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Trial registered on ANZCTR

Registration number

ACTRN12621000074897

Ethics application status

Approved

Date submitted

24/11/2020

Date registered

29/01/2021

Date last updated

16/11/2023

Date data sharing statement initially provided

29/01/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Impact of volatile gas versus intravenous general anaesthetic usage during management of endovascular retrieval of clot in ischaemic stroke on long-term patient outcomes

Scientific title

The feasibility and efficacy of a randomised controlled trial of propofol versus sevoflurane general anaesthesia on neurological recovery following endovascular clot retrieval in ischaemic stroke: PROSPER.

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1258-2245

Trial acronym

PROSPER

Linked study record

Health condition

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

Acute ischaemic stroke

Anaesthesia

Condition category

Condition code

Stroke

Ischaemic

Anaesthesiology

Anaesthetics

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

PROSPER will assess the feasibility of conducting a multi-site randomised control trial comparing two general anaesthetic techniques- volatile anaesthesia and total intravenous anaesthesia (TIVA) as maintenance of anaesthesia during endovascular thrombectomy for acute ischaemic stroke.

Prior to induction of anaesthesia, both treatment arms will be pre-oxygenated with 100% O2.
Anaesthetic protocols for the two treatment arms will then include:

1) Volatile group
Rapid sequence induction: intravenous delivery of propofol 1-3mg/kg, fentanyl 1-3mg/kg, suxamethonium 1-2mg/kg or rocuronium 1mg/kg or cisatracurium if contraindications to suxamethonium and rocuronium.
Maintenance: Inhalational delivery of sevoflurane at a minimum alveolar concentration (MAC) of 0.5-1 (end-tidal anaesthetic gas concentrations [ET] of 1.6-2.4) with other opioids and muscle relaxants as required, at the discretion of the treating anaesthetist.

2) TIVA group
Rapid sequence induction: intravenous infusion of propofol using propofol marsh model or Schneider model effect site concentration 1-5ng/ml, Remifentanil effect site concentration 1-5ng/ml, suxamethonium 1-2mg/kg or rocuronium 1mg/kg or cisatracurium if contraindications to suxamethonium and rocuronium.
Maintenance: Propofol at a target-controlled infusion (TCI) dose of of 1-5, remifentanil at TCI 1-5, plus other opioids and muscle relaxants as required, at the discretion of the treating anaesthetist.

In both groups the anaesthetist will aim for the following physiological targets, with techniques at their discretion:
Oxygen saturation over 94%
End tidal CO2 35-45
Systolic BP >140 prior to reperfusion, including during induction, and under 180 after reperfusion.
Vasopressor usage will be documented and analysed in the final analysis.

At the end of the case, the anaesthetist will ensure that the patient is fully reversed, pre-oxygenated, and extubated if possible. Patients will be managed post operatively to maintain systolic blood pressure less than 180mmHg.

Patients will be recovered in the theatre recovery area if possible. Patients who are unable to be extubated, for reasons of pre-existing anaesthetic concerns, or intraoperative complications, will be admitted to ICU intubated, and anaesthesia maintained using propofol infusion at the discretion of the anaesthetist and ICU team.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Comparator: maintenance of anaesthesia of inhalational delivery of sevoflurane at MAC 0.5-1 (ET 1.6-2.4)

Control group

Active

Outcomes

Primary outcome [1]

Feasibility of conducting a multi-site randomised control trial comparing two general anaesthetic techniques will be assessed by measuring the recruitment rate (comparing the number of people recruited to the number of potentially eligible participants). A successful recruitment rate would be one patient per week, or one third of estimated eligible patients. This will be assessed by an audit of eligible patients from theatre lists coupled with an audit of the study database.

Timepoint [1]

Assessed after the final participant has been enrolled into the study

Primary outcome [2]

Feasibility of conducting a multi-site randomised control trial comparing two general anaesthetic techniques will be assessed by measuring adherence to the two general anaesthetic maintenance protocols. Adherence will be deemed adequate if drug regimes are followed and blood pressure remains within protocol limits for 90% of the duration of the case.

Timepoint [2]

Assessed after the final participant has been enrolled into the study.

Primary outcome [3]

Feasibility of conducting a multi-site randomised control trial comparing two general anaesthetic techniques will be assessed by assessing data completion. Data completeness will be assessed as adequate if 95% of trial data is complete.

Timepoint [3]

Assessed after the final participant has been enrolled into the study

Secondary outcome [1]

Neurologic disability, as measured using the modified Rankin Scale

Timepoint [1]

90 days post-endovascular clot retrieval

Secondary outcome [2]

Early neurological recovery assessed as a composite of NIH stroke score 24 hours post procedure, length of stay in hospital and discharge destination. This will be assessed by audit of patient medical records.

Timepoint [2]

Composite of NIH stroke score assessed 24 hours post endovascular clot retrieval, length of stay in hospital as calculated in days, and discharge destination (home, nursing home, deceased).

Secondary outcome [3]

Blood pressure, as measured by continuous invasive BP measurement using arterial catheter into either arterial line or side port from radiology access.

Timepoint [3]

Monitored continuously intraoperatively for the duration of the procedure

Secondary outcome [4]

Cerebral blood flow, as measured by NIRS autoregulation index

Timepoint [4]

Monitored continuously intraoperatively for the duration of the procedure

Secondary outcome [5]

All-cause mortality, as determined using patient medical records

Timepoint [5]

90 days post endovascular clot retrieval

Secondary outcome [6]

Rate of peri-operative complications (symptomatic intracerebral haemorrhage, hemicraniectomy), as documented in the patient's medical record

Timepoint [6]

During the perioperative period, recorded until discharge from hospital following initial admission for endovascular clot retrieval.

Secondary outcome [7]

Vasopressor requirement during GA

Timepoint [7]

Documentation of any vasopressor use during procedure, as recorded on the digital anaesthetic record.

Secondary outcome [8]

Rate of unplanned intensive care admissions. This will be assessed by audit of patient medical records.

Timepoint [8]

Assessed perioperatively following endovascular clot retrieval, from admission until discharge from hospital for initial admission for clot retrieval procedure.

Eligibility

Key inclusion criteria

- Adult 18 years or over
- Clot suitable for retrieval as determined by radiologist and neurologist
- Physically independent prior to stroke, i.e., MRS less than or equal to 2 before stroke

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

-Intubated prior to arrival at radiology suite
-‘Rescue’ procedure for intraprocedural stroke, e.g., during carotid endarterectomy under general anaesthesia
-Contraindication to particular anaesthetic agent, e.g. history of malignant hyperthermia, propofol allergy
-ASA 5
-Anaesthetist refusal/ discomfort with alteration of individuals usual anaesthetic technique
-Subsequent or prior enrolment in another clot retrieval drug study

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)

Central randomisation by phone/fax/computer

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving 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

Efficacy

Statistical methods / analysis

The primary analysis will be performed unadjusted and according to the intention to treat principle. Thus, patients in the volatile group, who are required to remain intubated, and thus receive a propofol infusion post operatively, will be treated as part of the volatile group.

The primary analysis will measure the proportion of eligible patients that finish the trial protocol receiving intended therapy (Propofol or Sevoflurane). We consider greater than 1/3 recruitment feasible. With an estimated recruitment of 50% power 0.8 and 99% confidence, this requires 58 patients in total to differentiate from 33% (approximately 30 in each treatment arm). Data completeness will be assessed as adequate if 95% of trial data is complete.

The secondary outcomes of difference in mRS between the TIVA and volatile groups will be assessed using a chi square test looking at mRS 0-2, mRS 3-5 and mRS 6 between the groups. A p value of less than 0.05 will be considered significant.

The association between 90 day MRS and the following factors- baseline NIHSS, ASA, baseline MRS, age, sex, TICI score, time from symptom onset to reperfusion, invasive and non-invasive blood pressures, end tidal CO2, oxygen saturation, NIRS measured during the clot retrieval procedure, and extubation at end of case, will be examined using multivariate logistic regression.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/02/2021

Actual

18/06/2021

Date of last participant enrolment

Anticipated

30/06/2022

Actual

5/07/2023

Date of last data collection

Anticipated

30/09/2022

Actual

5/10/2023

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Princess Alexandra Hospital - Woolloongabba

Recruitment postcode(s) [1]

4102 - Woolloongabba

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Metro South Health

Address [1]

L7, Translation Research Institute
199 Ipswich Road
Woolloongabba QLD 4102

Country [1]

Australia

Primary sponsor type

Hospital

Name

Metro South Health via the Princess Alexandra Hospital

Address

199 Ipswich Road
Woolloongabba QLD 4102

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Metro South Health HREC

Ethics committee address [1]

Metro South Research
L7, Translation Research Institute
199 Ipswich Road
Woolloongabba QLD 4102

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

17/09/2020

Approval date [1]

19/11/2020

Ethics approval number [1]

55203 (SR)

Summary

Brief summary

Brief statement: Two types of general anaesthesia are given to patients to keep them asleep during the removal of clots causing large vessel strokes, most commonly either an anaesthetic gas (sevoflurane) delivered via inhalation, or medication (propofol) administered continuously through a drip. This study is a preliminary study looking to determine whether the choice of which of these methods used during the procedure makes a difference to how well a patient recovers. 

PROSPER will assess the feasibility of conducting a multi-site randomised control trial comparing two general anaesthetic techniques- volatile anaesthesia and total intravenous anaesthesia (TIVA) during endovascular thrombectomy for acute ischaemic stroke.

PROSPER will primarily assess the hypothesis that the trial protocol is feasible. 

Secondary outcome measures will include functional recovery at 90 days primarily using modified Rankin scale (mRS). We will assess the data for potential relationships between mRS scores and intra and post-operative blood pressures, near infrared spectrometry (NIRS) calculated optimal blood pressure, pre- and post-operative risk factors and thrombolysis. 

PROSPER will be a pilot study prospective randomised controlled trial. Prospective data will be collected by the anaesthetic and stroke teams at the PA hospital. This data will include:
•	Baseline patient characteristics 
•	Details of anaesthetic drugs administered
•	Physiological parameters measured during the clot retrieval procedure 
•	Radiological outcome of procedure (TICI (thrombolysis in cerebral infarction) score)
•	Clinical outcome measures 
•	Procedural complications, death rate and cause of death

Data will be analysed in 2 groups – Volatile anaesthetic only after induction versus TIVA only after induction. Patients who change groups during the procedure (becoming a mixed group) will be treated with intention to treat analysis.

We will report both feasibility for RCT and secondary outcomes.

Trial website

NA

Trial related presentations / publications

Public notes

Crimmins D, Highton D, Frankel A. (2018). Volatile versus total intravenous anaesthesia for endovascular clot retrievals in acute stroke: an audit of outcomes. J Neurosurg Anesthesiol, 30(4), 454

Lwin T, Crimmins D, Ayotte S, Redmond K, Leggett D, Shah D, Highton D. (2019). The relationship between blood pressure during stroke thrombectomy and outcome. J Neurosurg Anesthesiol, 31(4), 512

International 	“Volatile versus total intravenous anaesthesia for endovascular clot retrievals in acute stroke: an audit of outcomes” Society of Neuroanaesthesia and Neurocritical Care ASM, San Francisco, USA, October 2018	 
	
National	“Endovascular clot retrievals at the Princess Alexandra hospital: an audit of timeframes” Poster presentation only ANZCA ASM May 2018 Sydney, NSW

District	“Anaesthesia for clot retrievals at the Princess Alexandra Hospital – where have we come from, where are we going” Metro South Stroke Network meeting, Brisbane QLD 
November 2018

Contacts

Principal investigator

Name

Dr Danielle Crimmins

Address

Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102

Country

Australia

Phone

+61 07 3176 3162

Fax

+61 07 3176 5102

danielle.crimmins@health.qld.gov.au

Contact person for public queries

Name

Danielle Crimmins

Address

Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102

Country

Australia

Phone

+61 07 3176 3162

Fax

+61 07 3176 5102

danielle.crimmins@health.qld.gov.au

Contact person for scientific queries

Name

David Highton

Address

Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102

Country

Australia

Phone

+61 07 3176 3162

Fax

+61 07 3176 5102

david.highton@health.qld.gov.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Deidentified results for the purposes of replication of analysis will be provided upon reasonable request.

When will data be available (start and end dates)?

From publication until 2025

Available to whom?

Researchers, upon reasonable request

Available for what types of analyses?

Confirmatory statistics

How or where can data be obtained?

Contact CPI directly via email at danielle.crimmins@health.qld.gov.au

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
9149	Ethical approval					380578-(Uploaded-24-11-2020-10-05-34)-Study-related document.pdf

Results publications and other study-related documents

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No additional documents have been identified.

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