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Does a Single Intravenous Dose of Ketamine Reduce the Need for Supplemental Opioids in Post-Cesarean Section Patients?

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00486902
Recruitment Status : Completed
First Posted : June 15, 2007
Results First Posted : May 6, 2011
Last Update Posted : April 14, 2014
Information provided by (Responsible Party):
Cynthia Wong, Northwestern University

Tracking Information
First Submitted Date  ICMJE June 13, 2007
First Posted Date  ICMJE June 15, 2007
Results First Submitted Date  ICMJE March 15, 2011
Results First Posted Date  ICMJE May 6, 2011
Last Update Posted Date April 14, 2014
Study Start Date  ICMJE July 2006
Actual Primary Completion Date October 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2011)
Number of Subjects Requiring Supplemental Analgesia in the First 24 Hours Following Cesarean Delivery [ Time Frame: 24 hours ]
Request for oral hydrocodone/acetaminophen for pain not controlled by around the clock non-steroidal antiflammatory drugs in the first 24 hours following cesarean delivery.
Original Primary Outcome Measures  ICMJE
 (submitted: June 14, 2007)
Incidence of breakthrough pain and requirment for supplemental oral analgesia [ Time Frame: 24 hours ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2011)
  • Verbal Pain Scores (0 to 10) at First Analgesia Request [ Time Frame: 24 hours ]
    Numeric rating of pain scores (NRS) scale (0 to 10) at time of supplemental analgesia request. Zero is no pain and 10 is worst pain imaginable.
  • Cumulative Hydrocodone/Acetaminophen for Supplemental Analgesia to Treat Breakthrough Pain [ Time Frame: 72 hours ]
    Cumulative hydrocodone/acetaminophen for supplemental analgesia to treat breakthrough pain for 72 hours following cesarean delivery
  • Postoperative Nausea [ Time Frame: 24 hours ]
    Number of subjects reporting nausea in first 24 hours following cesarean delivery
  • Postoperative Vomiting [ Time Frame: 24 hours ]
    Number of subjects that vomited in the first 24 hours following cesarean delivery
  • Postperative Pruritus [ Time Frame: 24 hours ]
    Number of subjects with pruritus in the first 24 hours following cesarean delivery
  • Disturbing Dreams [ Time Frame: 72 hours ]
    Number of subject reporting disturbing dreams at 72 hours post cesarean delivery
Original Secondary Outcome Measures  ICMJE
 (submitted: June 14, 2007)
  • Verbal pain scores [ Time Frame: 24 hours ]
  • Requirement for supplemental analgesia to treat breakthrough pain [ Time Frame: 72 hours ]
  • Assessment of side effects, including sedation, nausea and vomiting, and psychodelic effects [ Time Frame: 24 hours ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Does a Single Intravenous Dose of Ketamine Reduce the Need for Supplemental Opioids in Post-Cesarean Section Patients?
Official Title  ICMJE Does a Single Intravenous Dose of Ketamine Reduce the Need for Supplemental Opioids in Post-Cesarean Section Patients?
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Ketamine Adverse Reaction
  • Effects of; Anesthesia, Spinal and Epidural, in Pregnancy
  • Complication of Labor and/or Delivery
Intervention  ICMJE
  • Drug: Ketamine
    Ketamine 10 mg diluted to 20 mL delivered over 10 minutes via an infusion pump set at 2ml/minute
    Other Name: N-methyl-D-aspartate (NMDA)
  • Drug: Placebo
    Saline 20 mL IV infusion delivered over 10 minutes via an infusion pump set at 2ml/minute
    Other Name: 0.9% Saline
Study Arms  ICMJE
  • Experimental: Ketamine
    Subjects receive IV ketamine 10 mg 5 minutes after infant delivery.
    Intervention: Drug: Ketamine
  • Placebo Comparator: Placebo
    Subjects receive IV Saline 20 mL 5 minutes after infant delivery
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 14, 2007)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 2008
Actual Primary Completion Date October 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Eligible women are at term (≥37 week gestation),
  • Healthy,
  • ASA class 1-2,
  • Scheduled for elective cesarean section whose anesthetic plan is for spinal anesthesia with intrathecal morphine and intravenous ketorolac analgesia for post operative analgesia

Exclusion Criteria:

  • Women with American Society of Anesthesiologists physical status >2,
  • Body mass index ≥40 kg/m2,
  • Known allergy to any of the study medications,
  • Contraindication to the spinal anesthesia,
  • History of substance abuse,
  • History of hallucinations,
  • Chronic opioid therapy,
  • Chronic pain.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00486902
Other Study ID Numbers  ICMJE 0524-030
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Cynthia Wong, Northwestern University
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE Northwestern University
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Cynthia A Wong, M.D. Northwestern University
PRS Account Northwestern University
Verification Date March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP