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

Cesarean Section Complications Clinical Trial

— PHENAD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03849508
• Other study ID #: CHRO-2018-10
• Status: Completed
• Phase: Phase 4
• Start date: February 27, 2019
• Est. completion date: December 2, 2020

Study information

• Verified date: May 2021
• Source: Centre Hospitalier Régional d'Orléans
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 124
• Est. completion date: December 2, 2020
• Est. primary completion date: December 2, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cesarean Section Complications
• Spinal Anesthesia

Intervention

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
• 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

Locations

Country	Name	City	State
France	Regional Hospital Center of ORLEANS	Orléans

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Régional d'Orléans

Country where clinical trial is conducted

France, 

References & Publications (9)

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:CD002251. doi: 10.1002/14651858.CD002251.pub3. [Epub ahead of print] Review. Update in: Cochrane Database Syst Rev. 2020 Jul 1;7:CD002251. — View Citation

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. — View Citation

Langesæter 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. Review. — View Citation

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. — View Citation

Mercier FJ, Augè 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. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Heart rate	number of heart beats per minute	From induction of spinal anesthesia until weaning of vasopressor
Secondary	Systolic blood pressure	Systolic blood pressure measured in mmHg	From induction of spinal anesthesia until weaning of vasopressor
Secondary	Mean blood pressure	Mean blood pressure measured in mmHg	From induction of spinal anesthesia until weaning of vasopressor
Secondary	Duration of bradycardia	Cumulative time in minutes with heart rate less than 60 beats/min	From induction of spinal anesthesia until weaning of vasopressor]
Secondary	Duration of hypotension with Mean blood pressure less than 65mmHg	Cumulative time in minutes	after applying spinal anesthesia until weaning of vasopressor
Secondary	Duration of hypotension with Systolic Blood Pressure less than 80mmHg	Cumulative time in minutes	after applying spinal anesthesia until weaning of vasopressor
Secondary	Duration of hypertension	Cumulative time in minutes with Systolic Blood Pressure more than 140mmHg	after applying spinal anesthesia until weaning of vasopressor
Secondary	Cardiac Output	Measured in L/min	after applying spinal anesthesia until weaning of vasopressor
Secondary	Stroke Volume	Measured in ml/beat	after applying spinal anesthesia until weaning of vasopressor
Secondary	Total Peripheral Resistance	Measured in dynes.sec.cm-5	after applying spinal anesthesia until weaning of vasopressor
Secondary	Maximum flow rate of study drug given	Measured in mcg/hour	after applying spinal anesthesia until weaning of vasopressor
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Maternal blood glucose concentration	concentration measured in mmol/l	at peripheral intravenous line placement
Secondary	Maternal blood glucose concentration	concentration measured in mmol/l	at umbilical cord clamping
Secondary	APGAR score	APGAR score of the fetus ranging from 0 to 10	1 minute after delivery
Secondary	APGAR score	APGAR score of the fetus ranging from 0 to 10	3 minutes after delivery
Secondary	APGAR score	APGAR score of the fetus ranging from 0 to 10	5 minutes after delivery
Secondary	APGAR score	APGAR score of the fetus ranging from 0 to 10	10 minutes after delivery
Secondary	Umbilical arterial potential hydrogen	potential hydrogen in the blood sample obtained from umbilical artery scaled from 1 to 14	At time of birth
Secondary	Fetal lactates	from umbilical artery blood sample, measured in mmol/l	At time of birth
Secondary	Umbilical arterial partial pressure of carbon dioxide	in the blood sample obtained from umbilical artery measured in mmHg	At time of birth
Secondary	Umbilical arterial partial pressure of oxygen	in the blood sample obtained from umbilical artery measured in mmHg	At time of birth
Secondary	Umbilical arterial base excess	in the blood sample obtained from umbilical artery measured in mmol/L	At time of birth
Secondary	Fetal blood glucose concentration at birth	from umbilical artery blood sample, measured in mmol/l	At time of birth
Secondary	Neonatal blood glucose concentration	Capillary blood glucose is measured in mmol/l	at 1 hour after birth
Secondary	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
Secondary	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