Depression, Postpartum, Pain, Postoperative
Conditions
Keywords
Cesarean Delivery
Brief summary
The purpose of this study is to identify a tolerable dose for postpartum ketamine infusion using a maximum tolerated dose (MTD) 3+3 design. A loading dose over 1 hour will be the MTD variable to be tested, as our data suggest that ketamine side effects occur with the loading dose. The investigators hypothesize that subanesthetic ketamine dose will be well tolerated and any noted side effects will be rated acceptable by postpartum women following cesarean delivery.
Detailed description
Pain management for women having a cesarean delivery is rather limited and risks poor pain control, depressed mood, and poor recovery following the cesarean delivery. Current cesarean pain management treatments ignore the multidimensionality of pain, including the influence of mood on pain. Recent evidence suggests that ketamine may provide successful post-surgical pain management, opioid reduction, and rapid reduction of depressive symptoms. The current study aims to identify an appropriate dose of ketamine for post-cesarean pain management while minimizing potential dose-dependent side effects in women following childbirth.
Interventions
DRUGKetamine (Ketalar) Dose Level 1
Loading Dose: 0.05 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours
DRUGKetamine (Ketalar) Dose Level 2
Loading Dose: 0.08 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours
DRUGKetamine (Ketalar) Dose Level 3
Loading Dose: 0.12 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours
DRUGKetamine (Ketalar) Dose Level 4
Loading Dose: 0.18 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours
Sponsors
National Institute of Mental Health (NIMH)
Grace Lim, MD, MS
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention model description
MTD 3+3 design
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Adults 18 years and older * Cesarean Delivery * American Society of Anesthesiologists Physical Status of 2 or 3 * Neuraxial anesthesia with neuraxial morphine * Term delivery ≥37 weeks gestation * Either planning not to breastfeed, OR receiving ketamine as part of routine clinical care
Exclusion criteria
* General anesthesia * Allergy to study medications * ASA PS 4 or higher * Contraindications to neuraxial anesthesia * Preterm delivery (\<37 weeks gestation) * Anticipated fetal-neonatal complex care plan * Participating in another pain intervention trial * Hypertensive disorder of pregnancy * Pre-eclampsia with severe features * Hemodynamic instability * Medical History exclusions: ketamine or PCP (phencyclidine) abuse, schizophrenia or psychosis, liver or renal insufficiency, uncontrolled hypertension, chest pain, arrhythmia, head trauma, or intracranial hypertension, uncontrolled thyroid disease, or other contraindications to ketamine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Ketamine | Between 0 to 24 hours postpartum | Maximum tolerated dose of ketamine is measured by dose that fewer than 33% of patients experience a dose-limiting toxicity (DLT) defined by intolerability. Tolerability will be defined as: lack of adverse events (adverse event defined as: severe unresolved hemodynamic effect: systolic blood pressure \<80 or \>160, heart rate \<40 or \>120). Intolerability will be defined as presence of any adverse event (i.e., severe unresolved hemodynamic effect: systolic blood pressure \<80 or \>160, heart rate \<40 or \>120). Outcome measure of tolerability and intolerability will be reported as n (%). The MTD was 0.18 mg/kg/hr for one hour, followed by 0.05 mg/kg/hr for 11 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Reported Acceptability of Any Reported Side Effects | Between 0 to 24-hours postpartum | Number (%) of patient cohort reporting acceptability at each ketamine dose. Patient reported acceptability was recorded from a 21-question survey that reviewed seven common side effects: dizziness, lightheadedness, bad dreams, hallucinations, nausea, vomiting, and itchiness. Unacceptability is defined as patients reporting any of seven side effects as unacceptable. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine (Ketalar) Dose Level 1 Ketamine (Ketalar) Dose Level 1: Loading Dose: 0.05 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours | 3 |
| Ketamine (Ketalar) Dose Level 2 Ketamine (Ketalar) Dose Level 2: Loading Dose: 0.08 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours | 3 |
| Ketamine (Ketalar) Dose Level 3 Ketamine (Ketalar) Dose Level 3: Loading Dose: 0.12 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours | 3 |
| Ketamine (Ketalar) Dose Level 4 Ketamine (Ketalar) Dose Level 4: Loading Dose: 0.18 mg/kg/hr X 1 hour; Maintenance Dose 0.05 mg/kg/hr x 12 hours | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | Ketamine (Ketalar) Dose Level 2 | Total | Ketamine (Ketalar) Dose Level 4 | Ketamine (Ketalar) Dose Level 3 | Ketamine (Ketalar) Dose Level 1 |
|---|---|---|---|---|---|
| Age, Continuous | 35.3 years STANDARD_DEVIATION 6 | 34.3 years STANDARD_DEVIATION 3.9 | 33.0 years STANDARD_DEVIATION 1.7 | 32.0 years STANDARD_DEVIATION 3.6 | 36.7 years STANDARD_DEVIATION 3.2 |
| Estimated Gestational Age at Delivery 37-weeks | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Estimated Gestational Age at Delivery 38-weeks | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Estimated Gestational Age at Delivery 39-weeks | 1 Participants | 8 Participants | 2 Participants | 2 Participants | 3 Participants |
| Estimated Gestational Age at Delivery 40-weeks | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 12 Participants | 3 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| History of Anxiety | 0 Participants | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| History of Depression | 3 Participants | 8 Participants | 2 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 9 Participants | 2 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 3 participants | 12 participants | 3 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 3 Participants | 12 Participants | 3 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Maximum Tolerated Dose of Ketamine
Maximum tolerated dose of ketamine is measured by dose that fewer than 33% of patients experience a dose-limiting toxicity (DLT) defined by intolerability. Tolerability will be defined as: lack of adverse events (adverse event defined as: severe unresolved hemodynamic effect: systolic blood pressure \<80 or \>160, heart rate \<40 or \>120). Intolerability will be defined as presence of any adverse event (i.e., severe unresolved hemodynamic effect: systolic blood pressure \<80 or \>160, heart rate \<40 or \>120). Outcome measure of tolerability and intolerability will be reported as n (%). The MTD was 0.18 mg/kg/hr for one hour, followed by 0.05 mg/kg/hr for 11 hours.
Time frame: Between 0 to 24 hours postpartum
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ketamine (Ketalar) Dose Level 1 | Maximum Tolerated Dose of Ketamine | Intolerability of Dose | 0 Participants |
| Ketamine (Ketalar) Dose Level 1 | Maximum Tolerated Dose of Ketamine | Tolerability of Dose | 3 Participants |
| Ketamine (Ketalar) Dose Level 2 | Maximum Tolerated Dose of Ketamine | Intolerability of Dose | 0 Participants |
| Ketamine (Ketalar) Dose Level 2 | Maximum Tolerated Dose of Ketamine | Tolerability of Dose | 3 Participants |
| Ketamine (Ketalar) Dose Level 3 | Maximum Tolerated Dose of Ketamine | Intolerability of Dose | 0 Participants |
| Ketamine (Ketalar) Dose Level 3 | Maximum Tolerated Dose of Ketamine | Tolerability of Dose | 3 Participants |
| Ketamine (Ketalar) Dose Level 4 | Maximum Tolerated Dose of Ketamine | Intolerability of Dose | 0 Participants |
| Ketamine (Ketalar) Dose Level 4 | Maximum Tolerated Dose of Ketamine | Tolerability of Dose | 3 Participants |
Secondary
Patient Reported Acceptability of Any Reported Side Effects
Number (%) of patient cohort reporting acceptability at each ketamine dose. Patient reported acceptability was recorded from a 21-question survey that reviewed seven common side effects: dizziness, lightheadedness, bad dreams, hallucinations, nausea, vomiting, and itchiness. Unacceptability is defined as patients reporting any of seven side effects as unacceptable.
Time frame: Between 0 to 24-hours postpartum
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ketamine (Ketalar) Dose Level 1 | Patient Reported Acceptability of Any Reported Side Effects | Acceptability of dose side effects | 3 Participants |
| Ketamine (Ketalar) Dose Level 1 | Patient Reported Acceptability of Any Reported Side Effects | Unacceptability of dose side effects | 0 Participants |
| Ketamine (Ketalar) Dose Level 2 | Patient Reported Acceptability of Any Reported Side Effects | Unacceptability of dose side effects | 1 Participants |
| Ketamine (Ketalar) Dose Level 2 | Patient Reported Acceptability of Any Reported Side Effects | Acceptability of dose side effects | 2 Participants |
| Ketamine (Ketalar) Dose Level 3 | Patient Reported Acceptability of Any Reported Side Effects | Acceptability of dose side effects | 3 Participants |
| Ketamine (Ketalar) Dose Level 3 | Patient Reported Acceptability of Any Reported Side Effects | Unacceptability of dose side effects | 0 Participants |
| Ketamine (Ketalar) Dose Level 4 | Patient Reported Acceptability of Any Reported Side Effects | Unacceptability of dose side effects | 0 Participants |
| Ketamine (Ketalar) Dose Level 4 | Patient Reported Acceptability of Any Reported Side Effects | Acceptability of dose side effects | 3 Participants |