Breastfeeding, Drug Effect, Obstetric Anesthesia Problems, Obstetric Pain, Opioid Use, Pain, Acute, Pain, Chronic, Postpartum Depression
Conditions
Brief summary
The objective of this study is evaluate the breastmilk transfer and pharmacokinetics (Part 1) and effectiveness (Part 2) of a post-cesarean delivery intravenous ketamine bolus-and-infusion strategy, as a preventive analgesic modality to reduce pain and opioid requirements. In Part 1, physiochemical analysis of pharmacokinetic/pharmacodynamic (PK/PD) and breastmilk transfer of ketamine and its metabolites will be assessed. Additionally calculated estimations for neonatal and infant exposure will be assessed. In Part 2, PK/PD assessments will continue in a larger cohort; endpoints will also include postpartum pain, depression scores, central sensitization measures, patient-reported postpartum recovery scores, breastfeeding, and parent-infant bonding, assessed in the acute post-cesarean period and up to 12 weeks postpartum in a randomized controlled trial.
Detailed description
Postpartum pain management strategies currently permit opioids for breakthrough pain, but strategies focused on minimizing or eliminating opioids are lacking. In the non-obstetric surgical population, modalities such as intravenous ketamine are well-recognized as effective adjuncts in opioid-reduction strategies for postoperative pain. Although there have been some studies of ketamine exposure in postpartum women without deleterious outcomes noted, these studies in pregnant and lactating women are limited by a lack of information on maternal pharmacokinetics, breastmilk secretion, and clinical effectiveness when used with standard multimodal analgesic approaches. There is also a lack of information on intermediate and long-term outcomes in this setting. This two-part trial will address these knowledge gap by advancing understanding of the safety and efficacy of ketamine and its metabolites in peripartum populations.
Interventions
DRUGKetamine
Subjects in the intervention arm will receive infusion dosing as noted in arm/group descriptions at the time of cord clamping. Duration of infusion will be 12 hours. Concentrations of ketamine and ketamine metabolites (nor-ketamine, NKET; and dehydro-nor-ketamine, DHNK) are measured in maternal plasma and urine as well as breastmilk. Maternal side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and over 15 hours after infusion discontinuation.
Sponsors
University of Pittsburgh
Grace Lim, MD, MS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Prospective observational open-label trial (Part 1)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 99 Years
Healthy volunteers
Yes
Inclusion criteria
* Adult female patients (i.e., ≥18 years of age) and able to provide informed consent * Cesarean Delivery, Scheduled or Non-Emergent (delivery within 15 minutes not necessary), or female weaning off of breastfeeding * Cesarean cohort: ASA PS 2 or 3, with or without E designation (delivery within 15 minutes not necessary), Scheduled or Non-Emergent * Spinal anesthesia with intrathecal morphine if Cesarean Delivery, Scheduled or Non-Emergent * Multimodal postop analgesia with IV ketorolac, PO NSAID, and PO APAP if Cesarean Delivery, Scheduled or Non-Emergent * Women who do not plan to breastfeed or who want to temporarily withhold breastfeeding or who are weaning off of breastfeeding (Part 1)
Exclusion criteria
* Cesarean Delivery under General Anesthesia * Allergies to study medications * ASA PS 4 or 4E * ASA PS with E designation because delivery within 15 minutes required * ASA PS greater than 4 (moribund patients) * Contraindications to spinal anesthesia * Contraindications to NSAIDs (gastric bypass, etc.) * Contraindication to any other multimodal analgesia medicine * Significant psychiatric history (depression and anxiety NOT
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ketamine (AUC) | 12 hour ketamine infusion | Plasma will be used to calculate area under the plasma concentration-time curve (AUC 0-∞) of ketamine levels during infusion. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug. |
| Steady State (Css) | 12 hours after ketamine infusion start | Ketamine steady state (Css) is defined as the concentration of drug in plasma at steady state. |
| Elimination Half Life (T1/2) for Ketamine | 27 hours postpartum or 24 hour CTRC appointment for weaning population | Postpartum maternal plasma serum will be used to calculate postpartum maternal ketamine half-life (T1/2). b. Elimination half-life (t½) is the time required for drug concentration to decrease by one-half at the end drug dosing. Elimination half-life was obtained from the slope of terminal elimination phase. |
| Volume of Distribution Steady State (Vdss) | 27 hours postpartum or 24 hour CTRC appointment for weaning population | Volume Distribution Steady State (Vdss) is the period of dynamic equilibrium of the drug calculated as the amount of drug in the body at time, t divided by the plasma concentration of the drug at time, t. |
| Ketamine Milk to Plasma Ratio (M:P) | 27 hours postpartum or 24 hour CTRC appointment for weaning population | Milk to plasma ratio for KET were calculated by dividing the concentration of the respective components Ketamine in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of ketamine and the metabolites would be higher in breastmilk than in maternal plasma concentrations. |
| Nor-ketamine Milk to Plasma Ratio | 27 hours postpartum or 24 hour CTRC appointment for weaning population | Milk to plasma ratio of the Ketamine metabolite, Norketamine, calculated as the percentage of the maternal ketamine dose found from breastmilk. Milk to plasma ratio for NKET was calculated by dividing the concentration of the respective components Ketamine and Ketamine metabolites in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of metabolites would be higher in breastmilk than in maternal plasma concentrations. |
| Hydroxynorketamine M:P Ratio | 27 hours postpartum or 24 hour CTRC appointment for weaning population | Milk to plasma ratio of the Ketamine metabolite, Hydroxynorketamine, calculated as the percentage of the maternal ketamine dose found from breastmilk. Milk to plasma ratio for hydroxynorketamine was calculated by dividing the concentration of the respective ketamine metabolites in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of the metabolites would be higher in breastmilk than in maternal plasma concentrations. |
| Relative Infant Dose of Ketamine (RID KET) | 27 hours postpartum or 24 hour CTRC appointment for weaning population | Relative infant dose will be calculated as the percentage of the maternal ketamine dose found from breastmilk. The relative infant dose was calculated from the concentrations of ketamine in breast milk at different times following ketamine administration to the women. The concentration of ketamine was converted to amount by multiplying with the volume of breast milk collected at various time intervals. The cumulative dose of ketamine was calculated. An RID ≤10% was considered low. |
| Relative Infant Dose of Ketamine Equivalent (Ketamine, Norketamine, Dehydro-norketamine) | 27 hours postpartum or 24 hour CTRC appointment for weaning population | Relative infant dose (RID) will be calculated as the percentage of the maternal ketamine dose found from breastmilk. The relative infant dose was calculated from the concentrations of ketamine and its metabolites (ketamine, norketamine & dehydro-norketamine) in breast milk at different times following ketamine administration to the women. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine Ketamine - IV after cord clamping; IV infusion for 12 hours OR in the weaning population IV Ketamine infusion for 12 hours in the Montefiore CTRC
Ketamine: Subjects in the intervention arm will receive bolus and infusion dosing as noted in arm/group descriptions at the time of cord clamping. Duration of infusion will be 12 hours. Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and over 15 hours after infusion discontinuation. For the weaning population, they will receive a 12 hour infusion in the CTRC and stay an additional 12 hours in the CTRC (or until discharged). Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and for 12 hours after infusion discontinuation. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Ketamine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 36.1 years STANDARD_DEVIATION 3.31 |
| Maternal Weight | 90.613 Kilograms (kg) |
| Number of pregnancies | 2 pregnancies |
| Parity | 2 live births |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 7 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Elimination Half Life (T1/2) for Ketamine
Postpartum maternal plasma serum will be used to calculate postpartum maternal ketamine half-life (T1/2). b. Elimination half-life (t½) is the time required for drug concentration to decrease by one-half at the end drug dosing. Elimination half-life was obtained from the slope of terminal elimination phase.
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Elimination Half Life (T1/2) for Ketamine | 364 Minutes | Standard Deviation 121 |
Primary
Hydroxynorketamine M:P Ratio
Milk to plasma ratio of the Ketamine metabolite, Hydroxynorketamine, calculated as the percentage of the maternal ketamine dose found from breastmilk. Milk to plasma ratio for hydroxynorketamine was calculated by dividing the concentration of the respective ketamine metabolites in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of the metabolites would be higher in breastmilk than in maternal plasma concentrations.
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Hydroxynorketamine M:P Ratio | 0.06 Ratio | Standard Deviation 0.015 |
Primary
Ketamine (AUC)
Plasma will be used to calculate area under the plasma concentration-time curve (AUC 0-∞) of ketamine levels during infusion. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug.
Time frame: 12 hour ketamine infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Ketamine (AUC) | 28.46 mcg*min/mL | Standard Deviation 9.97 |
Primary
Ketamine Milk to Plasma Ratio (M:P)
Milk to plasma ratio for KET were calculated by dividing the concentration of the respective components Ketamine in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of ketamine and the metabolites would be higher in breastmilk than in maternal plasma concentrations.
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Ketamine Milk to Plasma Ratio (M:P) | 3.15 Ratio | Standard Deviation 1.05 |
Primary
Nor-ketamine Milk to Plasma Ratio
Milk to plasma ratio of the Ketamine metabolite, Norketamine, calculated as the percentage of the maternal ketamine dose found from breastmilk. Milk to plasma ratio for NKET was calculated by dividing the concentration of the respective components Ketamine and Ketamine metabolites in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of metabolites would be higher in breastmilk than in maternal plasma concentrations.
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Nor-ketamine Milk to Plasma Ratio | 1.5 Ratio | Standard Deviation 0.19 |
Primary
Relative Infant Dose of Ketamine Equivalent (Ketamine, Norketamine, Dehydro-norketamine)
Relative infant dose (RID) will be calculated as the percentage of the maternal ketamine dose found from breastmilk. The relative infant dose was calculated from the concentrations of ketamine and its metabolites (ketamine, norketamine & dehydro-norketamine) in breast milk at different times following ketamine administration to the women.
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Relative Infant Dose of Ketamine Equivalent (Ketamine, Norketamine, Dehydro-norketamine) | 0.0217 % maternal dose in breast milk | Standard Deviation 0.027 |
Primary
Relative Infant Dose of Ketamine (RID KET)
Relative infant dose will be calculated as the percentage of the maternal ketamine dose found from breastmilk. The relative infant dose was calculated from the concentrations of ketamine in breast milk at different times following ketamine administration to the women. The concentration of ketamine was converted to amount by multiplying with the volume of breast milk collected at various time intervals. The cumulative dose of ketamine was calculated. An RID ≤10% was considered low.
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Relative Infant Dose of Ketamine (RID KET) | 0.0152 % Maternal ketamine in breastmilk | Standard Deviation 0.02 |
Primary
Steady State (Css)
Ketamine steady state (Css) is defined as the concentration of drug in plasma at steady state.
Time frame: 12 hours after ketamine infusion start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketamine | Steady State (Css) | 35.58 ng/mL |
Primary
Volume of Distribution Steady State (Vdss)
Volume Distribution Steady State (Vdss) is the period of dynamic equilibrium of the drug calculated as the amount of drug in the body at time, t divided by the plasma concentration of the drug at time, t.
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Volume of Distribution Steady State (Vdss) | 1076 Liters | Standard Deviation 617 |