Norepinephrine To Prevent Hypotension After Spinal Anesthesia For Cesarean Delivery: A Dose Finding Study

Spinal anesthesia is the most common anesthetic technique for elective Cesarean delivery (CD), but the most frequent unwanted side effect is hypotension, which can cause nausea and vomiting, as well as effects on the fetus. Prevention and treatment of maternal hypotension includes intravenous fluids and vasopressors. Phenylephrine is the most common vasopressor used for this purpose. However, it has been shown to reduce maternal heart rate and cardiac output, which may be a concern in an already compromised fetus. Norepinephrine is commonly used in high concentrations in intensive care and recent studies have suggested that in low concentrations it may be a better alternative to phenylephrine in elective CD, as it does not reduce the maternal heart rate or cardiac output. The optimum bolus dose of norepinephrine to prevent hypotension after spinal anesthesia in elective CD has not been elucidated. The investigators propose this study to determine the dose that would be effective in 90% of patients (ED90).

A previous study by Ngan Kee et al, using continuous infusion of norepinephrine to prevent hypotension in elective CD, suggested a potency ratio for norepinephrine to phenylephrine of approximately 16:1. Hence, the investigators hypothesise that the ED90 will be approximately 6 µg, given that the current phenylephrine bolus dose at the investigators' institution is approximately 100 µg.

Study Overview

• Status: Completed
• Conditions: Hypotension
• Intervention / Treatment: Drug: Norepinephrine; Drug: Normal Saline

Detailed Description

The use of norepinephrine to prevent and treat hypotension during cesarean delivery (CD) is new and data in the literature are scarce. A recent randomised controlled trial by Ngan Kee et al compared continuous infusions of norepinephrine and phenylephrine to prevent hypotension during CD. They showed that norepinephrine was effective at maintaining blood pressure, with a greater cardiac output and heart rate compared to phenylephrine. However, the effective bolus dose of norepinephrine needed to prevent maternal hypotension was not determined, and since this is a relatively new arena, no dose-response studies are available in the literature either. Therefore, it would be logical to establish the effective bolus dose of norepinephrine TO PREVENT HYPOTENSION during elective CD.

• Study Type: Interventional
• Enrollment (Actual): 40
• 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:

• Elective CD under spinal anesthesia
• Normal singleton pregnancy beyond 36 weeks gestation
• ASA physical status II/III
• Weight 50-100 kg, height 150-180 cm
• Age over 18 years
• Informed consent

Exclusion Criteria:

• Patient refusal
• Allergy or hypersensitivity to norepinephrine or sulfite
• Preexisting or pregnancy-induced hypertension
• Cardiovascular or cerebrovascular disease
• Fetal abnormalities
• History of diabetes, excluding gestational diabetes
• Use of monoamine oxidase inhibitors, triptyline or imipramine antidepressants

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Norepinephrine 3 micrograms/mL; 1mL of a solution of norepinephrine, containing 3 micrograms/mL in normal saline, will be given intravenously to a patient if her blood pressure decreases from baseline.	Drug: Norepinephrine; Other Names: Norepinephrine bitartrate; Drug: Normal Saline; 0.9% sodium chloride solution, used as a diluent.; Other Names: sodium chloride
Active Comparator: Norepinephrine 4 micrograms/mL; 1mL of a solution of norepinephrine, containing 4 micrograms/mL in normal saline, will be given intravenously to a patient if her blood pressure decreases from baseline.	Drug: Norepinephrine; Other Names: Norepinephrine bitartrate; Drug: Normal Saline; 0.9% sodium chloride solution, used as a diluent.; Other Names: sodium chloride
Active Comparator: Norepinephrine 5 micrograms/mL; 1mL of a solution of norepinephrine, containing 5 micrograms/mL in normal saline, will be given intravenously to a patient if her blood pressure decreases from baseline.	Drug: Norepinephrine; Other Names: Norepinephrine bitartrate; Drug: Normal Saline; 0.9% sodium chloride solution, used as a diluent.; Other Names: sodium chloride
Active Comparator: Norepinephrine 6 micrograms/mL; 1mL of a solution of norepinephrine, containing 6 micrograms/mL in normal saline, will be given intravenously to a patient if her blood pressure decreases from baseline.	Drug: Norepinephrine; Other Names: Norepinephrine bitartrate; Drug: Normal Saline; 0.9% sodium chloride solution, used as a diluent.; Other Names: sodium chloride
Active Comparator: Norepinephrine 7 micrograms/mL; 1mL of a solution of norepinephrine, containing 7 micrograms/mL in normal saline, will be given intravenously to a patient if her blood pressure decreases from baseline.	Drug: Norepinephrine; Other Names: Norepinephrine bitartrate; Drug: Normal Saline; 0.9% sodium chloride solution, used as a diluent.; Other Names: sodium chloride
Active Comparator: Norepinephrine 8 micrograms/mL; 1mL of a solution of norepinephrine, containing 8 micrograms/mL in normal saline, will be given intravenously to a patient if her blood pressure decreases from baseline.	Drug: Norepinephrine; Other Names: Norepinephrine bitartrate; Drug: Normal Saline; 0.9% sodium chloride solution, used as a diluent.; Other Names: sodium chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic blood pressure	The primary outcome of this study will be the success/response of the norepinephrine dose to maintain the systolic blood pressure at or above 80% of baseline, from induction of spinal anesthesia to delivery of the fetus.	30 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of Nausea	Presence of nausea in patients from induction of spinal anesthesia to delivery of the fetus.	30 minutes
Bradycardia: Heart rate less than 50 bpm	Heart rate less than 50 bpm, from induction of spinal anesthesia	30 minutes
Hypertension: Systolic blood pressure at or above 120% of baseline	Systolic blood pressure at or above 120% of baseline, from induction of spinal anesthesia to delivery of the fetus.	30 minutes
Umbilical artery pH	Umbilical artery pH	24 hours
Umbilical artery partial pressure of carbon dioxide	Umbilical artery partial pressure of carbon dioxide	24 hours
Umbilical artery partial pressure of oxygen	Umbilical artery partial pressure of oxygen	24 hours
Umbilical vein pH	Umbilical vein pH	24 hours
Umbilical vein partial pressure of carbon dioxide	Umbilical vein partial pressure of carbon dioxide	24 hours
Umbilical vein partial pressure of oxygen	Umbilical vein partial pressure of oxygen	24 hours
Presence of Vomiting	Presence of vomiting in patients from induction of spinal anesthesia to delivery of the fetus.	30 minutes
Upper sensory level of anesthetic block, assessed by pinprick upon delivery	Upper sensory level of anesthesia, assessed by pinprick upon delivery	30 minutes
Umbilical artery bicarbonate	Umbilical artery bicarbonate	24 hours
Umbilical artery base excess	Umbilical artery base excess	24 hours
Umbilical vein bicarbonate	Umbilical vein bicarbonate	24 hours
Umbilical vein base excess	Umbilical vein base excess	24 hours

Collaborators and Investigators

• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
• Investigators: Principal Investigator: Jose CA Carvalho, MD, PhD, Mount Sinai Hospital

Publications and helpful links

General Publications

• Onwochei DN, Ngan Kee WD, Fung L, Downey K, Ye XY, Carvalho JCA. Norepinephrine Intermittent Intravenous Boluses to Prevent Hypotension During Spinal Anesthesia for Cesarean Delivery: A Sequential Allocation Dose-Finding Study. Anesth Analg. 2017 Jul;125(1):212-218. doi: 10.1213/ANE.0000000000001846.

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: January 5, 2016
• First Submitted That Met QC Criteria: January 11, 2016
• First Posted (Estimate): January 13, 2016

Study Record Updates

• Last Update Posted (Estimate): August 31, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Cesarean section; blood pressure; spinal anesthesia; vasopressor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypotension; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine
• Other Study ID Numbers: 16-02

Plan for Individual participant data (IPD)

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