Establish a sufficient burden of disease (\>10%) in our population to warrant a full RCT
Ketamine to Prevent PPD After Cesarean
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.
Intervention / Treatment
Participants will be randomised to one of three groups (two interventional and one control).
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Ketamine 50 MG/ML (DRUG)Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion).
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Control (DRUG)Administration of 0.9% Sodium Chloride (N/S)
Condition or Disease
- Postpartum Depression
Phase
Study Design
| Study type: | INTERVENTIONAL |
|---|---|
| Status: | Completed |
| Study results: | No Results Available |
| Age: | 18 Years to 45 Years |
| Enrollment: | 25 (ACTUAL) |
| Funded by: | Other |
| Allocation: | Randomized |
| Primary Purpose: | Prevention |
MaskingThe ketamine and placebo study injectates (subcutaneous and intravenous) will be prepared, in way that does not allow differentiation, by pharmacy staff who are otherwise uninvolved in the study. Participants will be allocated to groups using a random sequence generator. The patients, investigators and outcome assessors will remain unaware of their group until data collection is complete for all participants. QUADRUPLE:
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Clinical Trial Dates
| Start date: | Nov 12, 2020 | ACTUAL |
|---|---|---|
| Primary Completion: | Aug 09, 2021 | ACTUAL |
| Completion Date: | Aug 09, 2021 | ACTUAL |
| Study First Posted: | Jan 14, 2020 | ACTUAL |
| Results First Posted: | Jan 26, 2023 | ACTUAL |
| Last Updated: | Jan 06, 2023 |
Sponsors / Collaborators
Lead Sponsor:
Washington University School of Medicine
Responsible Party:
N/A
Location
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:
* Depression during pregnancy • Breastfeeding problems
* Preterm birth/infant admission to neonatal intensive care (NICU)
* Traumatic birth experience
* History of depression
* 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.
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:
* Depression during pregnancy • Breastfeeding problems
* Preterm birth/infant admission to neonatal intensive care (NICU)
* Traumatic birth experience
* History of depression
* 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.
Participant Groups
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Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride.
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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.
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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.
Eligibility Criteria
| Sex: | Female |
|---|---|
| Minimum Age: | 18 |
| Maximum Age: | 45 |
| Age Groups: | Adult |
| Healthy Volunteers: | Yes |
Inclusion criteria:
* Term pregnancy
* Age 18-45 years of age
* Scheduled cesarean delivery under neuraxial anesthesia
Exclusion criteria:
* ASA classification IV or V
* History of psychotic episodes
* History of allergy to ketamine
* Inability to communicate in English or any other barrier to providing informed consent
* Term pregnancy
* Age 18-45 years of age
* Scheduled cesarean delivery under neuraxial anesthesia
Exclusion criteria:
* ASA classification IV or V
* History of psychotic episodes
* History of allergy to ketamine
* Inability to communicate in English or any other barrier to providing informed consent
Primary Outcomes
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Establish a recruitment rate of greater than 50% to confirm the feasibility of conducting an RCT in our population Twenty-five (20.7%) out of 121 women who were approached consented to participation. 2 were withdrawn with 23 completing participation.
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Ensure that the design of assessments and data collection make it possible to achieve a complete dataset in \>90% of participants
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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 Outcomes
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Intraoperative supplementary analgesia in morphine milligram equivalents
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Intraoperative supplementary analgesia
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Prevalence of participants with intraoperative hypotension of a systolic BP of less than 90
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Reported maximal level of intraoperative pain on the numerical rating scale 0 - 10, where 0 is no pain and 10 is the worst pain imaginable
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Incidence and severity (mild, moderate or severe) of nausea, vomiting, pruritus, dizziness, sedation, shivering, anxiety, euphoria, hallucinations, amnesia, blurred vision, diplopia, nystagmus
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Assays of venous blood samples
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Morphine equivalents
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Surgical site pain on a numerical rating scale of 0-10, where 0 is no pain and 10 is the worst pain imaginable.
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The EPDS is a validated measure of depressive symptoms in the postpartum period. The scale is scored between 0 - 30, a higher score represents greater depressive symptomatology. We report the study mean of each participant's mean EPDS score for their postpartum assessments
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Apgar score (0-10) comprised of an assessment of neonatal color, tone and crying. A higher score indicates healthier color, tone and crying.
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Incidence of admission
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An indication of whether breastfeeding has been successfully established (Yes or No).
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Prevalence of intraoperative hypertension as defined by number of participants with a systolic blood pressure greater than 140 mmHg
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Prevalence of intraoperative bradycardia, defined as number of participants with a heart rate of less than 40 bpm
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Prevalence of intraoperative tachycardia as defined by the number of participants with a heart rate greater than 110 bpm
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Mean Anxiety in the postpartum. General Anxiety Disorder 7-item Scale (GAD-7), ranges from 0 to 21. Higher scores indicate more severe anxiety.
More Details
| NCT Number: | NCT04227704 |
|---|---|
| Acronym: | |
| Other IDs: | 201910191 |
| Study URL: | https://clinicaltrials.gov/study/NCT04227704 |
Last updated: Sep 29, 2023