Carbetocin at Elective Cesarean Deliveries: A Dose-finding Study in Women With Twin Pregnancy.

Study Overview
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Brief Summary
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Poor uterine tone after the birth of a baby can cause excess bleeding (called postpartum hemorrhage or PPH). This is a major cause of maternal death worldwide. Uterotonic drugs are used to improve the muscle tone of the uterus after birth, and these are effective at reducing the incidence of PPH. The Society of Obstetricians and Gynecologists of Canada (SOGC) has recommended a single dose of 100 mcg of carbetocin at elective cesarean delivery to promote uterine contraction. In a study performed at Mount Sinai Hospital, the investigators have shown that smaller doses of carbetocin (14.8 mcg) are effective in achieving adequate uterine tone at elective cesarean section. In these dose-finding studies, women with multiple pregnancies have been excluded. Because women with multiple pregnancy have a higher risk of severe PPH, uterine atony, hysterectomy, prolonged hospital stay and death, it is plausible that a higher dose of carbetocin is required. This question remains unanswered. The hypothesis is that the ED90 of carbetocin in women with twin pregnancy undergoing elective cesarean delivery under regional anesthesia is greater than 20 mcg but less than 100 mcg.

Detailed Description
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There is a lack of consensus as to what the optimal uterotonic regime is globally. Furthermore, variability in the international guidelines regarding the choice of first line uterotonic in prevention of PPH adds to the confusion. With the widespread availability of carbetocin in some developed countries, including Canada, the question of which uterotonic to adopt and at which dose becomes even more difficult to ascertain. Studies that have currently been published suggest the ED90 doses of carbetocin and oxytocin provide adequate uterine contraction with possibly fewer side effects associated with the lower dose regimens. There is evidence to suggest that lower doses of both carbetocin provide equivalent uterine contractions with a better side effect profile in patients with a singleton pregnancy. However, there is no clinical dosing data specifically for patients with twin pregnancy. The results of our study will provide guidance to obstetric and anesthetic providers worldwide when deciding what dose of carbetocin to use in women with twin pregnancy.

Official Title
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Carbetocin at Elective Cesarean Deliveries: A Dose-finding Study in Women With Twin Pregnancy.

Conditions
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Postpartum Hemorrhage, Twin

Intervention / Treatment
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* Drug: Carbetocin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Twin Pregnancy Elective cesarean delivery under regional anesthesia Gestational age ≥ 36 weeks No known additional risk factors for postpartum hemorrhage Written informed consent to participate in this study Exclusion Criteria: Refusal to give written informed consent Allergy or hypersensitivity to oxytocin Conditions that may predispose to uterine atony and postpartum hemorrhage such as placenta previa, severe preeclampsia (as defined by SOGC guidelines (25)), polyhydramnios, uterine fibroids, previous history of uterine atony resulting in PPH, or bleeding diathesis and obesity, defined as pre-pregnancy BMI >40 Hepatic, renal, and vascular disease Use of general anesthesia prior to the administration of the study drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Biased coin up-and-down design.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Carbetocin 10mcg<br>Patient is given 10mcg of carbetocin intravenously over 1 minute, immediately upon delivery of the fetal head. | Drug: Carbetocin<br>* Carbetocin administered intravenously, over 1 minute following delivery of the fetal head.<br>* Other names: Duratocin;|
| Active Comparator: Carbetocin 20mcg<br>Patient is given 20mcg of carbetocin intravenously over 1 minute, immediately upon delivery of the fetal head. | Drug: Carbetocin<br>* Carbetocin administered intravenously, over 1 minute following delivery of the fetal head.<br>* Other names: Duratocin;|
| Active Comparator: Carbetocin 40mcg<br>Patient is given 40mcg of carbetocin intravenously over 1 minute, immediately upon delivery of the fetal head. | Drug: Carbetocin<br>* Carbetocin administered intravenously, over 1 minute following delivery of the fetal head.<br>* Other names: Duratocin;|
| Active Comparator: Carbetocin 60mcg<br>Patient is given 60mcg of carbetocin intravenously over 1 minute, immediately upon delivery of the fetal head. | Drug: Carbetocin<br>* Carbetocin administered intravenously, over 1 minute following delivery of the fetal head.<br>* Other names: Duratocin;|
| Active Comparator: Carbetocin 80mcg<br>Patient is given 80mcg of carbetocin intravenously over 1 minute, immediately upon delivery of the fetal head. | Drug: Carbetocin<br>* Carbetocin administered intravenously, over 1 minute following delivery of the fetal head.<br>* Other names: Duratocin;|
| Active Comparator: Carbetocin 100mcg<br>Patient is given 100mcg of carbetocin intravenously over 1 minute, immediately upon delivery of the fetal head. | Drug: Carbetocin<br>* Carbetocin administered intravenously, over 1 minute following delivery of the fetal head.<br>* Other names: Duratocin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Uterine tone 2 minutes: questionnaire | Uterine tone, defined as satisfactory or unsatisfactory by the obstetrician at 2 minutes after completion of the carbetocin injection. | 2 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Uterine tone 5 minutes: questionnaire | Uterine tone, defined as satisfactory or unsatisfactory by the obstetrician at 5 minutes after completion of the carbetocin injection. | 5 minutes | 
| Additional uterotonics administered | The drug, dosage and timing of any additional uterotonic medication given during surgery. | 1 hour | 
| Estimated blood loss | Blood loss will be calculated through the difference in hematocrit values assessed prior to surgery and 24 hours after the cesarean delivery. | 24 hours | 
| Intravenous fluid administered during surgery | The total volume (ml) of fluid administered from entering the operating room to skin closure. | 2 hours | 
| Hypotension: systolic blood pressure less than 80% of baseline | Systolic blood pressure < 80% of baseline, from drug administration until end of surgery | 2 hours | 
| Tachycardia: heart rate greater than 130% of baseline | Heart rate > 130% of baseline, from drug administration until end of surgery | 2 hours | 
| Bradycardia: heart rate less than 70% of baseline | Heart rate < 70% of baseline or a heart rate < 50bpm, from drug administration until end of surgery | 2 hours | 
| Presence of ventricular tachycardia: ECG | Presence of ventricular tachycardia as recorded by ECG, from drug administration until end of surgery | 2 hours | 
| Presence of atrial fibrillation: ECG | Presence of atrial fibrillation as recorded by ECG, from drug administration until end of surgery | 2 hours | 
| Presence of atrial flutter: ECG | Presence of atrial flutter as recorded by ECG, from drug administration until end of surgery | 2 hours | 
| Presence of nausea: questionnaire | The presence of nausea and number of episodes, from drug administration until end of surgery, as reported by the patient | 2 hours | 
| Presence of vomiting: questionnaire | The presence of vomiting and number of episodes, from drug administration until end of surgery | 2 hours | 
| Presence of chest pain: questionnaire | Any presence of chest pain, from drug administration until end of surgery, as reported by the patient | 2 hours | 
| Presence of shortness of breath: questionnaire | Any presence of shortness of breath, from drug administration until end of surgery, as reported by the patient | 2 hours | 
| Presence of headache: questionnaire | Any presence of headache, from drug administration until end of surgery, as reported by the patient | 2 hours | 
| Presence of flushing: questionnaire | Any presence of flushing, from drug administration until end of surgery | 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Twins, Postpartum hemorrhage, carbetocin, uterotonic, cesarean delivery