PoCKet: Ketamine to Prevent PPD After Cesarean
Study Details
Study Description
Brief Summary
The investigators plan to randomise participants to receive ketamine or placebo control subcutaneously or by 40-minute intravenous infusions and will follow them up for 42 days to assess the incidence of postpartum depression. This feasibility pilot study is designed to explore the adequacy of the study procedures and tolerability of the interventions.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
Postpartum depression (PPD)
PPD is one of the most common perinatal medical complications and can have a detrimental effect on both mother and baby. Suicide exceeds hemorrhage and hypertensive disorders as a cause of maternal mortality and maternal psychopathology interferes with the parent-infant relationship. It has been estimated to have a period prevalence of 19.2% in the first 3 postpartum months. The rapid decline in reproductive hormones is thought to contribute to the development of PPD in susceptible women, although the specific pathogenesis is unknown. The American College of Obstetricians and Gynecologists recommend that all women should be routinely screened for depressive symptoms in the perinatal period.
Risk factors for PPD include:
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Depression during pregnancy • Breastfeeding problems
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Preterm birth/infant admission to neonatal intensive care (NICU)
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Traumatic birth experience
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History of depression
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Anxiety during pregnancy
Ketamine's anti-depressant effect
Ketamine, a phencyclidine derivative, is a non-competitive antagonist at the N-methyl-D-aspartic acid (NMDA) receptor that is commonly used as an anesthetic or sedative agent and has proven analgesic effect after a variety of surgeries including CD, where it has also been shown to reduce shivering. It has been demonstrated to have a rapid anti-depressant effect in treatment-resistant depression outside of pregnancy. The most commonly employed intravenous (IV) dose for this purpose is 0.5 mg/kg over 40 minutes, as single or repeated infusions. It has been postulated that prolonged blockade of NMDA receptors causes long-term changes in signal transduction leading to sustained clinical improvement, some investigators have explored longer term infusions such as those used to treat chronic pain. A recent pilot study assessing the feasibility of a 96-hour (~0.5mg/kg/hr) infusion compared with a single 40-minute (0.5 mg/kg) infusion suggested a trend toward greater efficacy in the prolonged infusion but confirmation of a statistically significant result is awaited.
Ketamine and PPD
This promising anti-depressant effect has prompted investigation of ketamine as a preventative measure in patients undergoing CD. There have been 2 studies to date, one which failed to demonstrate any benefit from a bolus dose of 0.25 mg/kg and one which documented a large reduction (1 and 22% in the treatment and control, respectively) in the (6 week) period prevalence of postpartum depression after a 4 mg/kg dose of ketamine over 50 hours (~0.08 mg/kg/hr).
The prolonged IV infusion, was achieved by adding the ketamine to a sufentanil patient-controlled analgesic (PCA) pump with a background infusion. This PCA pump is a standard part of their post-cesarean analgesic regimen. In our institution, it is standard practice to discontinue IV infusions and to remove IV cannulae as early as it is safe to do so. This practice is essential to the attempts to enhance postoperative recovery and aid mother's bonding with their babies and facilitate their early-life care. This reflects patients' expectations and preferences and is in line with other maternity units across North America and Europe.
The natural course of PPD varies and, although it may resolve spontaneously within weeks, approximately 20% of women with PPD still have depression at 12 months and beyond. As many as 13% will still have depressive symptoms at 2 years and 40% will have a relapse. Considering the maternal suffering, disruption to the family, potential impairment of the social, emotional, and cognitive development of the child, and the rare cases of infanticide and suicide caused by PPD, the impact on families and society as a whole is difficult to overemphasize. An intervention that promises such a large reduction in this devastating disease warrants extensive research. In an attempt to achieve the benefit whilst employing methods more acceptable to our patients we have designed a pilot study to assess the feasibility of our study design and collect preliminary tolerability and efficacy data on ketamine administered by two alternative routes: 40-minute IV infusion (i.v.) and subcutaneous (s.c.) injection.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Control Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride. |
Drug: Control
Administration of 0.9% Sodium Chloride (N/S)
|
| Experimental: Ketamine SC Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride. |
Drug: Ketamine 50 MG/ML
Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion).
Drug: Control
Administration of 0.9% Sodium Chloride (N/S)
|
| Experimental: Ketamine IVI Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine. |
Drug: Ketamine 50 MG/ML
Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion).
Drug: Control
Administration of 0.9% Sodium Chloride (N/S)
|
Outcome Measures
Primary Outcome Measures
- The incidence of PPD, as defined as EPDS greater than 10 out of 30 [42 days postpartum]
Establish a sufficient burden of disease (>10%) in our population to warrant a full RCT
- Percentage of eligible patients consenting to participation [Through study completion, an average of 1 year]
Establish a recruitment rate of greater than 50% to confirm the feasibility of conducting an RCT in our population
- Percentage of patients with a complete dataset [Through study completion, an average of 1 year]
Ensure that the design of assessments and data collection make it possible to achieve a complete dataset in >90% of participants
- Number of patients in study arms experiencing one or more severe side effects [Through study completion, an average of 1 year]
Ascertain that neither of the chosen routes of administration of ketamine are intolerable to patients, as defined as the incidence of one or more severe side effects experienced by >10% of participants in that study arm.
Secondary Outcome Measures
- Dose of opiate analgesics administered [Intraoperative phase]
Intraoperative supplementary analgesia in morphine milligram equivalents
- Dose of ketorolac administered [Intraoperative phase]
Intraoperative supplementary analgesia
- Incidence of intraoperative hypotension of a systolic BP of less than 90 [Intraoperative phase]
Incidence of systolic BP less than 90 mmHg
- Maximum intraoperative pain (NRS) [Intraoperative phase]
Reported maximal level of intraoperative pain on the numerical rating scale 0 - 10
- Adverse effects [Intraoperative and 2 and 6 hours postoperatively]
Incidence and severity (mild, moderate or severe) of nausea, vomiting, pruritus, dizziness, sedation, shivering, anxiety, euphoria, hallucinations, amnesia, blurred vision, diplopia, nystagmus
- Plasma concentrations of ketamine [At baseline and approximately 20, 40 and 100 minutes postpartum]
Assays of venous blood samples
- Total opiate consumption in morphine equivalents [In the first 2 days postpartum]
Morphine equivalents
- Surgical site pain: numerical rating scale (NRS 0-10) [At 2, 6, 24 and 48 hours after delivery and on postpartum days 21 and 42]
On a numerical rating scale (NRS 0-10)
- Edinburgh Postpartum Depression Scale (0 - 30, a higher score represents greater depressive symptomatology) [On postpartum days 1, 2, 21 and 42]
Validated measure of depressive symptoms in the postpartum period
- Apgar scores [At 1 and 5 minutes after delivery]
Score out of 10, of neonatal status
- Admission to NICU [Postpartum day 1]
Incidence of admission
- Breastfeeding success [Postpartum days 1 and 2]
Yes or no
- Incidence of intraoperative hypertension of a systolic BP greater than 140 mmHg [Intraoperative phase]
Systolic hypertension of greater than 140 mmHg
- Incidence of intraoperative bradycardia of less than 40 bpm [Intraoperative phase]
Bradycardia less than 40 bpm
- Incidence of intraoperative tachycardia of greater than 110 bpm [Intraoperative phase]
Tachycardia greater than 110 bpm
- Incidence of Anxiety on the Generalized Anxiety Disorder- 7 item scaleGAD-7 [On day of surgery, and postpartum days 1, 2, 21 and 42]
Validated scale for anxiety. Score out of 21.
Eligibility Criteria
Criteria
Inclusion criteria:
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Term pregnancy
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Age 18-45 years of age
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Scheduled cesarean delivery under neuraxial anesthesia
Exclusion criteria:
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ASA classification IV or V
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History of psychotic episodes
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History of allergy to ketamine
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Inability to communicate in English or any other barrier to providing informed consent
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington University in St. Louis | Saint Louis | Missouri | United States | 63110 |
Sponsors and Collaborators
- Washington University School of Medicine
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 201910191