Investigating the Effect of Extracellular Calcium on Oxytocin-induced Human Myometrial Contractility In-vitro

Sponsor

Samuel Lunenfeld Research Institute, Mount Sinai Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT02274454

Collaborator

(none)

Enrollment

Location

Arms

3.9

Duration (Months)

10.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide and is caused most commonly by poor uterine muscle tone after delivery. The first line agent used in the prevention and treatment of PPH is oxytocin, which acts by binding with the oxytocin receptor (OTR) found on myometrial cells to cause uterine contraction. It does this by increasing levels of calcium within the myometrial cell, which promotes contraction. Women who require augmentation of labor with intravenous oxytocin because of inadequate labor progression have been shown to be at increased risk of PPH. In-vitro human myometrial models have shown that following prolonged exposure to oxytocin there is desensitization of the myometrium resulting in a significant reduction in contractility upon delivery of further oxytocin.

Optimal levels of calcium are very important for contraction of the uterine muscle. Too little calcium results in a reduced contraction. Too much calcium may result in either stronger contractions, or even possibly relaxation of the muscle and therefore a reduced contraction. The investigators currently do not know the effects of calcium on the desensitized uterine muscle.

The investigators hypothesize that myometrial contractility following desensitization of the myometrium would be reduced in myometrial samples exposed to low calcium, when compared to normal calcium or high calcium exposure. These results will help in establishing whether myometrial contraction can be augmented by increasing calcium levels within the body, or by optimizing normal physiological calcium levels, in the setting of a augmented prolonged labor, which is at higher risk of poor uterine contraction and PPH.

Condition or Disease	Intervention/Treatment	Phase
Postpartum Hemorrhage	Drug: Oxytocin Drug: Calcium	N/A

Detailed Description

The increased incidence of uterine atony and PPH following exogenous oxytocin administration during labor augmentation is related to myometrial OTR desensitization to oxytocin. Calcium is an important messenger required within the uterine muscle cell to result in muscle contraction following administration of oxytocin. A physiological level of calcium is known to provide optimal contractility to normal myometrium.

Characterization of the importance of low, normal or high calcium levels in a setting of prolonged exogenous oxytocin administration may provide guidance for the use of exogenous calcium as a uterotonic adjunct; or for the optimization of serum calcium levels during augmented labor. In the clinical setting of failed labor augmentation and OTR desensitization, the role of serum calcium levels is not currently known.

The investigators' previously validated in-vitro model provides a solid foundation for the study of myometrial contractility under controlled conditions, without any confounders that could be encountered in clinical settings.

The results of this study will provide insight into the effect of low, normal or high calcium levels on the oxytocin pretreated (desensitized) and non-pretreated myometrium. Based on oxytocin dose-response curves after pretreatment to oxytocin and then subsequent exposure to either low, normal or high levels of calcium, the investigators will be able to determine the role of calcium on desensitized myometrium.

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Investigating the Effect of Extracellular Calcium on Oxytocin-induced Human Myometrial Contractility In-vitro

Study Start Date :

Nov 1, 2014

Actual Primary Completion Date :

Mar 1, 2015

Actual Study Completion Date :

Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1.25mM Calcium-NO oxytocin pretreatment	Drug: Calcium Calcium will be applied to the myometrial strips in 3 concentrations; 1.25mM (low), 2.5mM (normal) and 5.0mM (high). Myometrial strips will be either oxytocin pretreated, or non-oxytocin pretreated.
Active Comparator: 2.5mM Calcium-NO oxytocin pretreatment	Drug: Calcium Calcium will be applied to the myometrial strips in 3 concentrations; 1.25mM (low), 2.5mM (normal) and 5.0mM (high). Myometrial strips will be either oxytocin pretreated, or non-oxytocin pretreated.
Active Comparator: 5.0mM Calcium-NO oxytocin pretreatment	Drug: Calcium Calcium will be applied to the myometrial strips in 3 concentrations; 1.25mM (low), 2.5mM (normal) and 5.0mM (high). Myometrial strips will be either oxytocin pretreated, or non-oxytocin pretreated.
Active Comparator: 1.25mM Calcium-WITH oxytocin pretreatment	Drug: Oxytocin Experiments will be conducted with some myometrial strips pretreated with oxytocin, and others without any oxytocin pretreatment Other Names: pitocin Drug: Calcium Calcium will be applied to the myometrial strips in 3 concentrations; 1.25mM (low), 2.5mM (normal) and 5.0mM (high). Myometrial strips will be either oxytocin pretreated, or non-oxytocin pretreated.
Active Comparator: 2.5mM Calcium-WITH oxytocin pretreatment	Drug: Oxytocin Experiments will be conducted with some myometrial strips pretreated with oxytocin, and others without any oxytocin pretreatment Other Names: pitocin Drug: Calcium Calcium will be applied to the myometrial strips in 3 concentrations; 1.25mM (low), 2.5mM (normal) and 5.0mM (high). Myometrial strips will be either oxytocin pretreated, or non-oxytocin pretreated.
Active Comparator: 5.0mM Calcium-WITH oxytocin pretreatment	Drug: Oxytocin Experiments will be conducted with some myometrial strips pretreated with oxytocin, and others without any oxytocin pretreatment Other Names: pitocin Drug: Calcium Calcium will be applied to the myometrial strips in 3 concentrations; 1.25mM (low), 2.5mM (normal) and 5.0mM (high). Myometrial strips will be either oxytocin pretreated, or non-oxytocin pretreated.

Outcome Measures

Primary Outcome Measures

Motility Index [8 hours]
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.

Secondary Outcome Measures

Amplitude of contraction [8 hours]
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.
Frequency of contraction [8 hours]
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.
Integrated area under response curve (AUC) [8 hours]

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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 CD or first repeat CD

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 CD
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 CD in labor
Patients on medications that could affect myometrial contractility, such as nifedipine, labetolol or magnesium sulphate.