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

NCT ID: NCT04053478

Last Updated: 2024-03-07

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 144 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-08
• Study Completion Date: 2024-12-31

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.

Studies have also investigated the use of vasopressin to limit hypotension during CD. There have been case reports of successful vasopressin usage to treat post-spinal hypotension after CD in patients with advanced idiopathic pulmonary arterial hypertension as well as severe mitral stenosis with pulmonary hypertension. Its effect was associated with hemodynamic stability without evidence of harm to the mother or child. 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 vessels can result in fetal acidosis, however, the mechanisms for these effects are unclear. The investigators hypothesize that ephedrine, phenylephrine and norepinephrine and vasopressin 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, as well as vasopressin1 and vasopressin2 receptors located in these tissues.

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 vessels. So far, no studies have directly explored the role of the aforementioned vasopressors on myometrial contractions and umbilical vessel 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.

Conditions

Hypotension

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Myometrium + Ephedrine

The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of ephedrine

Group Type: EXPERIMENTAL

Ephedrine

Intervention Type: DRUG

Ephedrine in solution, at applicable concentrations based on literature

Myometrium + Phenylephrine

The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of phenylephrine

Group Type: EXPERIMENTAL

Phenylephrine

Intervention Type: DRUG

Phenylephrine, at applicable concentrations based on literature

Myometrium + Norepinephrine

The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of norepinephrine

Group Type: EXPERIMENTAL

Norepinephrine

Intervention Type: DRUG

Norepinephrine, at applicable concentrations based on literature

Myometrium + Vasopressin

The myometrial samples are bathed in physiological salt solution (PSS) with increasing concentrations of vasopressin

Group Type: EXPERIMENTAL

Vasopressin

Intervention Type: DRUG

Vasopressin, at applicable concentrations based on literature

Umbilical artery + Ephedrine

The umbilical artery samples are bathed in physiological salt solution (PSS) with increasing concentrations of ephedrine

Group Type: EXPERIMENTAL

Ephedrine

Intervention Type: DRUG

Ephedrine in solution, at applicable concentrations based on literature

Umbilical artery + Phenylephrine

The umbilical artery samples are bathed in physiological salt solution (PSS) with increasing concentrations of phenylephrine

Group Type: EXPERIMENTAL

Phenylephrine

Intervention Type: DRUG

Phenylephrine, at applicable concentrations based on literature

Umbilical artery + Norepinephrine

The umbilical artery samples are bathed in physiological salt solution (PSS) with increasing concentrations of norepinephrine

Group Type: EXPERIMENTAL

Norepinephrine

Intervention Type: DRUG

Norepinephrine, at applicable concentrations based on literature

Umbilical artery + Vasopressin

The umbilical artery samples are bathed in physiological salt solution (PSS) with increasing concentrations of vasopressin

Group Type: EXPERIMENTAL

Vasopressin

Intervention Type: DRUG

Vasopressin, at applicable concentrations based on literature

Umbilical vein + Ephedrine

The umbilical vein samples are bathed in physiological salt solution (PSS) with increasing concentrations of ephedrine

Group Type: EXPERIMENTAL

Ephedrine

Intervention Type: DRUG

Ephedrine in solution, at applicable concentrations based on literature

Umbilical vein + Phenylephrine

The umbilical vein samples are bathed in physiological salt solution (PSS) with increasing concentrations of phenylephrine

Group Type: EXPERIMENTAL

Phenylephrine

Intervention Type: DRUG

Phenylephrine, at applicable concentrations based on literature

Umbilical vein + Norepinephrine

The umbilical vein samples are bathed in physiological salt solution (PSS) with increasing concentrations of norepinephrine

Group Type: EXPERIMENTAL

Norepinephrine

Intervention Type: DRUG

Norepinephrine, at applicable concentrations based on literature

Umbilical vein + Vasopressin

The umbilical vein samples are bathed in physiological salt solution (PSS) with increasing concentrations of vasopressin

Group Type: EXPERIMENTAL

Vasopressin

Intervention Type: DRUG

Vasopressin, at applicable concentrations based on literature

Interventions

Ephedrine

Ephedrine in solution, at applicable concentrations based on literature

Intervention Type: DRUG

Phenylephrine

Phenylephrine, at applicable concentrations based on literature

Intervention Type: DRUG

Norepinephrine

Norepinephrine, at applicable concentrations based on literature

Intervention Type: DRUG

Vasopressin

Vasopressin, at applicable concentrations based on literature

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 19 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Samuel Lunenfeld Research Institute, Mount Sinai Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mrinalini Balki, MD

Role: PRINCIPAL_INVESTIGATOR

MOUNT SINAI HOSPITAL

Locations

Mount Sinai Hospital

Toronto, Ontario, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Mrinalini Balki, MD

Role: CONTACT

mrinalini.balki@uhn.ca

416-586-4800 ext. 5270

Facility Contacts

Mrinalini Balki, MD

Role: primary

mrinalini.balki@uhn.ca

416-586-4800 ext. 5270

Other Identifiers

19-04

Identifier Type: -

Identifier Source: org_study_id