<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/NCT01691690</url>
  </required_header>
  <id_info>
    <org_study_id>IRB12-00097</org_study_id>
    <nct_id>NCT01691690</nct_id>
  </id_info>
  <brief_title>Analgesic Effect of IV Acetaminophen in Tonsillectomies</brief_title>
  <official_title>Analgesic Effect of Single Dose Intravenous Acetaminophen in Pediatric Patients Undergoing Tonsillectomy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nationwide Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Nationwide Children's Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Acetaminophen (paracetamol) is a first-line antipyretic and analgesic for mild and moderate&#xD;
      pain for pediatric patients. Its common use (particularly in oral form) is underscored by its&#xD;
      wide therapeutic window, safety profile, over the counter accessibility, lack of adverse&#xD;
      systemic effects (as compared with NSAIDS and opioids) when given in appropriate doses.&#xD;
&#xD;
      Although the exact anti-nociceptive mechanisms of acetaminophen continue to be elucidated,&#xD;
      these mechanisms appear to be multi-factorial and include central inhibition of the&#xD;
      cyclo-oxygenase (COX) enzyme leading to decreased production of prostaglandins from&#xD;
      arachidonic acid, interference with serotonergic descending pain pathways, indirect&#xD;
      activation of cannabinoid 1 (CB1) receptors and inhibition of nitric oxide pathways through&#xD;
      N-methyl-D-aspartate (NMDA) or substance P. Of the above mechanisms, the most commonly known&#xD;
      is that of central inhibition of COX enzymes by which the decreased production of&#xD;
      prostaglandins diminish the release of excitatory transmitters of substance P and glutamate&#xD;
      which are both involved in nociceptive transmission (Anderson, 2008; Smith, 2011).&#xD;
&#xD;
      To date, several studies have shown acetaminophen's opioid sparing effect in the pediatric&#xD;
      population when given by the rectal or intravenous routes (Korpela et al, 1999; Dashti et al,&#xD;
      2009; Hong et al, 2010).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Once enrolled, subjects will have a standardized anesthetic on the day of surgery:&#xD;
&#xD;
        1. Pre-medication with oral midazolam (0.5mg/kg to maximum dose of 20mg) given 15-20&#xD;
           minutes before induction&#xD;
&#xD;
        2. Inhalation induction with sevoflurane and a mixture of N20/02&#xD;
&#xD;
        3. Propofol 1-1.5 mg/kg to facilitate endotracheal intubation&#xD;
&#xD;
        4. Morphine 0.1 mg/kg given prior to intubation&#xD;
&#xD;
        5. Maintenance anesthesia with isoflurane, titrated to 0.8-1 Minimal Anesthetic&#xD;
           Concentration (MAC) with a mixture of Air/02&#xD;
&#xD;
        6. Acetaminophen IV (15 mg/kg) vs. saline placebo infused intraoperatively (randomized by&#xD;
           pharmacy)&#xD;
&#xD;
        7. Ondansetron (0.15 mg/kg, maximum dose of 4 mg) and dexamethasone (0.25 mg/kg, maximum&#xD;
           dose of 20 mg) for postoperative nausea prophylaxis.&#xD;
&#xD;
      Following surgery and extubation, baseline vitals will be obtained and pain scores will be&#xD;
      assessed in the post anesthesia care unit (PACU) via Faces, Legs, Activity, Cry,&#xD;
      Consolability Scale (FLACC).The presence of emergence delirium will be assessed via Pediatric&#xD;
      Agitation and Emergence Delirium scale (PAED). Those subjects whose pain score is assessed at&#xD;
      &lt; 4 will receive standard postoperative care and no analgesics. Assessed pain scores &gt; 4 will&#xD;
      receive 0.5mcg/kg fentanyl q10 minutes as needed. Variables such as time to extubation in the&#xD;
      PACU, time to first analgesic delivery, pain scores, # times/total dose of opioids given,&#xD;
      presence of sedation, nausea/vomiting, duration of oxygen requirement in PACU, whether or not&#xD;
      patient was discharged to floor on oxygen and total PACU time will be recorded during the&#xD;
      duration of the patient's PACU stay. Subjects will be discharged to the inpatient floor from&#xD;
      the PACU once standard discharge criteria have been met.&#xD;
&#xD;
      Following discharge from the PACU, standardized analgesics will be given for breakthrough&#xD;
      pain (oral oxycodone 0.1mg/kg q4hrs pro re nata (PRN) pain). Enrolled patients will be&#xD;
      followed during the duration of their inpatient stay. Duration of oxygen requirement on the&#xD;
      floor, pain scores and number of administered oxycodone doses on the floor will be monitored&#xD;
      and recorded.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">July 2016</completion_date>
  <primary_completion_date type="Actual">November 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>FLACC Pain Score Greater Than or Equal to 4</measure>
    <time_frame>0-60 mins post-operatively</time_frame>
    <description>The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a measurement used to assess pain for children between the ages of 2 months and 7 years or individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 with 0 representing no pain. 5 pain measurements were performed at 0, 5, 15, 30, and 60 minutes after PACU arrival. This is the number of participants who reached a FLACC score &gt;/= 4 at one or more time points.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Analgesics Administered After Arrival to Inpatient Ward and Number of Participants Requiring Each</measure>
    <time_frame>8-12 hours post-operatively</time_frame>
    <description>Analgesics administered after arrival to the inpatient ward included hydrocodone/acetaminophen, oxycodone, NSAIDS, acetaminophen, and morphine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time of First Opioid Analgesia in PACU</measure>
    <time_frame>0-90 minutes post-operatively</time_frame>
    <description>Mean time to first drug administration among patients requiring opioid analgesia in the PACU.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">250</enrollment>
  <condition>Adenotonsillitis</condition>
  <condition>Tonsillitis</condition>
  <arm_group>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>For this arm Morphine will be administered to manage pain.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen (paracetamol)</intervention_name>
    <description>Acetaminophen IV (15 mg/kg).</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal Saline Flush</intervention_name>
    <description>Saline placebo will be infused intraoperatively.</description>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>Midazolam (0.5mg/kg to maximum dose of 20mg) given 15-20 minutes before induction.</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
    <other_name>Versed</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sevoflurane</intervention_name>
    <description>Sevoflurane for anesthesia induction.</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitrous Oxide/Oxygen</intervention_name>
    <description>Combination of NO2 &amp; O2 for anesthesia induction.</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propofol</intervention_name>
    <description>Propofol 1-1.5 mg/kg to facilitate endotracheal intubation.</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Morphine</intervention_name>
    <description>Morphine 0.1 mg/kg given prior to intubation.</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ondansetron</intervention_name>
    <description>Ondansetron (0.15 mg/kg, maximum dose of 4 mg) for postoperative nausea prophylaxis.</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
    <other_name>Zofran</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Dexamethasone (0.25 mg/kg, maximum dose of 20 mg) for postoperative nausea prophylaxis.</description>
    <arm_group_label>IV Acetaminophen</arm_group_label>
    <arm_group_label>Saline placebo infused intraoperatively</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female patients aged 2 years and younger than 9 years old requiring&#xD;
             postoperative admission for tonsillectomy or adenotonsillectomy.&#xD;
&#xD;
          2. Functional status as assigned by the American Society of Anesthesiology (ASA)&#xD;
             classification of I (1), II (2) or III (3).&#xD;
&#xD;
          3. Have a parent/guardian who are able to provide written informed consent in accordance&#xD;
             with Human Investigations Committee/Institutional Review Board (HIC/IRB) regulations.&#xD;
&#xD;
          4. Have parent/guardian who are compliant with routine medical care, capable of&#xD;
             subjective evaluation and able to read, understand and sign the informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Male or female patients age greater than 9 years.&#xD;
&#xD;
          2. Have an American Society of Anesthesiologists Physical Status &gt; IV (4)(severe disease&#xD;
             that is life threatening).&#xD;
&#xD;
          3. Have a known hypersensitivity or allergy to acetaminophen.&#xD;
&#xD;
          4. Have a known allergy or intolerance to morphine or fentanyl.&#xD;
&#xD;
          5. Have received chronic opioid analgesic therapy prior to surgery.&#xD;
&#xD;
          6. Have renal disease.&#xD;
&#xD;
          7. Have hepatic disease.&#xD;
&#xD;
          8. Are morbidly obese (% BMI &gt; 95).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>9 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Arlyne Thung, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Nationwide Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth. 2008 Oct;18(10):915-21. doi: 10.1111/j.1460-9592.2008.02764.x.</citation>
    <PMID>18811827</PMID>
  </reference>
  <reference>
    <citation>Smith HS. Perioperative intravenous acetaminophen and NSAIDs. Pain Med. 2011 Jun;12(6):961-81. doi: 10.1111/j.1526-4637.2011.01141.x. Epub 2011 May 31.</citation>
    <PMID>21627768</PMID>
  </reference>
  <reference>
    <citation>Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of acetaminophen in pediatric day-case surgery. Anesthesiology. 1999 Aug;91(2):442-7. doi: 10.1097/00000542-199908000-00019.</citation>
    <PMID>10443608</PMID>
  </reference>
  <reference>
    <citation>Dashti GA, Amini S, Zanguee E. The prophylactic effect of rectal acetaminophen on postoperative pain and opioid requirements after adenotonsillectomy in children. Middle East J Anaesthesiol. 2009 Jun;20(2):245-9.</citation>
    <PMID>19583073</PMID>
  </reference>
  <reference>
    <citation>Hong JY, Kim WO, Koo BN, Cho JS, Suk EH, Kil HK. Fentanyl-sparing effect of acetaminophen as a mixture of fentanyl in intravenous parent-/nurse-controlled analgesia after pediatric ureteroneocystostomy. Anesthesiology. 2010 Sep;113(3):672-7. doi: 10.1097/ALN.0b013e3181e2c34b.</citation>
    <PMID>20693884</PMID>
  </reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>May 30, 2012</study_first_submitted>
  <study_first_submitted_qc>September 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2012</study_first_posted>
  <results_first_submitted>September 7, 2016</results_first_submitted>
  <results_first_submitted_qc>February 21, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">April 6, 2017</results_first_posted>
  <last_update_submitted>February 21, 2017</last_update_submitted>
  <last_update_submitted_qc>February 21, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 6, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Nationwide Children's Hospital</investigator_affiliation>
    <investigator_full_name>Arlyne Thung</investigator_full_name>
    <investigator_title>Clinical Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tonsillitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Morphine</mesh_term>
    <mesh_term>Nitrous Oxide</mesh_term>
    <mesh_term>Ondansetron</mesh_term>
    <mesh_term>Propofol</mesh_term>
    <mesh_term>Sevoflurane</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>IV Acetaminophen</title>
          <description>Patients will receive pre-medication with oral midazolam. Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction.&#xD;
Acetaminophen (paracetamol): Acetaminophen IV (15 mg/kg) will be infused intraoperatively over 15 minutes to evaluate the opioid-sparing effect and pain score reduction in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
        </group>
        <group group_id="P2">
          <title>Saline Placebo</title>
          <description>Patients will receive pre-medication with oral midazolam. Participants of this control arm will receive saline to establish a control model for evaluating opioid-sparing effect and pain score reduction compared to the intervention arm.&#xD;
Sodium Chloride (saline): 0.9% Sodium Chloride Placebo will be infused intraoperatively over 15 minutes to establish a control model while evaluating the pain score differences in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="125"/>
                <participants group_id="P2" count="125"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="118"/>
                <participants group_id="P2" count="121"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>IV Acetaminophen</title>
          <description>Patients will receive pre-medication with oral midazolam. Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction.&#xD;
Acetaminophen (paracetamol): Acetaminophen IV (15 mg/kg) will be infused intraoperatively over 15 minutes to evaluate the opioid-sparing effect and pain score reduction in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
        </group>
        <group group_id="B2">
          <title>Saline Placebo</title>
          <description>Patients will receive pre-medication with oral midazolam. Participants of this control arm will receive saline to establish a control model for evaluating opioid-sparing effect and pain score reduction compared to the intervention arm.&#xD;
Sodium Chloride (saline): 0.9% Sodium Chloride Placebo will be infused intraoperatively over 15 minutes to establish a control model while evaluating the pain score differences in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
        </group>
        <group group_id="B3">
          <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="118"/>
            <count group_id="B2" value="121"/>
            <count group_id="B3" value="239"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4.87" spread="1.53"/>
                    <measurement group_id="B2" value="4.84" spread="1.42"/>
                    <measurement group_id="B3" value="4.855" spread="1.476"/>
                  </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="62"/>
                    <measurement group_id="B2" value="59"/>
                    <measurement group_id="B3" value="121"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="56"/>
                    <measurement group_id="B2" value="62"/>
                    <measurement group_id="B3" value="118"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height (cm)</title>
          <units>centimeters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="109.31" spread="10.82"/>
                    <measurement group_id="B2" value="108.78" spread="10.37"/>
                    <measurement group_id="B3" value="109.04" spread="10.58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight (kg)</title>
          <units>kilograms</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18.85" spread="4.74"/>
                    <measurement group_id="B2" value="18.27" spread="4.02"/>
                    <measurement group_id="B3" value="18.56" spread="4.39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index (kg/m2)</title>
          <units>Kg/m2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15.56" spread="1.58"/>
                    <measurement group_id="B2" value="15.29" spread="1.36"/>
                    <measurement group_id="B3" value="15.42" spread="1.47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Procedure time (min)</title>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15.85" spread="5.78"/>
                    <measurement group_id="B2" value="16.65" spread="5.90"/>
                    <measurement group_id="B3" value="16.26" spread="5.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Extubation time (min)</title>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16.65" spread="7.68"/>
                    <measurement group_id="B2" value="15.38" spread="8.52"/>
                    <measurement group_id="B3" value="16.01" spread="8.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Post-Anesthetic Care Unit time (min)</title>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.57" spread="23.41"/>
                    <measurement group_id="B2" value="65.07" spread="19.40"/>
                    <measurement group_id="B3" value="64.82" spread="21.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Time to first analgesic on unit (min)</title>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="298.36" spread="97.52"/>
                    <measurement group_id="B2" value="297.09" spread="106.91"/>
                    <measurement group_id="B3" value="297.74" spread="101.97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>FLACC Pain Score Greater Than or Equal to 4</title>
        <description>The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a measurement used to assess pain for children between the ages of 2 months and 7 years or individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 with 0 representing no pain. 5 pain measurements were performed at 0, 5, 15, 30, and 60 minutes after PACU arrival. This is the number of participants who reached a FLACC score &gt;/= 4 at one or more time points.</description>
        <time_frame>0-60 mins post-operatively</time_frame>
        <group_list>
          <group group_id="O1">
            <title>IV Acetaminophen</title>
            <description>Patients will receive pre-medication with oral midazolam. Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction.&#xD;
Acetaminophen (paracetamol): Acetaminophen IV (15 mg/kg) will be infused intraoperatively over 15 minutes to evaluate the opioid-sparing effect and pain score reduction in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
          </group>
          <group group_id="O2">
            <title>Saline Placebo</title>
            <description>Patients will receive pre-medication with oral midazolam. Participants of this control arm will receive saline to establish a control model for evaluating opioid-sparing effect and pain score reduction compared to the intervention arm.&#xD;
Sodium Chloride (saline): 0.9% Sodium Chloride Placebo will be infused intraoperatively over 15 minutes to establish a control model while evaluating the pain score differences in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
          </group>
        </group_list>
        <measure>
          <title>FLACC Pain Score Greater Than or Equal to 4</title>
          <description>The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a measurement used to assess pain for children between the ages of 2 months and 7 years or individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 with 0 representing no pain. 5 pain measurements were performed at 0, 5, 15, 30, and 60 minutes after PACU arrival. This is the number of participants who reached a FLACC score &gt;/= 4 at one or more time points.</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="118"/>
                <count group_id="O2" value="121"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58"/>
                    <measurement group_id="O2" value="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Analgesics Administered After Arrival to Inpatient Ward and Number of Participants Requiring Each</title>
        <description>Analgesics administered after arrival to the inpatient ward included hydrocodone/acetaminophen, oxycodone, NSAIDS, acetaminophen, and morphine.</description>
        <time_frame>8-12 hours post-operatively</time_frame>
        <population>Comparing both groups for the time study subjects required breakthrough pain medication on the ward.</population>
        <group_list>
          <group group_id="O1">
            <title>IV Acetaminophen</title>
            <description>Patients will receive pre-medication with oral midazolam. Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction.&#xD;
Acetaminophen (paracetamol): Acetaminophen IV (15 mg/kg) will be infused intraoperatively over 15 minutes to evaluate the opioid-sparing effect and pain score reduction in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
          </group>
          <group group_id="O2">
            <title>Saline Placebo Infused Intraoperatively</title>
            <description>Patients will receive pre-medication with oral midazolam. Participants of this control arm will receive saline to establish a control model for evaluating opioid-sparing effect and pain score reduction compared to the intervention arm.&#xD;
Sodium Chloride (saline): 0.9% Sodium Chloride Placebo will be infused intraoperatively over 15 minutes to establish a control model while evaluating the pain score differences in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
          </group>
        </group_list>
        <measure>
          <title>Analgesics Administered After Arrival to Inpatient Ward and Number of Participants Requiring Each</title>
          <description>Analgesics administered after arrival to the inpatient ward included hydrocodone/acetaminophen, oxycodone, NSAIDS, acetaminophen, and morphine.</description>
          <population>Comparing both groups for the time study subjects required breakthrough pain medication on the ward.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="118"/>
                <count group_id="O2" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>hydrocodone/acetaminophen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="68"/>
                    <measurement group_id="O2" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>oxycodone</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31"/>
                    <measurement group_id="O2" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSAIDS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                    <measurement group_id="O2" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>acetaminophen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>morphine</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time of First Opioid Analgesia in PACU</title>
        <description>Mean time to first drug administration among patients requiring opioid analgesia in the PACU.</description>
        <time_frame>0-90 minutes post-operatively</time_frame>
        <group_list>
          <group group_id="O1">
            <title>IV Acetaminophen</title>
            <description>Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..&#xD;
Acetaminophen (paracetamol): Acetaminophen IV (15 mg/kg).&#xD;
Midazolam: Midazolam (0.5mg/kg to maximum dose of 20mg) given 15-20 minutes before induction.&#xD;
Sevoflurane: Sevoflurane for anesthesia induction.&#xD;
Nitrous Oxide/Oxygen: Combination of NO2 &amp; O2 for anesthesia induction.&#xD;
Propofol: Propofol 1-1.5 mg/kg to facilitate endotracheal intubation.&#xD;
Morphine: Morphine 0.1 mg/kg given prior to intubation.&#xD;
Ondansetron: Ondansetron (0.15 mg/kg, maximum dose of 4 mg) for postoperative nausea prophylaxis.&#xD;
Dexamethasone: Dexamethasone (0.25 mg/kg, maximum dose of 20 mg) for postoperative nausea prophylaxis.</description>
          </group>
          <group group_id="O2">
            <title>Saline Placebo Infused Intraoperatively</title>
            <description>For this arm Morphine will be administered to manage pain.&#xD;
Normal Saline Flush: Saline placebo will be infused intraoperatively.&#xD;
Midazolam: Midazolam (0.5mg/kg to maximum dose of 20mg) given 15-20 minutes before induction.&#xD;
Sevoflurane: Sevoflurane for anesthesia induction.&#xD;
Nitrous Oxide/Oxygen: Combination of NO2 &amp; O2 for anesthesia induction.&#xD;
Propofol: Propofol 1-1.5 mg/kg to facilitate endotracheal intubation.&#xD;
Morphine: Morphine 0.1 mg/kg given prior to intubation.&#xD;
Ondansetron: Ondansetron (0.15 mg/kg, maximum dose of 4 mg) for postoperative nausea prophylaxis.&#xD;
Dexamethasone: Dexamethasone (0.25 mg/kg, maximum dose of 20 mg) for postoperative nausea prophylaxis.</description>
          </group>
        </group_list>
        <measure>
          <title>Time of First Opioid Analgesia in PACU</title>
          <description>Mean time to first drug administration among patients requiring opioid analgesia in the PACU.</description>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="118"/>
                <count group_id="O2" value="121"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.80" spread="14.15"/>
                    <measurement group_id="O2" value="60.46" spread="20.51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data were collected for each patient from pre-operative registration, peri-operatively, until hospital discharge post-operatively (Data collection occurred over the course of a 24 hour period).</time_frame>
      <group_list>
        <group group_id="E1">
          <title>IV Acetaminophen</title>
          <description>Patients will receive pre-medication with oral midazolam. Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction.&#xD;
Acetaminophen (paracetamol): Acetaminophen IV (15 mg/kg) will be infused intraoperatively over 15 minutes to evaluate the opioid-sparing effect and pain score reduction in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
        </group>
        <group group_id="E2">
          <title>Saline Placebo</title>
          <description>Patients will receive pre-medication with oral midazolam. Participants of this control arm will receive saline to establish a control model for evaluating opioid-sparing effect and pain score reduction compared to the intervention arm.&#xD;
Sodium Chloride (saline): 0.9% Sodium Chloride Placebo will be infused intraoperatively over 15 minutes to establish a control model while evaluating the pain score differences in pediatric patients undergoing tonsillectomy or adenotonsillectomy procedures.&#xD;
Morphine (hydromorphone): Morphine (0.1 mg/kg) will be added to manage pain prior to intubation.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="121"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>2</frequency_threshold>
        <default_assessment>Non-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="11" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="121"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Post-operative nausea or vomiting (PONV)</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="121"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory complications</sub_title>
                <assessment>Systematic Assessment</assessment>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="121"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Dr. Arlyne Thung</name_or_title>
      <organization>Nationwide Children's Hospital</organization>
      <phone>(614) 722-4200</phone>
      <email>Arlyne.Thung@NationwideChildrens.org</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/NCT01691690
org study id: IRB12-00097
nct id: NCT01691690
lead sponsor: 
has dmc: No
Acetaminophen (paracetamol) is a first-line antipyretic and analgesic for mild and moderate
      pain for pediatric patients. Its common use (particularly in oral form) is underscored by its
      wide therapeutic window, safety profile, over the counter accessibility, lack of adverse
      systemic effects (as compared with NSAIDS and opioids) when given in appropriate doses.

      Although the exact anti-nociceptive mechanisms of acetaminophen continue to be elucidated,
      these mechanisms appear to be multi-factorial and include central inhibition of the
      cyclo-oxygenase (COX) enzyme leading to decreased production of prostaglandins from
      arachidonic acid, interference with serotonergic descending pain pathways, indirect
      activation of cannabinoid 1 (CB1) receptors and inhibition of nitric oxide pathways through
      N-methyl-D-aspartate (NMDA) or substance P. Of the above mechanisms, the most commonly known
      is that of central inhibition of COX enzymes by which the decreased production of
      prostaglandins diminish the release of excitatory transmitters of substance P and glutamate
      which are both involved in nociceptive transmission (Anderson, 2008; Smith, 2011).

      To date, several studies have shown acetaminophen's opioid sparing effect in the pediatric
      population when given by the rectal or intravenous routes (Korpela et al, 1999; Dashti et al,
      2009; Hong et al, 2010).
Once enrolled, subjects will have a standardized anesthetic on the day of surgery:

        1. Pre-medication with oral midazolam (0.5mg/kg to maximum dose of 20mg) given 15-20
           minutes before induction

        2. Inhalation induction with sevoflurane and a mixture of N20/02

        3. Propofol 1-1.5 mg/kg to facilitate endotracheal intubation

        4. Morphine 0.1 mg/kg given prior to intubation

        5. Maintenance anesthesia with isoflurane, titrated to 0.8-1 Minimal Anesthetic
           Concentration (MAC) with a mixture of Air/02

        6. Acetaminophen IV (15 mg/kg) vs. saline placebo infused intraoperatively (randomized by
           pharmacy)

        7. Ondansetron (0.15 mg/kg, maximum dose of 4 mg) and dexamethasone (0.25 mg/kg, maximum
           dose of 20 mg) for postoperative nausea prophylaxis.

      Following surgery and extubation, baseline vitals will be obtained and pain scores will be
      assessed in the post anesthesia care unit (PACU) via Faces, Legs, Activity, Cry,
      Consolability Scale (FLACC).The presence of emergence delirium will be assessed via Pediatric
      Agitation and Emergence Delirium scale (PAED). Those subjects whose pain score is assessed at
      < 4 will receive standard postoperative care and no analgesics. Assessed pain scores > 4 will
      receive 0.5mcg/kg fentanyl q10 minutes as needed. Variables such as time to extubation in the
      PACU, time to first analgesic delivery, pain scores, # times/total dose of opioids given,
      presence of sedation, nausea/vomiting, duration of oxygen requirement in PACU, whether or not
      patient was discharged to floor on oxygen and total PACU time will be recorded during the
      duration of the patient's PACU stay. Subjects will be discharged to the inpatient floor from
      the PACU once standard discharge criteria have been met.

      Following discharge from the PACU, standardized analgesics will be given for breakthrough
      pain (oral oxycodone 0.1mg/kg q4hrs pro re nata (PRN) pain). Enrolled patients will be
      followed during the duration of their inpatient stay. Duration of oxygen requirement on the
      floor, pain scores and number of administered oxycodone doses on the floor will be monitored
      and recorded.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: FLACC Pain Score Greater Than or Equal to 4
time frame: 0-60 mins post-operatively
description: The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a measurement used to assess pain for children between the ages of 2 months and 7 years or individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 with 0 representing no pain. 5 pain measurements were performed at 0, 5, 15, 30, and 60 minutes after PACU arrival. This is the number of participants who reached a FLACC score >/= 4 at one or more time points.
measure: Analgesics Administered After Arrival to Inpatient Ward and Number of Participants Requiring Each
time frame: 8-12 hours post-operatively
description: Analgesics administered after arrival to the inpatient ward included hydrocodone/acetaminophen, oxycodone, NSAIDS, acetaminophen, and morphine.
measure: Time of First Opioid Analgesia in PACU
time frame: 0-90 minutes post-operatively
description: Mean time to first drug administration among patients requiring opioid analgesia in the PACU.
arm group label: IV Acetaminophen
arm group type: Experimental
description: Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
arm group label: Saline placebo infused intraoperatively
arm group type: Placebo Comparator
description: For this arm Morphine will be administered to manage pain.
intervention type: Drug
intervention name: Acetaminophen (paracetamol)
description: Acetaminophen IV (15 mg/kg).
arm group label: IV Acetaminophen
intervention type: Drug
intervention name: Normal Saline Flush
description: Saline placebo will be infused intraoperatively.
arm group label: Saline placebo infused intraoperatively
intervention type: Drug
intervention name: Midazolam
description: Midazolam (0.5mg/kg to maximum dose of 20mg) given 15-20 minutes before induction.
arm group label: IV Acetaminophen
arm group label: Saline placebo infused intraoperatively
other name: Versed
intervention type: Drug
intervention name: Sevoflurane
description: Sevoflurane for anesthesia induction.
arm group label: IV Acetaminophen
arm group label: Saline placebo infused intraoperatively
intervention type: Drug
intervention name: Nitrous Oxide/Oxygen
description: Combination of NO2 & O2 for anesthesia induction.
arm group label: IV Acetaminophen
arm group label: Saline placebo infused intraoperatively
intervention type: Drug
intervention name: Propofol
description: Propofol 1-1.5 mg/kg to facilitate endotracheal intubation.
arm group label: IV Acetaminophen
arm group label: Saline placebo infused intraoperatively
intervention type: Drug
intervention name: Morphine
description: Morphine 0.1 mg/kg given prior to intubation.
arm group label: IV Acetaminophen
arm group label: Saline placebo infused intraoperatively
intervention type: Drug
intervention name: Ondansetron
description: Ondansetron (0.15 mg/kg, maximum dose of 4 mg) for postoperative nausea prophylaxis.
arm group label: IV Acetaminophen
arm group label: Saline placebo infused intraoperatively
other name: Zofran
intervention type: Drug
intervention name: Dexamethasone
description: Dexamethasone (0.25 mg/kg, maximum dose of 20 mg) for postoperative nausea prophylaxis.
arm group label: IV Acetaminophen
arm group label: Saline placebo infused intraoperatively
criteria: 
gender: All
minimum age: 2 Years
maximum age: 9 Years
healthy volunteers: No
last name: Arlyne Thung, MD
role: Principal Investigator
affiliation: Nationwide Children's Hospital
facility: 
country: United States
citation: Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth. 2008 Oct;18(10):915-21. doi: 10.1111/j.1460-9592.2008.02764.x.
PMID: 18811827
citation: Smith HS. Perioperative intravenous acetaminophen and NSAIDs. Pain Med. 2011 Jun;12(6):961-81. doi: 10.1111/j.1526-4637.2011.01141.x. Epub 2011 May 31.
PMID: 21627768
citation: Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of acetaminophen in pediatric day-case surgery. Anesthesiology. 1999 Aug;91(2):442-7. doi: 10.1097/00000542-199908000-00019.
PMID: 10443608
citation: Dashti GA, Amini S, Zanguee E. The prophylactic effect of rectal acetaminophen on postoperative pain and opioid requirements after adenotonsillectomy in children. Middle East J Anaesthesiol. 2009 Jun;20(2):245-9.
PMID: 19583073
citation: Hong JY, Kim WO, Koo BN, Cho JS, Suk EH, Kil HK. Fentanyl-sparing effect of acetaminophen as a mixture of fentanyl in intravenous parent-/nurse-controlled analgesia after pediatric ureteroneocystostomy. Anesthesiology. 2010 Sep;113(3):672-7. doi: 10.1097/ALN.0b013e3181e2c34b.
PMID: 20693884
responsible party type: Principal Investigator
investigator affiliation: Nationwide Children's Hospital
investigator full name: Arlyne Thung
investigator title: Clinical Assistant Professor
mesh term: Tonsillitis
mesh term: Acetaminophen
mesh term: Dexamethasone
mesh term: Midazolam
mesh term: Morphine
mesh term: Nitrous Oxide
mesh term: Ondansetron
mesh term: Propofol
mesh term: Sevoflurane
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 