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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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

Conditions
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Cesarean Section Complications, Spinal Anesthesia

Intervention / Treatment
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* Drug: Norepinephrine
* Drug: Phenylephrine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: phenylephrine<br>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<br>* 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<br>|
| Experimental: Norepinephrine<br>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<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cesarean section complications, spinal anesthesia, norepinephrine, maternal hemodynamic and cardiac output