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Trial registered on ANZCTR


Registration number
ACTRN12618000244202
Ethics application status
Approved
Date submitted
21/09/2017
Date registered
15/02/2018
Date last updated
18/02/2019
Date data sharing statement initially provided
18/02/2019
Date results information initially provided
18/02/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Comparison of two different medications for treating low blood pressure after spinal anesthesia for cesarean section
Scientific title
Relative potency of noradrenaline versus phenylephrine in the prevention of hypotension after spinal anesthesia for cesarean section
Secondary ID [1] 292916 0
'Nil known'
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pregnancy 304803 0
spinal anesthesia for cesarean delivery 304804 0
Condition category
Condition code
Anaesthesiology 304095 304095 0 0
Other anaesthesiology
Reproductive Health and Childbirth 304611 304611 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The noradrenaline treatment is considered the intervention treatment.
All participating subjects will receive a standardized spinal anesthesia for cesarean delivery.
Vasopressor solutions will be freshly prepared at room temperature immediately before cesarean section by an investigator A, who apart from preparing the syringes, has no other role in the study. Only the investigator A will be aware of the content and dose of the syringe with vasopressor. In addition to the investigator A, there will be another investigator-observer responsible for data collection throughout the caesarean delivery who will also ensure strict adherence to the study protocol. Also, there will be one anesthetist responsible for clinical management of the patient only. Neither investigator-observer, nor the anesthetist responsible for clinical management of the patient will be aware of the content of the syringe with vasopressor. All syringes will be identical, and the infusions will be run at the same rate, as explained bellow.
Each patient will be allocated to one of two groups according to a computer-generated randomized code. Both vasopressors will be made up in 60ml syringes with normal saline 0.9% w/v. A Syramed®µSP6000 (Arcomed AG Medical Systems, Regensdorf, Switzerland) syringe driver infusion pump will be used at a fixed rate of 60ml/h. Only the investigator A preparing the syringes will be aware which one is noradrenaline or phenylephrine group.
The first patient will receive intravenously either phenylephrine 1200mcg in normal saline 0.9% w/v 60ml at 60ml/h infusion rate (20mcg/min) or noradrenaline 96mcg in normal saline 0.9% w/v 60ml at 60ml/h infusion rate (1.6mcg/min) according to randomization list generated from computer. The infusion will be started immediately after spinal anesthesia is administered.
A maximum of 3000mcg of phenylephrine can be diluted in normal saline 0.9% w/v 60ml (infusion rate 50mcg/min) and 240mcg of noradrenaline in normal saline 0.9% w/v 60ml (infusion rate 4mcg/min).
The investigator-observer blinded to the nature of the vasopressor infusion will assess the efficacy of each solution. The presence of hypotension, hypertension, tachycardia and bradycardia will be recorded until the delivery of the baby, or 30 min after intrathecal injection, whichever is earlier.
Hypotension is defined as a fall in systolic arterial pressure to <80% of baseline value. Hypertension is defined as an increase in systolic arterial pressure to >120% of baseline value. Tachycardia is defined as a rise in heart rate to >130 beats/min and bradycardia as a fall to <60 beats/min. The presence of hypotension, as defined above, during the study period means that the dose of infusion is classified as ineffective. It is classified as effective if the allocated drug regimen prevents hypotension during the study period. The dose of vasopressor for the subsequent patient will be determined by the efficacy of the dose in the previous patient, according to the technique of up–down sequential allocation. After an effective outcome, the next patient in respective group will receive a dose reduced by 150 mcg of phenylephrine or 12 mcg of noradrenaline. After an ineffective outcome, the dose for the next patient will be increased by the same amount, in the respective group.

Intervention code [1] 299151 0
Prevention
Intervention code [2] 299152 0
Treatment: Drugs
Comparator / control treatment
Phenylephrine group is the control group as currently phenylephrine is considered as the standard vasopressor for preventing hypotension after spinal anesthesia for cesarean delivery. This study is designed to derive the median effective dose of noradrenaline required to maintain the blood pressure during spinal anesthesia for cesarean delivery and to find out the relative potency of noradrenaline versus phenylephrine.
Control group
Active

Outcomes
Primary outcome [1] 303419 0
1. Median effective dose (ED50) of noradrenaline and phenylephrine required to maintain the blood pressure during spinal anesthesia for cesarean delivery

2. To derive the median effective dose (ED50) of noradrenaline and phenylephrine we will be using the sequential allocation method. Up-down sequential allocation is a simple, robust and efficient method of identifying the median effective dose (ED50). The dose received by each of the subjects in the study is determined by the response of the previous subject. If the outcome is effective, the dose for the subsequent subject is decreased, while if ineffective it is increased. This approach derives the dose-response relationship and the ED50 is calculated using the Dixon and Massey formula
Timepoint [1] 303419 0
From administering the spinal anaesthesia until delivery of the foetus or 30 min after intrathecal injection, whichever is earlier.
Primary outcome [2] 304103 0
1. To derive the relative potency ratio of noradrenaline to phenylephrine.

2. The ratio between the dose of noradrenaline and phenyephrine used to maintain the blood pressure will be calculated to derive the relative potency
Timepoint [2] 304103 0
From administering the spinal anaesthesia until delivery of the foetus or 30 min after intrathecal injection, whichever is earlier.
Secondary outcome [1] 338889 0
1.Total dose of each vasopressor infused

2. Calculating the amount of drugs used by checking the status on the infusion pump
Timepoint [1] 338889 0
From administering the spinal anaesthesia until delivery of the foetus or 30 min after intrathecal injection, whichever is earlier.
Secondary outcome [2] 340992 0
1. ED95 dose, the amount of each drug per minute to maintain the blood pressure within 20% of the baseline

2. Statistical analysis
Timepoint [2] 340992 0
From administering the spinal anaesthesia until delivery of the foetus or 30 min after intrathecal injection, whichever is earlier.
Secondary outcome [3] 340993 0
1. CO, SV and SVR change in comparison to the baseline values

2. Non-invasive hemodynamic monitoring system ClearSight (Edwards Lifesciences, Irvine, California, USA)
Timepoint [3] 340993 0
From administering the spinal anaesthesia until delivery of the foetus or 30 min after intrathecal injection, whichever is earlier.
Secondary outcome [4] 340994 0
1. APGAR score in newborns at 1 and 5 minutes;

2. Neonatology notes
Timepoint [4] 340994 0
1 and 5 minutes after delivery
Secondary outcome [5] 340995 0
1. Uterine arterial and venous pH, PO2, PCO2 and standardized base excess

2. Blood gas analyzer
Timepoint [5] 340995 0
After delivery of the fetus
Secondary outcome [6] 340996 0
1. Nausea and vomiting scored on a scale of 0–2 (0, no nausea; 1, nausea but no vomiting; 2, nausea and vomiting


2. Observation; using the scoring system
Timepoint [6] 340996 0
From administering the spinal anaesthesia until delivery of the foetus or 30 min after intrathecal injection whichever is earlier.

Eligibility
Key inclusion criteria
The study population will consist of patients aged 18-45 years, ASA II, BMI 25-40kg/m2, height 150–180 cm, and who have a normal singleton pregnancy beyond 36 weeks gestation, undergoing elective cesarean delivery under spinal anesthesia.
Minimum age
18 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria: onset of labor, patients with gestational hypertension, history of diabetes, cardiovascular and cerebrovascular problems, fetal abnormalities and patients taking monoamine oxidase inhibitors or tricyclic antidepressants. Moreover, all patients with baseline arterial blood pressure >140/90, or heart rate <60 or >110 beats per minute will be excluded.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Each patient will be allocated to one of two groups according to a computer-generated randomized code. Both vasopressors will be made up in 60ml syringes with normal saline 0.9% w/v. A syringe driver infusion pump will be used at a fixed rate of 60ml/h. The investigator preparing the syringes will be the only one to be aware of the content of the syringes and will have no other role in the study. Another investigator-observer blinded to the nature of the vasopressor infusion will assess the efficacy of each solution. The presence of hypotension, hypertension, tachycardia and bradycardia will be recorded until the delivery of the baby, or 30 min after intrathecal injection, whichever is earlier.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each patient will be allocated to one of two groups according to a computer-generated randomized code.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Data will be expressed as mean (SD), median [range] and count. These will be analyzed using Student’s unpaired t-test, Mann–Whitney U-test and Fisher’s Exact tests as appropriate. The sequences will be analyzed using the up–down method of Dixon and Massey and with probit regression to estimate the median vasopressor dose and 95% CI for each vasopressor.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 9220 0
Qatar
State/province [1] 9220 0
Doha

Funding & Sponsors
Funding source category [1] 297546 0
Hospital
Name [1] 297546 0
Women's Hospital, Hamad Medical Corporation;
Address [1] 297546 0
PO BOX 3050
Anesthesia Department
Doha


Country [1] 297546 0
Qatar
Primary sponsor type
Hospital
Name
Women's Hospital, Hamad Medical Corporation;
Address
PO BOX 3050
Anesthesia Department
Doha
Country
Qatar
Secondary sponsor category [1] 296557 0
None
Name [1] 296557 0
Address [1] 296557 0
Country [1] 296557 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298642 0
HMC Institutional Review Board
Ethics committee address [1] 298642 0
Hamad Medical Corporation
HMC Institutional Review Board
Po Box 3050
Doha

Qatar
Ethics committee country [1] 298642 0
Qatar
Date submitted for ethics approval [1] 298642 0
01/05/2016
Approval date [1] 298642 0
18/06/2017
Ethics approval number [1] 298642 0
HMC IRB 16192/16

Summary
Brief summary
Hypotension after spinal anesthesia for cesarean section has an incidence of up to 80% without prophylactic management. Phenylephrine is well established as standard prophylactic vasopressor in maintaining the blood pressure, but recently it has been shown that noradrenaline had similar efficacy for maintaining blood pressure with additional benefits of providing greater maternal heart rate and cardiac output. However, the dosing range of noradrenaline for this purpose is unknown.
We will use well established method to find the median effective dose of noradrenaline and phenylephrine (ED50) required to maintain the blood pressure during spinal anesthesia for cesarean delivery and to derive the relative potency of noradrenaline versus phenylephrine. That will help us to understand the dosing range of noradrenaline used as a prophylactic vasoconstrictor after spinal anesthesia for cesarean delivery
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77746 0
Dr Mitko Kocarev
Address 77746 0
Hamad Medical Corporation
Anesthesia Department
Po Box 3050
Doha

Qatar
Country 77746 0
Qatar
Phone 77746 0
+97444392219
Fax 77746 0
Email 77746 0
mkocarev@hamad.qa
Contact person for public queries
Name 77747 0
Dr Mitko Kocarev
Address 77747 0
Hamad Medical Corporation
Anesthesia Department
Po Box 3050
Doha

Qatar
Country 77747 0
Qatar
Phone 77747 0
+97444392219
Fax 77747 0
Email 77747 0
mkocarev@hamad.qa
Contact person for scientific queries
Name 77748 0
Dr Roshan Fernando
Address 77748 0
Hamad Medical Corporation
Anesthesia Department
Po Box 3050
Doha

Qatar
Country 77748 0
Qatar
Phone 77748 0
+97444392219
Fax 77748 0
Email 77748 0
rfernando1@hamad.qa

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
These data were collected solely for this trial and not for external sharing.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – plain English summary
In summary, we determined the minimal infusion rates (median effective rate, ED50) of phenylephrine and noradrenaline in prevention of hypotension after spinal anesthesia for caesarean delivery and found that noradrenaline is more potent than phenylephrine by a factor of 12.6 for equivalent maternal blood pressure control. At the minimal infusion rates, noradrenaline does not provide greater cardiac output.