<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/NCT03036085</url>
  </required_header>
  <id_info>
    <org_study_id>2016P002754</org_study_id>
    <nct_id>NCT03036085</nct_id>
  </id_info>
  <brief_title>Liposomal Bupivacaine for Pain Control Following Thoracic Surgery.</brief_title>
  <official_title>Liposomal Bupivacaine Versus Bupivacaine for Postoperative Analgesia Following Video-assisted Thoracoscopic Surgery.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</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>
      The aims of the study are to compare the effectiveness and postoperative outcomes of&#xD;
      liposomal bupivacaine vs plain bupivacaine following video-assisted thoracoscopic surgery.&#xD;
      The investigators' hypothesis is that liposomal bupivacaine will decrease the postoperative&#xD;
      pain and will be associated with more favorable postoperative outcomes when compared to plain&#xD;
      bupivacaine following video-assisted thoracoscopic surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pain management remains a primary concern for many patients following thoracic surgery.&#xD;
      Suboptimal analgesia leads to numerous postoperative complications like reduced cardiac,&#xD;
      respiratory and gastrointestinal functions, more septic and thromboembolic complications,&#xD;
      increased incidence of developing chronic pain states, increased mortality in high-risk&#xD;
      patients with multiple comorbidities, and many others.&#xD;
&#xD;
      Opioids have a distinct role in the postoperative analgesia. Although opioids have positively&#xD;
      affected surgery for decades, they are associated with a number of potentially severe side&#xD;
      effects including prolonged ileus, nausea, vomiting, central nervous system and respiratory&#xD;
      depression, development of hyperalgesia, and the risk of dependency and abuse. These adverse&#xD;
      effects increase the overall cost of treatment for these patients and can potentially result&#xD;
      in longer hospital stays.&#xD;
&#xD;
      Local infiltration and regional blocks of local anesthetics are increasingly utilized during&#xD;
      thoracic surgery procedures as an alternative to epidural analgesia. Bupivacaine is widely&#xD;
      used for intercostal nerve blocks but its utility is limited by its short duration of action&#xD;
      (&lt;6 hours). Perineural catheters for continuous infusion of bupivacaine have been used to&#xD;
      overcome this limitation but the need of expensive pumps and the risk of significant&#xD;
      complications associated with the use of catheters (i.e. infection, septicemia, intravascular&#xD;
      migration etc) has limited its use.&#xD;
&#xD;
      Encapsulation of local anesthetics into liposomes is a novel method which extends drug&#xD;
      delivery. The use of multivesicular liposomes has been shown to provide a slow and steady&#xD;
      release of local anesthetics for several days after nonvascular administration. Liposomal&#xD;
      bupivacaine is a novel formulary of bupivacaine, is designed for a single-dose local&#xD;
      infiltration into the surgical site and produces postsurgical analgesia for up to 72-96&#xD;
      hours.&#xD;
&#xD;
      Liposomal bupivacaine is not currently licensed by the U.S. Food and Drug Administration for&#xD;
      peripheral nerve block but has been approved for single-dose infiltration into the surgical&#xD;
      site. However, it has been shown in two retrospective studies of patients with open&#xD;
      thoracotomies for lung, pleural or mediastinal pathologies that liposomal bupivacaine&#xD;
      intercostal nerve blockade is associated with increased pain control and decreased length of&#xD;
      hospital stay compared to thoracic epidural analgesia.&#xD;
&#xD;
      This is a single-blind randomized prospective research study comparing pain control and&#xD;
      postoperative outcomes following intercostal neural blockade with liposomal bupivacaine&#xD;
      versus plain bupivacaine plus epinephrine during video-assisted thoracoscopic surgical&#xD;
      procedures. Eligible patients would be all patients aged older than 18 years who undergo a&#xD;
      video-assisted thoracoscopic lung resection at Massachusetts General Hospital. Pregnant&#xD;
      women, prisoners, emergent cases, patients under 18 years, and patients with chronic pain,&#xD;
      documented alcohol or drug abuse and allergies to bupivacaine will be excluded from this&#xD;
      study.&#xD;
&#xD;
      Primary end point will be self-reported pain score on a visual analog scale from 0 to 10 at&#xD;
      postoperative day #1. By utilizing a mean difference in self-reported pain scores of 1 point&#xD;
      with a standard deviation of 2.5 points, a sample size of 100 patients per group would be&#xD;
      needed for a power (beta) of 0.8 and probability level (alpha) of 0.05. All patients would be&#xD;
      enrolled at Massachusetts General Hospital.&#xD;
&#xD;
      The video-assisted thoracoscopic surgeries and intercostal nerve blockade with plain&#xD;
      bupivacaine plus epinephrine or liposomal bupivacaine will be performed by all thoracic&#xD;
      surgeons at Massachusetts General Hospital. In the operating room after induction of general&#xD;
      anesthesia patients will be positioned in a lateral decubitus position, prepared and draped&#xD;
      in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will&#xD;
      be performed with liposomal bupivacaine (13.3 mg/ml) or 0.5% bupivacaine with 1% epinephrine.&#xD;
      In the liposomal bupivacaine group, a total dose of 266 mg of liposomal bupivacaine (one 20&#xD;
      ml vial of 13.3 mg/ml) per patient will be diluted to a total volume of 40 ml using 20 ml&#xD;
      normal saline. In the bupivacaine group 20 ml of 0.5% bupivacaine with 1% epinephrine will be&#xD;
      diluted to a total volume of 40 ml using 20 ml normal saline. From those 40 ml, 30 ml will be&#xD;
      used for the posterior intercostal nerve block and 10 ml will be injected locally into the&#xD;
      surgical wounds.&#xD;
&#xD;
      If immediate postoperative pain scores were rated 4/10 or greater, an intravenous patient&#xD;
      controlled analgesia device will be provided with hydromorphone 0.2 mg every 10 minutes or&#xD;
      nonopioid analgesics as needed. No narcotics will be given in the spinal space. Oral&#xD;
      metoclopramide or ondansetron will be given as needed to combat the side effects of the&#xD;
      narcotics.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 2017</start_date>
  <completion_date type="Anticipated">December 2017</completion_date>
  <primary_completion_date type="Anticipated">December 2017</primary_completion_date>
  <phase>Phase 2/Phase 3</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, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Patient self-reported pain visual analog scale score - Day 1</measure>
    <time_frame>Postoperative Day #1</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patient self-reported pain visual analog scale score - Day 3</measure>
    <time_frame>Postoperative Day #3</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient self-reported pain visual analog scale score - Discharge</measure>
    <time_frame>At the day of discharge from the hospital. Discharge day could be on average postoperative day #4 or #5.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time until first opioid usage</measure>
    <time_frame>After the surgery and until the participant receives the first opioid medication, assessed up to 10 days after surgery.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total opioid usage (in morphine equivalents)</measure>
    <time_frame>After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti-emetic usage</measure>
    <time_frame>After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Naloxone usage</measure>
    <time_frame>After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay</measure>
    <time_frame>After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative complications (e.g. pneumonia, pulmonary complications, wound infections etc)</measure>
    <time_frame>The first 30 days after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to ambulation</measure>
    <time_frame>After the surgery and until the participant starts ambulating during hospitalization, assessed up to 10 days after surgery.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to first bowel movement</measure>
    <time_frame>After the surgery and until the participant has the first bowel movement during hospitalization, assessed up to 10 days after surgery.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to chest tube removal</measure>
    <time_frame>After the surgery and until the participant has his/her chest tube removed during hospitalization, assessed up to 10 days after surgery.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak expiratory flow measurements</measure>
    <time_frame>Measured twice daily following surgery until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.</time_frame>
    <description>Measures air flowing in and out of the lungs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak expiratory flow measurements</measure>
    <time_frame>Measured twice daily the day at the first postoperative visit (usually within 10-30 days postoperatively)</time_frame>
    <description>Measures air flowing in and out of the lungs.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Pain, Postoperative</condition>
  <condition>Thoracic Diseases</condition>
  <condition>Local Anesthetics Causing Adverse Effects in Therapeutic Use</condition>
  <condition>Opioid Dependence</condition>
  <arm_group>
    <arm_group_label>Bupivacaine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with 0.5% bupivacaine with 1% epinephrine. In the bupivacaine group 20 ml of 0.5% bupivacaine with 1% epinephrine will be diluted to a total volume of 40 ml using 20 ml normal saline. From those 40 ml, 30 ml will be used for the posterior intercostal nerve block and 10 ml will be injected locally into the surgical wounds.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Liposomal bupivacaine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with liposomal bupivacaine (13.3 mg/ml). In the liposomal bupivacaine group, a total dose of 266 mg of liposomal bupivacaine (one 20 ml vial of 13.3 mg/ml) per patient will be diluted to a total volume of 40 ml using 20 ml normal saline.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liposomal bupivacaine</intervention_name>
    <description>In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with liposomal bupivacaine plus normal saline.</description>
    <arm_group_label>Liposomal bupivacaine</arm_group_label>
    <other_name>Exparel</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupivacaine</intervention_name>
    <description>In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with bupivacaine plus epinephrine plus normal saline.</description>
    <arm_group_label>Bupivacaine</arm_group_label>
    <other_name>Marcaine</other_name>
    <other_name>Marcain</other_name>
    <other_name>Sensorcaine</other_name>
    <other_name>Vivacaine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Epinephrine</intervention_name>
    <description>In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with bupivacaine plus epinephrine plus normal saline.</description>
    <arm_group_label>Bupivacaine</arm_group_label>
    <other_name>Adrenaline</other_name>
    <other_name>Adrenalin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal saline</intervention_name>
    <description>In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with liposomal bupivacaine plus normal saline or with bupivacaine plus epinephrine plus normal saline.</description>
    <arm_group_label>Bupivacaine</arm_group_label>
    <arm_group_label>Liposomal bupivacaine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Eligible patients would be all patients aged older than 18 years who undergo a&#xD;
             video-assisted thoracoscopic lung resection at Massachusetts General Hospital.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant women, prisoners, emergent cases, patients under 18 years, and patients with&#xD;
             chronic pain, documented alcohol or drug abuse and allergies to bupivacaine will be&#xD;
             excluded from this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Harald Ott, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Division of Thoracic Surgery, Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Konstantinos P. Economopoulos, MD, PhD</last_name>
    <phone>617-510-4641</phone>
    <email>keconomopoulos@mgh.harvard.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Harald Ott, MD</last_name>
    <phone>617-726-2311</phone>
    <email>hott@mgh.harvard.edu</email>
  </overall_contact_backup>
  <link>
    <url>http://www.hcahpsonline.org/Files/HCAHPS_Fact_Sheet_June_2015.pdf</url>
    <description>HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems) fact sheet</description>
  </link>
  <link>
    <url>http://www.exparel.com/hcp/pdf/EXPAREL_Prescribing_Information.pdf</url>
    <description>Exparel prescribing information</description>
  </link>
  <results_reference>
    <citation>Chen AH. Toxicity and allergy to local anesthesia. J Calif Dent Assoc. 1998 Sep;26(9):683-92.</citation>
    <PMID>9879238</PMID>
  </results_reference>
  <results_reference>
    <citation>Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003 Aug;97(2):534-540. doi: 10.1213/01.ANE.0000068822.10113.9E.</citation>
    <PMID>12873949</PMID>
  </results_reference>
  <results_reference>
    <citation>Luketich JD, Land SR, Sullivan EA, Alvelo-Rivera M, Ward J, Buenaventura PO, Landreneau RJ, Hart LA, Fernando HC. Thoracic epidural versus intercostal nerve catheter plus patient-controlled analgesia: a randomized study. Ann Thorac Surg. 2005 Jun;79(6):1845-9; discussion 1849-50. doi: 10.1016/j.athoracsur.2004.10.055.</citation>
    <PMID>15919269</PMID>
  </results_reference>
  <results_reference>
    <citation>Oderda GM, Said Q, Evans RS, Stoddard GJ, Lloyd J, Jackson K, Rublee D, Samore MH. Opioid-related adverse drug events in surgical hospitalizations: impact on costs and length of stay. Ann Pharmacother. 2007 Mar;41(3):400-6. doi: 10.1345/aph.1H386. Epub 2007 Mar 6.</citation>
    <PMID>17341537</PMID>
  </results_reference>
  <results_reference>
    <citation>Richard BM, Rickert DE, Newton PE, Ott LR, Haan D, Brubaker AN, Cole PI, Ross PE, Rebelatto MC, Nelson KG. Safety Evaluation of EXPAREL (DepoFoam Bupivacaine) Administered by Repeated Subcutaneous Injection in Rabbits and Dogs: Species Comparison. J Drug Deliv. 2011;2011:467429. doi: 10.1155/2011/467429. Epub 2011 Oct 5.</citation>
    <PMID>22013534</PMID>
  </results_reference>
  <results_reference>
    <citation>American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012 Feb;116(2):248-73. doi: 10.1097/ALN.0b013e31823c1030. No abstract available.</citation>
    <PMID>22227789</PMID>
  </results_reference>
  <results_reference>
    <citation>Chahar P, Cummings KC 3rd. Liposomal bupivacaine: a review of a new bupivacaine formulation. J Pain Res. 2012;5:257-64. doi: 10.2147/JPR.S27894. Epub 2012 Aug 14.</citation>
    <PMID>23049275</PMID>
  </results_reference>
  <results_reference>
    <citation>Golembiewski J, Dasta J. Evolving Role of Local Anesthetics in Managing Postsurgical Analgesia. Clin Ther. 2015 Jun 1;37(6):1354-71. doi: 10.1016/j.clinthera.2015.03.017. Epub 2015 Apr 10.</citation>
    <PMID>25866297</PMID>
  </results_reference>
  <results_reference>
    <citation>Kelly MA. Current Postoperative Pain Management Protocols Contribute to the Opioid Epidemic in the United States. Am J Orthop (Belle Mead NJ). 2015 Oct;44(10 Suppl):S5-8.</citation>
    <PMID>26447431</PMID>
  </results_reference>
  <results_reference>
    <citation>Khalil KG, Boutrous ML, Irani AD, Miller CC 3rd, Pawelek TR, Estrera AL, Safi HJ. Operative Intercostal Nerve Blocks With Long-Acting Bupivacaine Liposome for Pain Control After Thoracotomy. Ann Thorac Surg. 2015 Dec;100(6):2013-8. doi: 10.1016/j.athoracsur.2015.08.017. Epub 2015 Oct 24.</citation>
    <PMID>26507422</PMID>
  </results_reference>
  <results_reference>
    <citation>Rice DC, Cata JP, Mena GE, Rodriguez-Restrepo A, Correa AM, Mehran RJ. Posterior Intercostal Nerve Block With Liposomal Bupivacaine: An Alternative to Thoracic Epidural Analgesia. Ann Thorac Surg. 2015 Jun;99(6):1953-60. doi: 10.1016/j.athoracsur.2015.02.074. Epub 2015 Apr 23.</citation>
    <PMID>25912739</PMID>
  </results_reference>
  <results_reference>
    <citation>Uskova A, O'Connor JE. Liposomal bupivacaine for regional anesthesia. Curr Opin Anaesthesiol. 2015 Oct;28(5):593-7. doi: 10.1097/ACO.0000000000000240.</citation>
    <PMID>26308513</PMID>
  </results_reference>
  <results_reference>
    <citation>Biswas S, Verma R, Bhatia VK, Chaudhary AK, Chandra G, Prakash R. Comparison between Thoracic Epidural Block and Thoracic Paravertebral Block for Post Thoracotomy Pain Relief. J Clin Diagn Res. 2016 Sep;10(9):UC08-UC12. doi: 10.7860/JCDR/2016/19159.8489. Epub 2016 Sep 1.</citation>
    <PMID>27790554</PMID>
  </results_reference>
  <results_reference>
    <citation>Redan JA, Wells T, Reeder S, McCarus SD. Reducing Opioid Adverse Events: A Safe Way to Improve Outcomes. Surg Technol Int. 2016 Apr;28:101-9.</citation>
    <PMID>27042786</PMID>
  </results_reference>
  <results_reference>
    <citation>Clinicians' quick reference guide to postoperative pain management in adults. Pain Management Guideline Panel. Agency for Health Care Policy and Research, US Department of Health and Human Services. J Pain Symptom Manage. 1992 May;7(4):214-28.</citation>
    <PMID>1517644</PMID>
  </results_reference>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>December 9, 2016</study_first_submitted>
  <study_first_submitted_qc>January 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 30, 2017</study_first_posted>
  <last_update_submitted>January 25, 2017</last_update_submitted>
  <last_update_submitted_qc>January 25, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 30, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Harald Ott</investigator_full_name>
    <investigator_title>Associate Professor of Surgery</investigator_title>
  </responsible_party>
  <keyword>postoperative pain</keyword>
  <keyword>video-assisted thoracoscopic surgery (VATS)</keyword>
  <keyword>opioids</keyword>
  <keyword>bupivacaine</keyword>
  <keyword>liposomal bupivacaine</keyword>
  <keyword>analgesia</keyword>
  <keyword>local anesthetics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thoracic Diseases</mesh_term>
    <mesh_term>Pain, Postoperative</mesh_term>
    <mesh_term>Opioid-Related Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epinephrine</mesh_term>
    <mesh_term>Bupivacaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03036085
org study id: 2016P002754
nct id: NCT03036085
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The aims of the study are to compare the effectiveness and postoperative outcomes of
      liposomal bupivacaine vs plain bupivacaine following video-assisted thoracoscopic surgery.
      The investigators' hypothesis is that liposomal bupivacaine will decrease the postoperative
      pain and will be associated with more favorable postoperative outcomes when compared to plain
      bupivacaine following video-assisted thoracoscopic surgery.
Pain management remains a primary concern for many patients following thoracic surgery.
      Suboptimal analgesia leads to numerous postoperative complications like reduced cardiac,
      respiratory and gastrointestinal functions, more septic and thromboembolic complications,
      increased incidence of developing chronic pain states, increased mortality in high-risk
      patients with multiple comorbidities, and many others.

      Opioids have a distinct role in the postoperative analgesia. Although opioids have positively
      affected surgery for decades, they are associated with a number of potentially severe side
      effects including prolonged ileus, nausea, vomiting, central nervous system and respiratory
      depression, development of hyperalgesia, and the risk of dependency and abuse. These adverse
      effects increase the overall cost of treatment for these patients and can potentially result
      in longer hospital stays.

      Local infiltration and regional blocks of local anesthetics are increasingly utilized during
      thoracic surgery procedures as an alternative to epidural analgesia. Bupivacaine is widely
      used for intercostal nerve blocks but its utility is limited by its short duration of action
      (<6 hours). Perineural catheters for continuous infusion of bupivacaine have been used to
      overcome this limitation but the need of expensive pumps and the risk of significant
      complications associated with the use of catheters (i.e. infection, septicemia, intravascular
      migration etc) has limited its use.

      Encapsulation of local anesthetics into liposomes is a novel method which extends drug
      delivery. The use of multivesicular liposomes has been shown to provide a slow and steady
      release of local anesthetics for several days after nonvascular administration. Liposomal
      bupivacaine is a novel formulary of bupivacaine, is designed for a single-dose local
      infiltration into the surgical site and produces postsurgical analgesia for up to 72-96
      hours.

      Liposomal bupivacaine is not currently licensed by the U.S. Food and Drug Administration for
      peripheral nerve block but has been approved for single-dose infiltration into the surgical
      site. However, it has been shown in two retrospective studies of patients with open
      thoracotomies for lung, pleural or mediastinal pathologies that liposomal bupivacaine
      intercostal nerve blockade is associated with increased pain control and decreased length of
      hospital stay compared to thoracic epidural analgesia.

      This is a single-blind randomized prospective research study comparing pain control and
      postoperative outcomes following intercostal neural blockade with liposomal bupivacaine
      versus plain bupivacaine plus epinephrine during video-assisted thoracoscopic surgical
      procedures. Eligible patients would be all patients aged older than 18 years who undergo a
      video-assisted thoracoscopic lung resection at Massachusetts General Hospital. Pregnant
      women, prisoners, emergent cases, patients under 18 years, and patients with chronic pain,
      documented alcohol or drug abuse and allergies to bupivacaine will be excluded from this
      study.

      Primary end point will be self-reported pain score on a visual analog scale from 0 to 10 at
      postoperative day #1. By utilizing a mean difference in self-reported pain scores of 1 point
      with a standard deviation of 2.5 points, a sample size of 100 patients per group would be
      needed for a power (beta) of 0.8 and probability level (alpha) of 0.05. All patients would be
      enrolled at Massachusetts General Hospital.

      The video-assisted thoracoscopic surgeries and intercostal nerve blockade with plain
      bupivacaine plus epinephrine or liposomal bupivacaine will be performed by all thoracic
      surgeons at Massachusetts General Hospital. In the operating room after induction of general
      anesthesia patients will be positioned in a lateral decubitus position, prepared and draped
      in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will
      be performed with liposomal bupivacaine (13.3 mg/ml) or 0.5% bupivacaine with 1% epinephrine.
      In the liposomal bupivacaine group, a total dose of 266 mg of liposomal bupivacaine (one 20
      ml vial of 13.3 mg/ml) per patient will be diluted to a total volume of 40 ml using 20 ml
      normal saline. In the bupivacaine group 20 ml of 0.5% bupivacaine with 1% epinephrine will be
      diluted to a total volume of 40 ml using 20 ml normal saline. From those 40 ml, 30 ml will be
      used for the posterior intercostal nerve block and 10 ml will be injected locally into the
      surgical wounds.

      If immediate postoperative pain scores were rated 4/10 or greater, an intravenous patient
      controlled analgesia device will be provided with hydromorphone 0.2 mg every 10 minutes or
      nonopioid analgesics as needed. No narcotics will be given in the spinal space. Oral
      metoclopramide or ondansetron will be given as needed to combat the side effects of the
      narcotics.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Patient self-reported pain visual analog scale score - Day 1
time frame: Postoperative Day #1
measure: Patient self-reported pain visual analog scale score - Day 3
time frame: Postoperative Day #3
measure: Patient self-reported pain visual analog scale score - Discharge
time frame: At the day of discharge from the hospital. Discharge day could be on average postoperative day #4 or #5.
measure: Time until first opioid usage
time frame: After the surgery and until the participant receives the first opioid medication, assessed up to 10 days after surgery.
measure: Total opioid usage (in morphine equivalents)
time frame: After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.
measure: Anti-emetic usage
time frame: After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.
measure: Naloxone usage
time frame: After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.
measure: Length of hospital stay
time frame: After the surgery and until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.
measure: Postoperative complications (e.g. pneumonia, pulmonary complications, wound infections etc)
time frame: The first 30 days after surgery
measure: Time to ambulation
time frame: After the surgery and until the participant starts ambulating during hospitalization, assessed up to 10 days after surgery.
measure: Time to first bowel movement
time frame: After the surgery and until the participant has the first bowel movement during hospitalization, assessed up to 10 days after surgery.
measure: Time to chest tube removal
time frame: After the surgery and until the participant has his/her chest tube removed during hospitalization, assessed up to 10 days after surgery.
measure: Peak expiratory flow measurements
time frame: Measured twice daily following surgery until the participant is discharged from the hospital. Discharge day could be on average postoperative day #4 or #5.
description: Measures air flowing in and out of the lungs.
measure: Peak expiratory flow measurements
time frame: Measured twice daily the day at the first postoperative visit (usually within 10-30 days postoperatively)
description: Measures air flowing in and out of the lungs.
arm group label: Bupivacaine
arm group type: Active Comparator
description: Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with 0.5% bupivacaine with 1% epinephrine. In the bupivacaine group 20 ml of 0.5% bupivacaine with 1% epinephrine will be diluted to a total volume of 40 ml using 20 ml normal saline. From those 40 ml, 30 ml will be used for the posterior intercostal nerve block and 10 ml will be injected locally into the surgical wounds.
arm group label: Liposomal bupivacaine
arm group type: Experimental
description: Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with liposomal bupivacaine (13.3 mg/ml). In the liposomal bupivacaine group, a total dose of 266 mg of liposomal bupivacaine (one 20 ml vial of 13.3 mg/ml) per patient will be diluted to a total volume of 40 ml using 20 ml normal saline.
intervention type: Drug
intervention name: Liposomal bupivacaine
description: In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with liposomal bupivacaine plus normal saline.
arm group label: Liposomal bupivacaine
other name: Exparel
intervention type: Drug
intervention name: Bupivacaine
description: In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with bupivacaine plus epinephrine plus normal saline.
arm group label: Bupivacaine
other name: Marcaine
other name: Marcain
other name: Sensorcaine
other name: Vivacaine
intervention type: Drug
intervention name: Epinephrine
description: In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with bupivacaine plus epinephrine plus normal saline.
arm group label: Bupivacaine
other name: Adrenaline
other name: Adrenalin
intervention type: Drug
intervention name: Normal saline
description: In the operating room after induction of general anesthesia patients will be positioned in a lateral decubitus position, prepared and draped in a sterile fashion. Under thoracoscopic guidance, a posterior intercostal nerve block will be performed with liposomal bupivacaine plus normal saline or with bupivacaine plus epinephrine plus normal saline.
arm group label: Bupivacaine
arm group label: Liposomal bupivacaine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Harald Ott, MD
role: Principal Investigator
affiliation: Division of Thoracic Surgery, Massachusetts General Hospital
last name: Konstantinos P. Economopoulos, MD, PhD
phone: 617-510-4641
email: keconomopoulos@mgh.harvard.edu
last name: Harald Ott, MD
phone: 617-726-2311
email: hott@mgh.harvard.edu
url: http://www.hcahpsonline.org/Files/HCAHPS_Fact_Sheet_June_2015.pdf
description: HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems) fact sheet
url: http://www.exparel.com/hcp/pdf/EXPAREL_Prescribing_Information.pdf
description: Exparel prescribing information
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PMID: 1517644
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Harald Ott
investigator title: Associate Professor of Surgery
mesh term: Thoracic Diseases
mesh term: Pain, Postoperative
mesh term: Opioid-Related Disorders
mesh term: Epinephrine
mesh term: Bupivacaine
sharing ipd: No