Ketamine to Improve Recovery After Cesarean Delivery - Part 1 (KINETIC)

Evaluation of PK/PD, Breastmilk Transfer, and Effectiveness of Ketamine After Cesarean Delivery - Part 1

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.

Study Overview

• Status: Completed
• Conditions: Postpartum Depression; Pain, Acute; Drug Effect; Opioid Use; Pain, Chronic; Obstetric Pain; Breastfeeding; Obstetric Anesthesia Problems
• Intervention / Treatment: Drug: Ketamine

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Montefiore Hospital CTRC
    • Pittsburgh, Pennsylvania, United States, 15232
      • Minhnoi C Wroble Biglan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 exclusion criteria), uncontrolled hyperthyroidism, cardiac disease, fever, hypertension
• Adverse occurrence during caesarean section such as hemorrhage, need for transfusion, hemodynamic instability
• Placenta accreta spectrum or previa with large anticipated blood loss
• History of hallucinations, alcohol or illicit substance use/abuse, chronic opioid therapy, or chronic pain (chronic pain - defined by any condition requiring consistent follow up with pain specialist or daily administration of pain medications that could augment sedative effects)
• Pre-eclampsia with severe features

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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

Drug: Ketamine; 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.; Other Names: Ketalar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 hour ketamine infusion
Steady State (Css)	Ketamine steady state (Css) is defined as the concentration of drug in plasma at steady state.	12 hours after ketamine infusion start
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.	27 hours postpartum or 24 hour CTRC appointment for weaning population
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.	27 hours postpartum or 24 hour CTRC appointment for weaning population
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.	27 hours postpartum or 24 hour CTRC appointment for weaning population
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.	27 hours postpartum or 24 hour CTRC appointment for weaning population
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.	27 hours postpartum or 24 hour CTRC appointment for weaning population
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.	27 hours postpartum or 24 hour CTRC appointment for weaning population
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.	27 hours postpartum or 24 hour CTRC appointment for weaning population

Collaborators and Investigators

• Sponsor: Grace Lim, MD, MS
• Collaborators: University of Pittsburgh
• Investigators: Principal Investigator: Grace Lim, MD, MS, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2019
• Primary Completion (Actual): August 1, 2021
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: February 2, 2019
• First Submitted That Met QC Criteria: July 25, 2019
• First Posted (Actual): July 30, 2019

Study Record Updates

• Last Update Posted (Actual): December 20, 2022
• Last Update Submitted That Met QC Criteria: November 23, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Pain; Neurologic Manifestations; Pregnancy Complications; Puerperal Disorders; Depressive Disorder; Chronic Pain; Depression, Postpartum; Labor Pain; Acute Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: STUDY18120046

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No