Clinical trial NCT04037085: Ketamine to Improve Recovery After Cesarean Delivery - Part 1
Official title: Evaluation of PK/PD, Breastmilk Transfer, and Effectiveness of Ketamine After Cesarean Delivery - Part 1
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Obstetric Pain
Postpartum Depression
Breastfeeding
Pain, Acute
Pain, Chronic
Obstetric Anesthesia Problems
Drug Effect
Opioid Use
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: University of Pittsburgh
First posted: 2019-07-30
Enrollment: 8
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective observational open-label trial (Part 1)
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Ketamine (AUC)
timeFrame: 12 hour ketamine infusion
measure: Steady State (Css)
timeFrame: 12 hours after ketamine infusion start
measure: Elimination Half Life (T1/2) for Ketamine
timeFrame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
measure: Volume of Distribution Steady State (Vdss)
timeFrame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
measure: Ketamine Milk to Plasma Ratio (M:P)
timeFrame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
measure: Nor-ketamine Milk to Plasma Ratio
timeFrame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
measure: Hydroxynorketamine M:P Ratio
timeFrame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
measure: Relative Infant Dose of Ketamine (RID KET)
timeFrame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
measure: Relative Infant Dose of Ketamine Equivalent (Ketamine, Norketamine, Dehydro-norketamine)
timeFrame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
Secondary outcomes:
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Montefiore Hospital CTRC
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Minhnoi C Wroble Biglan
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Grace Lim, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: