Phenylephrine Versus Norepinephrine for Maintenance of Hemodynamic During Cesarean Section Under Spinal Anesthesia (PHENAD)

Randomized, Double-blind, Controlled Clinical Trial for Comparison of Continuous Phenylephrine Versus Norepinephrine Infusion for Maintenance of Hemodynamic Stability During Cesarean Section Under Spinal Anesthesia

Comparison between prophylactic continuous variable infusion of phenylephrine (starting dose 0,5mcg/kg/min) and norepinephrine tartrate (starting dose 0,1mcg/kg/min) to prevent hypotension and maintain cardiac output under spinal anesthesia during cesarean delivery.

Study Overview

• Status: Completed
• Conditions: Cesarean Section Complications; Spinal Anesthesia
• Intervention / Treatment: Drug: Phenylephrine; Drug: Norepinephrine

Detailed Description

Maternal hypotension is a frequent complication after spinal anesthesia for cesarean delivery. Many vasopressors have been studied and used, but the perfect vasopressor is yet to be found. Phenylephrine is the most common used in obstetric anesthesia but its cardiac depressant activity, being an only alpha-adrenergic agonistic, is linked to frequent side effects such as bradycardia and decreased cardiac output.

Norepinephrine is a vasopressor characterized by both alpha and minor beta-adrenergic agonistic activity, it has then a minimal cardiac depressant activity. Hence it would provide a better stability of hemodynamic and cardiac output, and appears as a better alternative to phenylephrine.

In this study, the investigators will compare prophylactic continuous variable infusion of both vasopressors. Phenylephrine started at the dose of 0,5mcg/kg/min and Norepinephrine tartrate started at the dose of 0,1mcg/kg/min. The doses will be adjusted according to maternal systolic blood pressure in order to prevent hypotension (defined by a systolic blood pressure under 80% of baseline).

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Orléans, France, 45067
    • Regional Hospital center of ORLEANS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Pregnancy higher than 36 weeks of amenorrhea
• Scheduled or semi-urgent (interval between decision and delivery by cesarean section higher than 12hours) cesarean section under spinal anesthesia

Exclusion Criteria:

• Extreme height (less than 140cm; higher than 180cm)
• Weight less than 50kg
• Weight higher than 120kg
• Cardiovascular disease with use of cardiac medication (including antihypertensive drug)
• Active neurological disease
• Anti-hypertension treatment.
• High blood pressure or severe pre-eclampsia
• American Society of Anesthesiologists physical status class higher than 3
• Placenta accrete/percreta
• Cesarean section scheduled under general anesthesia
• Contraindications to spinal anesthesia
• Minor (age less than 18 years old)
• Guardianship/ curatorship
• Anemia less than or equal to 8 g/dl
• Allergy to any study medication
• Simultaneous participation in another study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: phenylephrine; Spinal anesthesia with bupivacaine, sufentanil and morphine will be performed and prophylactic infusion of phenylephrine started at an initial rate of 0,5mcg/kg/ min. The rate will be adjusted according to maternal systolic blood pressure.	Drug: Phenylephrine; Drug: Phenylephrine variable infusion with a starting rate of 0,5μg/kg/min Drug: Hyperbaric Bupivacaine will be injected in the subarachnoid space with a dose of 8 to 12 mg adjusted according to height Drug: Sufentanil will be injected in the subarachnoid space with a dose of 2,5μg Drug: Morphine will be injected in the subarachnoid space with a dose of 100 μg
Experimental: Norepinephrine; Spinal anesthesia with bupivacaine, sufentanil and morphine will be performed and prophylactic infusion of norepinephrine tartrate started at an initial rate of 0,1mcg/kg/min. The rate will be adjusted according to maternal systolic blood pressure.	Drug: Norepinephrine; Drug: Norepinephrine Norepinephrine tartrate variable infusion with a starting rate of 0,1μg/kg/min (equivalent to norepinephrine base of 0.05 μg /Kg/min). Other name: Noradrenaline Drug: Hyperbaric Bupivacaine will be injected in the subarachnoid space with a dose of 8 to 12 mg adjusted according to height Drug: Sufentanil will be injected in the subarachnoid space with a dose of 2,5μg Drug: Morphine will be injected in the subarachnoid space with a dose of 100 μg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac output maintenance (measured in L/min by bioreactance).	Cardiac output values were analyses at eight points; Baseline measurement: patient placed in the supine position with the table tilted 10° left, before spinal anesthesia; Seven measurements at regular intervals: first measurement just after administration of spinal anesthesia in supine position with the table tilted 10° left and last measurement at umbilical cord clamping.	5 minutes before the induction of spinal anesthesia until umbilical cord clamping.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate	number of heart beats per minute	From induction of spinal anesthesia until weaning of vasopressor
Systolic blood pressure	Systolic blood pressure measured in mmHg	From induction of spinal anesthesia until weaning of vasopressor
Mean blood pressure	Mean blood pressure measured in mmHg	From induction of spinal anesthesia until weaning of vasopressor
Duration of bradycardia	Cumulative time in minutes with heart rate less than 60 beats/min	From induction of spinal anesthesia until weaning of vasopressor]
Duration of hypotension with Mean blood pressure less than 65mmHg	Cumulative time in minutes	after applying spinal anesthesia until weaning of vasopressor
Duration of hypotension with Systolic Blood Pressure less than 80mmHg	Cumulative time in minutes	after applying spinal anesthesia until weaning of vasopressor
Duration of hypertension	Cumulative time in minutes with Systolic Blood Pressure more than 140mmHg	after applying spinal anesthesia until weaning of vasopressor
Cardiac Output	Measured in L/min	after applying spinal anesthesia until weaning of vasopressor
Stroke Volume	Measured in ml/beat	after applying spinal anesthesia until weaning of vasopressor
Total Peripheral Resistance	Measured in dynes.sec.cm-5	after applying spinal anesthesia until weaning of vasopressor
Maximum flow rate of study drug given	Measured in mcg/hour	after applying spinal anesthesia until weaning of vasopressor
Total dose of study drug consumed	Total dose of study drug given from induction of spinal anesthesia to delivery of the fetus	after applying spinal anesthesia until weaning of vasopressor
Total Rescue Bolus Dose of atropine to maintain Systolic Blood Pressure	Total dose of atropine administered (mg)	after applying spinal anesthesia until weaning of vasopressor
Total Rescue Bolus Dose of ephedrine or other vasopressor to maintain Systolic Blood Pressure	Total dose of ephedrine or other vasopressor administered (mg)	after applying spinal anesthesia until weaning of vasopressor
Incidence of nausea or vomiting	The percentage of patients with nausea or vomiting (at least one episode)	after applying spinal anesthesia until weaning of vasopressor
Incidence of dizziness or malaise	The percentage of patients with dizziness or malaise (at least one episode)	after applying spinal anesthesia until weaning of vasopressor
Maternal blood glucose concentration	concentration measured in mmol/l	at peripheral intravenous line placement
Maternal blood glucose concentration	concentration measured in mmol/l	at umbilical cord clamping
APGAR score	APGAR score of the fetus ranging from 0 to 10	1 minute after delivery
APGAR score	APGAR score of the fetus ranging from 0 to 10	3 minutes after delivery
APGAR score	APGAR score of the fetus ranging from 0 to 10	5 minutes after delivery
APGAR score	APGAR score of the fetus ranging from 0 to 10	10 minutes after delivery
Umbilical arterial potential hydrogen	potential hydrogen in the blood sample obtained from umbilical artery scaled from 1 to 14	At time of birth
Fetal lactates	from umbilical artery blood sample, measured in mmol/l	At time of birth
Umbilical arterial partial pressure of carbon dioxide	in the blood sample obtained from umbilical artery measured in mmHg	At time of birth
Umbilical arterial partial pressure of oxygen	in the blood sample obtained from umbilical artery measured in mmHg	At time of birth
Umbilical arterial base excess	in the blood sample obtained from umbilical artery measured in mmol/L	At time of birth
Fetal blood glucose concentration at birth	from umbilical artery blood sample, measured in mmol/l	At time of birth
Neonatal blood glucose concentration	Capillary blood glucose is measured in mmol/l	at 1 hour after birth
Uterine and umbilical arteries Doppler with measurement of the pulsatility	pulsatility index of Gosling (peak systolic velocity - end diastolic velocity /mean velocity)	5 minutes before realization of spinal anesthesia
Uterine and umbilical arteries Doppler with measurement of the pulsatility	pulsatility index of Gosling (peak systolic velocity - end diastolic velocity /mean velocity)	5 minutes after induction of spinal anesthesia

Collaborators and Investigators

• Sponsor: Centre Hospitalier Régional d'Orléans
• Investigators: Principal Investigator: Olivier BELIN, Dr, CHR d'Orléans

Publications and helpful links

General Publications

• Mercier FJ, Auge M, Hoffmann C, Fischer C, Le Gouez A. Maternal hypotension during spinal anesthesia for caesarean delivery. Minerva Anestesiol. 2013 Jan;79(1):62-73. Epub 2012 Nov 18.
• Langesaeter E, Dyer RA. Maternal haemodynamic changes during spinal anaesthesia for caesarean section. Curr Opin Anaesthesiol. 2011 Jun;24(3):242-8. doi: 10.1097/ACO.0b013e32834588c5.
• Kinsella SM, Carvalho B, Dyer RA, Fernando R, McDonnell N, Mercier FJ, Palanisamy A, Sia ATH, Van de Velde M, Vercueil A; Consensus Statement Collaborators. International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia. Anaesthesia. 2018 Jan;73(1):71-92. doi: 10.1111/anae.14080. Epub 2017 Nov 1. No abstract available.
• Chooi C, Cox JJ, Lumb RS, Middleton P, Chemali M, Emmett RS, Simmons SW, Cyna AM. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev. 2017 Aug 4;8(8):CD002251. doi: 10.1002/14651858.CD002251.pub3.
• Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. Anesth Analg. 2010 Nov;111(5):1230-7. doi: 10.1213/ANE.0b013e3181f2eae1. Epub 2010 Sep 14.
• Ngan Kee WD. The use of vasopressors during spinal anaesthesia for caesarean section. Curr Opin Anaesthesiol. 2017 Jun;30(3):319-325. doi: 10.1097/ACO.0000000000000453.
• Vallejo MC, Attaallah AF, Elzamzamy OM, Cifarelli DT, Phelps AL, Hobbs GR, Shapiro RE, Ranganathan P. An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery. Int J Obstet Anesth. 2017 Feb;29:18-25. doi: 10.1016/j.ijoa.2016.08.005. Epub 2016 Aug 28.
• Ngan Kee WD, Lee SWY, Ng FF, Khaw KS. Prophylactic Norepinephrine Infusion for Preventing Hypotension During Spinal Anesthesia for Cesarean Delivery. Anesth Analg. 2018 Jun;126(6):1989-1994. doi: 10.1213/ANE.0000000000002243. Erratum In: Anesth Analg. 2019 Apr;128(4):e60.
• McLaughlin K, Wright SP, Kingdom JCP, Parker JD. Clinical Validation of Non-Invasive Cardiac Output Monitoring in Healthy Pregnant Women. J Obstet Gynaecol Can. 2017 Nov;39(11):1008-1014. doi: 10.1016/j.jogc.2017.02.015. Epub 2017 Jul 18.
• Belin O, Casteres C, Alouini S, Le Pape M, Dupont A, Boulain T. Manually Controlled, Continuous Infusion of Phenylephrine or Norepinephrine for Maintenance of Blood Pressure and Cardiac Output During Spinal Anesthesia for Cesarean Delivery: A Double-Blinded Randomized Study. Anesth Analg. 2022 Oct 24. doi: 10.1213/ANE.0000000000006244. [Epub ahead of print]

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2019
• Primary Completion (Actual): December 2, 2020
• Study Completion (Actual): December 2, 2020

Study Registration Dates

• First Submitted: February 4, 2019
• First Submitted That Met QC Criteria: February 20, 2019
• First Posted (Actual): February 21, 2019

Study Record Updates

• Last Update Posted (Actual): May 27, 2021
• Last Update Submitted That Met QC Criteria: May 26, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: norepinephrine; spinal anesthesia; cesarean section complications; maternal hemodynamic and cardiac output
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Respiratory System Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Norepinephrine; Phenylephrine; Oxymetazoline
• Other Study ID Numbers: CHRO-2018-10

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