Types of studies

We will include published, unpublished, and ongoing randomised controlled trials (RCTs).

Types of participants

Hospital inpatients diagnosed with aneurysmal SAH of any grade (Hunt‐Hess Scale, WFNS Grade, Fisher Scale) or location. Adults of both sexes will be eligible for inclusion. Patients may or may not have received surgical intervention. Diagnosis of SAH and the presence of a cerebral aneurysm will be made via imaging (cerebral angiogram, computed tomography (CT), CT‐angiogram, magnetic resonance (MR) angiogram). Patients with concomitant intraventricular haemorrhage will be eligible, provided that the intraventricular haemorrhage was secondary to an SAH, caused by rupture of a cerebral aneurysm. We will exclude SAH secondary to all other pathologies (e.g. trauma).

Types of interventions

We will include trials comparing subarachnoid thrombolysis with placebo, sham thrombolysis, or standard treatment. We will include studies utilising any route of administration into any anatomical site continuous with the subarachnoid space (various routes of thrombolysis have been utilised to date, including via craniotomy, EVD, and lumbar drains). Studies will be eligible for inclusion provided that the interval between symptom onset and initiation of treatment is not greater than 96 hours.

Types of outcome measures

Electronic searches

We will search the Cochrane Stroke Group Specialised Register and the following electronic databases:

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

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

• Embase Ovid (from 1974).

We will modify the subject strategies for databases modelled 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 RCTs and controlled clinical trials, as described in Section 4.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). 

Searching other resources

In an effort to identify further published, unpublished, and ongoing trials, we will additionally:

• search the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch);

• check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials;

• use Google Scholar to forward track references from included studies (scholar.google.co.uk/);

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

Selection of studies

Two of three review authors (MA, TH, and NS) will independently screen article titles and abstracts of the references identified as a result of the search, excluding obviously irrelevant reports. We will retrieve the full‐text articles for the remaining references, and two of three review authors (MA, TH, and NS) will independently screen the full‐text articles and identify studies for inclusion and record reasons for exclusion of the ineligible studies. Any disagreements will be resolved through discussion or by consulting an additional review author (EB) if required. 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.

Data extraction and management

Two review authors (EB and RB) will independently extract data from the included studies. Two review authors (EB and RB) will input these data into data extraction tables.

We will extract the following data points: study country, number of centres, number of participants in the intervention and control groups, mean and standard deviation of age of participants, male participant percentage, proportion of participants with a Fisher Scale score of > 2, proportion of participants with aneurysm occlusion (and the method of aneurysm occlusion), proportion of participants with hydrocephalus at baseline, proportion of participants with haematocephalus at baseline, proportion of participants who received EVD, the protocol for placebo or control treatment, intervention drug, intervention drug dose, intervention drug route of administration, intervention drug duration, and intervention drug time of onset. We will also extract the proportion of participants receiving the following drugs: nimodipine, antifibrinolytics, antiplatelets, heparin or heparinoids, statins, and preventative antibiotics. We will extract the specific indications, and inclusion/exclusion criteria for treatment.

Assessment of risk of bias in included studies

Two review authors (EB and TH) will independently assess risk of bias for each study using the criteria outlined in Section 8.2.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). Any disagreements will be resolved through discussion or by involving another review author (RB). We will assess risk of bias according to the following domains:

• bias arising from the randomisation process;

• bias due to deviations from intended interventions;

• bias due to missing outcome data;

• bias in measurement of the outcome;

• bias in selection of the reported result.

We will grade the risk of bias for each domain as low risk of bias, some concerns, or high risk of bias, and provide information from the study report together with a justification for our judgement in the 'Risk of bias' tables.

Measures of treatment effect

For poor functional outcome, we will dichotomise the modified Rankin Scale (mRS) into good functional outcome (mRS 0 to 3) and poor functional outcome (mRS 4 to 6). For other neurological outcome scales, we will recode these data into mRS values for analysis. We will report case fatality, haemorrhagic complications, cerebral artery vasospasm, delayed cerebral ischaemia, cerebral infarction, and hydrocephalus as dichotomous outcomes. We will report 95% confidence intervals (CIs) and a risk ratio (RR) for all outcomes. We will analyse all primary and secondary outcomes on an intention‐to‐treat basis.

Unit of analysis issues

The unit of analysis will be participants diagnosed with aneurysmal SAH. In order to prevent unit of analysis issues arising from multiple outcome time points, we will only use the last time point reported in each trial. Additionally, where a trial compares more than two groups, we will only include the paired analysis most appropriate to our review. We will resolve any unit of analysis issues that arise according to the standards set out in Section 6.2.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019).

Dealing with missing data

Where data or outcomes are missing from included studies, we will attempt to calculate or impute data points using the methods described in Section 10.12.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). Where replacement values are entered, we will perform sensitivity analyses to determine the effects of replacing missing data. We will additionally attempt to contact study authors to obtain any missing data.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity amongst the trials in each analysis. We will use a threshold of > 60% to indicate substantial heterogeneity.

Assessment of reporting biases

If we identify 10 or more studies, we will use a funnel plot analysis to assess reporting bias.

Data synthesis

Where we consider studies to be sufficiently similar, we will conduct a meta‐analysis by pooling the appropriate data with RevMan Web using a fixed‐effect model (RevMan Web 2019). If heterogeneity is > 60%, we will use a random‐effects model.

Subgroup analysis and investigation of heterogeneity

We will consider subgroup analysis by severity of haemorrhage, route of thrombolysis delivery, thrombolytic agent, thrombolytic dose, duration of thrombolytics administration, timing of thrombolytic drug onset, method of aneurysm occlusion, concomitant use of drugs (nimodipine, antifibrinolytics, antiplatelets, heparin or heparinoids, statins, and antibiotics). We will also attempt subanalysis by indication for initiation of treatment.

Sensitivity analysis

We will perform sensitivity analysis excluding studies with a high risk of bias.

Summary of findings and assessment of the certainty of the evidence

We will create a 'Summary of findings' table using the following outcomes: functional outcome, case fatality, haemorrhagic complications, cerebral artery vasospasm, delayed cerebral ischaemia, cerebral infarction, and hydrocephalus (Table 1). Where appropriate, we will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We will use the methods and recommendations described in Section 14.1 of the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE Handbook (Higgins 2019; Schünemann 2013), employing GRADEpro GDT software (GRADEpro GDT 2015). We will justify all decisions to downgrade the quality of studies using footnotes, and will make comments to aid the reader's understanding of the review where necessary.