Carbetocin at Elective Cesarean Deliveries: A Dose-finding Study in Women With BMI ≥ 40kg/m2

Postpartum hemorrhage (PPH) due to uterine atony is a major cause of maternal morbidity and mortality. Carbetocin is a uterotonic with a superior pharmacokinetic profile to oxytocin. In a study performed at Mount Sinai Hospital, the investigators have shown that smaller doses of carbetocin (14.8 mcg) are as effective in achieving adequate uterine tone at elective cesarean section compared to the current recommended dose of 100mcg. However, this study was limited to those women with a body mass index (BMI) of <40 kg/m2. Maternal obesity has been shown to increase the risks of hemorrhage secondary to uterine atony, therefore the investigators wish to perform a dose finding study to determine the ED90 of carbetocin at caesarean section in those women with a BMI>40.

Study Overview

• Status: Completed
• Conditions: Postpartum Hemorrhage
• Intervention / Treatment: Drug: Carbetocin

Detailed Description

Postpartum hemorrhage (PPH) is one of the leading causes of death during childbirth and accounts for an estimated 140,000 deaths per year worldwide. The World Health Organization (WHO) recommends active management of the third stage of labor to prevent PPH, even in low risk patients. Prophylactic uterotonic drugs administered after delivery are the main element of active management of the third stage and have been demonstrated to reduce the incidence of PPH by up to 40%.

Oxytocin is the most commonly used uterotonic in North America, however it has a very short duration of action and requires a continuous infusion to achieve sustained effect, with large doses associated with adverse effects like low blood pressure, nausea, vomiting, abnormal heart rhythms and changes on ECG. Carbetocin is a synthetic oxytocin analogue. It causes uterine contraction via the same mechanism as oxytocin. Its duration of action is 4 to 7 times that of oxytocin due to an increased biological half-life in plasma and at the oxytocin receptors in the uterus. 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. However this study was limited to those women with a BMI of <40 kg/m2

The prevalence of obesity is increasing in young women and some studies have shown that obese women have higher rates of caesarean delivery compared to non-obese women. Other studies have demonstrated an increased risk of hemorrhage due to poor uterine tone in obese women. Laboratory studies show that BMI alone appears to contribute to blunted uterine muscle responses and therefore contraction responses to oxytocin in obese women. Previous dose finding studies have excluded those women with a BMI of ≥40kgm2. Therefore, the investigators wish to perform a double-blind dose finding study using the biased coin up-and-down sequential allocation technique to determine the ED90 of carbetocin at caesarean section in those women with a BMI>40.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X5
      • Mount Sinai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• BMI ≥40kg/m2
• Elective cesarean delivery under regional anesthesia
• Gestational age ≥ 37 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 carbetocin or oxytocin
• Conditions (other than high BMI) that may predispose to uterine atony and postpartum hemorrhage such as placenta previa, multiple gestation, polyhydramnios, uterine fibroids, previous history of uterine atony and postpartum bleeding, or bleeding diathesis.
• Hepatic, renal, and vascular disease
• Use of general anesthesia prior to the administration of the study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative requirement for additional uterotonic medication	A request made by the obstetrician performing the cesarean delivery for additional uterotonic medication, due to bleeding or poor uterine tone.	1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Uterine tone 2 minutes	Uterine tone, defined as satisfactory or unsatisfactory by the obstetrician at 2 minutes after completion of the carbetocin injection.	2 minutes
Uterine tone 5 minutes	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.	45 minutes

Collaborators and Investigators

• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Publications and helpful links

General Publications

• Drew T, Balki M, Farine D, Ye XY, Downey K, Carvalho JCA. Carbetocin at elective caesarean section: a sequential allocation trial to determine the minimum effective dose in obese women. Anaesthesia. 2020 Mar;75(3):331-337. doi: 10.1111/anae.14944. Epub 2019 Dec 22. Erratum In: Anaesthesia. 2020 May;75(5):685. Downey, K [added].

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2018
• Primary Completion (Actual): May 16, 2019
• Study Completion (Actual): May 17, 2019

Study Registration Dates

• First Submitted: September 13, 2018
• First Submitted That Met QC Criteria: September 13, 2018
• First Posted (Actual): September 14, 2018

Study Record Updates

• Last Update Posted (Actual): June 7, 2019
• Last Update Submitted That Met QC Criteria: June 6, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: pregnancy; postpartum hemorrhage; Cesarean delivery; carbetocin
• Additional Relevant MeSH Terms: Pathologic Processes; Pregnancy Complications; Obstetric Labor Complications; Puerperal Disorders; Uterine Hemorrhage; Hemorrhage; Postpartum Hemorrhage; Physiological Effects of Drugs; Reproductive Control Agents; Oxytocics; Carbetocin
• Other Study ID Numbers: 18-07

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No