Prospective Effect of Intravenous Ketorolac on Opioid Use, EBL and Complications Following Cesarean Delivery
Condition: Analgesia, Obstetrical; Postpartum Hemorrhage; Opioid Use; Nonsteroidals (NSAIDs)Toxicity; Coagulation Defect; Postpartum; Postoperative Pain; Ketorolac Adverse Reaction; Blood Loss, Postoperative
MeSH terms: Postpartum Hemorrhage; Hemostatic Disorders; Blood Coagulation Disorders; Hemorrhage; Postoperative Hemorrhage
Study type: Interventional
Phase: Phase 4

Summary: 
      In this randomized, double-blind control trial to evaluate the effect of ketorolac given at
      the time of cord clamp has on estimated blood loss and postcesarean pain control. Patients
      will be randomized to either placebo or ketorolac prior to surgery. Those randomized to
      ketorolac will receive ketorolac at cord clamp and three additional doses every 6 hours
      (total 4 doses/24 hours). Those in the placebo group will receive normal saline during those
      time periods. Our primary outcome is to assess whether intra-operative ketorolac increases
      the estimated blood loss during Cesarean delivery.
    

Detailed description: 
      Background:

      Opioid analgesics are among the most common medication employed for post-cesarean delivery
      pain management. However, opioid side-effects such as, nausea, vomiting, urinary retention,
      and sedation are problematic and can adversely impact post-operative recovery. Non-steroidal
      anti-inflammatory medications have analgesic as well as anti-inflammatory properties making
      them an ideal alternative for opioid analgesics. Ketorolac, which can be given by either oral
      and parenteral routes, is frequently employed as a post-surgical analgesic in a variety of
      procedures including gynecologic and obstetric, and has comparable analgesic properties to
      opioids without the aforementioned side-effects.(1)

      Additionally, two studies have specifically evaluated administration of ketorolac in the
      treatment of post-cesarean section pain in patients receiving either patient controlled
      intravenous analgesia or patient controlled epidural analgesia.(2, 3) However, due to the
      known inhibition of prostaglandin synthesis, several retrospective and observational studies
      have suggested that ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs) may be
      associated with an increase in estimated blood loss (EBL) and uterine atony.(4,5) This
      research showed in vivo defects in platelet function, however a recent meta-analysis in a
      variety of different surgical procedures suggest there is no clinically significant
      difference in EBL attributed to the administration of ketorolac compared to placebo.(6)

      Despite this, there still exists significant resistance to the intraoperative and
      post-operative use of ketorolac due to concerns of increasing EBL. This is particularly true
      with regard to cesarean sections, which, due to the nature of the procedure is associated
      with an EBL higher than found in many other surgeries and possibly leading to increased
      morbidity. To our knowledge there have only been three previous studies that specifically
      examined the use of ketorolac with cesarean delivery.

      El-Tahan et al, administered ketorolac preoperatively and focused on the blunting of
      sympathetic response to intubation of healthy patients undergoing cesarean section under
      general anesthesia. This study evaluated only a single low dose followed by intraoperative
      infusion. Although they did look at intraoperative EBL, they did not give additional
      postoperative doses or assess postoperative bleeding.(7) Lowder et al and Pavy et al looked
      at postoperative use of ketorolac on pain control and EBL, but no intraoperative dose of
      ketorolac was given.(2,3)

      To our knowledge, there have been no studies that evaluated intraoperative ketorolac on
      post-operative opioid analgesic use and EBL during cesarean delivery with epidural analgesia
      and intra-epidural administration of morphine.

      Screening/Eligibility Visit:

      Patients admitted to MacDonald Women's Hospital for scheduled or non-scheduled, non-urgent
      Cesarean delivery will be screened for potential eligibility. Potential participants will be
      then be approached to confirm they meet inclusion and exclusion requirements. Patients will
      then be consented with an IRB-approved informed consent prior to enrollment.

      Randomization & Blinding:

      Patients will be randomized to receive either ketorolac 30 mg in 1 ml (n=35) or normal saline
      1 ml (n=35). Randomization will be performed by the Investigational Pharmacy in a block of
      four design. No one involved with patient care, enrollment or data collection will have
      access to the unblinding key until completion of the study. The randomization key will be
      kept in the Investigational Research Pharmacy, and they will prepare the medications
      accordingly. Upon arrival in the OR, the anesthesiologist will open an envelope that will
      contain the kit number corresponding to the patient's study identification number. The
      anesthesiologist or anesthetist will remove the assigned kit from the Omnicell. Patients,
      clinicians and study staff will be unaware of the patient's assigned study group. Upon study
      completion by all patients, the randomization key will be provided to the study staff upon
      request.

      Brief Study Methods:

      After obtaining written informed consent, the Investigation Research Pharmacy an envelope
      that will contain the kit number corresponding to the patient's study identification number.
      Basic demographic information is collected from the patient. Each patient will undergo
      combined spinal-epidural anesthesia with our standard cesarean induction dose of hyperbaric
      0.75% bupivacaine 1.5 ml intrathecally and fentanyl 100mcg epidurally. 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 proceed using the standard procedures
      established in our institution. Once the newborn is delivered and the cord is clamped, the
      first dose of the ketorolac/placebo will be administered by the anesthesiologist or
      anesthetist. Any additional medications required for sedation or pain control during the
      remainder of the surgery (hydromorphone and acetaminophen) will be given, as appropriate for
      patient comfort. Prior to the completion of the procedure, the patient will receive epidural
      morphine 3 mg per the standard protocols. Postoperatively, the patient will receive the
      corresponding three additional scheduled doses of ketorolac/placebo every 6 hours.
      Supplemental analgesia will be administered according to a standard post-operative pain
      management protocol on labor and delivery with acetaminophen and intravenous hydromorphone
      provided, as needed for pain control.

      Exposures and their measurement:

      Exposure: Ketorolac 30 mg IV or Normal Saline 1 ml (Placebo) IV

      Measurements: See outcomes and their measurements

      Outcomes and their measurement:

      Primary outcome: Estimated Blood Loss (EBL) will be compared between groups. Secondary
      outcomes: Rate of Post-Partum Hemorrhage, Corrected Change in Hct on POD1, Uterotonic Doses,
      Units of Packed Reb Blood Cell Transfused, Hydromorphone Use, Total Hydromorphone Dose,
      Anti-emetic Doses, Pruritus Doses, Percentile Change in Systolic Blood Pressure at 6, 12, and
      24 hours, Percentile Change in Diastolic Blood Pressure at 6, 12, and 24 hours, and Pain
      score at 0 and 15 minutes and 1, 6, 12 and 24 Hours post-Cesarean Delivery.

      Confounders and their measurement:

      Many confounders should be limited by the nature of an RCT in a select patient population and
      pre- and intra-operative exclusion criteria. Additional potential confounders, including
      intraoperative fluid volume administration and patient adherence to study medication, will be
      recorded. Posthoc analysis will be performed to determine if any differences between groups
      were significant.

      Analysis plan:

      Data will be assessed for normality using histograms, QQ plots and Shapiro-Wilk test.
      Demographic, obstetric, and perioperative data will be presented as mean (standard
      deviation), median [interquartile range] or count (percentage), as appropriate. Between-group
      comparisons will be assessed using the t-test and Wilcoxon signed-rank test, as appropriate.
      For dichotomized outcomes, a Chi-square test will be performed to assess the proportions
      between groups.

      Sample size justification:

      A priori power analysis was performed to determine the sample size. Based on our prior
      retrospective study, we knew that the mean estimated blood loss for uncomplicated Cesarean
      deliveries was 814 ml with a standard deviation of 242 ml. We set our difference between
      groups to 186 ml. This would detect an EBL of >1,000 ml in the ketorolac group, a value large
      enough to classify the ketorolac group as post-partum hemorrhage and potentially escalate
      care and lead to additional maternal morbidity. With an alpha error of 0.05 and a power of
      80%, we estimated that a sample size of 28 patients per group would be needed or 56 total
      patients enrolled. We had concern for loss after enrollment due to acuity, cases after 4 pm
      and exclusion criteria including intraoperative EBL and obstetric refusal. We planned for the
      loss of 20% of enrolled patients and increased the total study enrollment number to 70.
    

Intervention name(s): Ketorolac; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Patients in the experimental arm will receive ketorolac 30 mg in 1 ml at the time of cord clamp and then for 3 more doses every 6 hours.; Patients in the control arm will receive normal saline 1 ml at the time of cord clamp and then for 3 more doses every 6 hours.
Other intervention name(s): Toradol
Intervention MeSH terms: Ketorolac
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Analgesia, Obstetrical; Blood Loss, Surgical; Analgesics, Opioid/administration & dosage; Cyclooxygenase Inhibitors/administration & dosage; Cesarean Delivery; Female; Humans; Ketorolac/administration & dosage; Hydromorphone/administration & dosage; Pain, Postoperative/drug therapy; Pregnancy; Morphine/administration & dosage; Cesarean Section Complications; Ketorolac