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

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ClinicalTrials.gov Identifier: NCT04703088
Recruitment Status : Not yet recruiting
First Posted : January 11, 2021
Last Update Posted : January 12, 2021
Sponsor:
Collaborator:
CHU de Quebec-Universite Laval
Information provided by (Responsible Party):
Romain LANCHON, Laval University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Hypotension Anesthesia; Adverse Effect, Spinal and Epidural Cesarean Section Drug: Ondansetron 4 MG Drug: 0.9% Saline Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized blinded parallel assignment
Masking: Double (Participant, Care Provider)
Masking Description:

Studied medication will be administered to the patient after randomization by the investigators (two anesthesia residents or two staff anesthesiologists) who will not be involved in subsequent anesthetic management of the patients. The investigators will also program the infusion rate of norepinephrine at the start of each case and will be the only persons aware of the assigned infusion rate. The investigators will hide the infusion rate with an opaque paper cover over the infusion display during the case.

The investigators will also collect all the data during each procedures. To summarize, the anesthesiologist in charge of the patient will not know which treatment will be injected and the rate of the pump infusion

Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : June 2021
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04703088


Contacts
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Contact: Romain LANCHON +1 418-525-4444 ext 47565 romain.lanchon@gmail.com

Sponsors and Collaborators
Laval University
CHU de Quebec-Universite Laval
Publications:
Dixon, W. J. The Up-and-Down Method for Small Samples. J. Am. Stat. Assoc. (2012).

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Responsible Party: Romain LANCHON, Principal Investigator, Laval University
ClinicalTrials.gov Identifier: NCT04703088    
Other Study ID Numbers: 2021-5610
First Posted: January 11, 2021    Key Record Dates
Last Update Posted: January 12, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Romain LANCHON, Laval University:
Spinal Anesthesia
Hypotension, Vascular
Ondansetron Hydrochloride
Norepinephrine
Vasoconstrictor Agents
Cesarean section
Physiological Effects of Drugs
Molecular Mechanisms of Pharmacological Action
Additional relevant MeSH terms:
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Hypotension
Vascular Diseases
Cardiovascular Diseases
Ondansetron
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipruritics
Dermatologic Agents
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Anti-Anxiety Agents