In Vitro Optimization of Oxytocin-induced Myometrial Contractility by Propranolol

Study Overview
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Brief Summary
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The rates of cesarean deliveries (CD) and postpartum hemorrhage (PPH) are on the rise, with failed induction and augmentation of labor as major contributing factors. Oxytocin is commonly used for labor induction, as well as during the third stage of labor to minimize the risk of primary PPH. At delivery, it is imperative that the uterus responds effectively to parenteral oxytocin. Poor response to oxytocin following delivery is commonly due to prolonged labor with oxytocin augmentation that is known to desensitize the myometrium. Despite the option of several second line uterotonic agents, none of them are as effective as oxytocin in controlling PPH. Given that poor uterine muscle contraction is the root cause of both failed induction or augmentation (leading to a CD in labor) and uterine atony (leading to PPH), there is an urgent and clinically important need to investigate novel methods to enhance oxytocin-induced myometrial contractions. Propranolol, a beta adrenergic receptor agonist, has the potential to improve myometrial contractions by virtue of its ability to inhibit catecholamine production. The investigators plan to investigate the effects of propranolol in both naive and desensitized myometrium, in order to better understand its potential role in improving labor induction and reducing the risk of PPH following oxytocin exposure during labor. The investigators hypothesize that propranolol is likely to potentiate the action of oxytocin upon human myometrium, to ultimately help improve the success of labor induction/augmentation and treatment of PPH.

Detailed Description
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Myometrial samples will be used to investigate the effect of propranolol on uterine contractions when exposed to high and low doses of oxytocin (to simulate PPH treatment and labor induction respectively). The tissue will also be frozen at the end of the experiment, and Western blotting will be used to investigate the effect of propranolol on the expression patterns and cellular distribution of the oxytocin receptor and beta-adrenergic receptor and their signaling pathways in desensitized myometrium.

Official Title
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In Vitro Optimization of Oxytocin-induced Myometrial Contractility by Propranolol - Potential Applications in Induction of Labour and Treatment of Postpartum Hemorrhage

Conditions
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Postpartum Hemorrhage

Intervention / Treatment
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* Drug: Oxytocin
* Drug: Propranolol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who give written consent to participate in this study Patients with gestational age 37-41 weeks Non-laboring patients, not exposed to exogenous oxytocin Patients requiring primary Cesarean delivery or first repeat Cesarean delivery 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 delivery 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 sulfate

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Dose Oxytocin<br>The myometrial samples are bathed in an oxytocin solution at increasing concentrations (from 10 -12M to 10 -9M) | Drug: Oxytocin<br>* Oxytocin in solution, ranging from 10 -12M to 10 -5M<br>* Other names: pitocin;|
| Active Comparator: Propranolol<br>The myometrial samples are bathed in a propranol solution at 10 -6M | Drug: Propranolol<br>* Propranolol in solution, 10-6M<br>|
| Active Comparator: Propranolol + low dose oxytocin<br>The myometrial samples are bathed in an oxytocin solution at increasing concentrations (from 10 -12M to 10 -9M) plus propranol (10 -6M) | Drug: Oxytocin<br>* Oxytocin in solution, ranging from 10 -12M to 10 -5M<br>* Other names: pitocin;Drug: Propranolol<br>* Propranolol in solution, 10-6M<br>|
| Active Comparator: High Dose Oxytocin<br>The myometrial samples are bathed in an oxytocin solution (10 -5M), followed by increasing concentrations of oxytocin (from 10 -8M to 10 -5M) | Drug: Oxytocin<br>* Oxytocin in solution, ranging from 10 -12M to 10 -5M<br>* Other names: pitocin;|
| Active Comparator: High Dose Oxytocin, Propranolol-pretreated<br>The myometrial samples are bathed in an oxytocin solution (10 -5M) plus propranolol (10 -6M), followed by increasing concentrations of oxytocin (from 10 -8M to 10 -5M) | Drug: Oxytocin<br>* Oxytocin in solution, ranging from 10 -12M to 10 -5M<br>* Other names: pitocin;Drug: Propranolol<br>* Propranolol in solution, 10-6M<br>|
| Active Comparator: High dose oxytocin + propranolol<br>The myometrial samples are bathed in an oxytocin solution (10 -5M), followed by increasing concentrations of oxytocin (from 10 -8M to 10 -5M) plus propranolol (10 -6M) | Drug: Oxytocin<br>* Oxytocin in solution, ranging from 10 -12M to 10 -5M<br>* Other names: pitocin;Drug: Propranolol<br>* Propranolol in solution, 10-6M<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motility index | Motility index (MI) takes into account both the amplitude and frequency of the myometrial contraction. It is a calculated outcome, based on the formula: frequency/(10 x amplitude). The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber. | 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amplitude of contraction | 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. | 3 hours | 
| Frequency of contraction | 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 hours | 
| Integrated area under response curve (AUC) |  | 3 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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propranolol, oxytocin, uterine contraction