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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] 302297 0
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 319047 0
Anaesthesia 319048 0
Condition category
Condition code
Stroke 317003 317003 0 0
Ischaemic
Anaesthesiology 318125 318125 0 0
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] 318585 0
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] 325112 0
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] 325112 0
Assessed after the final participant has been enrolled into the study
Primary outcome [2] 326106 0
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] 326106 0
Assessed after the final participant has been enrolled into the study.
Primary outcome [3] 326107 0
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] 326107 0
Assessed after the final participant has been enrolled into the study
Secondary outcome [1] 386882 0
Neurologic disability, as measured using the modified Rankin Scale
Timepoint [1] 386882 0
90 days post-endovascular clot retrieval
Secondary outcome [2] 386883 0
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] 386883 0
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] 386885 0
Blood pressure, as measured by continuous invasive BP measurement using arterial catheter into either arterial line or side port from radiology access.
Timepoint [3] 386885 0
Monitored continuously intraoperatively for the duration of the procedure
Secondary outcome [4] 386886 0
Cerebral blood flow, as measured by NIRS autoregulation index
Timepoint [4] 386886 0
Monitored continuously intraoperatively for the duration of the procedure
Secondary outcome [5] 386888 0
All-cause mortality, as determined using patient medical records
Timepoint [5] 386888 0
90 days post endovascular clot retrieval
Secondary outcome [6] 386889 0
Rate of peri-operative complications (symptomatic intracerebral haemorrhage, hemicraniectomy), as documented in the patient's medical record
Timepoint [6] 386889 0
During the perioperative period, recorded until discharge from hospital following initial admission for endovascular clot retrieval.
Secondary outcome [7] 390140 0
Vasopressor requirement during GA
Timepoint [7] 390140 0
Documentation of any vasopressor use during procedure, as recorded on the digital anaesthetic record.
Secondary outcome [8] 390141 0
Rate of unplanned intensive care admissions. This will be assessed by audit of patient medical records.
Timepoint [8] 390141 0
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?
No
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
58
Accrual to date
Final
60
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 17521 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 31251 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 306722 0
Government body
Name [1] 306722 0
Metro South Health
Country [1] 306722 0
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] 307270 0
None
Name [1] 307270 0
Address [1] 307270 0
Country [1] 307270 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306892 0
Metro South Health HREC
Ethics committee address [1] 306892 0
Metro South Research
L7, Translation Research Institute
199 Ipswich Road
Woolloongabba QLD 4102
Ethics committee country [1] 306892 0
Australia
Date submitted for ethics approval [1] 306892 0
17/09/2020
Approval date [1] 306892 0
19/11/2020
Ethics approval number [1] 306892 0
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 105370 0
Dr Danielle Crimmins
Address 105370 0
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102
Country 105370 0
Australia
Phone 105370 0
+61 07 3176 3162
Fax 105370 0
+61 07 3176 5102
Email 105370 0
[email protected]
Contact person for public queries
Name 105371 0
Danielle Crimmins
Address 105371 0
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102
Country 105371 0
Australia
Phone 105371 0
+61 07 3176 3162
Fax 105371 0
+61 07 3176 5102
Email 105371 0
[email protected]
Contact person for scientific queries
Name 105372 0
David Highton
Address 105372 0
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102
Country 105372 0
Australia
Phone 105372 0
+61 07 3176 3162
Fax 105372 0
+61 07 3176 5102
Email 105372 0
[email protected]

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 [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9149Ethical approval    380578-(Uploaded-24-11-2020-10-05-34)-Study-related document.pdf



Results publications and other study-related documents

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