Title: Effects of Ephedrine, Phenylephrine and Norepinephrine on Contractility of Human Myometrium and Umbilical Arteries: An In-vitro Study

Sponsor

Samuel Lunenfeld Research Institute, Mount Sinai Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04053478

Collaborator

(none)

Enrollment

Location

Arms

40.8

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Hypotension is one of the most common adverse effects of spinal anesthesia for cesarean deliveries, affecting as many as 55-90% of mothers. Hypotension during cesarean deliveries can have detrimental effects on the mother and neonate. Various vasopressors, such as ephedrine, phenylephrine and more recently norepinephrine, have been used for the prevention and treatment of hypotension at cesarean deliveries.

Ephedrine was historically considered as the gold standard vasopressor for the management of hypotension during cesarean deliveries. This was based on studies in animal models that showed preserved uteroplacental circulation with ephedrine and not with phenylephrine. However, multiple studies in the past several decades have shown that phenylephrine compared with ephedrine results in a more favorable fetal acid-base status. Consequently, the use of phenylephrine for blood pressure management during cesarean deliveries increased. Recently, norepinephrine was introduced in the obstetrical practice for the management of hypotension at cesarean deliveries, due to its ability to maintain maternal cardiac output better than phenylephrine. However, much controversy still exists surrounding the choice of vasopressor in the obstetric population, in large part due to their varying efficacies, and maternal and fetal effects.

Vasopressors used for the treatment of hypotension during cesarean deliveries can have significant direct or indirect effects on the perfusion of uteroplacental and umbilical vessels. Reduction of uteroplacental perfusion and constriction of umbilical arteries can result in fetal acidosis, however, the mechanisms for these effects are unclear. The investigators hypothesize that ephedrine, phenylephrine and norepinephrine have variable effects on the contractility of pregnant myometrium and umbilical arteries due to their variable actions on adrenergic alpha (α) and beta (β) receptors located in these tissues.

Condition or Disease	Intervention/Treatment	Phase
Hypotension	Drug: Ephedrine Drug: Phenylephrine Drug: Norepinephrine	N/A

Detailed Description

One of the major concerns addressed in the literature is the risk of fetal acidosis related to the use of vasopressors, which varies according to the type of drug used. Since severe fetal acidosis is associated with a two- and four-fold increase in neonatal morbidity and mortality, respectively, it is important to understand the mechanism by which these medications may contribute to fetal acidosis.

It is well known that reduced uteroplacental blood flow can result in impaired fetal oxygenation and fetal acidosis. This can occur indirectly via compression of vessels due to myometrial contractions or directly by vasoactive effects on umbilical arteries. So far, no studies have directly explored the role of the aforementioned vasopressors on myometrial contractions and umbilical artery vasoconstriction. An in-vitro approach in isolated tissues will eliminate many clinical confounding variables, allowing direct comparison of the drugs in a controlled environment, and providing insight into the contractile mechanisms responsible for their neonatal effects.

There is currently no consensus as to which vasopressor is best for the management of hypotension in obstetric patients and the mitigation of fetal acidosis. A survey of the members of the Society of Obstetric Anesthesia and Perinatology suggested significant variation in the practice of vasopressor use during cesarean deliveries. The evidence from animal studies contradicts the effects seen in human studies. This is possibly related to species differences in adrenergic receptor distribution, affinity to vasopressors, or placental transfer of vasopressors. It is well known that reduced uteroplacental blood flow can result in impaired fetal oxygenation and fetal acidosis. This can occur indirectly via compression of vessels due to myometrial contractions or directly by vasoactive effects on umbilical arteries. However, none of the studies so far have directly explored the role of the aforementioned vasopressors on myometrial contractions and umbilical artery vasoconstriction. An in-vitro approach in isolated tissues will eliminate many clinical confounding variables, allowing direct comparison of the drugs in a controlled environment, and providing insight into the contractile mechanisms responsible for their neonatal effects.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

32 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Title: Effects of Ephedrine, Phenylephrine and Norepinephrine on Contractility of Human Myometrium and Umbilical Arteries: An In-vitro Study

Actual Study Start Date :

Jul 8, 2019

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Myometrium + Ephedrine The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of ephedrine (from 10 -10M to 10 -3M)	Drug: Ephedrine Ephedrine in solution, 10 -10m to 10 -3M
Experimental: Myometrium + Phenylephrine The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of phenylephrine(from 10 -10M to 10 -3M)	Drug: Phenylephrine Phenylephrine, 10 -10m to 10 -3M
Experimental: Myometrium + Norepinephrine The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of norepinephrine(from 10 -10M to 10 -3M)	Drug: Norepinephrine Norepinephrine, 10 -10m to 10 -3M
Experimental: Umbilical artery + Ephedrine The umbilical artery samples are bathed in physiological salt solution (PSS) with increasing concentrations of ephedrine (from 10 -10M to 10 -3M)	Drug: Ephedrine Ephedrine in solution, 10 -10m to 10 -3M
Experimental: Umbilical artery + Phenylephrine The umbilical artery samples are bathed in physiological salt solution (PSS) with increasing concentrations of phenylephrine(from 10 -10M to 10 -3M)	Drug: Phenylephrine Phenylephrine, 10 -10m to 10 -3M
Experimental: Umbilical artery + Norepinephrine The umbilical artery samples are bathed in physiological salt solution (PSS) with increasing concentrations of norepinephrine(from 10 -10M to 10 -3M)	Drug: Norepinephrine Norepinephrine, 10 -10m to 10 -3M

Outcome Measures

Primary Outcome Measures

Motility index [4 hours]
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.

Secondary Outcome Measures

Amplitude of contraction [4 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 [4 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) [4 hours]

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 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
Patients of 19-40 years
Non-laboring patients, not exposed to exogenous oxytocin
Patients requiring elective primary or first repeat caesarean delivery
Patients undergoing caesarean delivery under spinal anesthesia

Exclusion Criteria:

Patients who refuse to give written informed consent
Patients who require general anesthesia
Patients in labor and those receiving oxytocin for induction of labor
Emergency caesarean delivery in labor
Patients who have had previous uterine surgery or >1 previous caesarean delivery
Patients with any condition predisposing to uterine atony
Patients on medications that could affect myometrial contractility, such as insulin, nifedipine, labetolol or magnesium sulfate.