Clinical trial NCT06248593: Continuous Infusion of Norepinephrine vs Phenylephrine During Spinal Anesthesia for Cesarean Section (INPEACE)
Official title: Manually Controlled Continuous Infusion of Norepinephrine vs Phenylephrine During Spinal Anesthesia for Cesarean Section: A Double-blinded Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Cesarean Section Complications
Hypotension
Keywords: hypotension
norepinephrine
cesarean delivery
Obstetric anesthesia
Spinal anesthesia
Phenylephrine
Lead sponsor: Hassan II University
Sponsor class: OTHER
First posted: 2024-02-08
Enrollment: 140
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: It's a randomized, double-blind, two-arm, parallel, non-inferiority, controlled trial, which tha aim is to test the hypothesis that neonatal outcome, as assessed by umbilical artery pH, is at least as good (non-inferior) when prophylactic continuous manually controlled infusion of norepinephrine is used to maintain blood pressure during spinal anaesthesia for elective cesarean delivery compared with the same infusion modalities of phenylephrine with more stable blood pressure and less bradycardia.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to compare norepinephrine and ephedrine in maintaining blood pressure during spinal anaesthesia for elective cesarean delivery. The main questions it aims to answer are:

* Do phenylephrine and norepinephrine administered as manually controlled continuous infusion during elective cesarean delivery have different effects on neonatal outcome ?
* Do phenylephrine and norepinephrine administered as manually controlled continuous infusion during elective cesarean delivery have different effects on maternal hemodynamics? Participants will receive either phenylephrine or norepinephrine infusion, at the time of performing spinal anesthesia, the infusion rate will be adjusted manually depending on maternal arterial pressure.

Detailed description: It's a randomized, double-blind, two-arm, parallel, non-inferiority, controlled trial that will be conducted in Hassan II University Hospital, Fes, Morocco. The aim of this study is to test the hypothesis that neonatal outcome, as assessed by potential of hydrogen (pH) of umbilical artery, is at least as good (non-inferior) when prophylactic continuous manually controlled infusion of norepinephrine (NE) is used to maintain blood pressure during spinal anaesthesia for elective cesarean delivery compared with the same infusion modalities of phenylephrine (PHE) with more stable blood pressure and less bradycardia.

Before starting the study, a simple randomization sequence will generate codes for two equal-sized groups. One code for each patient will be placed into a sealed, opaque, sequentially numbered envelope by a research assistant, who is not involved in patient management or data collection.

Another person not involved in subsequent patient care or assessement either, will open the envelope for each patient shortly before commencement of the study and prepared two identical 50-mL syringes according to the code contained in the envelops, patients will be randomly allocated to receive PHE or NE infusion. All the syringes were labelled as "study drug", To standardize and study the effects without affecting the potency of the drugs, vasopressor doses were taken in an equipotent ratio (12.5:1) for PHE:NE based on previous studies.

The medication used in this study are :

* NE : 4 ml vial of norepinephrine bitartrate injection, 2 mg/ml.
* PHE : 10 ml Phenylephrine hydrochloride pre-filled syringe 50 μg/ml. In group PHE, The infusion is prepared by taking 1 mg of phenylephrine (2 prefilled syringe equals to 20 ml) and diluting it with 0.9% normal saline (NS) to attain a total volume of 40 mL and a concentration of 25 μg/mL.

In group NE, Norepinephrine infusion will be prepared by taking one vial (8 mg) of norepinephrine, and diluting it with 496 ml of 0.9% normal saline (NS) to attain a concentration of NE of 16 µg/ml. 10 ml of this solution Will be diluted in 0.9% NS to reach a total volume of 40 mL and a concentration of 4 μg/mL of NE which correspond to 2 µg/ml of norepinephrine base.

Eleven milligrams of hyperbaric bupivacaine in addition to 20 μg fentanyl will be injected in the L2-L3, L3-L4 or L4-L5 intervertebral space using a 25-gauge pencil-point spinal needle in the sitting position. Block success will be assessed by sensory blockade level using pinprick test and surgery would not begin unless the sensory block reached T6 level. Patients with inadequate sensory blockade would receive general anesthesia for cesarean delivery, and will be excluded from the study.

Simultaneously with the intrathecal injection, rapid intravenous vascular volume expansion by 1000ml NS solution will be started, with a pressure infuser bag inflated.

The infusion will be initiated at a rate of 96 mL/hour (1.6 mL/minute), that correspond to a phenylephrine rate infusion of 40 μg/minute or norepinephrine rate infusion of 6.4 μg/minute. Both vasopressor infusions will be started at the same time that cerebrospinal fluid is obtained before the injection of the local anesthetic into the cerebrospinal fluid. and then manually adjusted within the range 0-144 mL/h : PHE (0-60 μg/min), NE (0-9.6 µg/min), according to values of systolic blood pressure (SBP) measured noninvasively and recorded at 1-minute intervals along the intraoperative period, with the objective of maintaining values near baseline, according to this modalities (table 1). Heart rate (HR) will be monitored continuously and recorded at 1-min interval.

SBP (% of baseline) Infusion rate (ml/min)) NE delivery rate (µg/min) PHE delivery rate (µg/min) \>120% or \>140 mmhg 0 0 0 100-120% 48 3.2 20 90-100% 96 6.4 40 80-90% 120 8 50 \<80% 144 9.6 60

Table : Algorithm of manually controlled infusion rate and its corresponding amount of study drug (norepinephrine or phenylephrine depending on randomisation)

A researcher in the theater will manage the infusions and collect the data for analysis. Episodes of hypotension, hypertension, bradycardia and tachycardia will be recorded.

Intraoperative hypertension (defined as SBP greater than 120% of the baseline or \> 140 mmhg) will be managed by stopping temporarily drug infusion. The infusion is resumed when blood pressure return to \< 120% of the SBP baseline).

Postspinal hypotension (defined as decreased SBP less than 80% of the baseline or SBP\< 90 mmhg reading during the period from intrathecal injection to delivery of the fetus) will be managed by increasing vasopressor infusion dose according to study protocol infusion above. In case of persistant postspinal hypotension despite increasing vasopressor doses, it's will be managed by 2-ml bolus of the infusion which correspond for parturients with NE infusion to 8µg and those with PHE to 50 μg. Additional vasopressor bolus will be given if SBP did not respond to the first dose within 2 min despite continuing the infusion.

In case of persistence of hypotension, A rescue bolus of at least ephedrine 6 mg is recommended, and repeated according to the severity and persistence of the hypotension.

After delivery and in the absence of hemorrhage, the vasopressor flow rate will be reduced in steps of 20 mL∙h-1, while maintaining an SBP \>80% of baseline, a minimum delay of 5 minutes between 2 flow reductions is recommended to avoid secondary hypotension.

Intraoperative bradycardia (defined as heart rate less than 60 beats per minute without hypotension will be managed by stopping the vasopressor infusion.

If bradycardia is associated with hypotension, the patient will be managed by IV ephedrine 9 mg. If bradycardia persist or decrease below 50 beats/min after the previous measures, an IV atropine bolus (0.5 mg) should be given.

Umbilical arterial blood (UA) will be sampled from a double-clamped segment of umbilical cord by using arterial blood gas syringes. Within 20 min after clamping, umbilical blood gas will be analyzed with a bedside Blood gas Analyzer System.

Eligibility criteria: Inclusion Criteria:

* Full-term, singleton, pregnant women, nonlaboring.
* Scheduled for elective cesarean delivery under spinal anesthesia,
* American Society of Anesthesiologists physical status : 1 or 2
* Baseline systolic BP between 90 and 140 mm Hg.

Exclusion Criteria:

* Known fetal abnormality.
* Preexisting or pregnancy-induced hypertension, cardiovascular, cerebrovascular or kidney disease.
* Contraindication to spinal anesthesia.
* Peripartum hemorrhage.
* Body mass index above 40 kg/m2.

Primary outcomes:
measure: Umbilical artery pH
timeFrame: Immediately after delivery
Secondary outcomes:
measure: Umbilical artery base excess
timeFrame: Immediately after delivery
measure: Umbilical artery partial pressure of oxygen
timeFrame: Immediately after delivery
measure: Umbilical artery partial pressure of carbon dioxide
timeFrame: Immediately after delivery
measure: APGAR score
timeFrame: 1 min after delivery
measure: APGAR score
timeFrame: 5 min after delivery
measure: Number of newborns admitted to neonatal intensive care unit
timeFrame: Within 24 hours after delivery
measure: Blood glucose level from arterial umbilical cord blood gases
timeFrame: Immediately after delivery
measure: Number of hypotensive episodes
timeFrame: from intrathecal injection to delivery of the fetus
measure: Number of severe hypotensive episodes.
timeFrame: from intrathecal injection to delivery of the fetus
measure: Number of episodes of bradycardia before delivery
timeFrame: From intrathecal injection to delivery of the fetus.
measure: Number of Hypertension episodes
timeFrame: In the intraoperative period.
measure: Number of episodes of Tachycardia
timeFrame: In the intraoperative period.
measure: Number of episodes of nausea
timeFrame: From induction of spinal anesthesia to the end of the cesarean section.
measure: Number of episodes of vomiting
timeFrame: From induction of spinal anesthesia to the end of the cesarean section.
measure: Total dose of study drug given until delivery of the fetus.
timeFrame: From induction of spinal anesthesia to the delivery of the fetus
measure: Total dose of intraoperative study drug given.
timeFrame: From induction of spinal anesthesia to the end of the cesarean section.
measure: Total dose of ephedrine from induction of spinal anesthesia to delivery of the fetus.
timeFrame: from induction of spinal anesthesia to delivery of the fetus.
measure: Total dose of intraoperative corrective boluses of ephedrine
timeFrame: From induction of spinal anesthesia to the end of the cesarean section.
measure: Total dose of corrective boluses of atropine from induction of spinal anesthesia to delivery of the fetus.
timeFrame: from induction of spinal anesthesia to delivery of the fetus.
measure: Total dose of Intraoperative corrective boluses of atropine
timeFrame: From induction of spinal anesthesia to the end of the cesarean section.
Other outcomes:
Locations:
city: Fes
country: Morocco
facility: University hospital Hassan II
city: Fes
country: Morocco
facility: University hospital Hassan II
Study officials:
affiliation: University hospital Hassan II, Fes, Morocco
name: Mohamed Adnane Berdai, MD-PhD
role: PRINCIPAL_INVESTIGATOR
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