Types of studies

We will include all randomised controlled trials (RCTs) with a parallel (e.g. cluster or individual) design. We will include studies reported as full‐text, those published as abstract only, and unpublished data. We will not include quasi‐randomised trials, i.e. studies in which participants are allocated to intervention groups based on methods that are not truly random, such as hospital number or date of birth.

Types of participants

We will consider the inclusion of participants of any gender and any age with acute ischaemic stroke defined by any related extracranial or intracranial artery occlusion, irrespective of the time at which the patient underwent any type of endovascular intervention. All patients who experienced the onset of stroke symptoms will be included, and grouped into those with an unknown length of symptom onset and those with symptoms for less or more than six hours. We will only consider participants with large vessel occlusion (LVO) undergoing endovascular treatment under anaesthesia for inclusion, i.e. the anaesthesia type will be the unique difference between the control and experimental groups. Acute ischaemic stroke will be defined as an occlusion of the internal and/or common carotid artery (extracranial) or any intracranial artery occlusion diagnosed by at least one valid objective test (e.g. DUS or angiography by tomography, magnetic resonance or digital subtraction). All trials involving patients with LVO who underwent an endovascular procedure will be considered, irrespective of the degree or the method used to determine the degree of the brain ischaemic injury. If we find studies with mixed populations (e.g. haemorrhagic and ischaemic stroke), and only a subset of the participants meet our inclusion criteria, i.e. ischaemic stroke with LVO, we will attempt to obtain data for the subgroup of interest from the triallists for inclusion in our review. For studies with mixed populations, such as haemorrhagic and ischaemic stroke, which we cannot get data from the subgroup of interest, but for which at least 50% of the study population are of interest, we will include all participants in our analysis. Moreover, we will explore the effect of this decision in a sensitivity analysis. We will exclude studies where less than 50% of the population are of interest and the subgroup of interest data are not available.

Types of interventions

We will include trials comparing one type of anaesthesia versus another with any combination of interventions, providing that the co‐treatments are balanced between the experimental and control arms. We will also include studies that compare different types and doses of drugs. We do not foresee identifying any study comparing placebo anaesthesia, but we will consider them if we do.

We will consider the following interventions.

• Local anaesthesia.

• Conscious sedation anaesthesia (CSA).

• Monitored anaesthesia care (MAC).

• General anaesthesia (GA).

Possible comparisons include:

• general anaesthesia versus conscious sedation anaesthesia;

• general anaesthesia versus local anaesthesia;

• general anaesthesia versus monitored anaesthesia care;

• general anaesthesia versus conscious sedation anaesthesia plus local anaesthesia;

• any combination of the above interventions versus any combination.

Types of outcome measures

Electronic searches

• Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library; latest issue);

• MEDLINE Ovid (from 1946) (Appendix 1);

• Embase Ovid (from 1974);

• Literatura Latino‐Americana e do Caribe em Ciências da Saúde (LILACS) (from 1982), via Virtual Health Library;

• Indice Bibliográfico Español de Ciencias de la Salud (IBECS), via Virtual Health Library.

We will model the subject strategies for databases on the search strategy designed for MEDLINE by the Cochrane Stroke Group’s Information Specialist (Appendix 1). We will combine all search strategies deployed with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying RCT and controlled clinical trials, as described in the Chapter 4 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2019).

We will search the following ongoing trial registers:

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov/);

• World Health Organization (WHO) International Clinical Trials Registry Platform (who.int/ictrp/en/);

• Stroke Trials Registry (www.strokecenter.org/trials/).

Searching other resources

In an effort to identify further published, unpublished and ongoing trials, we will:

• check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials and search Google Scholar to forward track relevant references (scholar.google.co.uk/);

• contact original trial authors for clarification and further data if trial reports are unclear;

• where necessary, contact experts/triallists/organisations in the field to obtain additional information on relevant trials using a standard letter template (Appendix 2); and

• conduct a search of various grey literature sources, dissertation and theses databases, and databases of conference abstracts, including:

  • British Library EThOS (UK E‐Theses Online Service);

  • ProQuest Dissertation and Theses Global.

Selection of studies

Two review authors (RT, CNBC) will independently screen titles and abstracts of the references obtained as a result of our searching activities and will exclude obviously irrelevant reports using the Covidence tool (Covidence). We will retrieve the full text articles for the remaining references and two review authors (RT, CNBC) will independently screen the full text articles and identify studies to determine and record reasons for exclusion of the ineligible studies. We will resolve any disagreements through discussion or, if required, we will consult a third review author (RLGF). We will collate multiple reports of the same study so that each study, rather than each reference, is the unit of interest in the review. We will record the selection process and complete a PRISMA flow diagram (Moher 2010).

Data extraction and management

We will use a data collection form for study characteristics and outcome data, which we will pilot on at least one study in the review. Two review authors (RT, CNBC) will independently extract data from the included studies. We will extract the following study characteristics.

• Methods: study design, total duration of study, details of any 'run in' period, number of study centres, and the location, study setting and date of study.

• Participants: number randomised, number lost to follow‐up/withdrawn, number analysed, mean age, age range, gender, severity of condition, diagnostic criteria, inclusion criteria and exclusion criteria.

• Interventions: intervention, comparison, concomitant medications and excluded medications.

• Outcomes: primary and secondary outcomes specified and collected, and time points reported.

• Notes: funding for trial, and notable conflicts of interest of trial authors.

We will resolve disagreements by consensus or by involving a third review author (RLGF). One review author (RT) will transfer data into Review Manager (RevMan 2014). We will double‐check that the data are entered correctly by comparing the data presented in the systematic review with the data extraction form. A second review author (CNBC) will spot‐check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (RT, CNBC) will independently assess the risk of bias for each study using the criteria outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We will resolve any disagreements by discussion or by involving another review author (RLGF). We will assess the risk of bias according to the following domains.

• Random sequence generation.

• Allocation concealment.

• Blinding of participants and personnel.

• Blinding of outcome assessment.

• Incomplete outcome data.

• Selective outcome reporting.

• Other bias.

In cluster‐randomised trials, we will consider particular biases, as recommended in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions: 1) recruitment bias; 2) baseline imbalance; 3) loss of clusters; 4) incorrect analysis; and 5) comparability with individually‐randomised trials (Higgins 2017). We will grade each potential source of bias as high, low, or unclear and provide a quote from the study report, together with a justification for our judgment in the 'Risk of bias' table. We will summarise the 'Risk of bias' judgements across different studies for each of the domains listed. Where information on the risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table. When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Measures of treatment effect

We will analyse dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). We will analyse continuous data using the mean difference (MD) when the same scale/score is used, or the standardised mean difference (SMD) when different scales/scores are used, with 95% CIs. We will enter data presented as a scale with a consistent direction of effect. We will narratively describe skewed data reported as medians and interquartile ranges.

Unit of analysis issues

Individuals will be the unit of analysis. If trials include multiple intervention arms, we will consider only the arms relevant to the scope of our review. Where a study includes multiple intervention groups, we will combine groups to create a single pair‐wise comparison.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as an abstract only). Where possible, we will use the RevMan calculator to calculate missing standard deviations using other data from the trial, such as confidence intervals. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. For all outcomes, we will follow intention‐to‐treat (ITT) principles to the greatest degree possible, where we will analyse participants in their randomised group regardless of the intervention received. We will use available‐case data for the denominator if ITT data are not available.

We will present study‐level data so that missing and unclear data are clearly indicated and to make any unpublished data acquired from investigators available.

Assessment of heterogeneity

We will inspect forest plots visually to consider the direction and magnitude of effects and the degree of overlap between confidence intervals. We will use the I² statistic to measure heterogeneity among the trials in each analysis; we acknowledge that there is substantial uncertainty in the value of I² when there is only a small number of studies. If we identify substantial heterogeneity, we will report it and explore possible causes by pre‐specified subgroup analysis. We will consider an I² > 50% as substantial heterogeneity. If an I² > 50%, we will explore the individual trial characteristics to identify potential sources of heterogeneity (Deeks 2019).

Assessment of reporting biases

We will use funnel plots to investigate reporting biases if we identify 10 or more studies, as recommended in Chapter 13 by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019b).

Data synthesis

We will synthesise the data using Review Manager 5 (RevMan 2014). We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants, and the underlying clinical question are similar enough for pooling to be appropriate.

If we are confident that trials are estimating the same underlying treatment effect, i.e. the included studies are homogenous (considering population, interventions, comparators and outcome characteristics), we will use a fixed‐effect meta‐analysis. If clinical heterogeneity is sufficient to expect that underlying treatment effects differ between trials, or if at least substantial heterogeneity is identified, we will use a random‐effects meta‐analysis. If there is substantial clinical, methodological, or statistical heterogeneity across trials that prevents the pooling of data, we will use a narrative approach to data synthesis (Deeks 2019).

We will address all outcomes listed in the Types of outcome measures section in the 'Results' section of the review under the heading 'Effects of interventions', with outcomes addressed in the order in which they are shown in Types of outcome measures.

We will include the results of individual studies and any statistical summary of these in 'Data and analyses' tables in the review.

GRADE and 'Summary of findings' table

We will create a 'Summary of findings' table for the early time point using the following outcomes: 1) functional outcome at the end of the scheduled follow‐up; 2) neurological impairment; 3) stroke‐related mortality; 4) all intracranial haemorrhage; 5) target artery revascularisation status; 6) time to revascularisation; 7) adverse events.

We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of a body of evidence as it relates to the studies that contribute data to the meta‐analyses for the pre‐specified outcomes (Atkins 2004). We will use methods and recommendations described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schunemann 2019) using the GRADEproGDT software (GradePro 2015). We will create a separate 'Summary of findings' table for each comparison, for example: 1) general anaesthesia versus conscious sedation anaesthesia; 2) general anaesthesia versus local anaesthesia; 3) general anaesthesia versus monitored anaesthesia care; and 4) general anaesthesia versus conscious sedation anaesthesia plus local anaesthesia. We will justify all decisions to downgrade the quality of studies using footnotes, and we will make comments to aid the reader's understanding of the review where necessary.

Two review authors (RT, CNBC), working independently, will make judgements about evidence quality, with disagreements resolved by discussion or involving a third review author (RLGF). We will justify, document, and incorporate judgements into the reporting of results for each outcome.

We plan to extract study data, format our comparisons in data tables and prepare a 'Summary of findings' table before writing the results and conclusions of our review. A template 'Summary of findings' table is included as Table 2.

Subgroup analysis and investigation of heterogeneity

We plan to carry out these subgroup analyses when there are six or more studies included in a single analysis, all with sufficient information to determine the subgroups.

• Participant characteristics:

• • age: e.g. adults (18 years to 74 years) and elderly (75 years and over);

  • co‐morbidities: e.g. diabetes, tobacco addiction;

  • artery occlusion site: e.g. common or internal carotid artery; anterior, medial or posterior cerebral artery; vertebrobasilar system and hemisphere side;

  • ASPECTS score (until 6 versus more than 6) (Barber 2000).

• Intervention characteristics:

• • types of drugs: e.g. analgesic, anti‐muscarinic, anxiolytic, barbiturates, benzodiazepines, dissociative, hypnotic, inhaled anaesthetics, opioids, muscle relaxants, vasoactive;

  • doses of drugs;

  • time from stroke onset until the start of the revascularisation (in minutes);

  • anaesthesia duration (in minutes);

  • blood pressure during intervention.

We will use the following outcomes, i.e. primary outcomes, in subgroup analyses.

• Functional outcome at the end of the scheduled follow‐up.

• Neurologic impairment.

We will use the formal test for subgroup differences in Review Manager 5 (RevMan 2014), and base our interpretation on this.

Sensitivity analysis

We plan to carry out the following sensitivity analyses, to test whether key methodological factors or decisions have affected the main result. These analyses will be grouped according to study design (individual, or cluster).

• Only studies with a low risk of bias will be included. We will consider a study to have a low risk of bias overall if there is no high‐risk judgement in any of the four main domains, i.e. random sequence generation, allocation concealment, incomplete outcome data, and selective reporting.

• We will examine both the fixed‐effect model and the random‐effects model meta‐analyses, and will explore the differences between the two estimates.

• If we identify studies with missing data that are unobtainable, we will repeat analyses excluding these studies to determine their impact on the primary analyses.

We will use the following outcomes (i.e. the primary outcomes) in the sensitivity analyses.

• Functional outcome at the end of the scheduled follow‐up.

• Neurological impairment.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline the remaining uncertainties in the area.