The Relaxant Effect of Nitroglycerin on Oxytocin Desensitized Human Myometrium

Study Overview
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Brief Summary
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Oxytocin causes myometrial contraction via the oxytocin receptor (OTR). Desensitization of the OTR after exposure to oxytocin has been demonstrated in previous studies. The resultant need for a higher oxytocin dose to cause adequate uterine contraction in vivo has also been demonstrated in laboring women having received oxytocin for labor augmentation. Achieving rapid uterine relaxation can be invaluable for maternal and fetal wellbeing in some acute obstetric emergency settings. Nitroglycerin has become a commonly used agent for achieving rapid uterine relaxation amongst obstetric anesthesiologists. Previous studies have concluded that oxytocin can be used to re-establish uterine tone following nitroglycerin mediated relaxation. However, no studies to date have looked at the effects of nitroglycerin mediated relaxation of uterine muscle that has undergone oxytocin receptor desensitization. Nor has the response to oxytocin re-exposure and return of contractility in desensitized myometrium (following nitroglycerin) been examined. The investigators hypothesize that nitroglycerin will reduce and inhibit uterine contractions in both oxytocin pre-treated myometrium, as well as untreated myometrium in a dose dependent fashion, but that myometrium that has undergone OTR desensitization will require less nitroglycerin for contractions to abate. The investigators also expect that the dose of oxytocin required to re-establish equivalent contractions will be higher in the myometrial samples which have undergone nitroglycerin mediated relaxation.

Detailed Description
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Oxytocin and nitroglycerin have opposing actions on the myometrium. The pharmacological properties of quick onset and offset of action of nitroglycerin have made this the preferred drug to be used in acute scenarios where uterine relaxation is necessary. As nitroglycerin causes changes to intracellular calcium levels and the ability uterine muscle to engage in effective contraction, it is plausible that the effects of nitroglycerin may interfere with subsequent uterine contractility and action of oxytocin. The situation where a difficult fetal extraction is encountered at cesarean section may be in two broad groups of patients. Those pre-exposed to oxytocin and those with an oxytocin naïve myometrium. Given the large observational variation in dosages of nitroglycerin usage seen in the literature we feel it is vital to investigate whether pre-exposure to oxytocin impacts on the ability of nitroglycerin to relax uterine smooth muscle. Furthermore, once the uterus has relaxed following nitroglycerin exposure, is there a need for higher doses of oxytocin to be administered in order to re-engage the uterus in effective contraction? And is this requirement further exacerbated by the phenomenon of oxytocin receptor desensitization? These clinically important questions will be addressed by the design of this in vitro myometrial study.

Official Title
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The Relaxant Effect of Nitroglycerin on Oxytocin Desensitized Human Myometrium and the Return of Contractility on Re-exposure to Oxytocin- an in Vitro Study

Conditions
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Postpartum Hemorrhage

Intervention / Treatment
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* Drug: Oxytocin
* Drug: Nitroglycerin


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 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 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 with medical/pregnancy related conditions, such as diabetes, preeclampsia and essential hypertension

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 |
| --- | --- |
| No Intervention: Control group<br>No oxytocin desensitization (pretreatment), no nitroglycerin | |
| Active Comparator: Oxytocin desensitized - no nitroglycerin<br>Pretreated with oxytocin, no nitroglycerin exposure | Drug: Oxytocin<br>* Oxytocin 10-5M solution<br>* Other names: Duratocin, pitocin;|
| Active Comparator: Oxytocin desensitized - plus nitroglycerin<br>Pretreated with oxytocin followed by nitroglycerin exposure | Drug: Oxytocin<br>* Oxytocin 10-5M solution<br>* Other names: Duratocin, pitocin;Drug: Nitroglycerin<br>* Nitroglycerin 25-1000mcg<br>|
| Active Comparator: Non oxytocin desensitized - plus nitroglycerin<br>No oxytocin pretreatment, followed by nitroglycerin exposure | Drug: Nitroglycerin<br>* Nitroglycerin 25-1000mcg<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. | 8 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. | 8 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. | 8 hours | 
| Integrated area under response curve (AUC) |  | 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uterine contraction, Oxytocin, Nitroglycerin