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Postpartum hemorrhage (PPH) continues to be an increasing problem globally. Uterotonics play an essential role in the pharmacological management of uterine atony. Carbetocin, a long acting analog of oxytocin has been recommended as a first line uterotonic for PPH prophylaxis at cesarean delivery. Considering many woman have associated comorbidities and are at high risk of PPH, finding alternative pharmacological agents is essential. Calcium is a key factor for myometrial contractions and calcium blood levels can be low at the end of pregnancy. Both hypocalcemia and hypercalcemia could lead to a decrease in myometrial contractions. It is already been demonstrated that in both desensitized and naïve myometrium, normocalcemia provides a better uterine tone compared to hypo and hypercalcemia when oxytocin is given as the first uterotonic drug.
Currently, the role of extracelullar calcium in carbetocin- induced contractility is unknown. This will be the first ex vivo study to test the effects of extracellular calcium on oxytocin pretreated and naive myometrium. The results of this study will provide evidence on the use of this safe drug in clinical practice, particularly in women with labour arrest, and provide alternative pharmacological strategies to both prevention and treatment of PPH, thus improving our clinical practice.
The investigators hypothesize that extracellular normocalcemia would provide superior carbetocin-mediated contractility in both naive and oxytocin-pretreated myometrium compared with hypercalcemia and hypocalcemia.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Calcium 1.25nM with NO oxytocin pre-exposure | Active Comparator | Dose-response testing with 1.25nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with NO oxytocin pre-exposure |
|
| Calcium 2.5nM with NO oxytocin pre-exposure | Active Comparator | Dose-response testing with 2.5nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with NO oxytocin pre-exposure |
|
| Calcium 5.0nM with NO oxytocin pre-exposure | Active Comparator | Dose-response testing with 5.0nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with NO oxytocin pre-exposure |
|
| Calcium 1.25nM with oxytocin pre-exposure | Active Comparator | Dose-response testing with 1.25nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with oxytocin pre-exposure |
|
| Calcium 2.5nM with oxytocin pre-exposure |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Oxytocin | Drug | Oxytocin 10-5M will be added to 3 groups of myometrial strips for 2 hours to induce desensitization. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Motility index | 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. | 4 hours |
| 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. | 4 hours |
| Frequency of contraction |
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Inclusion Criteria:
Exclusion criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Mrinalini Balki, MD | Contact | 416-586-480 | 5270 | mrinalini.balki@uhn.ca |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mount Sinai Hospital | Recruiting | Toronto | Ontario | M5G1X5 | Canada |
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| ID | Term |
|---|---|
| D006473 | Postpartum Hemorrhage |
| ID | Term |
|---|---|
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D010121 | Oxytocin |
| C020731 | carbetocin |
| D002118 | Calcium |
| ID | Term |
|---|---|
| D010909 | Pituitary Hormones, Posterior |
| D010907 | Pituitary Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
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| Active Comparator |
Dose-response testing with 2.5nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with oxytocin pre-exposure |
|
| Calcium 5.0nM with oxytocin pre-exposure | Active Comparator | Dose-response testing with 5.0nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with oxytocin pre-exposure |
|
| Carbetocin | Drug | Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M |
|
| Calcium | Drug | Calcium chloride in the following concentrations:1.25mM, 2.5mM and 5.0mM. |
|
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. |
| 4 hours |
| Integrated area under response curve (AUC) | 4 hours |
| D011644 | Puerperal Disorders |
| D014592 | Uterine Hemorrhage |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006730 |
| Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008673 | Metals, Alkaline Earth |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D008670 | Metals |
| D001779 | Blood Coagulation Factors |
| D001685 | Biological Factors |