<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/NCT03007381</url>
  </required_header>
  <id_info>
    <org_study_id>KANGAROO</org_study_id>
    <nct_id>NCT03007381</nct_id>
  </id_info>
  <brief_title>Ketorolac for Analgesia followiNG Autologous Breast RecOnstructiOn</brief_title>
  <acronym>KANGAROO</acronym>
  <official_title>Ketorolac for Analgesia followiNG Autologous Breast RecOnstructiOn</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nova Scotia Health Authority</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Nova Scotia Health Authority</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that has been&#xD;
      shown to reduce breakthrough narcotic consumption following orthopaedic, neurosurgical, and&#xD;
      obstetrical procedures. The morphine-sparing effect of ketorolac may reduce respiratory and&#xD;
      central nervous system depression post operatively, while still providing adequate pain&#xD;
      control for patients. Patients undergoing abdominally based microsurgical breast&#xD;
      reconstruction may particularly benefit from ketorolac postoperatively, and ultimately be&#xD;
      safely discharged from hospital sooner than their counterparts receiving standard of care.&#xD;
&#xD;
      Research Question: In adult women post-mastectomy, undergoing abdominally based microsurgical&#xD;
      breast reconstruction, does a postoperative regimen of intravenous ketorolac tromethamine, in&#xD;
      addition to standard of care, reduce the length of postoperative hospital stay compared with&#xD;
      an intravenous sham saline regimen?&#xD;
&#xD;
      Study Design: A single center, explanatory, placebo-controlled, 1:1 allocation, 2-arm,&#xD;
      parallel group, superiority, randomized, and double blinded, controlled trial.&#xD;
&#xD;
      Population: The study population includes all females &gt;18 years old post mastectomy&#xD;
      consenting to abdominally based microsurgical breast reconstruction.&#xD;
&#xD;
      Intervention and Comparator: The intervention will be ketorolac 30 mg IV every 6 hours&#xD;
      postoperatively for 72 hours. The comparator will be a sham intravenous administration of&#xD;
      normal saline.&#xD;
&#xD;
      Outcomes: The primary outcome is hospital length of stay postoperatively. Secondary outcomes&#xD;
      include visual analog scale for pain, breakthrough narcotic consumption, surgical drain&#xD;
      outputs, hematoma, and other complications.&#xD;
&#xD;
      Sample Size: Available data provided estimates for average length of hospital stay and&#xD;
      standard deviation. A minimally clinically significant difference of 1 day was decided on due&#xD;
      to expert opinion. Based on a power of 80% and alpha of 0.05, and inflated to account for&#xD;
      attrition and efficiency losses, a total of 50 patients (25 per group) will be required for&#xD;
      this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Breast reconstruction (BR) is commonly requested following mastectomy, and recent measures&#xD;
      have been taken to ensure patient access is universal. Transferring autologous tissue from&#xD;
      the abdomen using microvascular surgical techniques provides a reliable reconstruction method&#xD;
      with high levels of patient satisfaction, and is routinely performed. However, the surgery is&#xD;
      relatively complex and lengthy; operative times can exceed six hours and hospital stay ranges&#xD;
      from 5-9 days. During each patient's postoperative course she must meet certain milestones&#xD;
      before discharge. It has been shown that beyond the necessary monitoring of the viability of&#xD;
      the free flap, pain and a patient's ability to mobilize are important modifiable barriers to&#xD;
      discharge.&#xD;
&#xD;
      Pain control following autologous BR is multimodal, but predominantly relies on opioids.&#xD;
      Narcotics provide effective analgesia, but have a well-known side effect profile that&#xD;
      includes drowsiness, nausea, vomiting, sedation, central nervous system and respiratory&#xD;
      depression. Each of these potential adverse effects limits patients' mobility after surgery.&#xD;
      Respiratory depression is particularly disadvantageous, as these patients have undergone&#xD;
      major abdominal musculature dissection that also disrupts their mechanics of breathing 10 .&#xD;
      This may have the counterproductive effect of limiting patient mobilization, and ultimately&#xD;
      delay discharge. In a health care system where resources are at a premium and costs are&#xD;
      climbing, any inexpensive intervention that allows for an earlier and safe discharge is&#xD;
      worthy of consideration.&#xD;
&#xD;
      No standard approach to postoperative pain control in free flap BR exists. Most protocols are&#xD;
      institution dependent, and variably incorporate narcotics, nonsteroidal anti-inflammatory&#xD;
      drugs (NSAIDs), acetaminophen and other agents. In addition, these medications are given via&#xD;
      oral, intramuscular, or intravenous routes. Recent studies have investigated the use of&#xD;
      transversus abdominis plane blocks as an analgesic adjunct, and patients are often provided&#xD;
      with patient-controlled analgesia (PCA) pumps in the early postoperative period.&#xD;
&#xD;
      Ketorolac tromethamine is an NSAID, which is approved by Health Canada for short-term pain&#xD;
      control (Toradol, Hoffmann-La Roche Limited, 7070 Mississauga Road Mississauga, Ontario).&#xD;
      Ketorolac provides better pain control than the most commonly used NSAIDs, and its potency is&#xD;
      comparable to that of morphine. However, it does not have the same listed side effects of&#xD;
      drowsiness and respiratory depression as do narcotics. Surgeons often cite concern regarding&#xD;
      postoperative bleeding when using NSAIDs, however recent reviews have convincingly&#xD;
      demonstrated the safety for use of NSAIDs in plastic surgery. A previous observational study&#xD;
      has also shown the safety of ketorolac specifically following autologous BR. The routine&#xD;
      addition of ketorolac following surgery has been shown to reduce patients' narcotic&#xD;
      requirements in other fields of surgery, such as orthopaedics and gynaecology.&#xD;
&#xD;
      Given the abovementioned advantages of ketorolac, and the particular propensity for&#xD;
      abdominally based free flap BR patients to be negatively affected by narcotic side effects,&#xD;
      we hypothesize that the addition of ketorolac to a routine multimodal postoperative analgesia&#xD;
      regimen will reduce hospital stay by a day or more.&#xD;
&#xD;
      The comparator for this study will be a placebo. Patients randomized both to the control&#xD;
      group and those randomized to the intervention group will receive standard of care&#xD;
      postoperatively, which will include pain control with scheduled acetaminophen and pro re nata&#xD;
      oral and subcutaneous hydromorphone. In addition, control patients will receive a placebo&#xD;
      with the same scheduling as the study drug, ketorolac. The rationale for this choice is to&#xD;
      limit potential sources of bias, such as the patient and her care team, and maximize the&#xD;
      accuracy of the primary outcome and patient-completed questionnaires that will serve as a&#xD;
      secondary outcome. Other authors have previously successfully used placebos for ketorolac in&#xD;
      their study design.&#xD;
&#xD;
      The majority of surgeons at our institution currently do not employ ketorolac in their&#xD;
      postoperative pain control regimen. Thus, there exists clinical equipoise for patients&#xD;
      considering participating and potentially being randomized into the control group, when&#xD;
      compared with declining participation and receiving usual care.&#xD;
&#xD;
      This study will be single-centered and conducted in Nova Scotia, Canada. The Halifax&#xD;
      Infirmary is a level III trauma center with multiple board certified Plastic surgeons who&#xD;
      have undertaken extra training in microsurgery.&#xD;
&#xD;
      Participants will be removed from the study upon request. Her data up until that point will&#xD;
      be used for statistical analysis, however she would no longer receive the intervention.&#xD;
      Modifications to intervention dosing would occur if a participant develops any drug&#xD;
      hypersensitivity reaction. Additionally any major harm attributed to ketorolac will prompt a&#xD;
      termination of the intervention.&#xD;
&#xD;
      Each patient will undergo uni- or bilateral abdominally based free flap harvest,&#xD;
      microsurgical anastomoses, and flap inset. Following randomization, the study drug will be&#xD;
      sent to the main operating theatre, and attached to the patient's medical chart. At the&#xD;
      conclusion of surgery, each patient will be administered their first dose of the study drug.&#xD;
      Its content will depend on the patient's randomized group. If randomized to the ketorolac&#xD;
      intervention group, the IV minibag will contain 30 mg of ketorolac tromethamine, or if in the&#xD;
      control group it will be a sham normal saline IV minibag. They then will continue to receive&#xD;
      their assigned drug every 6 hours for 72 hours. Patients all receive 1:1 care from nursing&#xD;
      staff in the early postoperative period, and their nurse will administer all drugs given on&#xD;
      the surgical ward.&#xD;
&#xD;
      All patients who have enrolled will receive the usual care for the postoperative period. The&#xD;
      study drug will be in addition to usual flap monitoring, patient vital sign monitoring,&#xD;
      progression of mobilization, drain management, along with the other care provided for these&#xD;
      patients. Patients also will have the same background analgesic and anti-emetics medications&#xD;
      ordered postoperatively, which is included on a standardized pre-printed order form at the&#xD;
      Halifax Infirmary for this particular surgery.&#xD;
&#xD;
      Potential participants will first be introduced to the study following their initial&#xD;
      consultation for BR. If the patient consents for abdominally based microsurgical BR, then the&#xD;
      study will be reviewed, allowing time for any questions to be asked, and the risks and&#xD;
      benefits to be discussed. The patient will be sent home with a study package that includes a&#xD;
      copy of the study consent form and protocol. The study will be reviewed again at a&#xD;
      preoperative appointment, allowing time for any follow up questions to be asked. This is a&#xD;
      routine appointment intended for markings and patient questions regarding surgery, and the&#xD;
      patient will officially be enrolled in the study if she wishes to participate at either&#xD;
      time-point - the initial consultation or the preoperative appointment. Following the surgery,&#xD;
      each patient will remain active in the study until her discharge from hospital. No follow up&#xD;
      appointments or data will be scheduled or recorded for the purposes of the study (although&#xD;
      follow up will occur as per usual with these patients and their respective surgeon).&#xD;
      Therefore total enrolment time for each patient will be from the appointment immediately&#xD;
      before surgery to her discharge from hospital.&#xD;
&#xD;
      A computer-generated algorithm will be used to randomize patients in a 1:1 allocation into&#xD;
      the intervention or control group during surgery. Randomization will be stratified by&#xD;
      laterality of the reconstruction (i.e. bi- or unilateral) because this could affect&#xD;
      participant pain levels. Randomization will be managed and maintained by a third party&#xD;
      service, not otherwise involved in the study, in the hospital pharmacy department. Allocation&#xD;
      methods will not be disclosed to study investigators. Following randomization, the study drug&#xD;
      will be sent to the main operating theatre, and given at the conclusion of the surgery. Both&#xD;
      the intervention and control drug will be of the same storage and opacity to prevent&#xD;
      identification by the patient or care providers. From there, the patient will then be&#xD;
      administered the same drug according to the randomization result, based on delivery by the&#xD;
      third party pharmacy service.&#xD;
&#xD;
      Randomization will be carried out within the pharmacy department placing patients into either&#xD;
      the intervention or control group. The intervention and control intravenous drugs will be&#xD;
      prepared in the same style IV minibag with the same volume and opacity of fluid. The fluids&#xD;
      will be of similar viscosity. Once similar appearances and features are confirmed the&#xD;
      prepared drug will be sent to the operating theatre or the ward as required depending on the&#xD;
      time point.&#xD;
&#xD;
      During the conduction of this study all involved trial participants, clinicians, data&#xD;
      collectors, event adjudicators, and data analysts will be blinded to the grouping of&#xD;
      patients. All study medications will be stored in the hospital pharmacy department by a third&#xD;
      party. Following randomization, treatment drugs will be dispensed by the pharmacy and then&#xD;
      administered by nursing staff. The third party service will maintain records linking a&#xD;
      patient unique identifier to her study group. Post hoc analysis to assess whether staff could&#xD;
      identify between the intervention and placebo will be conducted.&#xD;
&#xD;
      Harms will be classified as either minor or major. Minor harms will include surgical site&#xD;
      infection and those listed from prior clinical trials on the drug monograph, namely:&#xD;
&#xD;
      Common Clinical Trial Adverse Drug Reactions (&gt;1%): Dyspepsia, abdominal pain, nausea,&#xD;
      constipation, diarrhea, flatulence, gastrointestinal fullness, peptic ulcers, headache,&#xD;
      dizziness, somnolence, edema&#xD;
&#xD;
      Less Common Clinical Trial Adverse Drug Reactions (≤ 1%): Eructation, stomatitis, vomiting,&#xD;
      anorexia, duodenal ulcer, gastritis, increased appetite, melena, mouth ulceration, rectal&#xD;
      bleeding, sore mouth, abnormal dreams, anxiety, depression, dry mouth, insomnia, nervousness,&#xD;
      paresthesia, tinnitus, taste perversion, abnormal vision, blurred vision, deafness,&#xD;
      lacrimation disorder, weight gain, alkaline phosphatase increase, BUN increased, excessive&#xD;
      thirst, generalized edema, hyperuricemia, pruritus, rash, burning sensation, asthenia, pain,&#xD;
      back pain, face edema, hernia, arthralgia, myalgia, joint disorder, chest pain, chest pain&#xD;
      substernal, migraine, dyspnea, asthma, epistaxis, hematuria, increased urinary frequency,&#xD;
      oliguria, polyuria, anemia, purpura&#xD;
&#xD;
      No major harms are anticipated. Major harms will include but are not limited to (* indicates&#xD;
      possible association with oral ketorolac from drug monograph, &lt;1%):&#xD;
&#xD;
      Surgical site hemorrhage requiring re-exploration in the main operating theatre&#xD;
      Gastrointestinal hemorrhage* Pulmonary embolus Death&#xD;
&#xD;
      Any harm identified by care providers during enrolment of the study will be communicated to&#xD;
      the principal and sub investigators. Minor harms will be communicated within 5 days. Any&#xD;
      major harm will be communicated to the research ethics board within 24 hours. Complications&#xD;
      will be managed medically in standard fashion, and the research will have no bearing on&#xD;
      patient care. Emergency unblinding will be available to the patients' care providers at all&#xD;
      times, as above.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    No funding.&#xD;
  </why_stopped>
  <start_date type="Anticipated">November 2017</start_date>
  <completion_date type="Anticipated">June 2019</completion_date>
  <primary_completion_date type="Anticipated">January 2019</primary_completion_date>
  <phase>Phase 4</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Length of hospital stay postoperatively</measure>
    <time_frame>measured when the patient leaves the hospital, averages between 3-9 days</time_frame>
    <description>recorded in days beginning post operative day number one</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Visual analog scale for pain</measure>
    <time_frame>every 6 hours for 72 hours</time_frame>
    <description>Standard for for visual analog scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Narcotic consumption</measure>
    <time_frame>72 hours</time_frame>
    <description>Total narcotic consumption over first 72 hours converted to morphine equivalence</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical drain output</measure>
    <time_frame>72 hours</time_frame>
    <description>Total surgical drain output over first 72 hours</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hematoma</measure>
    <time_frame>measured when the patient leaves the hospital, averages between 3-9 days</time_frame>
    <description>Any hematoma requiring management in the operating room</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>measured when the patient leaves the hospital, averages between 3-9 days</time_frame>
    <description>Any infection requiring antibiotics, or flap complications requiring management in the operating room</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Breast Cancer Female</condition>
  <arm_group>
    <arm_group_label>Ketorolac tromethamine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each patient will undergo mastectomy(ies) if immediate reconstruction is being performed, followed by uni- or bilateral abdominally based free flap harvest, microsurgical anastomoses, and flap inset. If randomized to the ketorolac intervention group, then the participant will receive 30 mg of intravenous (IV) ketorolac tromethamine. The anaesthetist will give participants their first study drug intravenously at the conclusion of surgery. The participant will then continue to receive their assigned drug every 6 hours for 72 hours, for a total of 13 doses. Patients all receive 1:1 care from nursing staff in the early postoperative period, and their nurse will administer all drugs given on the surgical ward.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal Saline</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Each patient will undergo mastectomy(ies) if immediate reconstruction is being performed, followed by uni- or bilateral abdominally based free flap harvest, microsurgical anastomoses, and flap inset. If randomized to the control group the patient will be given a sham IV medication. The sham medication will be normal saline at the same volume as ketorolac, which corresponds to 3 ccs. The anaesthetist will give participants their first study drug intravenously at the conclusion of surgery. The participant will then continue to receive their assigned drug every 6 hours for 72 hours, for a total of 13 doses. Patients all receive 1:1 care from nursing staff in the early postoperative period, and their nurse will administer all drugs given on the surgical ward.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketorolac Tromethamine</intervention_name>
    <description>Intravenous analgesic</description>
    <arm_group_label>Ketorolac tromethamine</arm_group_label>
    <other_name>Toradol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal Saline</intervention_name>
    <description>Sham comparator</description>
    <arm_group_label>Normal Saline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients 18 years of age or older will be offered inclusion if they are scheduled to&#xD;
             undergo unilateral or bilateral postmastectomy abdominally based free flap BR&#xD;
             postmastectomy, either in a delayed fashion or at the time of initial mastectomy(ies).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients will be excluded if they meet any of the exclusion criteria: male; revision&#xD;
             surgery; a planned pedicled flap reconstruction; any previous diagnosis of chronic&#xD;
             renal disease, gastric ulcers, or bleeding disorder; acetaminophen, NSAID or specific&#xD;
             ketorolac sensitivity or allergy; pregnancy; or opioid tolerance defined as&#xD;
             preoperative opioid use greater than 50 mg.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joseph P Corkum, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NSHA</affiliation>
  </overall_official>
  <reference>
    <citation>Bonde C, Khorasani H, Eriksen K, Wolthers M, Kehlet H, Elberg J. Introducing the fast track surgery principles can reduce length of stay after autologous breast reconstruction using free flaps: A case control study. J Plast Surg Hand Surg. 2015;49(6):367-71. doi: 10.3109/2000656X.2015.1062387. Epub 2015 Jul 10.</citation>
    <PMID>26161838</PMID>
  </reference>
  <reference>
    <citation>Zhong T, Ojha M, Bagher S, Butler K, Srinivas C, McCluskey SA, Clarke H, O'Neill AC, Novak CB, Hofer SOP. Transversus abdominis plane block reduces morphine consumption in the early postoperative period following microsurgical abdominal tissue breast reconstruction: a double-blind, placebo-controlled, randomized trial. Plast Reconstr Surg. 2014 Nov;134(5):870-878. doi: 10.1097/PRS.0000000000000613.</citation>
    <PMID>25347623</PMID>
  </reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <last_update_submitted>August 13, 2017</last_update_submitted>
  <last_update_submitted_qc>August 13, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 16, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Nova Scotia Health Authority</investigator_affiliation>
    <investigator_full_name>Joey Corkum</investigator_full_name>
    <investigator_title>Physician</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketorolac</mesh_term>
    <mesh_term>Ketorolac Tromethamine</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/NCT03007381
org study id: KANGAROO
nct id: NCT03007381
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Background: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that has been
      shown to reduce breakthrough narcotic consumption following orthopaedic, neurosurgical, and
      obstetrical procedures. The morphine-sparing effect of ketorolac may reduce respiratory and
      central nervous system depression post operatively, while still providing adequate pain
      control for patients. Patients undergoing abdominally based microsurgical breast
      reconstruction may particularly benefit from ketorolac postoperatively, and ultimately be
      safely discharged from hospital sooner than their counterparts receiving standard of care.

      Research Question: In adult women post-mastectomy, undergoing abdominally based microsurgical
      breast reconstruction, does a postoperative regimen of intravenous ketorolac tromethamine, in
      addition to standard of care, reduce the length of postoperative hospital stay compared with
      an intravenous sham saline regimen?

      Study Design: A single center, explanatory, placebo-controlled, 1:1 allocation, 2-arm,
      parallel group, superiority, randomized, and double blinded, controlled trial.

      Population: The study population includes all females >18 years old post mastectomy
      consenting to abdominally based microsurgical breast reconstruction.

      Intervention and Comparator: The intervention will be ketorolac 30 mg IV every 6 hours
      postoperatively for 72 hours. The comparator will be a sham intravenous administration of
      normal saline.

      Outcomes: The primary outcome is hospital length of stay postoperatively. Secondary outcomes
      include visual analog scale for pain, breakthrough narcotic consumption, surgical drain
      outputs, hematoma, and other complications.

      Sample Size: Available data provided estimates for average length of hospital stay and
      standard deviation. A minimally clinically significant difference of 1 day was decided on due
      to expert opinion. Based on a power of 80% and alpha of 0.05, and inflated to account for
      attrition and efficiency losses, a total of 50 patients (25 per group) will be required for
      this study.
Breast reconstruction (BR) is commonly requested following mastectomy, and recent measures
      have been taken to ensure patient access is universal. Transferring autologous tissue from
      the abdomen using microvascular surgical techniques provides a reliable reconstruction method
      with high levels of patient satisfaction, and is routinely performed. However, the surgery is
      relatively complex and lengthy; operative times can exceed six hours and hospital stay ranges
      from 5-9 days. During each patient's postoperative course she must meet certain milestones
      before discharge. It has been shown that beyond the necessary monitoring of the viability of
      the free flap, pain and a patient's ability to mobilize are important modifiable barriers to
      discharge.

      Pain control following autologous BR is multimodal, but predominantly relies on opioids.
      Narcotics provide effective analgesia, but have a well-known side effect profile that
      includes drowsiness, nausea, vomiting, sedation, central nervous system and respiratory
      depression. Each of these potential adverse effects limits patients' mobility after surgery.
      Respiratory depression is particularly disadvantageous, as these patients have undergone
      major abdominal musculature dissection that also disrupts their mechanics of breathing 10 .
      This may have the counterproductive effect of limiting patient mobilization, and ultimately
      delay discharge. In a health care system where resources are at a premium and costs are
      climbing, any inexpensive intervention that allows for an earlier and safe discharge is
      worthy of consideration.

      No standard approach to postoperative pain control in free flap BR exists. Most protocols are
      institution dependent, and variably incorporate narcotics, nonsteroidal anti-inflammatory
      drugs (NSAIDs), acetaminophen and other agents. In addition, these medications are given via
      oral, intramuscular, or intravenous routes. Recent studies have investigated the use of
      transversus abdominis plane blocks as an analgesic adjunct, and patients are often provided
      with patient-controlled analgesia (PCA) pumps in the early postoperative period.

      Ketorolac tromethamine is an NSAID, which is approved by Health Canada for short-term pain
      control (Toradol, Hoffmann-La Roche Limited, 7070 Mississauga Road Mississauga, Ontario).
      Ketorolac provides better pain control than the most commonly used NSAIDs, and its potency is
      comparable to that of morphine. However, it does not have the same listed side effects of
      drowsiness and respiratory depression as do narcotics. Surgeons often cite concern regarding
      postoperative bleeding when using NSAIDs, however recent reviews have convincingly
      demonstrated the safety for use of NSAIDs in plastic surgery. A previous observational study
      has also shown the safety of ketorolac specifically following autologous BR. The routine
      addition of ketorolac following surgery has been shown to reduce patients' narcotic
      requirements in other fields of surgery, such as orthopaedics and gynaecology.

      Given the abovementioned advantages of ketorolac, and the particular propensity for
      abdominally based free flap BR patients to be negatively affected by narcotic side effects,
      we hypothesize that the addition of ketorolac to a routine multimodal postoperative analgesia
      regimen will reduce hospital stay by a day or more.

      The comparator for this study will be a placebo. Patients randomized both to the control
      group and those randomized to the intervention group will receive standard of care
      postoperatively, which will include pain control with scheduled acetaminophen and pro re nata
      oral and subcutaneous hydromorphone. In addition, control patients will receive a placebo
      with the same scheduling as the study drug, ketorolac. The rationale for this choice is to
      limit potential sources of bias, such as the patient and her care team, and maximize the
      accuracy of the primary outcome and patient-completed questionnaires that will serve as a
      secondary outcome. Other authors have previously successfully used placebos for ketorolac in
      their study design.

      The majority of surgeons at our institution currently do not employ ketorolac in their
      postoperative pain control regimen. Thus, there exists clinical equipoise for patients
      considering participating and potentially being randomized into the control group, when
      compared with declining participation and receiving usual care.

      This study will be single-centered and conducted in Nova Scotia, Canada. The Halifax
      Infirmary is a level III trauma center with multiple board certified Plastic surgeons who
      have undertaken extra training in microsurgery.

      Participants will be removed from the study upon request. Her data up until that point will
      be used for statistical analysis, however she would no longer receive the intervention.
      Modifications to intervention dosing would occur if a participant develops any drug
      hypersensitivity reaction. Additionally any major harm attributed to ketorolac will prompt a
      termination of the intervention.

      Each patient will undergo uni- or bilateral abdominally based free flap harvest,
      microsurgical anastomoses, and flap inset. Following randomization, the study drug will be
      sent to the main operating theatre, and attached to the patient's medical chart. At the
      conclusion of surgery, each patient will be administered their first dose of the study drug.
      Its content will depend on the patient's randomized group. If randomized to the ketorolac
      intervention group, the IV minibag will contain 30 mg of ketorolac tromethamine, or if in the
      control group it will be a sham normal saline IV minibag. They then will continue to receive
      their assigned drug every 6 hours for 72 hours. Patients all receive 1:1 care from nursing
      staff in the early postoperative period, and their nurse will administer all drugs given on
      the surgical ward.

      All patients who have enrolled will receive the usual care for the postoperative period. The
      study drug will be in addition to usual flap monitoring, patient vital sign monitoring,
      progression of mobilization, drain management, along with the other care provided for these
      patients. Patients also will have the same background analgesic and anti-emetics medications
      ordered postoperatively, which is included on a standardized pre-printed order form at the
      Halifax Infirmary for this particular surgery.

      Potential participants will first be introduced to the study following their initial
      consultation for BR. If the patient consents for abdominally based microsurgical BR, then the
      study will be reviewed, allowing time for any questions to be asked, and the risks and
      benefits to be discussed. The patient will be sent home with a study package that includes a
      copy of the study consent form and protocol. The study will be reviewed again at a
      preoperative appointment, allowing time for any follow up questions to be asked. This is a
      routine appointment intended for markings and patient questions regarding surgery, and the
      patient will officially be enrolled in the study if she wishes to participate at either
      time-point - the initial consultation or the preoperative appointment. Following the surgery,
      each patient will remain active in the study until her discharge from hospital. No follow up
      appointments or data will be scheduled or recorded for the purposes of the study (although
      follow up will occur as per usual with these patients and their respective surgeon).
      Therefore total enrolment time for each patient will be from the appointment immediately
      before surgery to her discharge from hospital.

      A computer-generated algorithm will be used to randomize patients in a 1:1 allocation into
      the intervention or control group during surgery. Randomization will be stratified by
      laterality of the reconstruction (i.e. bi- or unilateral) because this could affect
      participant pain levels. Randomization will be managed and maintained by a third party
      service, not otherwise involved in the study, in the hospital pharmacy department. Allocation
      methods will not be disclosed to study investigators. Following randomization, the study drug
      will be sent to the main operating theatre, and given at the conclusion of the surgery. Both
      the intervention and control drug will be of the same storage and opacity to prevent
      identification by the patient or care providers. From there, the patient will then be
      administered the same drug according to the randomization result, based on delivery by the
      third party pharmacy service.

      Randomization will be carried out within the pharmacy department placing patients into either
      the intervention or control group. The intervention and control intravenous drugs will be
      prepared in the same style IV minibag with the same volume and opacity of fluid. The fluids
      will be of similar viscosity. Once similar appearances and features are confirmed the
      prepared drug will be sent to the operating theatre or the ward as required depending on the
      time point.

      During the conduction of this study all involved trial participants, clinicians, data
      collectors, event adjudicators, and data analysts will be blinded to the grouping of
      patients. All study medications will be stored in the hospital pharmacy department by a third
      party. Following randomization, treatment drugs will be dispensed by the pharmacy and then
      administered by nursing staff. The third party service will maintain records linking a
      patient unique identifier to her study group. Post hoc analysis to assess whether staff could
      identify between the intervention and placebo will be conducted.

      Harms will be classified as either minor or major. Minor harms will include surgical site
      infection and those listed from prior clinical trials on the drug monograph, namely:

      Common Clinical Trial Adverse Drug Reactions (>1%): Dyspepsia, abdominal pain, nausea,
      constipation, diarrhea, flatulence, gastrointestinal fullness, peptic ulcers, headache,
      dizziness, somnolence, edema

      Less Common Clinical Trial Adverse Drug Reactions (≤ 1%): Eructation, stomatitis, vomiting,
      anorexia, duodenal ulcer, gastritis, increased appetite, melena, mouth ulceration, rectal
      bleeding, sore mouth, abnormal dreams, anxiety, depression, dry mouth, insomnia, nervousness,
      paresthesia, tinnitus, taste perversion, abnormal vision, blurred vision, deafness,
      lacrimation disorder, weight gain, alkaline phosphatase increase, BUN increased, excessive
      thirst, generalized edema, hyperuricemia, pruritus, rash, burning sensation, asthenia, pain,
      back pain, face edema, hernia, arthralgia, myalgia, joint disorder, chest pain, chest pain
      substernal, migraine, dyspnea, asthma, epistaxis, hematuria, increased urinary frequency,
      oliguria, polyuria, anemia, purpura

      No major harms are anticipated. Major harms will include but are not limited to (* indicates
      possible association with oral ketorolac from drug monograph, <1%):

      Surgical site hemorrhage requiring re-exploration in the main operating theatre
      Gastrointestinal hemorrhage* Pulmonary embolus Death

      Any harm identified by care providers during enrolment of the study will be communicated to
      the principal and sub investigators. Minor harms will be communicated within 5 days. Any
      major harm will be communicated to the research ethics board within 24 hours. Complications
      will be managed medically in standard fashion, and the research will have no bearing on
      patient care. Emergency unblinding will be available to the patients' care providers at all
      times, as above.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Length of hospital stay postoperatively
time frame: measured when the patient leaves the hospital, averages between 3-9 days
description: recorded in days beginning post operative day number one
measure: Visual analog scale for pain
time frame: every 6 hours for 72 hours
description: Standard for for visual analog scale
measure: Narcotic consumption
time frame: 72 hours
description: Total narcotic consumption over first 72 hours converted to morphine equivalence
measure: Surgical drain output
time frame: 72 hours
description: Total surgical drain output over first 72 hours
measure: Hematoma
time frame: measured when the patient leaves the hospital, averages between 3-9 days
description: Any hematoma requiring management in the operating room
measure: Adverse events
time frame: measured when the patient leaves the hospital, averages between 3-9 days
description: Any infection requiring antibiotics, or flap complications requiring management in the operating room
arm group label: Ketorolac tromethamine
arm group type: Experimental
description: Each patient will undergo mastectomy(ies) if immediate reconstruction is being performed, followed by uni- or bilateral abdominally based free flap harvest, microsurgical anastomoses, and flap inset. If randomized to the ketorolac intervention group, then the participant will receive 30 mg of intravenous (IV) ketorolac tromethamine. The anaesthetist will give participants their first study drug intravenously at the conclusion of surgery. The participant will then continue to receive their assigned drug every 6 hours for 72 hours, for a total of 13 doses. Patients all receive 1:1 care from nursing staff in the early postoperative period, and their nurse will administer all drugs given on the surgical ward.
arm group label: Normal Saline
arm group type: Sham Comparator
description: Each patient will undergo mastectomy(ies) if immediate reconstruction is being performed, followed by uni- or bilateral abdominally based free flap harvest, microsurgical anastomoses, and flap inset. If randomized to the control group the patient will be given a sham IV medication. The sham medication will be normal saline at the same volume as ketorolac, which corresponds to 3 ccs. The anaesthetist will give participants their first study drug intravenously at the conclusion of surgery. The participant will then continue to receive their assigned drug every 6 hours for 72 hours, for a total of 13 doses. Patients all receive 1:1 care from nursing staff in the early postoperative period, and their nurse will administer all drugs given on the surgical ward.
intervention type: Drug
intervention name: Ketorolac Tromethamine
description: Intravenous analgesic
arm group label: Ketorolac tromethamine
other name: Toradol
intervention type: Drug
intervention name: Normal Saline
description: Sham comparator
arm group label: Normal Saline
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joseph P Corkum, MD
role: Principal Investigator
affiliation: NSHA
citation: Bonde C, Khorasani H, Eriksen K, Wolthers M, Kehlet H, Elberg J. Introducing the fast track surgery principles can reduce length of stay after autologous breast reconstruction using free flaps: A case control study. J Plast Surg Hand Surg. 2015;49(6):367-71. doi: 10.3109/2000656X.2015.1062387. Epub 2015 Jul 10.
PMID: 26161838
citation: Zhong T, Ojha M, Bagher S, Butler K, Srinivas C, McCluskey SA, Clarke H, O'Neill AC, Novak CB, Hofer SOP. Transversus abdominis plane block reduces morphine consumption in the early postoperative period following microsurgical abdominal tissue breast reconstruction: a double-blind, placebo-controlled, randomized trial. Plast Reconstr Surg. 2014 Nov;134(5):870-878. doi: 10.1097/PRS.0000000000000613.
PMID: 25347623
responsible party type: Principal Investigator
investigator affiliation: Nova Scotia Health Authority
investigator full name: Joey Corkum
investigator title: Physician
mesh term: Ketorolac
mesh term: Ketorolac Tromethamine
sharing ipd: No