ONDANSETRON AND EFFECTIVE DOSE IN 50% OF SUBJECTS OF PROPHYLACTIC NOREPINEPHRINE INFUSIONS FOR PREVENTING SPINAL ANESTHESIA-INDUCED HYPOTENSION DURING CESAREAN DELIVERY

January 9, 2021 updated by: Romain LANCHON, Laval University

A PROSPECTIVE, RANDOMIZED, DOUBLE-BLINDED STUDY OF THE EFFECT OF A STANDARD DOSE OF INTRAVENOUS ONDANSETRON ON THE EFFECTIVE DOSE IN 50% OF SUBJECTS OF PROPHYLACTIC NOREPINEPHRINE INFUSIONS FOR PREVENTING SPINAL ANESTHESIA-INDUCED HYPOTENSION DURING CESAREAN DELIVERY

Spinal anesthesia is the preferred technique for elective cesarean section as per ASA guidelines. Hypotension is the main complication of this technique and is secondary to both sympatholysis and its associated decrease in systemic vascular resistance and to the Bezold-Jarisch reflex, which causes hypotension and bradycardia in response to noxious stimuli detected in the cardiac ventricles. In pregnant patients, spinal anesthesia induced hypotension is worsened by compression of the aorta and inferior vena cava by the gravid uterus. In this setting, hypotension could lead to uteroplacental hypoperfusion and fetal distress.

In its 2020 guidelines for enhanced recovery after cesarean section, SOAP states that preventing spinal-induced hypotension is an important strategy to enhance maternal and neonatal outcomes in cesarean delivery

Recent studies showed that 5-hydroxytryptamine-3 receptor antagonists, mostly used as nausea and vomiting prophylaxis agents, also contributed to inhibit the Bezold-Jarisch reflex and its associated hemodynamic consequences. Ondansetron is the most studied molecule in this field.

Many recent studies and meta-analyses show renewed interest in the use of norepinephrine as a first line agent for preventing and treating spinal anesthesia-induced hypotension in obstetric anesthesia practice instead of phenylephrine. Norepinephrine has the advantage of a better cardiac output and cardiac frequency as compared to phenylephrine without any fetal side effect. The combination of ondansetron and phenylephrine for the prevention of spinal anesthesia-induced hypotension has been studied, but not the combination of ondansetron and norepinephrine.

The main objective of this study is to evaluate the sparing effect of a standard dose of ondansetron on norepinephrine consumption during elective cesarean section under spinal anesthesia by determining the effective dose in 50% of subjects (ED50) of a prophylactic norepinephrine infusion after receiving a single dose of 4 mg of ondansetron or a saline control.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Vital signs are measured in the preparation area before entrance in the operation theater. The following measures are taken in the supine position every three minutes for three measures: blood pressure and cardiac frequency. The mean blood pressure and cardiac frequency become the reference measure for each patient.

Upon entrance in the operation theater, anesthesia care is given in a standardized manner:

  • Supine positioning of the parturient on the operating table
  • Standard monitoring of vitals signs every minute for the time of the study, including systolic, diastolic an mean blood pressures, cardiac frequency and SpO2
  • 18G intravenous catheter insertion on the forearm
  • Randomization of the patient in one of the two groups followed by blind administration of ondansetron or saline
  • 5 minute wait period before sitting the patient for spinal anesthesia
  • Standardized spinal anesthesia: Whitacre 25G spinal needle, L4-L5 intervertebral space, hyperbaric bupivacaine 12mg + fentanyl 10 mcg + morphine 100 mcg
  • Upon injection of the spinal medication: 1000 ml Ringer lactate coloading and start of the iv norepinephrine infusion upon study protocol.
  • Evaluation of the sensitive block level at 5 and 10 minutes, a level of T6 is needed to start surgery
  • Nausea and vomiting prophylaxis in both groups with metoclopramide 10 mg and dexamethasone 4 mg if no contraindication. Nausea and vomiting per cesarean section will be treated with dimenhydrinate 25 mg
  • Bradycardia (HR below 60) will be treated with atropine 0,4 mg
  • Multimodal post-operative analgesia with intra rectal acetaminophen 1000 mg and indomethacin 100 mg

Norepinephrine infusion protocol:

  • The rate of the infusion pump is blindly set in mcg/kg/min by one of the investigators before the entrance of the patient and the anesthesia team in the operating room. The setting is hidden from the main physician at all times and the perfusion is started when the spinal medication is injected.
  • For the first patient of each group (saline and ondansetron) the norepinephrine infusion is started at 0,05 mcg/kg/min until the end of the study
  • Hypotension (as defined as a value inferior or equal to 80% of the systolic blood pressure reference value) is treated by the anesthesiologist with a 4 mcg bolus of norepinephrine from a prepared syringe of norepinephrine 4 mcg/ml
  • Hypertension (as defined as a value superior or equal to 120% of the systolic blood pressure reference value) is treated by stopping the norephineprine infusion and restarting it when the value is inferior to 120% of the reference value.
  • For the following patients, the norepinephrine infusion rate will be adjusted by up and down allocation following the results of the previous patient: if no hypotension occurred (no bolus needed): the infusion rate is decreased by 0,005 mcg/kg/min (for example from 0,05 mcg/kg/min to 0,045 mcg/kg/min) / if at least one hypotension occurred (at least one bolus needed): the infusion rate is increased by 0,005 mcg/kg/min (for example from 0,05 mcg/kg/min to 0,055 mcg/kg/min)

The study is stopped at the fetal delivery.

Study Type

Interventional

Enrollment (Anticipated)

60

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • parturients with a singleton pregnancy at term (37 week's gestation and more)
  • elective cesarean delivery under spinal anesthesia
  • American Society of Anesthesiologists physical status < III

Exclusion Criteria:

  • patient refusal
  • allergy or hypersensitivity to Norepinephrine or Ondansetron
  • Use of monoamine oxidase inhibitors, triptyline or imipramine antidepressants
  • Long QT syndrome or another cause of prolonged QT
  • significant preexisting maternal disease (cardiovascular or cerebrovascular disease or coagulopathy, diabetes mellitus)
  • pre-existing or pregnancy-induced hypertension
  • pathological pregnancy (ruptured membranes, pre-eclampsia, placenta praevia, gestational diabetes)
  • body mass index < 18 or > 40
  • height < 150 or > 180
  • fetal abnormalities
  • contraindication to spinal anesthesia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: INTERVENTION GROUP - ONDANSETRON
2 mL of a solution of Ondansetron containing 2mg/ml in a 3 ml syringe will be given intravenously to a patient five minutes before positioning for induction of spinal anesthesia
Drug: Ondansetron 4 MG
2 mL of a solution of Ondansetron containing 2mg/ml in a 3 ml syringe will be given intravenously to a patient five minutes before positioning for induction of spinal anesthesia
Placebo Comparator: CONTROL GROUP - NORMAL SALINE
2 mL of 0.9% Saline in a 3 ml syringe will be given intravenously to a patient five minutes before positioning for induction of spinal anesthesia
Drug: 0.9% Saline
2 mL of 0,9% Saline in a 3 ml syringe will be given intravenously to a patient five minutes before positioning for induction of spinal anesthesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ED50 Norepinephrine
Time Frame: At the fetal delivery
The effective dose in 50% of subjects (ED50) of a prophylactic norepinephrine infusion for preventing hypotension in patients who received a single dose of intravenous ondansetron 4mg or saline control five minutes before spinal anesthesia for elective cesarean delivery
At the fetal delivery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total consumption of Norepinephrine
Time Frame: At the fetal delivery
The total consumption of Norepinephrine (mcg/kg) in the two groups (pump infusion and bolus)
At the fetal delivery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Laval University

Collaborators

CHU de Quebec-Universite Laval

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

June 1, 2021

Primary Completion (Anticipated)

August 1, 2021

Study Completion (Anticipated)

August 1, 2021

Study Registration Dates

First Submitted

January 7, 2021

First Submitted That Met QC Criteria

January 7, 2021

First Posted (Actual)

January 11, 2021

Study Record Updates

Last Update Posted (Actual)

January 12, 2021

Last Update Submitted That Met QC Criteria

January 9, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2021-5610

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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