Spontaneous and Oxytocin-induced Contractility After Exposure to Intravenous Anesthetic Agents: an In-vitro Study in Human Myometrium

• ClinicalTrials.gov Identifier: NCT03852797
• Recruitment Status: Recruiting
• First Posted: February 25, 2019
• Last Update Posted: January 5, 2021
• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
• Information provided by (Responsible Party): Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Study Description

Brief Summary:

Poor uterine tone after the birth of a baby may cause serious bleeding (called postpartum hemorrhage or PPH). This is a major cause of maternal death worldwide. In the developed world the cesarean section rate is increasing. There are two modalities for anesthesia for cesarean section; general and regional (eg. spinal anesthetic). General anesthesia has been associated with increased blood loss compared to regional and the reasons for this may be multifactorial. Some of the anesthesia gases have been studied and there is laboratory evidence to suggest that these gases may reduce the tone of the uterus and therefore cause increased blood loss due to poor uterine tone. To date there has been little study on the intravenous anesthesia agents. These agents are usually administered to anaesthetise the patient at the start of surgery (induction of anesthesia), however they can also be used instead of the gases to keep the patient asleep using a 'total intravenous anesthesia' technique. Laboratory work in rats has suggested that high doses of these intravenous drugs might reduce uterine tone, thus increasing the risk of blood loss. Interestingly, at low doses one of these drugs (ketamine) may actually increase uterine tone. Only one of these drugs has been studied in human uterine tissue. The investigators plan to compare three anaesthesia induction agents on human uterine tissue under physiological conditions in the laboratory.

This study will be the first to compare these three drugs on human tissue. The investigators plan to determine the impact of these drugs on spontaneous uterine contractility and also contractilty induced by oxytocin, which is the drug most commonly administered to help contract the uterus after birth. This is important as it will help inform anesthesiologists as to the best drug to use depending on the clinical circumstance.

The investigators hypothesize that the intravenous induction agents will cause a dose dependent decrease in spontaneous uterine contractility, similar to what has been described in the rat model. The investigators also expect that exposure to high concentrations of intravenous anesthesia induction agents will cause a blunted contractile response to oxytocin.

Condition or disease	Intervention/treatment	Phase
Postpartum Hemorrhage	Drug: Oxytocin; Drug: Ketamine; Drug: Propofol; Drug: Etomidate	Not Applicable

Detailed Description:

There is an increasing need to fully understand the mechanisms that contribute to the higher blood loss after general anesthesia during cesarean section therefore it is important the investigators identify all pharmacological contributors to poor uterine tone. Furthermore, anesthesiologists are increasingly called upon to care for women undergoing a range of in-utero fetal surgeries which require a careful balanced anesthetic and strict control of uterine tone.

This will be the first study that compares the three commonly used intravenous anesthesia agents on human myometrium: ketamine, etomidate and propofol. This study is required to allow doctors make informed decisions about which anesthesia agent is most suitable to manage their patient depending on clinical circumstances.

The specific objective of this project is to investigate the pharmacological dose-response profiles of different anesthesia induction agents by in-vitro isometric tension measurements of contractions in gravid human myometrium. The investigators will study both spontaneous and oxytocin induced contractility.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Spontaneous and Oxytocin-induced Contractility After Exposure to Intravenous Anesthetic Agents: an In-vitro Study in Human Myometrium
• Actual Study Start Date: March 28, 2019
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Ketamine; The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of ketamine (from 10 -7M to 10 -4M)	Drug: Ketamine; Ketamine in solution, 10-4M to 10-7M; Other Name: ketamine HCl
Active Comparator: Ketamine + oytocin; The myometrial samples are bathed in an oxytocin solution (20nM) with increasing concentrations of ketamine (from 10 -7M to 10 -4M)	Drug: Oxytocin; Oxytocin solution, 20nM concentration; Other Name: pitocin; Drug: Ketamine; Ketamine in solution, 10-4M to 10-7M; Other Name: ketamine HCl
Active Comparator: Propofol; The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of propofol (from 10 -7M to 10 -4M)	Drug: Propofol; Propofol in solution, 10-4M to 10-7M
Active Comparator: Propofol + oytocin; The myometrial samples are bathed in an oxytocin solution (20nM) with increasing concentrations of propofol (from 10 -7M to 10 -4M)	Drug: Oxytocin; Oxytocin solution, 20nM concentration; Other Name: pitocin; Drug: Propofol; Propofol in solution, 10-4M to 10-7M
Active Comparator: Etomidate; The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of etomidate (from 10 -7M to 10 -4M)	Drug: Etomidate; Etomidate in solution, 10-4M to 10-7M
Active Comparator: Etomidate + oytocin; The myometrial samples are bathed in an oxytocin solution (20nM) with increasing concentrations of etomidate (from 10 -7M to 10 -4M)	Drug: Oxytocin; Oxytocin solution, 20nM concentration; Other Name: pitocin; Drug: Etomidate; Etomidate in solution, 10-4M to 10-7M

Outcome Measures

Primary Outcome Measures :

1. Motility index [ Time Frame: 4 hours ]

   Motility index (MI) is a calculated outcome, based on the formula: frequency/(10 x amplitude).

   Frequency and amplitude are secondary outcome measures as described below.

   The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.

Secondary Outcome Measures :

1. Amplitude of contraction [ Time Frame: 4 hours ]
   The maximum extent of uterine muscle contraction, measured in grams (g). The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.
2. Frequency of contraction [ Time Frame: 4 hours ]

   The number of contractions in uterine muscle (myometrium) over 10 minutes, spontaneously and in response to an agonist.

   The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.

3. Integrated area under response curve (AUC) [ Time Frame: 4 hours ]

Eligibility Criteria

• Ages Eligible for Study: 19 Years to 50 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Patients who give written consent to participate in this study
• Patients with gestational age 37-41 weeks
• Patients of 19-50 years
• Non-laboring patients, not exposed to exogenous oxytocin
• Patients requiring primary Cesarean section or first repeat Cesarean section
• Patients undergoing Cesarean section under spinal anesthesia

Exclusion Criteria:

• Patients who refuse to give written informed consent
• Patients who require general anesthesia
• Patients who had previous uterine surgery or more than one previous Cesarean section
• Patients with any condition predisposing to uterine atony and postpartum hemorrhage, such as abnormal placentation, multiple gestation, preeclampsia, macrosomia, polyhydramnios, uterine fibroids, bleeding diathesis, chorioamnionitis, or a previous history of postpartum bleeding
• Emergency Cesarean section in labor
• Patients on medications that could affect myometrial contractility, such as nifedipine, labetolol or magnesium sulphate.
• Patients who have been exposed to oxytocin prior or during the cesarean section.

Contacts and Locations

Contacts

Contact: Mrinalini Balki, MD; 416-586-5270; mrinalini.balki@uhn.ca

Locations

Canada, Ontario

Mount Sinai Hospital; Recruiting

Toronto, Ontario, Canada, M5G1X5

Contact: Mrinalini Balki, MD 416-586-5270 mrinalini.balki@uhn.ca

Sub-Investigator: Jose Carvalho, MD

Sub-Investigator: Thomas Drew, MD

Sponsors and Collaborators

Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Investigators

• Principal Investigator: Mrinalini Balki, MD; MOUNT SINAI HOSPITAL

More Information

• Responsible Party: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
• ClinicalTrials.gov Identifier: NCT03852797
• Other Study ID Numbers: 19-01
• First Posted: February 25, 2019
• Last Update Posted: January 5, 2021
• Last Verified: January 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Samuel Lunenfeld Research Institute, Mount Sinai Hospital:

uterine contraction; oxytocin; ketamine; propofol; etomidate

Additional relevant MeSH terms:

Postpartum Hemorrhage; Hemorrhage; Pathologic Processes; Obstetric Labor Complications; Pregnancy Complications; Puerperal Disorders; Uterine Hemorrhage; Ketamine; Propofol; Etomidate; Oxytocin; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anesthetics, Dissociative; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Oxytocics; Reproductive Control Agents