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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]

Nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Neonatal acid-base status.

Anaesthesia for elective caesarean section

Condition category

Condition code

Anaesthesiology

Anaesthetics

Reproductive Health and Childbirth

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]

Treatment: Drugs

Intervention code [2]

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]

Neonatal acid-base status at birth, as determined by uterine artery pH.

Timepoint [1]

Cord blood taken at time of birth.

Secondary outcome [1]

Uterine venous pH, pCO2, pO2, standard base excess; p(A-V)CO2 difference, and incidence of umbilical venous pH < 7.20

Timepoint [1]

Cord blood taken at time of birth.

Secondary outcome [2]

Incidence of maternal hypotension (defined as a reduction in systolic blood pressure by at least 10% below baseline, using an automated sphygmomanometer).

Timepoint [2]

From injection of spinal anaesthetic drugs until delivery of the neonate

Secondary outcome [3]

Incidence of maternal bradycardia (defined as a fall in heart rate below 60 beats per minute, using a pulse oximeter)

Timepoint [3]

From injection of spinal anaesthetic drugs until delivery of the neonate

Secondary outcome [4]

Incidence of maternal hypertension (defined as an increase in systolic blood pressure of at least 10% above baseline, using an automated sphygmomanometer).

Timepoint [4]

From injection of spinal anaesthetic drugs until delivery of the neonate

Secondary outcome [5]

Neonatal Apgar scores at 1 and 5 minutes.

Timepoint [5]

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

Sex

Females

Can healthy volunteers participate?

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

1/11/2012

Actual

4/02/2013

Date of last participant enrolment

Anticipated

30/04/2015

Actual

26/06/2015

Date of last data collection

Anticipated

Actual

Sample size

Target

180

Accrual to date

Final

186

Recruitment in Australia

Recruitment state(s)

Recruitment postcode(s) [1]

6168 - Rockingham

Funding & Sponsors

Funding source category [1]

Other

Name [1]

ANZCA

Address [1]

Australian and New Zealand College of Anaesthetists

ANZCA House, 630 St Kilda Road, Melbourne Vic 3004

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Women and Newborn Health Services Ethics Committee

Ethics committee address [1]

Room 134
Level 1
Children's Clinical Research Facility
Princess Margaret Hospital
GPO Box D184
Perth WA 6840

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/08/2012

Approval date [1]

30/01/2013

Ethics approval number [1]

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

Dr Nolan McDonnell

Address

Department of Anaesthesia and Pain Medicine King Edward Memorial Hospital Bagot Road Subiaco WA 6008

Country

Australia

Phone

+61893402222

Fax

+61893402227

nolan.mcdonnell@health.wa.gov.au

Contact person for public queries

Name

Michael Paech

Address

Department of Anaesthesia and Pain Medicine
King Edward Memorial Hospital
Bagot Road
Subiaco WA 6008

Country

Australia

Phone

+61893402222

Fax

+61893402227

michael.paech@health.wa.gov.au

Contact person for scientific queries

Name

Michael Paech

Address

Department of Anaesthesia and Pain Medicine
King Edward Memorial Hospital
Bagot Road
Subiaco WA 6008

Country

Australia

Phone

+61893402222

Fax

+61893402227

michael.paech@health.wa.gov.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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