completion_date>
  <primary_completion_date type="Actual">August 2014</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Median Effective Dose (ED50) and ED95 of Rapidly Administered Ketamine</measure>
    <time_frame>Dose administration through 5 minutes</time_frame>
    <description>ED50 is the dose of rapidly administered ketamine that achieves effective sedation in 50% of patients. ED95 is the dose of ketamine that can provide effective sedation in 95% of children undergoing abscess drainage or fracture reduction. ED95 will be calculated for the 3 age groups (2-5, 6-11 and 12-17) independently for both the procedures: abscess drainage and fracture reduction.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>ED95</measure>
    <time_frame>Dose administration through 5 minutes</time_frame>
    <description>ED95 is the dose of ketamine effective for 95% of children. this outcome is estimated from ED50.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Vomiting</measure>
    <time_frame>Administration of ketamine through 2 week follow up call</time_frame>
    <description>patients who experienced vomiting while in the ED or after discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Wisconsin Sedation Scale Score of 2 or Less at 1 Minute After First Dose of Ketamine</measure>
    <time_frame>Dose administration through 1 minute</time_frame>
    <description>This is a measure of sedation effectiveness; to assess the effectiveness of first dose of ketamine administered.&#xD;
Possible values for the scale range from 0 to 6. A sedation score of 2 or less is considered adequate sedation. Values more than 2 indicate state of inadequate sedation. higher values indicate the need for additional doses of sedation.&#xD;
Patients who achieved a score of 2 or less are considered effective sedation and a score of &gt;2 are considered ineffective sedations.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Total Sedation Time</measure>
    <time_frame>Time of administration of ketamine through sedation recovery</time_frame>
    <description>during recovery, all participants are monitored for recovery to baseline at which point participants are ready for discharge. we will document the time from induction to recovery to aldrete score of 10.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">111</enrollment>
  <condition>Abscess</condition>
  <condition>Fracture</condition>
  <arm_group>
    <arm_group_label>Ketamine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>participants who get the ketamine sedation will be enrolled. there is no control or comparison group.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketamine</intervention_name>
    <description>participants who need ketamine sedation for abscess drainage or fracture reduction will be approached for enrollment. there is no comparison group. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
    <arm_group_label>Ketamine</arm_group_label>
    <other_name>Ketalar</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Healthy children (ASA Physical Status I and II) 2-17 yrs old who require deep sedation for&#xD;
        abscess incision and drainage in the St. Louis Children's Hospital Emergency Unit&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Fever (temperature ≥ 38 0Celcius) due to upper respiratory infection.&#xD;
&#xD;
          2. Obesity (BMI &gt; 2SD for age and sex) or undernourishment (BMI &lt; 2SD for age and sex)&#xD;
&#xD;
          3. Children with psychosis/psychiatric diagnosis (currently under the care of&#xD;
             psychiatrist and/or taking psychiatric medication. ADHD is not an exclusion criterion)&#xD;
&#xD;
          4. Previous adverse reactions with ketamine sedation&#xD;
&#xD;
          5. Receipt of opioid analgesic in the ED (oxycodone/morphine etc) prior to sedation&#xD;
&#xD;
          6. Multiple abscesses (2 or more) requiring I &amp; D&#xD;
&#xD;
          7. Non -English speaking families&#xD;
&#xD;
          8. Children under foster care.&#xD;
&#xD;
          9. Previous participation in current research study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>sri s chinta, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>St Louis Children's hospital, Washington university</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63123</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>August 8, 2012</study_first_submitted>
  <study_first_submitted_qc>August 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 21, 2012</study_first_posted>
  <results_first_submitted>February 12, 2018</results_first_submitted>
  <results_first_submitted_qc>February 12, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">March 12, 2018</results_first_posted>
  <last_update_submitted>April 4, 2019</last_update_submitted>
  <last_update_submitted_qc>April 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ketamine sedation</keyword>
  <keyword>pediatric</keyword>
  <keyword>abscess drainage</keyword>
  <keyword>fracture reduction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Abscess</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketamine</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>children between 2-18 years of age who presented to st louis children's hospital emergency department between april 2012 and august 2014 with a fracture that needed reduction or a skin abscess that needed drainage under sedation were approached for enrollment.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Fracture Reduction Group 2-5 Years</title>
          <description>children between 2-5 years who needs ketamine sedation for fracture reduction in the emergency department are enrolled in this group.</description>
        </group>
        <group group_id="P2">
          <title>Fracture Reduction Group 6-11 Years</title>
          <description>children between 6-11 years who needs ketamine sedation for fracture reduction in the emergency department are enrolled in this group.</description>
        </group>
        <group group_id="P3">
          <title>Fracture Reduction Group 12-17 Years</title>
          <description>children between 12-17 years who needs ketamine sedation for fracture reduction in the emergency department are enrolled in this group.</description>
        </group>
        <group group_id="P4">
          <title>Abscess Drainage Group 2-5 Years</title>
          <description>children between 2-5 years who needs ketamine sedation for abscess drainage in the emergency department are enrolled in this group.</description>
        </group>
        <group group_id="P5">
          <title>Abscess Drainage Group 6-11 Years</title>
          <description>children between 6-11 years who needs ketamine sedation for abscess drainage in the emergency department are enrolled in this group.</description>
        </group>
        <group group_id="P6">
          <title>Abscess Drainage Group 12-17 Years</title>
          <description>children between 12-17 years who needs ketamine sedation for abscess drainage in the emergency department are enrolled in this group.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="20"/>
                <participants group_id="P3" count="20"/>
                <participants group_id="P4" count="21"/>
                <participants group_id="P5" count="20"/>
                <participants group_id="P6" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="20"/>
                <participants group_id="P3" count="20"/>
                <participants group_id="P4" count="20"/>
                <participants group_id="P5" count="20"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Fracture Reduction Group 2-5 Years</title>
          <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="B2">
          <title>Fracture Reduction Group 6-11 Years</title>
          <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="B3">
          <title>Fracture Reduction Group 12-17 Years</title>
          <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="B4">
          <title>Abscess Drainage Group 2-5 Years</title>
          <description>participants who need ketamine sedation for abscess drainage will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="B5">
          <title>Abscess Drainage Group 6-11 Years</title>
          <description>participants who need ketamine sedation for abscess drainage will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="B6">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="20"/>
            <count group_id="B4" value="20"/>
            <count group_id="B5" value="20"/>
            <count group_id="B6" value="100"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4.8" lower_limit="2.9" upper_limit="5.9"/>
                    <measurement group_id="B2" value="9.2" lower_limit="6" upper_limit="11.9"/>
                    <measurement group_id="B3" value="13.7" lower_limit="12.6" upper_limit="16.9"/>
                    <measurement group_id="B4" value="2.9" lower_limit="2" upper_limit="5.1"/>
                    <measurement group_id="B5" value="7.2" lower_limit="6.4" upper_limit="11.9"/>
                    <measurement group_id="B6" value="7.2" lower_limit="2.9" upper_limit="11.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="11"/>
                    <measurement group_id="B6" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="19"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="9"/>
                    <measurement group_id="B6" value="65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>african american</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="9"/>
                    <measurement group_id="B5" value="8"/>
                    <measurement group_id="B6" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="10"/>
                    <measurement group_id="B5" value="12"/>
                    <measurement group_id="B6" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Patients who received Opioids prior to sedation</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="19"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>time between opioid administration and sedation start time</title>
          <units>minutes</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="116" lower_limit="20" upper_limit="383"/>
                    <measurement group_id="B2" value="96" lower_limit="1" upper_limit="251"/>
                    <measurement group_id="B3" value="129" lower_limit="27" upper_limit="401"/>
                    <measurement group_id="B4" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="B5" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="B6" value="116" lower_limit="1" upper_limit="401"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>fracture characteristics</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Non displaced fracture</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>displaced fracture but not overriding</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>displaced fracture and overriding</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>no fracture</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="20"/>
                    <measurement group_id="B5" value="20"/>
                    <measurement group_id="B6" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Median Effective Dose (ED50) and ED95 of Rapidly Administered Ketamine</title>
        <description>ED50 is the dose of rapidly administered ketamine that achieves effective sedation in 50% of patients. ED95 is the dose of ketamine that can provide effective sedation in 95% of children undergoing abscess drainage or fracture reduction. ED95 will be calculated for the 3 age groups (2-5, 6-11 and 12-17) independently for both the procedures: abscess drainage and fracture reduction.</description>
        <time_frame>Dose administration through 5 minutes</time_frame>
        <population>100 children were enrolled in 5 different groups depending on the age and type of procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Fracture Reduction Group 2-5 Years</title>
            <description>children between 2-5 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O2">
            <title>Fracture Reduction Group 6-11 Years</title>
            <description>children between 6-11 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O3">
            <title>Fracture Reduction Group 12-17 Years</title>
            <description>children between 12-17 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O4">
            <title>Abscess Drainage Group 2-5 Years</title>
            <description>children between 2-5 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O5">
            <title>Abscess Drainage Group 6-11 Years</title>
            <description>children between 6-11 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Effective Dose (ED50) and ED95 of Rapidly Administered Ketamine</title>
          <description>ED50 is the dose of rapidly administered ketamine that achieves effective sedation in 50% of patients. ED95 is the dose of ketamine that can provide effective sedation in 95% of children undergoing abscess drainage or fracture reduction. ED95 will be calculated for the 3 age groups (2-5, 6-11 and 12-17) independently for both the procedures: abscess drainage and fracture reduction.</description>
          <population>100 children were enrolled in 5 different groups depending on the age and type of procedure.</population>
          <units>mg/kg of ketamine dose</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
                <count group_id="O4" value="20"/>
                <count group_id="O5" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.7" lower_limit="0.6" upper_limit="0.9"/>
                    <measurement group_id="O2" value="0.5" lower_limit="0.5" upper_limit="0.7"/>
                    <measurement group_id="O3" value="0.6" lower_limit="0.5" upper_limit="0.8"/>
                    <measurement group_id="O4" value="0.9" lower_limit="0.7" upper_limit="1.1"/>
                    <measurement group_id="O5" value="0.6" lower_limit="0.4" upper_limit="0.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>ED95</title>
        <description>ED95 is the dose of ketamine effective for 95% of children. this outcome is estimated from ED50.</description>
        <time_frame>Dose administration through 5 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Fracture Reduction Group 2-5 Years</title>
            <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
          </group>
          <group group_id="O2">
            <title>Fracture Reduction Group 6-11 Years</title>
            <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
          </group>
          <group group_id="O3">
            <title>Fracture Reduction Group 12-17 Years</title>
            <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
          </group>
          <group group_id="O4">
            <title>Abscess Drainage Group 2-5 Years</title>
            <description>participants who need ketamine sedation for abscess drainage will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
          </group>
          <group group_id="O5">
            <title>Abscess Drainage Group 6-11 Years</title>
            <description>participants who need ketamine sedation for abscess drainage will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
          </group>
        </group_list>
        <measure>
          <title>ED95</title>
          <description>ED95 is the dose of ketamine effective for 95% of children. this outcome is estimated from ED50.</description>
          <units>mg/kg of ketamine dose</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
                <count group_id="O4" value="20"/>
                <count group_id="O5" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.7"/>
                    <measurement group_id="O2" value="0.7"/>
                    <measurement group_id="O3" value="0.8"/>
                    <measurement group_id="O4" value="1.1"/>
                    <measurement group_id="O5" value="1.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Vomiting</title>
        <description>patients who experienced vomiting while in the ED or after discharge</description>
        <time_frame>Administration of ketamine through 2 week follow up call</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Fracture Reduction Group 2-5 Years</title>
            <description>children between 2-5 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O2">
            <title>Fracture Reduction Group 6-11 Years</title>
            <description>children between 6-11 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O3">
            <title>Fracture Reduction Group 12-17 Years</title>
            <description>children between 12-17 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O4">
            <title>Abscess Drainage Group 2-5 Years</title>
            <description>children between 2-5 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O5">
            <title>Abscess Drainage Group 6-11 Years</title>
            <description>children between 6-11 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
        </group_list>
        <measure>
          <title>Vomiting</title>
          <description>patients who experienced vomiting while in the ED or after discharge</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
                <count group_id="O4" value="20"/>
                <count group_id="O5" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>vomiting in the ED</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Vomiting after discharge</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No vomiting</title>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="16"/>
                    <measurement group_id="O3" value="16"/>
                    <measurement group_id="O4" value="17"/>
                    <measurement group_id="O5" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Wisconsin Sedation Scale Score of 2 or Less at 1 Minute After First Dose of Ketamine</title>
        <description>This is a measure of sedation effectiveness; to assess the effectiveness of first dose of ketamine administered.&#xD;
Possible values for the scale range from 0 to 6. A sedation score of 2 or less is considered adequate sedation. Values more than 2 indicate state of inadequate sedation. higher values indicate the need for additional doses of sedation.&#xD;
Patients who achieved a score of 2 or less are considered effective sedation and a score of &gt;2 are considered ineffective sedations.</description>
        <time_frame>Dose administration through 1 minute</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Fracture Reduction Group 2-5 Years</title>
            <description>children between 2-5 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O2">
            <title>Fracture Reduction Group 6-11 Years</title>
            <description>children between 6-11 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O3">
            <title>Fracture Reduction Group 12-17 Years</title>
            <description>children between 12-17 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O4">
            <title>Abscess Drainage Group 2-5 Years</title>
            <description>children between 2-5 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O5">
            <title>Abscess Drainage Group 6-11 Years</title>
            <description>children between 6-11 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Wisconsin Sedation Scale Score of 2 or Less at 1 Minute After First Dose of Ketamine</title>
          <description>This is a measure of sedation effectiveness; to assess the effectiveness of first dose of ketamine administered.&#xD;
Possible values for the scale range from 0 to 6. A sedation score of 2 or less is considered adequate sedation. Values more than 2 indicate state of inadequate sedation. higher values indicate the need for additional doses of sedation.&#xD;
Patients who achieved a score of 2 or less are considered effective sedation and a score of &gt;2 are considered ineffective sedations.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
                <count group_id="O4" value="20"/>
                <count group_id="O5" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="9"/>
                    <measurement group_id="O3" value="10"/>
                    <measurement group_id="O4" value="13"/>
                    <measurement group_id="O5" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Total Sedation Time</title>
        <description>during recovery, all participants are monitored for recovery to baseline at which point participants are ready for discharge. we will document the time from induction to recovery to aldrete score of 10.</description>
        <time_frame>Time of administration of ketamine through sedation recovery</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Fracture Reduction Group 2-5 Years</title>
            <description>children between 2-5 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O2">
            <title>Fracture Reduction Group 6-11 Years</title>
            <description>children between 6-11 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O3">
            <title>Fracture Reduction Group 12-17 Years</title>
            <description>children between 12-17 years of age who need fracture reduction under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O4">
            <title>Abscess Drainage Group 2-5 Years</title>
            <description>children between 2-5 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
          <group group_id="O5">
            <title>Abscess Drainage Group 6-11 Years</title>
            <description>children between 6-11 years of age who need abscess drainage under ketamine sedation are enrolled in this group.</description>
          </group>
        </group_list>
        <measure>
          <title>Total Sedation Time</title>
          <description>during recovery, all participants are monitored for recovery to baseline at which point participants are ready for discharge. we will document the time from induction to recovery to aldrete score of 10.</description>
          <units>minutes</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
                <count group_id="O4" value="20"/>
                <count group_id="O5" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patients requiring single dose of ketamine</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25" lower_limit="15" upper_limit="30"/>
                    <measurement group_id="O2" value="22.5" lower_limit="15" upper_limit="31"/>
                    <measurement group_id="O3" value="25" lower_limit="25" upper_limit="30"/>
                    <measurement group_id="O4" value="20.5" lower_limit="13" upper_limit="40"/>
                    <measurement group_id="O5" value="17.5" lower_limit="10" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>patients requiring more than single dose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35" lower_limit="25" upper_limit="85"/>
                    <measurement group_id="O2" value="25" lower_limit="15" upper_limit="50"/>
                    <measurement group_id="O3" value="45" lower_limit="20" upper_limit="80"/>
                    <measurement group_id="O4" value="27.5" lower_limit="16" upper_limit="40"/>
                    <measurement group_id="O5" value="35" lower_limit="10" upper_limit="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>from the day of enrollment up to 2 weeks.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Fracture Reduction Group 2-5 Years</title>
          <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="E2">
          <title>Fracture Reduction Group 6-11 Years</title>
          <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="E3">
          <title>Fracture Reduction Group 12-17 Years</title>
          <description>participants who need ketamine sedation for fracture reduction will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="E4">
          <title>Abscess Drainage Group 2-5 Years</title>
          <description>participants who need ketamine sedation for abscess drainage will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
        <group group_id="E5">
          <title>Abscess Drainage Group 6-11 Years</title>
          <description>participants who need ketamine sedation for abscess drainage will be approached for enrollment. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="20"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>dysphoria, ag</sub_title>
                <description>patients who experienced dysphoria during sedation or recovery period</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>SRI SANKAR CHINTA PI</name_or_title>
      <organization>washington university in st louis</organization>
      <phone>3144544661</phone>
      <email>schinta@wustl.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01669642
org study id: 201112017
nct id: NCT01669642
lead sponsor: 
has dmc: Yes
The purpose of the study is to find the dose of rapidly administered ketamine in 3 different
      pediatric age groups (2-5, 6-11 and 12-17) for abscess drainage and fracture reduction.

      Ketamine is the most common drug administered to children to facilitate painful procedures in
      the emergency setting because it achieves potent sedation, pain relief and amnesia with
      minimal adverse cardiopulmonary effects.(1-5) However, the 1-2 hour recovery period (1,6)
      associated with standard ketamine administration guidelines(7) strains work flow because it
      requires bedside one-on-one nurse monitoring in a treatment room, tying up these limited and
      valuable resources. Consequently, a combination of two other drugs, propofol + fentanyl
      (P/F), with recovery of 20-30 minutes, is rapidly gaining popularity for procedural sedation
      despite more frequent respiratory depression, apnea and hypotension caused by this
      technique.(2,4,8,9)

      The investigators believe recovery associated with our novel method for administering
      ketamine is significantly shorter than with the standard larger dose more slowly administered
      ketamine technique(7). Through the investigators clinical experience, the investigators have
      found rapid infusion of smaller than standard doses of ketamine safely achieves the drug's
      sedative effect, with the benefit of more rapid recovery due to the use of a smaller dose.
      However, this novel technique challenges published beliefs that time of recovery from
      ketamine sedation does not differ significantly with the dose administered, within the usual
      dose ranges, and that rapid infusion may cause respiratory depression, similar to that seen
      with other classes of sedative-analgesic drugs.(7,10) the investigators believe the slow
      infusion recommended by standard guidelines(7) requires a larger ketamine dose necessary to
      achieve effective sedation, and, consequently, prolongs recovery. It is the prolonged
      recovery that has prompted increased use of other less safe but briefer sedatives, such as
      propofol/fentanyl. By demonstrating patients recover rapidly with new ketamine technique,
      without increased adverse cardiopulmonary effects, the investigators will provide clinicians
      with an important new method for ketamine procedural sedation. The investigators believe
      clinicians will prefer more rapid recovery ketamine technique because it is safer and reduces
      pain and distress better than the propofol/fentanyl combination for sedation.

      The investigators complete proposal requires two steps. In Step One, this proposal, the
      investigators will determine the minimum effective dose of rapidly infused ketamine that
      achieves deep sedation for at least 5 minutes in 95% of children (ED95). Two groups of
      patients will be studied: one group is patients undergoing abscess incision and drainage and
      the other group is patients undergoing fracture reduction in our Emergency Department. The
      investigators believe that the ED95 is different for both the groups as the severity of pain
      is different. The investigators will compare the safety and recovery times to published
      standard ketamine techniques. In the following study, Step Two, the investigators will
      compare this novel technique, in a blinded randomized trial using the ED95 ketamine dose
      determined in Step One to the standard ketamine technique to determine if the novel technique
      results in significantly shorter recovery without an increase in the frequency of adverse
      effects. The study the investigators are proposing in this submission is Step One only.
During fracture reduction in children, the investigators found less distress using
      ketamine+midazolam (K/M) sedation (P<0.0001) and less hypoxia (5% vs. 25%) compared to
      sedation with fentanyl+midazolam (F/M)(1). Others also found less hypoxia with K/M (4%)
      compared to propofol+fentanyl (P/F) (18-31%)(2,4). Because of the greater safety and efficacy
      determined in these and similar studies, ketamine is now the most common drug administered
      for procedural sedation of children undergoing painful procedures in the ED.(7) For the past
      15 years, the investigators have sedated about 2,500 children each year with ketamine in the
      St. Louis Children's Emergency Department for setting broken bones, debriding burns, draining
      abscesses, and other very painful procedures. Midazolam was co-administered with ketamine in
      early studies to reduce dysphoria during recovery, but this practice has since been shown not
      to be beneficial. For the past 5-10 years the investigators have used ketamine without
      midazolam and have seen no change in how children wake up from ketamine sedation.(6,11)

      Ketamine administration in the investigators previous studies (1,3) was similar to recent
      recommendations (1.5-2 mg/kg I.V. infused over 30-60 sec)(7). Problematically, while most of
      these ED procedures such as fracture reduction, burn debridement, or abscess incision and
      drainage, require only 5-10 minutes of deep sedation, this standard ketamine technique
      results in recovery periods of 60-120 minutes(1,3,6). During recovery, patients remain in
      treatment rooms to be monitored one-on-one by nurses for respiratory depression, airway
      obstruction, vomiting and other potentially life-threatening adverse events, thus tying up
      these limited resources(10). This long recovery has led to increased use of propofol based
      techniques which have more rapid recovery (20-30 minutes) but cause increased respiratory
      depression and hypotension and less effective sedation(2-6,9). Because of ketamine's greater
      safety and efficacy profile, the investigators have been interested in developing alternative
      ketamine administration regimens that result in more rapid recovery, similar to propofol. If
      successful in hastening recovery, the investigators believe that the relative lack of
      respiratory depression and greater analgesia with ketamine will improve patient safety by
      encouraging continued use of ketamine as the preferred technique for procedural sedation in
      children undergoing painful procedures in the ED.

      To explore new techniques for hastening recovery from sedation, the investigators took
      advantage of the uniqueness of ketamine. Rapid administration of opioid and gabaergic drugs
      such as fentanyl and propofol significantly augments the drugs' beneficial effects, but it
      also markedly increases respiratory depression, apnea and hypotension.(13) Cautions that
      rapid infusion of ketamine may cause brief respiratory depression stem from early anesthesia
      trials using doses larger than those typically used for sedation.(7) Although not formally
      studied, for the past 5 years the investigators have observed no adverse effects with rapid
      administration of 0.5-1.5 mg/kg ketamine doses for brief painful procedures like fracture
      reduction and abscess incision & drainage in children in the Emergency Unit of St. Louis
      Children's Hospital.

      Lipophilic drugs used for procedural sedation-analgesia, such as ketamine, fentanyl, and
      propofol rapidly diffuse from the bloodstream into the brain. A disproportionately high
      percentage of the cardiac output goes to the brain, thus a large portion of a drug injected
      intravenously initially goes into the brain's circulation on first pass through the heart and
      exerts clinical effects within a single circulation time, usually < 60 seconds. The drug
      remaining in the bloodstream circulates throughout the body and diffuses into muscle, bone
      and fat, causing the blood concentration to fall. The blood-brain concentration gradient then
      favors drug diffusion out of the brain and the patient awakens.

      Rapid infusion of sedative drugs increases central nervous system clinical effects by
      directing a larger portion of the drug into the brain. A rapidly injected dose of drug
      travels as a more concentrated bolus into the brain circulation than a slowly injected dose
      that is diluted by the passing blood. With rapid injection, therefore, the initial
      blood-brain concentration gradient is greater and a larger portion of the dose initially
      enters the brain, causing deeper sedation. Smaller doses, rapidly injected, therefore can be
      used to achieve deep sedation similar to that of larger doses injected more slowly. With the
      smaller dose, the blood-brain concentration gradient subsequently reverses more rapidly and
      "wake up time" is shorter. Because rapid increases in brain concentration of ketamine does
      not cause respiratory depression, unlike that seen with fentanyl or propofol, this rapid
      infusion technique can be used with ketamine.

      The purpose of this research project is to determine formally the minimum dose of ketamine
      that, when rapidly infused, achieves 5 minutes of deep sedation in 95% of patients (ED95).
      The investigators will use the up and down method (15) which is a standard method in
      anesthesiology to find the mean effective dose. Five minutes is typically enough time to
      perform these brief painful procedures. The investigators anticipate the ED95 will be smaller
      than the standard recommended ketamine dose and thus patients will wake up faster.

      Of special note, determination of the "standard dose and rate of administration of
      ketamine"(7) has been based upon our and others' studies in which the dose and rate of
      infusion of ketamine were not carefully controlled and, in fact, varied widely(1,3,4,7).
      Thus, the "standard recommendation for administration of ketamine" is somewhat anecdotal and
      has not been precisely determined. Our proposed study will be the first to precisely
      determine a minimum effective ketamine dose.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Supportive Care
masking: None (Open Label)
measure: Median Effective Dose (ED50) and ED95 of Rapidly Administered Ketamine
time frame: Dose administration through 5 minutes
description: ED50 is the dose of rapidly administered ketamine that achieves effective sedation in 50% of patients. ED95 is the dose of ketamine that can provide effective sedation in 95% of children undergoing abscess drainage or fracture reduction. ED95 will be calculated for the 3 age groups (2-5, 6-11 and 12-17) independently for both the procedures: abscess drainage and fracture reduction.
measure: ED95
time frame: Dose administration through 5 minutes
description: ED95 is the dose of ketamine effective for 95% of children. this outcome is estimated from ED50.
measure: Vomiting
time frame: Administration of ketamine through 2 week follow up call
description: patients who experienced vomiting while in the ED or after discharge
measure: Number of Participants With Wisconsin Sedation Scale Score of 2 or Less at 1 Minute After First Dose of Ketamine
time frame: Dose administration through 1 minute
description: This is a measure of sedation effectiveness; to assess the effectiveness of first dose of ketamine administered.
Possible values for the scale range from 0 to 6. A sedation score of 2 or less is considered adequate sedation. Values more than 2 indicate state of inadequate sedation. higher values indicate the need for additional doses of sedation.
Patients who achieved a score of 2 or less are considered effective sedation and a score of >2 are considered ineffective sedations.
measure: Total Sedation Time
time frame: Time of administration of ketamine through sedation recovery
description: during recovery, all participants are monitored for recovery to baseline at which point participants are ready for discharge. we will document the time from induction to recovery to aldrete score of 10.
arm group label: Ketamine
arm group type: Experimental
description: participants who get the ketamine sedation will be enrolled. there is no control or comparison group.
intervention type: Drug
intervention name: Ketamine
description: participants who need ketamine sedation for abscess drainage or fracture reduction will be approached for enrollment. there is no comparison group. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.
arm group label: Ketamine
other name: Ketalar
criteria: 
gender: All
minimum age: 2 Years
maximum age: 17 Years
healthy volunteers: No
last name: sri s chinta, MD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
responsible party type: Sponsor
mesh term: Abscess
mesh term: Ketamine
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 