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Trial registered on ANZCTR


Registration number
ACTRN12612000996864
Ethics application status
Approved
Date submitted
11/09/2012
Date registered
17/09/2012
Date last updated
16/10/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised study to see if two drugs that increase blood pressure, namely phenylephrine and metaraminol, are equally effective to preventing blood pressure falls and in resulting in a healthy baby, at the time of spinal anaesthesia for elective caesarean section
Scientific title
A randomised clinical trial at the time of spinal anaesthesia for elective caesarean section to investigate the effect of equipotent phenylephrine and metaraminol infusions on neonatal outcome
Secondary ID [1] 281135 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neonatal acid-base status. 287305 0
Anaesthesia for elective caesarean section 287428 0
Condition category
Condition code
Anaesthesiology 287640 287640 0 0
Anaesthetics
Reproductive Health and Childbirth 287762 287762 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Metaraminol intravenous infusion at 25 mcg/min commenced at the time of spinal anaesthesia for elective caesarean section and completed at the time of delivery
Intervention code [1] 285599 0
Treatment: Drugs
Intervention code [2] 285676 0
Prevention
Comparator / control treatment
Active comparitor is a phenylephrine intravenous infusion at 50 mcg/min commenced at the time of spinal anaesthesia for elective caesarean section and completed at the time of delivery
Control group
Active

Outcomes
Primary outcome [1] 287895 0
Neonatal acid-base status at birth, as determined by uterine artery pH.
Timepoint [1] 287895 0
Cord blood taken at time of birth.
Secondary outcome [1] 299001 0
Uterine venous pH, pCO2, pO2, standard base excess; p(A-V)CO2 difference, and incidence of umbilical venous pH < 7.20
Timepoint [1] 299001 0
Cord blood taken at time of birth.
Secondary outcome [2] 299002 0
Incidence of maternal hypotension (defined as a reduction in systolic blood pressure by at least 10% below baseline, using an automated sphygmomanometer).
Timepoint [2] 299002 0
From injection of spinal anaesthetic drugs until delivery of the neonate
Secondary outcome [3] 299003 0
Incidence of maternal bradycardia (defined as a fall in heart rate below 60 beats per minute, using a pulse oximeter)
Timepoint [3] 299003 0
From injection of spinal anaesthetic drugs until delivery of the neonate
Secondary outcome [4] 299004 0
Incidence of maternal hypertension (defined as an increase in systolic blood pressure of at least 10% above baseline, using an automated sphygmomanometer).
Timepoint [4] 299004 0
From injection of spinal anaesthetic drugs until delivery of the neonate
Secondary outcome [5] 299005 0
Neonatal Apgar scores at 1 and 5 minutes.
Timepoint [5] 299005 0
1 and 5 minutes after birth of the neonate

Eligibility
Key inclusion criteria
1. Women undergoing elective Caesarean section
under spinal or combined spinal epidural (CSE)
anaesthesia
2. Gestational age > 37 weeks
3. Singleton pregnancy
4. ASA I and II
5. Height between 150 and 190 cm
6. Weight between 50 and 115 kg
7. Body mass index (BMI) between 20 and 35 kg/m2
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindication to spinal or CSE anaesthesia
2. Diabetes mellitus
3. Preeclampsia, pregnancy-induced hypertension or
essential hypertension
4. Cardiovascular or cerebrovascular disease
5. Fetal abnormality or intrauterine growth restriction
6. Failure to establish block to cold to T4
7. Supplementary epidural anaesthesia prior to
delivery of the baby
8. Conversion to general anaesthesia
9. Excessive shivering that makes blood pressure
monitoring unreliable

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Recruitment will take place at pre-admission clinics, in the Labour and Birthing Suite, the Maternal-Fetal Assessment Unit or a hospital ward, as appropriate. Group assignment based on computer generated randomisation sequence will be by sealed opaque envelope, numbered sequentially.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Consenting women will be randomised by computer-generated random number sequence to either phenylephrine (Group P) or metaraminol (Group M).
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 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Non-inferiority trial

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 in Australia
Recruitment state(s)
WA
Recruitment postcode(s) [1] 9367 0
6168 - Rockingham

Funding & Sponsors
Funding source category [1] 285924 0
Other
Name [1] 285924 0
ANZCA
Address [1] 285924 0
Australian and New Zealand College of Anaesthetists

ANZCA House, 630 St Kilda Road, Melbourne Vic 3004
Country [1] 285924 0
Australia
Primary sponsor type
Hospital
Name
King Edward Memorial Hospital for Women
Address
374 Bagot Rd, Subiaco, WA 6008
Country
Australia
Secondary sponsor category [1] 284744 0
None
Name [1] 284744 0
Address [1] 284744 0
Country [1] 284744 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287950 0
Women and Newborn Health Services Ethics Committee
Ethics committee address [1] 287950 0
Room 134
Level 1
Children's Clinical Research Facility
Princess Margaret Hospital
GPO Box D184
Perth WA 6840
Ethics committee country [1] 287950 0
Australia
Date submitted for ethics approval [1] 287950 0
28/08/2012
Approval date [1] 287950 0
30/01/2013
Ethics approval number [1] 287950 0

Summary
Brief summary
Caesarean section is one of the most commonly performed procedures in Australia and many other countries. Approximately 80-90% of all caesarean sections performed in developed countries are conducted under regional anaesthesia. Due to the high incidence of maternal hypotension after spinal anaesthesia for elective caesarean delivery (approximately 70-80% in the absence of prophylaxis with sympathomimetic drugs), it has become routine practice in many centres worldwide to administer a sympathomimetic drug to support the blood pressure, either prophylactically, which is more effective, or as treatment. Phenylephrine has been extensively investigated and has become the first-line sympathomimetic drug for prophylactic continuous infusion.

Spinal anaesthesia induces systemic vasodilation and a mild fall in arterial pressure, accompanied initially by a compensatory rise in heart rate and cardiac output. Preventing reduced maternal cardiac output and a substantial fall in maternal arterial pressure (and possibly prevention of even minor reductions in blood pressure of less than 10% from baseline values) is considered fundamental to avoiding maternal nausea, vomiting, syncope and neonatal hypoxaemia and acidosis. Phenylephrine, which has almost no beta-agonist activity, and in higher doses causes a baroreceptor mediated reflex bradycardia, reduction in stroke volume because of increased afterload, shift of blood into the splanchnic venous circulation decreasing venous return and thus a dose-dependent fall in cardiac output. These factors may, if severe, be detrimental to placental perfusion.
An alternative sympathomimetic drug and alpha-adrenergic agonist is metaraminol. This drug differs from phenylephrine in having mixed direct and indirect alpha- and beta-agonist effects (although direct alpha- effects predominate at clinical doses). It is more effective than ephedrine in maintaining arterial pressure and its pharmacological properties suggest it might have advantages over phenylephrine, by maintaining cardiac output more effectively. Limited evaluation shows it is associated with excellent neonatal outcomes and metaraminol is widely used in non-obstetric clinical practice.

There are no human data comparing phenylephrine and metaraminol in pregnancy. We have established that the potency ratio between these drugs is approximately 1:4-5, so infusions will be commenced at equipotency, based on a well supported dose of phenylephrine. The rate of metaraminol will be consistent with the only previous human trials, in which it was used at 250 mcg/min initially and maximum rates approached 500 mcg/min.
This non-inferiority study will compare these two well-known sympathomimetic drugs with respect to neonatal and maternal outcome. Should metaraminol be found to compare favourably with phenyephrine, it would provide good evidence that it is a suitable option in this setting.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34650 0
Dr Nolan McDonnell
Address 34650 0
Department of Anaesthesia and Pain Medicine King Edward Memorial Hospital Bagot Road Subiaco WA 6008
Country 34650 0
Australia
Phone 34650 0
+61893402222
Fax 34650 0
+61893402227
Email 34650 0
nolan.mcdonnell@health.wa.gov.au
Contact person for public queries
Name 17897 0
Prof Michael Paech
Address 17897 0
Department of Anaesthesia and Pain Medicine
King Edward Memorial Hospital
Bagot Road
Subiaco WA 6008
Country 17897 0
Australia
Phone 17897 0
+61893402222
Fax 17897 0
+61893402227
Email 17897 0
michael.paech@health.wa.gov.au
Contact person for scientific queries
Name 8825 0
Prof Michael Paech
Address 8825 0
Department of Anaesthesia and Pain Medicine
King Edward Memorial Hospital
Bagot Road
Subiaco WA 6008
Country 8825 0
Australia
Phone 8825 0
+61893402222
Fax 8825 0
+61893402227
Email 8825 0
michael.paech@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary