Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section

August 24, 2025 updated by: Hector J. Lacassie, MD, Pontificia Universidad Catolica de Chile

Determination of the 90% Effective Dose of the Initial Bolus of Norepinephrine in Elective Cesarean Section: An Up-Down Study

The investigators are aiming to determine what is the effective intravenous dose required of an initial bolus of norepinephrine prior to a maintenance infusion to prevent a 20% decrease in maternal blood pressure from baseline following the administration of spinal anesthesia for elective cesarean section in healthy parturients

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Previous studies have focused on determining the most appropriate doses for infusion administration of norepinephrine, and although current data allows us to conclude that the optimal initial dose would be around 0.05 mcg/kg/min, there are still reasonable doubts regarding the initial bolus dose prior to an infusion.

The primary outcome is to determine the 90% effective dose (ED90) of an initial bolus of norepinephrine in elective cesarean section under spinal anesthesia to prevent arterial hypotension.

The investigators hypothesize that the bolus ED90 of norepinephrine will be in the vicinity of 0.15 μg/kg, taking as reference the lower limit of a previous study (Lyu et. al.) and the dose used in equipotency studies with phenylephrine.

After approval by the Ethics Committee of Pontificia Universidad Católica de Chile and obtaining written informed consent, full-term pregnant patients, ASA II or III, scheduled for elective cesarean section will be prospectively included. The study will be registered in Clinical Trials and will be guided by the guidelines of the Helsinki declaration.

Inclusion criteria will be age between 18 and 40 years, elective caesarean section and singleton term pregnancy. Exclusion criteria will be hypertensive disorders of pregnancy; cardiovascular disease; baseline systolic BP <100 mmHg; height less than 145 cm or greater than 180 cm; weight less than 40 kg or greater than 100 kg, need for uterine exteriorization during surgery or coagulation disorders. The study will follow the 2010 Consolidated Standards for Reporting Trials (CONSORT) guidelines.

Patients will be randomly assigned to two sequences (A and B) who receive the study drug, norepinephrine. The initial bolus doses of norepinephrine will be 0.15 and 0.13 µg/kg.

Patients, the anesthesiologist involved in the patient's care, surgeons, data collectors and outcome adjudicators will be blinded to the initial dose of norepinephrine administered.

Anesthetic care will be according to institutional standards, which include preoperative fasting and non-invasive hemodynamic monitoring. After arrival in the operating room, patients will be positioned supine with left lateral tilt, to measure baseline blood pressure (BP) and heart rate after a brief resting period and averaging 3 consecutive measurements in which systolic BP varies <10%.

A peripheral intravenous (IV) line (caliber ≥18G) will be placed into an upper extremity vein under local anesthesia. Continuous low-rate fluids will be administered for patency purposes, but without prior hydration (pre-hydration). The patients will then be positioned in the left lateral decubitus position for the anesthetic puncture.

After skin disinfection and infiltration of the skin with 2% w/v lidocaine, subarachnoid anesthesia will be performed. A 25G Whitacre spinal needle (Pencan Braun, Germany) will be inserted through an introducer at the estimated intervertebral level L3-4 or L4-5. After confirming spontaneous cerebrospinal fluid reflux, 1.4 ml of hyperbaric bupivacaine 0.75% w/v (10.5 mg), fentanyl 0.4 ml (20 μg) and morphine 0.1 ml (50 μg) will be injected intrathecally. The patient will then be returned to the supine position with left lateral tilt for uterine displacement. Rapid intravenous cohydration will be started up to a total of 15 ml/kg, after which the infusion rate will be reduced to a maintenance rate. The upper sensory block level will be assessed using discrimination with ice. For comparison purposes, the upper dermatomal level of the blockade at 10 minutes after intrathecal injection will be recorded for each patient for warm discrimination and touch. The decision to allow surgery to commence will be based on the clinical judgment of the treating anesthesiologist.

Once the intrathecal anesthetic dose has been administered and the patient is positioned in the supine position, the study dose of norepinephrine will be administered as a rapid intravenous bolus. The first patients in each sequence receive a dose of 0.15 or 0.13 µg/kg (depending on the sequence they were randomised), the latter two levels lower than reported in a previous study in which the initial dose was calculated under these conditions9, which is recommended for this type of design11. This will be followed by a continuous infusion of norepinephrine at a dose of 0.05 µg/kg/min and titrating according to hemodynamic parameters.

The infusion syringe will contain 20 ml of norepinephrine solution (8 μg/ml) to be administered by a preprogrammed syringe pump at 0.05 µg/kg/min. The syringe for the initial bolus will be 20 ml and will contain norepinephrine at 1 µg/ml, allowing the dose corresponding to 0.13 or 0.15 µg/kg to be administered rounded to the nearest whole number (e.g. for 67 kg it is 10.05 µg, i.e. 10 ml (10 µg) will be administered).

Maternal blood pressure and heart rate will be recorded noninvasively every 1 minute immediately after spinal anesthesia until delivery, after which it will be monitored every 3 minutes.

The primary outcome will be the presence of arterial hypotension within 10 minutes of anesthesia administration. Post-spinal arterial hypotension will be defined as systolic BP decreasing to less than 80% of baseline. Norepinephrine (8 μg bolus) will be administered if the patient develops arterial hypotension despite study treatment. Severe post-spinal arterial hypotension will be defined if systolic BP decreases to <60% of baseline. Bradycardia will be defined as a heart rate below 50 beats per minute, where 0.3 mg of atropine will be administered. A rescue bolus will be re-administered if arterial hypotension or bradycardia is not corrected within one minute.

Arterial hypertension will be defined as a greater than 20% increase in baseline systolic BP and norepinephrine infusion will be discontinued.

Successive doses will be determined with the up-and-down k-in-row design method for ED90 determination:

  • Failure: the dose should be increased in one level (+0.02 µg/kg) after failure to respond (arterial hypotension);
  • Success: decrease in one level (-0.02 µg/kg) upon successful response (no arterial hypotension), but only after observing at least k-consecutive positive responses at the same dose (in this case, k=7); otherwise, remain at the same dose11.
  • Reject: Any problem during the execution of the protocol that prevents the evaluation of the intervention (failure in spinal anesthesia, drug error, withdrawal from the study, etc.) will be considered as a reject, which will condition the administration of the same dose to the next patient randomized to that group.

The sequences will be run in parallel until the total sample size of each is reached.

Systolic BP and heart rate values will be recorded at the end of each BP measurement cycle. Oxygen will not be routinely administered. The attending anesthesiologist will be free to override the protocol and administer alternative or additional medications at any time if deemed clinically indicated based on his/her clinical judgment. This could include administration of additional bolus norepinephrine (8 µg), ephedrine (10 mg) or atropine (0.3 mg) intravenously for the treatment of bradycardia associated with arterial hypotension. Treatment of bradycardia not associated with arterial hypotension will be managed expectantly by discontinuing all study medications.

After fetal delivery and umbilical cord sample will be taken for blood gas and glycaemia. After placental separation a uterotonic will be administered according to standard institutional management.

Any manifestations secondary to the use of norepinephrine will be recorded, such as: headache, hypertension, pain on injection site or changes in skin colour. Nausea or vomiting during the study period shall also be recorded.

Cesarean delivery will be performed using a traditional Pfannenstiel technique, with no uterine exteriorization.

Statistical analysis The primary outcome of the study will be the incidence of arterial hypotension in the first 10 minutes after spinal anesthesia.

For the sample size calculation, a total of 60 patients will be considered, which is the general recommendation to be used to determine the 90% effective dose (ED90), which balances the minimum number of subjects and would still provide a useful estimate11. In addition, sample sizes N>40 will give an exact lower 95% confidence interval (95%CI) limit for probability of response of 0.76 for an estimate at ED90.

Data will be summarized descriptively using mean (standard difference (SD), median [interquartiles] and count (%) as appropriate. Gaussian distribution will be assessed using the D'Agostino Omnibus, Kolmogorov-Smirnov and normality plot methods.

The investigators will use the up-and-down k-in-a-row design method. The confidence intervals obtained can guarantee sufficient coverage for 95% in this type of design. We will estimate the 90% effective dose and 95% CI of norepinephrine to prevent arterial hypotension. The dose-response will be modelled using isotonic and probit regression, with and without the pooled adjacent violators algorithm (PAVA), as sensitivity analyses, in addition to the Firth penalised maximum likelihood estimation regression (Firth PMLE Regression). Probabilities of response (95%CI) will be estimated for all doses tested.

For secondary outcomes, comparisons will be made between groups and between patients with arterial hypotension versus those without, using Student t-, Mann-Whitney U- and Fisher exact statistics, as appropriate. Nominal data shall be compared using the χ2 test. A p-value<0.05 will be considered significant. Bonferroni and Tukey-Kramer corrections will be applied to keep the type I error (α) at 0.05 so that the significance criterion is p<0.017 (0.05/3) for blood pressure measurements that are repeated over time.

Statistical analyses will be performed in R (RStudio v. 2021.09.0 Build 351), jamovi ((https://www.jamovi.org), Stata 17.0, Stata Inc., College Station TX and Number Cruncher Statistical Systems (NCSS) 2024, NCSS Inc., Kaysville UT.

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 4

Contacts and Locations

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

Study Locations

  • Chile
    • RM
      • Santiago, RM, Chile, 8330024
        • Hospital Clinico, Pontificia Universidad Catolica de Chile

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

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Full-term singleton pregnant patients
  • ASA II or III
  • Scheduled for elective cesarean section
  • Age between 18 and 40 years.

Exclusion Criteria:

  • Hypertensive disorders of pregnancy
  • Cardiovascular disease
  • Baseline systolic BP <100 mmHg
  • Height less than 145 cm or greater than 180 cm
  • Weight less than 40 kg or greater than 100 kg
  • Need for uterine exteriorization during surgery
  • Coagulation disorders.

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: Prevention
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sequence A
Patients will be randomly assigned to sequence A who receive the study drug, norepinephrine. The initial bolus doses of norepinephrine will be 0.15 µg/kg.
Drug: Norepinephrine

The outcome of patient n in each sequence will determine the dose to be allocated patient n+1.

Successive doses will be determined with the up-and-down k-in-row design method for ED90 determination:

  • Failure: the dose should be increased in one level (+0.02 µg/kg) after failure to respond (arterial hypotension);
  • Success: decrease in one level (-0.02 µg/kg) upon successful response (no arterial hypotension), but only after observing at least k-consecutive positive responses at the same dose (in this case, k=7); otherwise, remain at the same dose.

This will be done until each sequence completes n=30.
Experimental: Sequence B
Patients will be randomly assigned to sequence B who receive the study drug, norepinephrine. The initial bolus doses of norepinephrine will be 0.13 µg/kg.
Drug: Norepinephrine

The outcome of patient n in each sequence will determine the dose to be allocated patient n+1.

Successive doses will be determined with the up-and-down k-in-row design method for ED90 determination:

  • Failure: the dose should be increased in one level (+0.02 µg/kg) after failure to respond (arterial hypotension);
  • Success: decrease in one level (-0.02 µg/kg) upon successful response (no arterial hypotension), but only after observing at least k-consecutive positive responses at the same dose (in this case, k=7); otherwise, remain at the same dose.

This will be done until each sequence completes n=30.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hypotension
Time Frame: First 10 minutes after spinal anesthesia dose.
The primary outcome will be the presence of arterial hypotension within 10 minutes of anesthesia administration. Post-spinal arterial hypotension will be defined as systolic BP decreasing to less than 80% of baseline.
First 10 minutes after spinal anesthesia dose.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maternal side effects
Time Frame: First 10 minutes after spinal injection
Any manifestations secondary to the use of norepinephrine will be recorded, such as: headache, hypertension, pain on injection site or changes in skin colour. Nausea or vomiting during the study period shall also be recorded.
First 10 minutes after spinal injection
Fetal side effects
Time Frame: Until completion of the surgical procedure
After fetal delivery and umbilical cord sample will be taken for blood gas and glycemia.
Until completion of the surgical procedure

Collaborators and Investigators

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

Sponsor

Pontificia Universidad Catolica de Chile

Investigators

  • Study Chair: Ivonne Vargas Celis, MD, Presidente, Comité Ético Científico Salud de la Universidad Católica

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 (Actual)

April 1, 2025

Primary Completion (Actual)

August 1, 2025

Study Completion (Actual)

August 2, 2025

Study Registration Dates

First Submitted

August 25, 2024

First Submitted That Met QC Criteria

August 25, 2024

First Posted (Actual)

August 28, 2024

Study Record Updates

Last Update Posted (Estimated)

August 29, 2025

Last Update Submitted That Met QC Criteria

August 24, 2025

Last Verified

August 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 240816002

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The whole database will be shared upon reasonable request.

IPD Sharing Time Frame

november 2025-novembre 2027

IPD Sharing Access Criteria

Researchers after reaonable request, looking at similar outcomes as ours.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • CSR

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.

Clinical Trials on Pain

Clinical Trials on Norepinephrine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Togo

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe