xml: <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/NCT06033729</url>
    </required_header>
    <id_info>
      <org_study_id>CBM 20-12</org_study_id>
      <nct_id>NCT06033729</nct_id>
    </id_info>
    <brief_title>Remifentanil Target Controlled Infusion Versus Standard of Care for Conscious Sedation During EBUS-TBNA</brief_title>
    <official_title>Remifentanil Target Controlled Infusion Versus Standard of Care for Conscious Sedation During US-guided Transbronchial Needle Aspiration (EBUS-TBNA): a Randomized, Prospective, Control Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Scarlata, Simone, M.D.</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Scarlata, Simone, M.D.</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        Background: endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a&#xD;
        minimally invasive procedure for diagnosing and staging mediastinal lymph node lesions in&#xD;
        lung cancer. Adequate sedation is crucial for patient comfort and diagnostic accuracy.&#xD;
        Different sedation modalities, including moderate sedation/conscious sedation, deep sedation,&#xD;
        and general anesthesia, are utilized. This study aims to evaluate patient comfort and&#xD;
        satisfaction levels of healthcare providers (bronchoscopists and anesthesiologists) when&#xD;
        administering remifentanil through Target Controlled Infusion (TCI) for conscious sedation&#xD;
        during EBUS-TBNA. A prospective randomized study design compares this approach to the&#xD;
        standard sedation protocol involving midazolam, fentanyl, and/or propofol.&#xD;
  &#xD;
        Methods: this study will enroll 30 eligible patients randomly divided into two groups. Group&#xD;
        1, &quot;REMIFENTANIL TCI&quot;, underwent EBUS-TBNA under conscious sedation with remifentanil TCI&#xD;
        infusion targeting a concentration of 3-6 ng/ml. Group 2, &quot;STANDARD&quot;, received conscious&#xD;
        sedation with a combination of midazolam, fentanyl, and/or propofol administered in boluses&#xD;
        based on clinical requirements. Complications, safety, and satisfaction levels of the&#xD;
        operator, anesthesiologist, and patients will be evaluated.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        BACKGROUND Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a&#xD;
        minimally invasive procedure that has gained major relevance in diagnosis lung cancer and&#xD;
        staging of mediastinal lymph nodes (LN). Adequate sedation is an important part of the&#xD;
        procedure since it improves patient's comfort and tolerance potentially positively affecting&#xD;
        the diagnostic yield. It is also considered a standard of care for patients undergoing&#xD;
        fiberoptic bronchoscopy unless specifically contraindicated.&#xD;
  &#xD;
        The choice of the different level of sedation (from conscious to moderate to deep sedation)&#xD;
        has always been challenging and, to date, no standardized practice exists. Deep sedation may&#xD;
        be preferred in those cases where additional procedures such as placement of endobronchial&#xD;
        stents, are required, or in order to make the procedure more suitable by limiting the&#xD;
        patients motion. In remaining cases, conscious sedation allows to complain with the clinical&#xD;
        demand without affecting respiratory and cardiovascular function, decreasing the cough reflex&#xD;
        and maintaining sufficient swallowing capacity.&#xD;
  &#xD;
        Not appropriate sedation can have serious complications, including respiratory depression or&#xD;
        even arrest, hypoxia and/or hypercapnia, and cardiovascular and neurological side effects.&#xD;
  &#xD;
        Commonly used drugs for sedation include propofol and a combination of benzodiazepines and&#xD;
        opioids. However, achieving the ideal level of sedation can be challenging, since it may&#xD;
        occasionally lead to over sedation, with detrimental effects. These risks are even greater if&#xD;
        the patients present with lung disease, obesity, or heart disease. Conversely, under sedation&#xD;
        can result in discomfort for the patient and challenging procedure it for the healthcare&#xD;
        provider. Furthermore, benzodiazepines and medium-long-acting opioids continue their effect&#xD;
        even after the procedure is finished, thus lasting the negative effects of these drugs over&#xD;
        the time of the procedure.&#xD;
  &#xD;
        In a recent case series, Scarlata and colleagues have provided a preliminary evidence of a&#xD;
        TCI remifentanil protocol safety and effectiveness, providing an ideal and performant&#xD;
        condition for bronchoscopists and a satisfactory comfort for patients.&#xD;
  &#xD;
        Using a TCI continuous infusion protocol of Remifentanil can exploit the sedative, analgesic&#xD;
        and antitussive capabilities of this short-acting opioid, achieving a level of conscious&#xD;
        sedation that ensures an adequate level of comfort for the patient while at the same time&#xD;
        decreases the incidence of side effects typical of deep sedation. The patient remains&#xD;
        contactable and can respond and execute commands, such as breathing, swallowing, etc.&#xD;
  &#xD;
        TCI is a method of continuous drug administration where the infusion of the drug is remotely&#xD;
        controlled. There are different administration algorithms and there is the possibility to&#xD;
        titrate the target concentration both at the effect site (CNS) and in the plasma.&#xD;
  &#xD;
        There are numerous studies confirming the efficacy of remifentanil administered by TCI during&#xD;
        intubation with an awake patient, and the advantages of the latter compared to other&#xD;
        techniques, such as propofol infusion. One study determined the efficacy of infused&#xD;
        remifentanil and propofol for bronchial endoscopy procedures, but did not use the TCI&#xD;
        technique for infusion. There are no clinical studies assessing endoscopic transbronchial&#xD;
        needle biopsy procedures with remifentanil infusion in TCI mode.&#xD;
  &#xD;
        The aim of this study is therefore to conduct a prospective, randomized, controlled trial to&#xD;
        evaluate the administration of remifentanil in TCI for conscious sedation during EBUS-TBNA&#xD;
        procedures, the degree of patient and operator satisfaction and the relative advantages and&#xD;
        disadvantages versus the of standard sedation protocol with midazolam and/or fentanyl and/or&#xD;
        propofol.&#xD;
  &#xD;
        METHODS This is a single center, randomized, investigator initiated clinical trial of 30&#xD;
        patients undergoing EBUS-TBNA for mediastinal staging of lung cancer. Patients were randomly&#xD;
        assigned to one of two groups: Group 1 &quot;REMIFENTANIL TCI&quot; (Experimental Group): the patients&#xD;
        performed the EBUS-TBNA procedure under conscious sedation with infusion of Remifentanil TCI&#xD;
        with a target between 3 and 6 ng/ml; Group 2 &quot;STANDARD&quot; (Control Group): the patients&#xD;
        performed the EBUS-TBNA procedure in conscious sedation with the association of midazolam&#xD;
        and/or fentanyl and/or propofol in refracted boluses based on clinical needs (agitation,&#xD;
        unsatisfactory level of sedation or not collaborative patient) and according to the&#xD;
        anesthesiologist's clinical judgement.&#xD;
  &#xD;
        After obtaining a signed informed consent the patient was randomly allocated 1:1 to the group&#xD;
        &quot;REMIFENTANIL TCI&quot; or &quot;STANDARD&quot;. A research randomizer software was used for randomization&#xD;
        (iRANDOMIZER-SHMOOPI LLC-version 2.5). Both the bronchoscopist and the research assistant&#xD;
        administrating the questionnaires were blinded to the assigned group. It was not possible to&#xD;
        blind anesthesiologists involved in the patient's care.&#xD;
  &#xD;
        The procedures used in this study adhere to the tenets of the Declaration of Helsinki.&#xD;
  &#xD;
        Study treatment The ASA scale, the Mallampati score, the presence of OSAS were recorded prior&#xD;
        of the procedure. Also, data about the underlying oncological disease, whether chemotherapy&#xD;
        and/or radiotherapy was performed, and the indication for the EBUS-TBNA test (diagnostic,&#xD;
        staging, re-staging, or both diagnostic and staging at the same moment) were collected.&#xD;
  &#xD;
        The patient candidate for the endoscopic procedure underwent continuous monitoring of vital&#xD;
        signs. ECG with precordial leads, continuous finger pulse oximetry, and noninvasive&#xD;
        intermittent blood pressure measurements were monitored. Each patient was preoxygenated for&#xD;
        about 5 minutes by administering O2 with nasal goggles at 3L/min or higher, if required.&#xD;
  &#xD;
        Lidocaine was topically nebulized at the level of the mucous membranes of the oropharynx.&#xD;
        Oxybuprocaine 4mg/ml was also nebulized at the level of the vocal cords via the eco-endoscope&#xD;
        before passing the glottic plane in all patients.&#xD;
  &#xD;
        Remifentanil group conscious sedation protocol (intra venous remifentanil in TCI). Drug&#xD;
        administration begun 5 minutes before the procedure. The achievement of the ideal target&#xD;
        occurs starting from an initial target at the effect site of 1 ng/ml and gradually increasing&#xD;
        the desired target on the pump by 0.5 ng/ml at a time, until reaching a target between 3 and&#xD;
        6 ng/ml and an adequate level of sedation (Ramsey Score between 2-3).&#xD;
  &#xD;
        Desired target was achieved by automatic infusion pumps (Infusomat® Space® Large Volume Pump,&#xD;
        Braun medical inc) If, despite the maximum target, a satisfactory level of sedation was not&#xD;
        reached, repeated boluses of propofol were given as clinically needed and the case considered&#xD;
        as protocol failure.&#xD;
  &#xD;
        Patients in the STANDARD Group performed the EBUS-TBNA with bolus administration of midazolam&#xD;
        and/or fentanyl and/or propofol. Shortly before the start of the procedure they received 1-2&#xD;
        mg bolus midazolam and/or 50-100 range bolus fentanyl until they reach the level of sedation&#xD;
        (Ramsey Score 2-3). In addition, repeated boluses of propofol could have been given according&#xD;
        to clinical needs (state of agitation of the patient, requests from the operator due to&#xD;
        difficulties in carrying out the procedure).&#xD;
  &#xD;
        Data were collected about the procedure performed, any changes in vital signs that occurred&#xD;
        during the procedure and the depth of sedation.&#xD;
  &#xD;
        Anesthesiologist, bronchoscopist and patient's satisfaction tools At the end of the&#xD;
        procedure, the patient was given a satisfaction questionnaire to evaluate the degree of&#xD;
        satisfaction. The 0-5 Likert numerical scale was used to evaluate the symptoms onset of cough&#xD;
        (0 none-5 very much), sore throat (0-5), chest pain (0-5), shortness of breath (0 eupnoea- 5&#xD;
        worsening dyspnea), presence of memories (0 none - 5 vivid memories), and perioperative&#xD;
        comfort (0 none - 5 excellent). The operator who performed the procedure and the sedation&#xD;
        were also subjected to a satisfaction questionnaire which assessed the overall satisfaction&#xD;
        (1 much worse than usual - 5 much better than usual).&#xD;
  &#xD;
        Statistical Analysis The analysis was performed on an intention to treat basis, regardless of&#xD;
        actual compliance with the intended intervention.&#xD;
  &#xD;
        A two-tailed p value equal or less than 0.05 was considered as statistically significant. All&#xD;
        tests, except for the primary outcome, were considered merely exploratory. When individual&#xD;
        items were missing from a scale, the percent of missing values and, if more than 10% was&#xD;
        calculated, the scale score was considered missing and therefore made unavailable for&#xD;
        analysis. All the analyses were conducted using STATA (StataCorp. 2021. Stata Statistical&#xD;
        Software: Release 17. College Station, TX: StataCorp LLC.).&#xD;
  &#xD;
        Outcome analysis Primary and secondary endpoints will be compared between the two groups of&#xD;
        treatment by means of Student's t-test (or the Mann-Whitney U test, if necessary) for&#xD;
        continuous quantitative variables and by means of the χ2 test (or Fisher's exact test ) for&#xD;
        qualitative variables.&#xD;
  &#xD;
        Sample size determination Our previously published case series showed that the overall&#xD;
        satisfaction rate for both the patient and the bronchoscopist were very high in the&#xD;
        remifentanil TCI group (mean Likert score above 4/5 against a mean value ranging from 2 to 3&#xD;
        in the standard group as available in the literature). Enrolling 30 patients (fifteen for&#xD;
        each group) would have provided with 80% power at an alpha level of 0.05.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Completed</overall_status>
    <start_date type="Actual">September 20, 2021</start_date>
    <completion_date type="Actual">January 17, 2023</completion_date>
    <primary_completion_date type="Actual">July 1, 2022</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Informed consent was obtained from each patient or legally authorized representative prior to enrollment in this study.&#xD;
  After obtaining a signed informed consent the patient was randomly allocated 1:1 to the group &quot;REMIFENTANIL TCI&quot; or &quot;STANDARD&quot;. A research randomizer software was used for randomization (iRANDOMIZER-SHMOOPI LLC-version 2.5).</intervention_model_description>
      <primary_purpose>Supportive Care</primary_purpose>
      <masking>Double (Participant, Outcomes Assessor)</masking>
      <masking_description>The bronchoscopist, the patient and the research assistant administrating the questionnaires were blinded to the assigned group. It was not possible to blind anesthesiologists involved in the patient's care.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Patient, bronchoscopist and anesthesiologist's comfort and satisfaction to the procedure.</measure>
      <time_frame>At patient's dismission from bronchoscopy suit</time_frame>
      <description>the patient was given a satisfaction questionnaire to evaluate the degree of satisfaction. The 0-5 Likert numerical scale was used to evaluate the symptoms onset of cough (0 none-5 very much), sore throat (0-5), chest pain (0-5), shortness of breath (0 eupnoea- 5 worsening dyspnea), presence of memories (0 none - 5 vivid memories), and perioperative comfort (0 none - 5 excellent). The operator who performed the procedure and the sedation were also subjected to a satisfaction questionnaire which assessed the overall satisfaction (1 much worse than usual - 5 much better than usual).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>propofol boluses administered</measure>
      <time_frame>During the procedure</time_frame>
      <description>Number and dosage of any propofol boluses administered (both in the experimental group and in the control group)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Procedure time</measure>
      <time_frame>During the procedure</time_frame>
      <description>Total duration of the procedure (in minutes)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Level of sedation</measure>
      <time_frame>During the procedure</time_frame>
      <description>Level of sedation achieved (Ramsey score)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Over sedation</measure>
      <time_frame>During the procedure</time_frame>
      <description>Episodes of over-sedation (Ramsey score &gt; 3)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Desaturation</measure>
      <time_frame>Up to an hour from the end of the procedure</time_frame>
      <description>Desaturation episodes</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Hypotension</measure>
      <time_frame>Up to an hour from the end of the procedure</time_frame>
      <description>Episodes of hypotension (SBP &lt;90 mmHg)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Bradycardia</measure>
      <time_frame>Up to an hour from the end of the procedure</time_frame>
      <description>Episodes of Bradycardia (HR&lt;60)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Bradypnea or respiratory arrest</measure>
      <time_frame>Up to an hour from the end of the procedure</time_frame>
      <description>Episodes of bradypnea (RR&lt;10)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cough</measure>
      <time_frame>Up to two hours from the end of the procedure</time_frame>
      <description>Excessive cough (Unconfortable, unconstrained cough affecting patient's and operator comfort)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Airway support</measure>
      <time_frame>Up to an hour from the and of the procedure</time_frame>
      <description>Need for airway support</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Sampled lymph nodes</measure>
      <time_frame>During the procedure</time_frame>
      <description>Number of lymph nodes sampled during the procedure.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Sampled lesions</measure>
      <time_frame>During the procedure</time_frame>
      <description>Number of masses sampled during the procedure.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Number of biopsies per limph node</measure>
      <time_frame>During the procedure</time_frame>
      <description>Number of biopsies per single lymph node needed to obtain a confident sample size according to a visual on-site evaluation.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Number of biopsies per mass</measure>
      <time_frame>During the procedure</time_frame>
      <description>Number of biopsies per single mass needed to obtain a confident sample size according to a visual on-site evaluation</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Actual">30</enrollment>
    <condition>Lung Cancer</condition>
    <condition>Lung; Node</condition>
    <condition>Sedation Complication</condition>
    <condition>Endoscopy</condition>
    <arm_group>
      <arm_group_label>Group 1 &quot;REMIFENTANIL TCI&quot; (Experimental Group)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>the patients performed the EBUS-TBNA procedure under conscious sedation with infusion of Remifentanil TCI with a target between 3 and 6 ng/ml;</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Group 2 &quot;STANDARD&quot; (Control Group)</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>the patients performed the EBUS-TBNA procedure in conscious sedation with the association of midazolam and/or fentanyl and/or propofol in refracted boluses based on clinical needs (agitation, unsatisfactory level of sedation or not collaborative patient) and according to the anesthesiologist's clinical judgement.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Remifentanil TCI</intervention_name>
      <description>REMI-TCI administration begun 5 minutes before the procedure, starting from an initial target at the effect site of 1 ng/ml and gradually increasing by 0.5 ng/ml until reaching an adequate level of sedation (Ramsey score between 2-3).</description>
      <arm_group_label>Group 1 &quot;REMIFENTANIL TCI&quot; (Experimental Group)</arm_group_label>
      <other_name>REMI - target control infusion</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Midazolam injection</intervention_name>
      <description>Bolus administration of midazolam (1-2 mg)and/or until a Ramsey score 2-3 was reached</description>
      <arm_group_label>Group 2 &quot;STANDARD&quot; (Control Group)</arm_group_label>
      <other_name>Bolus administration of midazolam</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Fentanyl</intervention_name>
      <description>Bolus adminitration of fentanyl (50-100 mcg) until a Ramsey score 2-3 was reached</description>
      <arm_group_label>Group 2 &quot;STANDARD&quot; (Control Group)</arm_group_label>
      <other_name>Bolus administration of Fentanyl</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Propofol</intervention_name>
      <description>Bolus adminitration of propofol until a Ramsey score 2-3 was reached</description>
      <arm_group_label>Group 2 &quot;STANDARD&quot; (Control Group)</arm_group_label>
      <other_name>Bolus administration of Propofol</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  patients aged 18-80 years,&#xD;
  &#xD;
            -  clinical fit to undergo the planned procedure, according to the American Society of&#xD;
               Anesthesiologists physical status classification.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  current chronic opioid treatment,&#xD;
  &#xD;
            -  substance abuse or drug use;&#xD;
  &#xD;
            -  pregnancy,&#xD;
  &#xD;
            -  history of allergy to related medications;&#xD;
  &#xD;
            -  severe coagulation dysfunction;&#xD;
  &#xD;
            -  severe hepatic&#xD;
  &#xD;
            -  renal dysfunction;&#xD;
  &#xD;
            -  history of abnormal recovery from anesthesia;&#xD;
  &#xD;
            -  acute respiratory failure;&#xD;
  &#xD;
            -  inability or unwillingness to provide informed consent.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>Università Campus Bio Medico</name>
        <address>
          <city>Roma</city>
          <zip>00128</zip>
          <country>Italy</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <results_reference>
      <citation>Wahidi MM, Jain P, Jantz M, Lee P, Mackensen GB, Barbour SY, Lamb C, Silvestri GA. American College of Chest Physicians consensus statement on the use of topical anesthesia, analgesia, and sedation during flexible bronchoscopy in adult patients. Chest. 2011 Nov;140(5):1342-1350. doi: 10.1378/chest.10-3361.</citation>
      <PMID>22045879</PMID>
    </results_reference>
    <results_reference>
      <citation>Aswanetmanee P, Limsuwat C, Kabach M, Alraiyes AH, Kheir F. The role of sedation in endobronchial ultrasound-guided transbronchial needle aspiration: Systematic review. Endosc Ultrasound. 2016 Sep-Oct;5(5):300-306. doi: 10.4103/2303-9027.191608.</citation>
      <PMID>27803902</PMID>
    </results_reference>
    <results_reference>
      <citation>Scarlata S, Costa F, Pascarella G, Strumia A, Antonelli Incalzi R, Agro FE. Remifentanil Target-Controlled Infusion for Conscious Sedation in Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA): A Case Series. Clin Drug Investig. 2020 Oct;40(10):985-988. doi: 10.1007/s40261-020-00960-0. No abstract available.</citation>
      <PMID>32767252</PMID>
    </results_reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 21, 2023</study_first_submitted>
    <study_first_submitted_qc>September 9, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 9, 2023</last_update_submitted>
    <last_update_submitted_qc>September 9, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Scarlata, Simone, M.D.</investigator_affiliation>
      <investigator_full_name>Simone Scarlata</investigator_full_name>
      <investigator_title>Associate Professor in Internal Medicine</investigator_title>
    </responsible_party>
    <keyword>endobronchial ultrasound</keyword>
    <keyword>mediastinal staging of lung cancer</keyword>
    <keyword>sedation in endoscopic procedures</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lung Neoplasms</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Fentanyl</mesh_term>
      <mesh_term>Midazolam</mesh_term>
      <mesh_term>Remifentanil</mesh_term>
      <mesh_term>Propofol</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06033729
  org study id: CBM 20-12
  nct id: NCT06033729
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  Background: endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a
        minimally invasive procedure for diagnosing and staging mediastinal lymph node lesions in
        lung cancer. Adequate sedation is crucial for patient comfort and diagnostic accuracy.
        Different sedation modalities, including moderate sedation/conscious sedation, deep sedation,
        and general anesthesia, are utilized. This study aims to evaluate patient comfort and
        satisfaction levels of healthcare providers (bronchoscopists and anesthesiologists) when
        administering remifentanil through Target Controlled Infusion (TCI) for conscious sedation
        during EBUS-TBNA. A prospective randomized study design compares this approach to the
        standard sedation protocol involving midazolam, fentanyl, and/or propofol.
  
        Methods: this study will enroll 30 eligible patients randomly divided into two groups. Group
        1, "REMIFENTANIL TCI", underwent EBUS-TBNA under conscious sedation with remifentanil TCI
        infusion targeting a concentration of 3-6 ng/ml. Group 2, "STANDARD", received conscious
        sedation with a combination of midazolam, fentanyl, and/or propofol administered in boluses
        based on clinical requirements. Complications, safety, and satisfaction levels of the
        operator, anesthesiologist, and patients will be evaluated.
  BACKGROUND Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a
        minimally invasive procedure that has gained major relevance in diagnosis lung cancer and
        staging of mediastinal lymph nodes (LN). Adequate sedation is an important part of the
        procedure since it improves patient's comfort and tolerance potentially positively affecting
        the diagnostic yield. It is also considered a standard of care for patients undergoing
        fiberoptic bronchoscopy unless specifically contraindicated.
  
        The choice of the different level of sedation (from conscious to moderate to deep sedation)
        has always been challenging and, to date, no standardized practice exists. Deep sedation may
        be preferred in those cases where additional procedures such as placement of endobronchial
        stents, are required, or in order to make the procedure more suitable by limiting the
        patients motion. In remaining cases, conscious sedation allows to complain with the clinical
        demand without affecting respiratory and cardiovascular function, decreasing the cough reflex
        and maintaining sufficient swallowing capacity.
  
        Not appropriate sedation can have serious complications, including respiratory depression or
        even arrest, hypoxia and/or hypercapnia, and cardiovascular and neurological side effects.
  
        Commonly used drugs for sedation include propofol and a combination of benzodiazepines and
        opioids. However, achieving the ideal level of sedation can be challenging, since it may
        occasionally lead to over sedation, with detrimental effects. These risks are even greater if
        the patients present with lung disease, obesity, or heart disease. Conversely, under sedation
        can result in discomfort for the patient and challenging procedure it for the healthcare
        provider. Furthermore, benzodiazepines and medium-long-acting opioids continue their effect
        even after the procedure is finished, thus lasting the negative effects of these drugs over
        the time of the procedure.
  
        In a recent case series, Scarlata and colleagues have provided a preliminary evidence of a
        TCI remifentanil protocol safety and effectiveness, providing an ideal and performant
        condition for bronchoscopists and a satisfactory comfort for patients.
  
        Using a TCI continuous infusion protocol of Remifentanil can exploit the sedative, analgesic
        and antitussive capabilities of this short-acting opioid, achieving a level of conscious
        sedation that ensures an adequate level of comfort for the patient while at the same time
        decreases the incidence of side effects typical of deep sedation. The patient remains
        contactable and can respond and execute commands, such as breathing, swallowing, etc.
  
        TCI is a method of continuous drug administration where the infusion of the drug is remotely
        controlled. There are different administration algorithms and there is the possibility to
        titrate the target concentration both at the effect site (CNS) and in the plasma.
  
        There are numerous studies confirming the efficacy of remifentanil administered by TCI during
        intubation with an awake patient, and the advantages of the latter compared to other
        techniques, such as propofol infusion. One study determined the efficacy of infused
        remifentanil and propofol for bronchial endoscopy procedures, but did not use the TCI
        technique for infusion. There are no clinical studies assessing endoscopic transbronchial
        needle biopsy procedures with remifentanil infusion in TCI mode.
  
        The aim of this study is therefore to conduct a prospective, randomized, controlled trial to
        evaluate the administration of remifentanil in TCI for conscious sedation during EBUS-TBNA
        procedures, the degree of patient and operator satisfaction and the relative advantages and
        disadvantages versus the of standard sedation protocol with midazolam and/or fentanyl and/or
        propofol.
  
        METHODS This is a single center, randomized, investigator initiated clinical trial of 30
        patients undergoing EBUS-TBNA for mediastinal staging of lung cancer. Patients were randomly
        assigned to one of two groups: Group 1 "REMIFENTANIL TCI" (Experimental Group): the patients
        performed the EBUS-TBNA procedure under conscious sedation with infusion of Remifentanil TCI
        with a target between 3 and 6 ng/ml; Group 2 "STANDARD" (Control Group): the patients
        performed the EBUS-TBNA procedure in conscious sedation with the association of midazolam
        and/or fentanyl and/or propofol in refracted boluses based on clinical needs (agitation,
        unsatisfactory level of sedation or not collaborative patient) and according to the
        anesthesiologist's clinical judgement.
  
        After obtaining a signed informed consent the patient was randomly allocated 1:1 to the group
        "REMIFENTANIL TCI" or "STANDARD". A research randomizer software was used for randomization
        (iRANDOMIZER-SHMOOPI LLC-version 2.5). Both the bronchoscopist and the research assistant
        administrating the questionnaires were blinded to the assigned group. It was not possible to
        blind anesthesiologists involved in the patient's care.
  
        The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
  
        Study treatment The ASA scale, the Mallampati score, the presence of OSAS were recorded prior
        of the procedure. Also, data about the underlying oncological disease, whether chemotherapy
        and/or radiotherapy was performed, and the indication for the EBUS-TBNA test (diagnostic,
        staging, re-staging, or both diagnostic and staging at the same moment) were collected.
  
        The patient candidate for the endoscopic procedure underwent continuous monitoring of vital
        signs. ECG with precordial leads, continuous finger pulse oximetry, and noninvasive
        intermittent blood pressure measurements were monitored. Each patient was preoxygenated for
        about 5 minutes by administering O2 with nasal goggles at 3L/min or higher, if required.
  
        Lidocaine was topically nebulized at the level of the mucous membranes of the oropharynx.
        Oxybuprocaine 4mg/ml was also nebulized at the level of the vocal cords via the eco-endoscope
        before passing the glottic plane in all patients.
  
        Remifentanil group conscious sedation protocol (intra venous remifentanil in TCI). Drug
        administration begun 5 minutes before the procedure. The achievement of the ideal target
        occurs starting from an initial target at the effect site of 1 ng/ml and gradually increasing
        the desired target on the pump by 0.5 ng/ml at a time, until reaching a target between 3 and
        6 ng/ml and an adequate level of sedation (Ramsey Score between 2-3).
  
        Desired target was achieved by automatic infusion pumps (Infusomat® Space® Large Volume Pump,
        Braun medical inc) If, despite the maximum target, a satisfactory level of sedation was not
        reached, repeated boluses of propofol were given as clinically needed and the case considered
        as protocol failure.
  
        Patients in the STANDARD Group performed the EBUS-TBNA with bolus administration of midazolam
        and/or fentanyl and/or propofol. Shortly before the start of the procedure they received 1-2
        mg bolus midazolam and/or 50-100 range bolus fentanyl until they reach the level of sedation
        (Ramsey Score 2-3). In addition, repeated boluses of propofol could have been given according
        to clinical needs (state of agitation of the patient, requests from the operator due to
        difficulties in carrying out the procedure).
  
        Data were collected about the procedure performed, any changes in vital signs that occurred
        during the procedure and the depth of sedation.
  
        Anesthesiologist, bronchoscopist and patient's satisfaction tools At the end of the
        procedure, the patient was given a satisfaction questionnaire to evaluate the degree of
        satisfaction. The 0-5 Likert numerical scale was used to evaluate the symptoms onset of cough
        (0 none-5 very much), sore throat (0-5), chest pain (0-5), shortness of breath (0 eupnoea- 5
        worsening dyspnea), presence of memories (0 none - 5 vivid memories), and perioperative
        comfort (0 none - 5 excellent). The operator who performed the procedure and the sedation
        were also subjected to a satisfaction questionnaire which assessed the overall satisfaction
        (1 much worse than usual - 5 much better than usual).
  
        Statistical Analysis The analysis was performed on an intention to treat basis, regardless of
        actual compliance with the intended intervention.
  
        A two-tailed p value equal or less than 0.05 was considered as statistically significant. All
        tests, except for the primary outcome, were considered merely exploratory. When individual
        items were missing from a scale, the percent of missing values and, if more than 10% was
        calculated, the scale score was considered missing and therefore made unavailable for
        analysis. All the analyses were conducted using STATA (StataCorp. 2021. Stata Statistical
        Software: Release 17. College Station, TX: StataCorp LLC.).
  
        Outcome analysis Primary and secondary endpoints will be compared between the two groups of
        treatment by means of Student's t-test (or the Mann-Whitney U test, if necessary) for
        continuous quantitative variables and by means of the χ2 test (or Fisher's exact test ) for
        qualitative variables.
  
        Sample size determination Our previously published case series showed that the overall
        satisfaction rate for both the patient and the bronchoscopist were very high in the
        remifentanil TCI group (mean Likert score above 4/5 against a mean value ranging from 2 to 3
        in the standard group as available in the literature). Enrolling 30 patients (fifteen for
        each group) would have provided with 80% power at an alpha level of 0.05.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Informed consent was obtained from each patient or legally authorized representative prior to enrollment in this study.
  After obtaining a signed informed consent the patient was randomly allocated 1:1 to the group "REMIFENTANIL TCI" or "STANDARD". A research randomizer software was used for randomization (iRANDOMIZER-SHMOOPI LLC-version 2.5).
  primary purpose: Supportive Care
  masking: Double (Participant, Outcomes Assessor)
  masking description: The bronchoscopist, the patient and the research assistant administrating the questionnaires were blinded to the assigned group. It was not possible to blind anesthesiologists involved in the patient's care.
  measure: Patient, bronchoscopist and anesthesiologist's comfort and satisfaction to the procedure.
  time frame: At patient's dismission from bronchoscopy suit
  description: the patient was given a satisfaction questionnaire to evaluate the degree of satisfaction. The 0-5 Likert numerical scale was used to evaluate the symptoms onset of cough (0 none-5 very much), sore throat (0-5), chest pain (0-5), shortness of breath (0 eupnoea- 5 worsening dyspnea), presence of memories (0 none - 5 vivid memories), and perioperative comfort (0 none - 5 excellent). The operator who performed the procedure and the sedation were also subjected to a satisfaction questionnaire which assessed the overall satisfaction (1 much worse than usual - 5 much better than usual).
  measure: propofol boluses administered
  time frame: During the procedure
  description: Number and dosage of any propofol boluses administered (both in the experimental group and in the control group)
  measure: Procedure time
  time frame: During the procedure
  description: Total duration of the procedure (in minutes)
  measure: Level of sedation
  time frame: During the procedure
  description: Level of sedation achieved (Ramsey score)
  measure: Over sedation
  time frame: During the procedure
  description: Episodes of over-sedation (Ramsey score > 3)
  measure: Desaturation
  time frame: Up to an hour from the end of the procedure
  description: Desaturation episodes
  measure: Hypotension
  time frame: Up to an hour from the end of the procedure
  description: Episodes of hypotension (SBP <90 mmHg)
  measure: Bradycardia
  time frame: Up to an hour from the end of the procedure
  description: Episodes of Bradycardia (HR<60)
  measure: Bradypnea or respiratory arrest
  time frame: Up to an hour from the end of the procedure
  description: Episodes of bradypnea (RR<10)
  measure: Cough
  time frame: Up to two hours from the end of the procedure
  description: Excessive cough (Unconfortable, unconstrained cough affecting patient's and operator comfort)
  measure: Airway support
  time frame: Up to an hour from the and of the procedure
  description: Need for airway support
  measure: Sampled lymph nodes
  time frame: During the procedure
  description: Number of lymph nodes sampled during the procedure.
  measure: Sampled lesions
  time frame: During the procedure
  description: Number of masses sampled during the procedure.
  measure: Number of biopsies per limph node
  time frame: During the procedure
  description: Number of biopsies per single lymph node needed to obtain a confident sample size according to a visual on-site evaluation.
  measure: Number of biopsies per mass
  time frame: During the procedure
  description: Number of biopsies per single mass needed to obtain a confident sample size according to a visual on-site evaluation
  arm group label: Group 1 "REMIFENTANIL TCI" (Experimental Group)
  arm group type: Experimental
  description: the patients performed the EBUS-TBNA procedure under conscious sedation with infusion of Remifentanil TCI with a target between 3 and 6 ng/ml;
  arm group label: Group 2 "STANDARD" (Control Group)
  arm group type: Active Comparator
  description: the patients performed the EBUS-TBNA procedure in conscious sedation with the association of midazolam and/or fentanyl and/or propofol in refracted boluses based on clinical needs (agitation, unsatisfactory level of sedation or not collaborative patient) and according to the anesthesiologist's clinical judgement.
  intervention type: Drug
  intervention name: Remifentanil TCI
  description: REMI-TCI administration begun 5 minutes before the procedure, starting from an initial target at the effect site of 1 ng/ml and gradually increasing by 0.5 ng/ml until reaching an adequate level of sedation (Ramsey score between 2-3).
  arm group label: Group 1 "REMIFENTANIL TCI" (Experimental Group)
  other name: REMI - target control infusion
  intervention type: Drug
  intervention name: Midazolam injection
  description: Bolus administration of midazolam (1-2 mg)and/or until a Ramsey score 2-3 was reached
  arm group label: Group 2 "STANDARD" (Control Group)
  other name: Bolus administration of midazolam
  intervention type: Drug
  intervention name: Fentanyl
  description: Bolus adminitration of fentanyl (50-100 mcg) until a Ramsey score 2-3 was reached
  arm group label: Group 2 "STANDARD" (Control Group)
  other name: Bolus administration of Fentanyl
  intervention type: Drug
  intervention name: Propofol
  description: Bolus adminitration of propofol until a Ramsey score 2-3 was reached
  arm group label: Group 2 "STANDARD" (Control Group)
  other name: Bolus administration of Propofol
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: No
  facility: 
  country: Italy
  citation: Wahidi MM, Jain P, Jantz M, Lee P, Mackensen GB, Barbour SY, Lamb C, Silvestri GA. American College of Chest Physicians consensus statement on the use of topical anesthesia, analgesia, and sedation during flexible bronchoscopy in adult patients. Chest. 2011 Nov;140(5):1342-1350. doi: 10.1378/chest.10-3361.
  PMID: 22045879
  citation: Aswanetmanee P, Limsuwat C, Kabach M, Alraiyes AH, Kheir F. The role of sedation in endobronchial ultrasound-guided transbronchial needle aspiration: Systematic review. Endosc Ultrasound. 2016 Sep-Oct;5(5):300-306. doi: 10.4103/2303-9027.191608.
  PMID: 27803902
  citation: Scarlata S, Costa F, Pascarella G, Strumia A, Antonelli Incalzi R, Agro FE. Remifentanil Target-Controlled Infusion for Conscious Sedation in Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA): A Case Series. Clin Drug Investig. 2020 Oct;40(10):985-988. doi: 10.1007/s40261-020-00960-0. No abstract available.
  PMID: 32767252
  responsible party type: Principal Investigator
  investigator affiliation: Scarlata, Simone, M.D.
  investigator full name: Simone Scarlata
  investigator title: Associate Professor in Internal Medicine
  mesh term: Lung Neoplasms
  mesh term: Fentanyl
  mesh term: Midazolam
  mesh term: Remifentanil
  mesh term: Propofol
  sharing ipd: No