Does a Single Intravenous Dose of Ketamine Reduce the Need for Supplemental Opioids in Post-Cesarean Section Patients?
Condition: Ketamine Adverse Reaction; Effects of; Anesthesia, Spinal and Epidural, in Pregnancy; Complication of Labor and/or Delivery
MeSH terms: Obstetric Labor Complications
Study type: Interventional

Summary: 
      Pain control after cesarean delivery is associated with improved breastfeeding and infant
      rooming-in times. In addition, inadequate analgesia leads to elevated plasma catecholamine
      concentrations, which negatively affect every organ system. There is growing evidence that
      ketamine, N-methyl-D-aspartate receptor antagonist, is efficacious when used as an adjuvant
      in postoperative pain control. A 2006 Cochrane Collaboration systemic review and
      meta-analysis concluded, "Ketamine in subanesthetic doses….is effective in reducing morphine
      requirements in the first 24 hours after surgery."

      Ketamine's prolonged analgesic effect, despite its short half-life and its use in low doses,
      is theorized to be due to blockade of spinal cord central sensitization. Central
      sensitization is a phenomenon whereby repeated painful stimulus leads to more severe pain
      perception over time despite no change in the intensity of the painful stimulus.Ketamine may
      also prevent the development of acute opioid tolerance. Ketamine's analgesic effects have
      also demonstrated in the obstetric population. Post-cesarean delivery morphine requirements
      in women who received ketamine as part of a general anesthesia technique were decreased.
      Similary, low-dose ketamine in conjunction with bupivacaine-only spinal anesthesia reduced
      postoperative analgesic requirements compared to bupivacaine-only spinal anesthesia and
      bupivacaine-fentanyl spinal anesthesia.

      In the United States, healthy women scheduled for elective cesarean delivery commonly receive
      spinal anesthesia with bupivacaine-fentanyl-morphine. To our knowledge, IV ketamine has not
      been studied as an adjuvant to this regimen in the analgesic management in post-cesarean
      delivery patients. Multimodal therapy for postoperative pain control is widely practiced due
      to the advantage it provides in blocking multiple pain pathways while minimizing side effects
      of each individual pain medication. We hypothesize that low dose intravenous ketamine will
      improve multi-modal post-cesarean analgesia compared to placebo. The purpose of this study is
      to evaluate this hypothesis and study the possible side effects of this regimen in
      combination with bupivacaine-fentanyl-morphine spinal anesthesia.
    

Detailed description: 
      Eligible women for elective cesarean section admitted to the Labor and Delivery Unit of
      Prentice Women's Hospital will be approached for study participation immediately after the
      routine preanesthetic evaluation. This occurs shortly after admission to the Labor and
      Delivery Unit. Women who agree to participate will give written, informed consent at this
      time.

      Subjects will be prepared preoperatively in the usual fashion with intravenous (IV) access,
      aspiration prophylaxis and intraoperative monitoring. Preincision antibiotics will be given
      and uterotonic medications will be used as per usual practice after delivery.

      The anesthesiologist will perform a spinal anesthetic per routine with the subject in the
      sitting position using sterile technique at the L3-4 interspace (± one vertebral interspace).
      The spinal anesthetic will consist of 12 mg of hyperbaric bupivacaine + 15 μg fentanyl + 150
      μg of morphine. The subject will be placed supine with left lateral tilt to alleviate
      aortocaval compression. Cesarean section will commence after adequate anesthesia is assured
      to a T4 sensory level to pinprick. Vasopressors and IV fluids will be administered at the
      anesthesiologist's discretion per usual practice.

      At the time of delivery, subjects will be randomized to one of two groups using a computer
      generated random number table. Randomization will be blocked based on whether the cesarean
      procedure is a primary or a repeat procedure. Randomization assignments will be kept in
      sequentially numbered opaque envelopes. The envelope will be opened by a research nurse who
      will prepare a 20 mL syringe labeled "study drug". The syringe will be given to the
      anesthesiologist blinded to the treatment group who will subsequently administer the study
      drug. Subjects randomized to the treatment group will receive ketamine 10 mg (ketamine 10
      mg/mL) diluted to 20 mL with 0.9% preservative free saline. Subjects randomized to the
      placebo group will receive 20 mL preservative free saline.

      The study drug will be administered into the intravenous line via an infusion pump over 10
      minutes. Five minutes after placebo or drug administration, the anesthesiologist will ask the
      subject if she has nausea, vomiting and pruritus. Nausea and pruritus will be graded as none,
      mild, moderate or severe; and vomiting as present or absent. Any spontaneous complaints of
      psychedelic effects will be noted at this time. Sedation will be assessed via the Richmond
      agitation-sedation scale (RASS [see Appendix 1]).

      Upon completion of the cesarean section, the subject will be transported to the post
      anesthesia recovery unit. Patients will receive ketorolac 30 mg every 6 hours time 4 doses
      beginning shortly after admission to the PACU.

      At 1 h, 4 h, 8 h, 12 h and at 24 h after administration of the study drug, the subject's pain
      will be assessed using the numeric rating scale for pain NRS 0-10 (see Appendix 2). Patients
      may request rescue analgesia if they are experiencing discomfort. The time of first rescue
      analgesia request will be noted, and the NRS will be determined at the time of request for
      rescue analgesia.

      Rescue medication will consist of hydrocodone 10 mg plus acetaminophen 325 mg per os. An
      additional dose of hydrocodone 10 mg plus acetaminophen 325 mg will be provided after 1 hour
      if the pain is not relieved to the subject's satisfaction. These are routine oral analgesic
      medications for postoperative cesarean delivery analgesia. Standard orders will be written
      for monitoring sedation and respiratory rate, and treatment of side effects (nausea,
      vomiting, pruritus and respiratory depression). The total amount of rescue medication will be
      determined for each subject after 24, 48 and 72 hours.

      The presence of nausea, vomiting, and pruritus will be assessed at the same time intervals as
      the NRS for pain: 1 h, 4 h, 8 h, 12 h and 24 h after IV infusion of ketamine or placebo. The
      subjective psychedelic effects of ketamine and morphine will be assessed using a set of
      true/false questions from the LSD and morphine short form of the Addiction Research Center
      Inventory, ARCI (Appendix 3). These questions will be administered verbally by the
      anesthesiologist or researcher blinded to the treatment group upon admission to the PACU and
      at 4 h.

      The following data will be collected in addition to the primary and secondary outcome data:
      maternal age, height, weight, prepregnancy weight, gestational age and IV fluids administered
      during cesarean section. In addition, all intraoperative and postoperative medications will
      be recorded, including those administered for the treatment of side effects listed above.

      Protocol specific analgesia assessment ends 24 hours after administration of the study drug.
      At 72 hours the subject will be asked about her satisfaction with postoperative analgesia
      (100 mm scale, 0 mm = not satisfied at all, 100 mm = very satisfied). One telephone follow-up
      evaluation 2 weeks after delivery will again, assess for satisfaction with analgesia and
      average pain (NRS) since the procedure.
    

Intervention name(s): Ketamine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Ketamine 10 mg diluted to 20 mL delivered over 10 minutes via an infusion pump set at 2ml/minute; Saline 20 mL IV infusion delivered over 10 minutes via an infusion pump set at 2ml/minute
Other intervention name(s): N-methyl-D-aspartate (NMDA); 0.9% Saline
Intervention MeSH terms: Ketamine; N-Methylaspartate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Ketamine; Spinal Anesthesia; C-section