<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/NCT03805607</url>
  </required_header>
  <id_info>
    <org_study_id>2018P000625</org_study_id>
    <nct_id>NCT03805607</nct_id>
  </id_info>
  <brief_title>IV Ketorolac on Platelet Function Post-Cesarean Delivery</brief_title>
  <acronym>KetoPltAgg</acronym>
  <official_title>Prospective Evaluation of the Effects of IV Ketorolac on Platelet Function Post-Cesarean Delivery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beth Israel Deaconess Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Society for Obstetric Anesthesia and Perinatology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Beth Israel Deaconess Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cesarean delivery has become the most common surgical procedure in the US. Non-steroidal&#xD;
      anti-inflammatory drugs (NSAIDs) have been shown to improve the quality of post-cesarean&#xD;
      analgesia and markedly reduce opioid consumption. The effect of NSAIDs on healthy volunteers&#xD;
      results in inhibition of platelet aggregation and prolonged bleeding time. However, in the&#xD;
      obstetric population, the presence and degree of platelet inhibition after NSAID exposure is&#xD;
      less clear. The investigators plan to use Platelet Aggregometry and Thromboelastography (TEG)&#xD;
      to evaluate the effect of ketorolac on platelets.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cesarean delivery has become the most common surgical procedure in the US, with over 1.2&#xD;
      million cesarean deliveries performed each year. The addition of non-steroidal&#xD;
      anti-inflammatory drugs (NSAIDs) to a post-cesarean analgesic regimen has been shown to&#xD;
      improve the quality of post-cesarean analgesia and markedly reduce opioid consumption. As a&#xD;
      result, fewer patients incur opioid related side-effects such as nausea and vomiting,&#xD;
      respiratory compromise, sedation, and impaired breast-feeding.&#xD;
&#xD;
      The effect of NSAIDs on healthy volunteers is relatively well-described. Most commonly,&#xD;
      NSAIDs inhibit membrane-bound cyclooxygenase 1 (COX-1), the enzyme responsible for the&#xD;
      production of the platelet agonist thromboxane A2. This ultimately results in inhibition of&#xD;
      platelet aggregation and prolonged bleeding time. However, in the obstetric population, the&#xD;
      presence and degree of platelet inhibition after NSAID exposure is less clear. This has&#xD;
      limited the incorporation of NSAIDs into protocols for postpartum analgesia following&#xD;
      cesarean delivery.&#xD;
&#xD;
      Platelet Function Assessment 100 (PFA) assays, with collagen/epinephrine and collagen/ADP&#xD;
      (adenosine diphosphate) as agonists, can reliably test for platelet inhibition. PFA has been&#xD;
      utilized to examine the anti-platelet effects of platelet inhibitors including NSAIDs in&#xD;
      studies involving non-obstetric patients. Similarly, platelet aggregometry has been used to&#xD;
      evaluate the platelet inhibitory effects of NSAIDs. Thromboelastography (TEG) has been shown&#xD;
      in numerous studies to represent in-vivo clot strength and function.&#xD;
&#xD;
      Research in this field is needed as physiologic changes of pregnancy combined with&#xD;
      significant surgical blood loss and hemodilution at cesarean delivery may alter the effect on&#xD;
      maternal platelet function. This has become more pressing as postpartum thromboprophylaxis is&#xD;
      likely to be more commonly considered for patients after cesarean delivery. In their most&#xD;
      recent unofficial guidelines, the American Society of Regional Anesthesia state that NSAIDs&#xD;
      should not be used with thromboprophylaxis after patients received neuraxial blockade (ASRA&#xD;
      App). However, to the best of our knowledge, there is limited data, only utilizing bleeding&#xD;
      time,5 examining the potential platelet inhibitory effect of NSAIDs in a low-risk healthy&#xD;
      cohort undergoing cesarean delivery.&#xD;
&#xD;
      Protocol:&#xD;
&#xD;
      Brief Study Protocol After obtaining Institutional Review Board (IRB) approval, patients will&#xD;
      be randomly assigned to receive either IV ketorolac 30 mg (n=15) or normal saline (n=15)&#xD;
      based on a pre-assigned randomization sequence. The assignment for each patient will be kept&#xD;
      in sealed opaque envelopes. After obtaining written informed consent, an anesthesiologist not&#xD;
      involved in the study will open the envelope and will prepare the study drug. The patient and&#xD;
      the study investigators will be blinded to the study drug.&#xD;
&#xD;
      Baseline platelet count, coagulation parameters (activated partial thromboplastin time&#xD;
      (APTT), prothrombin time (PT), Fibrinogen) and TEG parameters will be measured&#xD;
      pre-operatively on the day of surgery. Routine lab work obtained at this time will require 10&#xD;
      ml of blood, while study related tests will require 5.4 ml. Each patient will undergo either&#xD;
      spinal or combined spinal epidural anesthesia with our standard cesarean induction dose of&#xD;
      hyperbaric intrathecal 0.75% bupivacaine 1.5 ml, intrathecal fentanyl 25 micrograms and&#xD;
      intrathecal morphine 250 micrograms. The patient will be moved to the supine position with&#xD;
      left lateral uterine displacement. When a T6 sensory level to pinprick is achieved, cesarean&#xD;
      delivery will be allowed to proceed. At the completion of the surgery, Platelet Aggregometry&#xD;
      and TEG parameters will be performed to assess for intraoperative changes to TEG and&#xD;
      establish baseline Platelet Aggregometry values. A total volume of 18.9 ml of blood will be&#xD;
      withdrawn for the study at this time. While under the effect of the spinal medication,&#xD;
      meaning that the patient is unable to fill sharp in their feet, the patient may elect to have&#xD;
      this blood and the subsequent blood drawn from their foot to avoid unnecessary pain. These&#xD;
      blood draws would only be performed by an anesthesiologist and only if a suitable site was&#xD;
      identified. Performing venipucture for lab draws in the feet is not known to increase the&#xD;
      risk of complications from blood draws when compared to the upper extremity. The study drug&#xD;
      will be administered upon completion of the case. Platelet Aggregometry and TEG parameters&#xD;
      will be performed 10 min after study drug administration. An additional volume of 18.9 ml of&#xD;
      blood will be withdrawn for the study at this time. After blood samples have been obtained,&#xD;
      patients in each group will receive the alternate therapy (ie placebo group receives&#xD;
      ketorolac and ketorolac receives placebo), allowing both groups to benefit from the analgesic&#xD;
      effect of ketorolac. Supplemental analgesia will be administered according to a standard&#xD;
      post-operative pain management protocol on labor and delivery.&#xD;
&#xD;
      Statistical analysis: Data will be assessed for normality using normality plots and the&#xD;
      Kolmogorov-Smirnov test. Demographic, obstetric, and perioperative data will be presented as&#xD;
      mean (SD) or median [interquartile range]. Between-group comparisons will be assessed using&#xD;
      the unpaired t test and Mann-Whitney U test, where appropriate. Within-group before vs. after&#xD;
      NSAID exposure changes will be assessed using the paired t test and Wilcoxon signed rank&#xD;
      test, where appropriate. The percentage change from baseline for each PFA, TEG, and lab&#xD;
      parameter will also be calculated.&#xD;
&#xD;
      Sample size justification: There is limited data on the affect of ketorolac on quantitative&#xD;
      coagulation studies, particularly in the obstetric population. Based on available data from a&#xD;
      prior study examining platelet inhibition of non-opioid analgesics, a PFA closure time ≥173&#xD;
      seconds can be used to classify platelet inhibition. Using the aforementioned data on&#xD;
      epinephrine-induced PFA closure time, the investigators estimate that, before and after&#xD;
      ketorolac exposure, 25% and 70% patients respectively would exhibit prolonged PFA closure&#xD;
      times. With an alpha error of 0.05 and a beta error of 0.8, the investigators estimated that&#xD;
      a sample size of 18 patients per group would provide 80% power. Additional studies have&#xD;
      examined the affect of ketorolac on platelet aggregometry. Platelet aggregometry to collagen&#xD;
      was diminished in the ketorolac group from preoperative to poststudy drug data points (90.8%&#xD;
      +/- 7.6% to 60.5% +/- 32.5%; P &lt; 0.01). With an alpha error of 0.05 and a beta error of 0.8,&#xD;
      the investigators estimated that a sample size of 19 patients per group would provide 80%&#xD;
      power.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 18, 2021</start_date>
  <completion_date type="Anticipated">August 2023</completion_date>
  <primary_completion_date type="Actual">February 3, 2022</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>
    <intervention_model_description>Randomized Placebo-Controlled Trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Placebo (normal saline) or ketorolac in syringe prepared by the investigational pharmacy with study patient number and blinding key maintained by investigational pharmacy until time of unblinding.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Platelet Aggregometry Light Transmission</measure>
    <time_frame>15 minutes after dosing of placebo or ketorolac</time_frame>
    <description>Platelet Aggregometry uses measurements platelet rich blood or serum samples and activating agents to analyze the percent change in light transmission as a marker of platelet aggregation.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Thromboelastogram parameters including Reaction time (R)</measure>
    <time_frame>15 minutes after dosing of placebo or ketorolac</time_frame>
    <description>Thromboelastogram parameters including Reaction time (R)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thromboelastogram parameters including Angle (alpha)</measure>
    <time_frame>15 minutes after dosing of placebo or ketorolac</time_frame>
    <description>Thromboelastogram parameters including Angle (alpha)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thromboelastogram parameters including Kinetics (K)</measure>
    <time_frame>15 minutes after dosing of placebo or ketorolac</time_frame>
    <description>Thromboelastogram parameters including Kinetics (K)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thromboelastogram parameters including Maximum Amplitude (MA)</measure>
    <time_frame>15 minutes after dosing of placebo or ketorolac</time_frame>
    <description>Thromboelastogram parameters including Maximum Amplitude (MA)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Analgesia, Obstetrical</condition>
  <condition>Coagulation Defect; Postpartum</condition>
  <condition>Nonsteroidals (NSAIDs)Toxicity</condition>
  <condition>Postpartum Hemorrhage</condition>
  <condition>Postoperative Pain</condition>
  <condition>Ketorolac Adverse Reaction</condition>
  <condition>Blood Loss, Postoperative</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>1 ml of normal saline</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ketorolac</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 mg of ketorolac in 1 ml</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketorolac Tromethamine 30 MG/ML</intervention_name>
    <description>Ketorolac 30 mg</description>
    <arm_group_label>Ketorolac</arm_group_label>
    <other_name>ketorolac</other_name>
    <other_name>Ketorolac Tromethamine</other_name>
    <other_name>Ketorolac Injectable Solution</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Normal Saline</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo</other_name>
    <other_name>Normal Saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant&#xD;
&#xD;
          -  Undergoing routine, scheduled cesarean section&#xD;
&#xD;
          -  Gestation &gt;37 weeks&#xD;
&#xD;
          -  Singleton gestation&#xD;
&#xD;
          -  Intraoperative anesthesia - 1.5 ml of intrathecal bupivicaine 0.75%, 25mcg of&#xD;
             intrathecal fentanyl and 250 mcg of intrathecal morphine via Spinal or Combined Spinal&#xD;
             Epidural&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pre-eclampsia with severe features or HELLP&#xD;
&#xD;
          -  Allergy to NSAIDs&#xD;
&#xD;
          -  Pre-existing bleeding disorder&#xD;
&#xD;
          -  Other major risk factor for postpartum hemorrhage (placenta accreta, large uterine&#xD;
             fibroid)&#xD;
&#xD;
          -  Chronic kidney disease&#xD;
&#xD;
          -  Plt count less than 100k&#xD;
&#xD;
          -  Gastric ulcer or gastric bleeding&#xD;
&#xD;
          -  Pre-existing uterine bleeding or disseminated intravascular coagulation&#xD;
&#xD;
          -  Patient or Obstetrician refusal&#xD;
&#xD;
          -  Intraoperative exclusion criteria - Postpartum hemorrhage (EBL &gt;1000 ml) or unplanned&#xD;
             intraoperative extension of surgery&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Blackburn A, Stevens JD, Wheatley RG, Madej TH, Hunter D. Balanced analgesia with intravenous ketorolac and patient-controlled morphine following lower abdominal surgery. J Clin Anesth. 1995 Mar;7(2):103-8. doi: 10.1016/0952-8180(94)00040-b.</citation>
    <PMID>7598916</PMID>
  </reference>
  <reference>
    <citation>Diemunsch P, Alt M, Diemunsch AM, Treisser A. Post cesarean analgesia with ketorolac tromethamine and uterine atonia. Eur J Obstet Gynecol Reprod Biol. 1997 Apr;72(2):205-6. doi: 10.1016/s0301-2115(96)02682-6. No abstract available.</citation>
    <PMID>9134403</PMID>
  </reference>
  <reference>
    <citation>Pavy TJ, Paech MJ, Evans SF. The effect of intravenous ketorolac on opioid requirement and pain after cesarean delivery. Anesth Analg. 2001 Apr;92(4):1010-4. doi: 10.1097/00000539-200104000-00038.</citation>
    <PMID>11273941</PMID>
  </reference>
  <reference>
    <citation>Lowder JL, Shackelford DP, Holbert D, Beste TM. A randomized, controlled trial to compare ketorolac tromethamine versus placebo after cesarean section to reduce pain and narcotic usage. Am J Obstet Gynecol. 2003 Dec;189(6):1559-62; discussion 1562. doi: 10.1016/j.ajog.2003.08.014.</citation>
    <PMID>14710063</PMID>
  </reference>
  <reference>
    <citation>El-Tahan MR, Warda OM, Yasseen AM, Attallah MM, Matter MK. A randomized study of the effects of preoperative ketorolac on general anaesthesia for caesarean section. Int J Obstet Anesth. 2007 Jul;16(3):214-20. doi: 10.1016/j.ijoa.2007.01.012. Epub 2007 Apr 24.</citation>
    <PMID>17459695</PMID>
  </reference>
  <reference>
    <citation>Elhakim M, Fathy A, Amine H, Saeed A, Mekawy M. Effect of i.v. tenoxicam during caesarean delivery on platelet activity. Acta Anaesthesiol Scand. 2000 May;44(5):555-9. doi: 10.1034/j.1399-6576.2000.00512.x.</citation>
    <PMID>10786742</PMID>
  </reference>
  <reference>
    <citation>Gobble RM, Hoang HLT, Kachniarz B, Orgill DP. Ketorolac does not increase perioperative bleeding: a meta-analysis of randomized controlled trials. Plast Reconstr Surg. 2014 Mar;133(3):741-755. doi: 10.1097/01.prs.0000438459.60474.b5.</citation>
    <PMID>24572864</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 8, 2019</study_first_submitted>
  <study_first_submitted_qc>January 13, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 15, 2019</study_first_posted>
  <last_update_submitted>March 28, 2023</last_update_submitted>
  <last_update_submitted_qc>March 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beth Israel Deaconess Medical Center</investigator_affiliation>
    <investigator_full_name>John J. Kowalczyk</investigator_full_name>
    <investigator_title>Instructor in Anaesthesia</investigator_title>
  </responsible_party>
  <keyword>Cesarean Section Complications</keyword>
  <keyword>Blood Loss, Surgical</keyword>
  <keyword>Coagulation Defect; Postpartum</keyword>
  <keyword>Nonsteroidals (NSAIDs)Toxicity</keyword>
  <keyword>Postpartum Hemorrhage</keyword>
  <keyword>Ketorolac</keyword>
  <keyword>Cesarean Delivery</keyword>
  <keyword>Platelet Function</keyword>
  <keyword>Cyclooxygenase Inhibitors/administration &amp; dosage</keyword>
  <keyword>Female</keyword>
  <keyword>Humans</keyword>
  <keyword>Ketorolac/administration &amp; dosage</keyword>
  <keyword>Pain, Postoperative/drug therapy</keyword>
  <keyword>Pregnancy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Postpartum Hemorrhage</mesh_term>
    <mesh_term>Hemostatic Disorders</mesh_term>
    <mesh_term>Blood Coagulation Disorders</mesh_term>
    <mesh_term>Hemorrhage</mesh_term>
    <mesh_term>Postoperative Hemorrhage</mesh_term>
  </condition_browse>
  <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>
    <ipd_description>Individual participant data (IPD) will not be shared.</ipd_description>
  </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/NCT03805607
org study id: 2018P000625
nct id: NCT03805607
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Cesarean delivery has become the most common surgical procedure in the US. Non-steroidal
      anti-inflammatory drugs (NSAIDs) have been shown to improve the quality of post-cesarean
      analgesia and markedly reduce opioid consumption. The effect of NSAIDs on healthy volunteers
      results in inhibition of platelet aggregation and prolonged bleeding time. However, in the
      obstetric population, the presence and degree of platelet inhibition after NSAID exposure is
      less clear. The investigators plan to use Platelet Aggregometry and Thromboelastography (TEG)
      to evaluate the effect of ketorolac on platelets.
Cesarean delivery has become the most common surgical procedure in the US, with over 1.2
      million cesarean deliveries performed each year. The addition of non-steroidal
      anti-inflammatory drugs (NSAIDs) to a post-cesarean analgesic regimen has been shown to
      improve the quality of post-cesarean analgesia and markedly reduce opioid consumption. As a
      result, fewer patients incur opioid related side-effects such as nausea and vomiting,
      respiratory compromise, sedation, and impaired breast-feeding.

      The effect of NSAIDs on healthy volunteers is relatively well-described. Most commonly,
      NSAIDs inhibit membrane-bound cyclooxygenase 1 (COX-1), the enzyme responsible for the
      production of the platelet agonist thromboxane A2. This ultimately results in inhibition of
      platelet aggregation and prolonged bleeding time. However, in the obstetric population, the
      presence and degree of platelet inhibition after NSAID exposure is less clear. This has
      limited the incorporation of NSAIDs into protocols for postpartum analgesia following
      cesarean delivery.

      Platelet Function Assessment 100 (PFA) assays, with collagen/epinephrine and collagen/ADP
      (adenosine diphosphate) as agonists, can reliably test for platelet inhibition. PFA has been
      utilized to examine the anti-platelet effects of platelet inhibitors including NSAIDs in
      studies involving non-obstetric patients. Similarly, platelet aggregometry has been used to
      evaluate the platelet inhibitory effects of NSAIDs. Thromboelastography (TEG) has been shown
      in numerous studies to represent in-vivo clot strength and function.

      Research in this field is needed as physiologic changes of pregnancy combined with
      significant surgical blood loss and hemodilution at cesarean delivery may alter the effect on
      maternal platelet function. This has become more pressing as postpartum thromboprophylaxis is
      likely to be more commonly considered for patients after cesarean delivery. In their most
      recent unofficial guidelines, the American Society of Regional Anesthesia state that NSAIDs
      should not be used with thromboprophylaxis after patients received neuraxial blockade (ASRA
      App). However, to the best of our knowledge, there is limited data, only utilizing bleeding
      time,5 examining the potential platelet inhibitory effect of NSAIDs in a low-risk healthy
      cohort undergoing cesarean delivery.

      Protocol:

      Brief Study Protocol After obtaining Institutional Review Board (IRB) approval, patients will
      be randomly assigned to receive either IV ketorolac 30 mg (n=15) or normal saline (n=15)
      based on a pre-assigned randomization sequence. The assignment for each patient will be kept
      in sealed opaque envelopes. After obtaining written informed consent, an anesthesiologist not
      involved in the study will open the envelope and will prepare the study drug. The patient and
      the study investigators will be blinded to the study drug.

      Baseline platelet count, coagulation parameters (activated partial thromboplastin time
      (APTT), prothrombin time (PT), Fibrinogen) and TEG parameters will be measured
      pre-operatively on the day of surgery. Routine lab work obtained at this time will require 10
      ml of blood, while study related tests will require 5.4 ml. Each patient will undergo either
      spinal or combined spinal epidural anesthesia with our standard cesarean induction dose of
      hyperbaric intrathecal 0.75% bupivacaine 1.5 ml, intrathecal fentanyl 25 micrograms and
      intrathecal morphine 250 micrograms. The patient will be moved to the supine position with
      left lateral uterine displacement. When a T6 sensory level to pinprick is achieved, cesarean
      delivery will be allowed to proceed. At the completion of the surgery, Platelet Aggregometry
      and TEG parameters will be performed to assess for intraoperative changes to TEG and
      establish baseline Platelet Aggregometry values. A total volume of 18.9 ml of blood will be
      withdrawn for the study at this time. While under the effect of the spinal medication,
      meaning that the patient is unable to fill sharp in their feet, the patient may elect to have
      this blood and the subsequent blood drawn from their foot to avoid unnecessary pain. These
      blood draws would only be performed by an anesthesiologist and only if a suitable site was
      identified. Performing venipucture for lab draws in the feet is not known to increase the
      risk of complications from blood draws when compared to the upper extremity. The study drug
      will be administered upon completion of the case. Platelet Aggregometry and TEG parameters
      will be performed 10 min after study drug administration. An additional volume of 18.9 ml of
      blood will be withdrawn for the study at this time. After blood samples have been obtained,
      patients in each group will receive the alternate therapy (ie placebo group receives
      ketorolac and ketorolac receives placebo), allowing both groups to benefit from the analgesic
      effect of ketorolac. Supplemental analgesia will be administered according to a standard
      post-operative pain management protocol on labor and delivery.

      Statistical analysis: Data will be assessed for normality using normality plots and the
      Kolmogorov-Smirnov test. Demographic, obstetric, and perioperative data will be presented as
      mean (SD) or median [interquartile range]. Between-group comparisons will be assessed using
      the unpaired t test and Mann-Whitney U test, where appropriate. Within-group before vs. after
      NSAID exposure changes will be assessed using the paired t test and Wilcoxon signed rank
      test, where appropriate. The percentage change from baseline for each PFA, TEG, and lab
      parameter will also be calculated.

      Sample size justification: There is limited data on the affect of ketorolac on quantitative
      coagulation studies, particularly in the obstetric population. Based on available data from a
      prior study examining platelet inhibition of non-opioid analgesics, a PFA closure time ≥173
      seconds can be used to classify platelet inhibition. Using the aforementioned data on
      epinephrine-induced PFA closure time, the investigators estimate that, before and after
      ketorolac exposure, 25% and 70% patients respectively would exhibit prolonged PFA closure
      times. With an alpha error of 0.05 and a beta error of 0.8, the investigators estimated that
      a sample size of 18 patients per group would provide 80% power. Additional studies have
      examined the affect of ketorolac on platelet aggregometry. Platelet aggregometry to collagen
      was diminished in the ketorolac group from preoperative to poststudy drug data points (90.8%
      +/- 7.6% to 60.5% +/- 32.5%; P < 0.01). With an alpha error of 0.05 and a beta error of 0.8,
      the investigators estimated that a sample size of 19 patients per group would provide 80%
      power.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized Placebo-Controlled Trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Placebo (normal saline) or ketorolac in syringe prepared by the investigational pharmacy with study patient number and blinding key maintained by investigational pharmacy until time of unblinding.
measure: Platelet Aggregometry Light Transmission
time frame: 15 minutes after dosing of placebo or ketorolac
description: Platelet Aggregometry uses measurements platelet rich blood or serum samples and activating agents to analyze the percent change in light transmission as a marker of platelet aggregation.
measure: Thromboelastogram parameters including Reaction time (R)
time frame: 15 minutes after dosing of placebo or ketorolac
description: Thromboelastogram parameters including Reaction time (R)
measure: Thromboelastogram parameters including Angle (alpha)
time frame: 15 minutes after dosing of placebo or ketorolac
description: Thromboelastogram parameters including Angle (alpha)
measure: Thromboelastogram parameters including Kinetics (K)
time frame: 15 minutes after dosing of placebo or ketorolac
description: Thromboelastogram parameters including Kinetics (K)
measure: Thromboelastogram parameters including Maximum Amplitude (MA)
time frame: 15 minutes after dosing of placebo or ketorolac
description: Thromboelastogram parameters including Maximum Amplitude (MA)
arm group label: Placebo
arm group type: Placebo Comparator
description: 1 ml of normal saline
arm group label: Ketorolac
arm group type: Experimental
description: 30 mg of ketorolac in 1 ml
intervention type: Drug
intervention name: Ketorolac Tromethamine 30 MG/ML
description: Ketorolac 30 mg
arm group label: Ketorolac
other name: ketorolac
other name: Ketorolac Tromethamine
other name: Ketorolac Injectable Solution
intervention type: Drug
intervention name: Placebos
description: Normal Saline
arm group label: Placebo
other name: Placebo
other name: Normal Saline
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
citation: Blackburn A, Stevens JD, Wheatley RG, Madej TH, Hunter D. Balanced analgesia with intravenous ketorolac and patient-controlled morphine following lower abdominal surgery. J Clin Anesth. 1995 Mar;7(2):103-8. doi: 10.1016/0952-8180(94)00040-b.
PMID: 7598916
citation: Diemunsch P, Alt M, Diemunsch AM, Treisser A. Post cesarean analgesia with ketorolac tromethamine and uterine atonia. Eur J Obstet Gynecol Reprod Biol. 1997 Apr;72(2):205-6. doi: 10.1016/s0301-2115(96)02682-6. No abstract available.
PMID: 9134403
citation: Pavy TJ, Paech MJ, Evans SF. The effect of intravenous ketorolac on opioid requirement and pain after cesarean delivery. Anesth Analg. 2001 Apr;92(4):1010-4. doi: 10.1097/00000539-200104000-00038.
PMID: 11273941
citation: Lowder JL, Shackelford DP, Holbert D, Beste TM. A randomized, controlled trial to compare ketorolac tromethamine versus placebo after cesarean section to reduce pain and narcotic usage. Am J Obstet Gynecol. 2003 Dec;189(6):1559-62; discussion 1562. doi: 10.1016/j.ajog.2003.08.014.
PMID: 14710063
citation: El-Tahan MR, Warda OM, Yasseen AM, Attallah MM, Matter MK. A randomized study of the effects of preoperative ketorolac on general anaesthesia for caesarean section. Int J Obstet Anesth. 2007 Jul;16(3):214-20. doi: 10.1016/j.ijoa.2007.01.012. Epub 2007 Apr 24.
PMID: 17459695
citation: Elhakim M, Fathy A, Amine H, Saeed A, Mekawy M. Effect of i.v. tenoxicam during caesarean delivery on platelet activity. Acta Anaesthesiol Scand. 2000 May;44(5):555-9. doi: 10.1034/j.1399-6576.2000.00512.x.
PMID: 10786742
citation: Gobble RM, Hoang HLT, Kachniarz B, Orgill DP. Ketorolac does not increase perioperative bleeding: a meta-analysis of randomized controlled trials. Plast Reconstr Surg. 2014 Mar;133(3):741-755. doi: 10.1097/01.prs.0000438459.60474.b5.
PMID: 24572864
responsible party type: Principal Investigator
investigator affiliation: Beth Israel Deaconess Medical Center
investigator full name: John J. Kowalczyk
investigator title: Instructor in Anaesthesia
mesh term: Postpartum Hemorrhage
mesh term: Hemostatic Disorders
mesh term: Blood Coagulation Disorders
mesh term: Hemorrhage
mesh term: Postoperative Hemorrhage
mesh term: Ketorolac
mesh term: Ketorolac Tromethamine
sharing ipd: No
ipd description: Individual participant data (IPD) will not be shared.