# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=en - IsLinearized=false - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Creator=LaTeX with hyperref package - Subject= DOI: 10.1093/esj/aakag043, European Stroke Journal, 11, 5, 7 5 2026. Abstract: Aneurysmal subarachnoid haemorrhage (aSAH) results from the rupture of an intracranial aneurysm. The case-fatality after aSAH is approximately 40% and those who survive often have functional, cognitive or emotional sequelae. We prepared guidelines according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology, using data from meta-analyses, randomised trials, prospective observational and case–control studies, prospective registries with external validation and single-arm cohort studies with > 50 patients with aSAH. Based on high levels of evidence, we recommend oral administration of nimodipine and regular coiling over clipping if both aneurysm treatment options are equally suitable in patients who are in good clinical condition, and recommend against the routine use of antifibrinolytic drugs prior to aneurysm treatment and against the use of tirilazad, statins, magnesium sulphate or endothelin receptor antagonists. Because of lower levels of evidence, no evidence-based recommendations can be made for the prophylactic use of antiplatelet drugs or external lumbar drainage, hypertension induction, treatment of the ruptured aneurysm with endovascular devices other than coils or endovascular treatment of vasospasm. We formulated 37 expert-consensus statements, which include, among others, the suggestions to treat aSAH patients in a dedicated neuro-ICU or high care unit in a centre that treats at least 70 patients with aSAH per year or at least 35 patients with aSAH per year in geographically remote areas, and to treat the ruptured aneurysm within 24 h after ictus provided that the most dedicated team of experts is available. These guidelines present up-to-date recommendations and expert-consensus statements on key aspects in the management of aSAH patients. - Producer=Acrobat Distiller 23.0 (Windows) - CreationDate=D:20260507200146+05'30' - ModDate=D:20260507201020+05'30' - Custom.PDFVersion=1.5 - Title=European Stroke Organisation (ESO), European Association of Neurosurgical Societies (EANS) and European Society for Minimally Invasive Neurological Therapy (ESMINT) guideline on aneurysmal subarachnoid haemorrhage - dc:format=application/pdf - dc:title=European Stroke Organisation (ESO), European Association of Neurosurgical Societies (EANS) and European Society for Minimally Invasive Neurological Therapy (ESMINT) guideline on aneurysmal subarachnoid haemorrhage - dc:creator=Ramos-Pachon Anna Writing - original draftWriting - review & editing,Terecoasa Elena-Oana Writing - original draftWriting - review & editing,Willett Nicola Writing - original draftWriting - review & editing,Cuadrado-Godia Elisa ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Gaberel Thomas ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Gizewski Elke Ruth ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Helbok Raimund ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Ho Leonard Formal analysis,Hugelshofer Michael ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Korja Miikka ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Meling Torstein R. ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Psychogios Marios-Nikos ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Rinkel Gabriel J. E. ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Taschner Christian A. ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Vajkoczy Peter ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing,Etminan Nima ConceptualizationData curationInvestigationMethodologyWriting - original draftWriting - review & editing - dc:description=DOI: 10.1093/esj/aakag043, European Stroke Journal, 11, 5, 7 5 2026. Abstract: Aneurysmal subarachnoid haemorrhage (aSAH) results from the rupture of an intracranial aneurysm. The case-fatality after aSAH is approximately 40% and those who survive often have functional, cognitive or emotional sequelae. We prepared guidelines according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology, using data from meta-analyses, randomised trials, prospective observational and case–control studies, prospective registries with external validation and single-arm cohort studies with > 50 patients with aSAH. Based on high levels of evidence, we recommend oral administration of nimodipine and regular coiling over clipping if both aneurysm treatment options are equally suitable in patients who are in good clinical condition, and recommend against the routine use of antifibrinolytic drugs prior to aneurysm treatment and against the use of tirilazad, statins, magnesium sulphate or endothelin receptor antagonists. Because of lower levels of evidence, no evidence-based recommendations can be made for the prophylactic use of antiplatelet drugs or external lumbar drainage, hypertension induction, treatment of the ruptured aneurysm with endovascular devices other than coils or endovascular treatment of vasospasm. We formulated 37 expert-consensus statements, which include, among others, the suggestions to treat aSAH patients in a dedicated neuro-ICU or high care unit in a centre that treats at least 70 patients with aSAH per year or at least 35 patients with aSAH per year in geographically remote areas, and to treat the ruptured aneurysm within 24 h after ictus provided that the most dedicated team of experts is available. These guidelines present up-to-date recommendations and expert-consensus statements on key aspects in the management of aSAH patients. - dc:subject=assessment,clipping,coiling,delayed cerebral ischaemia,endovascular repair,grading of recommendations,guideline,hydrocephalus,management,medical management,rebleeding,subarachnoid haemorrhage,systematic review - dc:rights=© The Author(s) 2026. Published by Oxford University Press on behalf of the European Stroke Organisation. - xmprights:marked=True - xmp:createdate=2026-05-07T20:01:46+05:30 - xmp:creatortool=LaTeX with hyperref package - xmp:modifydate=2026-05-07T20:10:20+05:30 - xmp:metadatadate=2026-05-07T20:10:20+05:30 - pdf:producer=Acrobat Distiller 23.0 (Windows) - pdfx:pdfversion=1.5 - xmpmm:documentid=uuid:13dfd6f9-4f07-4f42-9e6e-4cbc4cda8526 - xmpmm:instanceid=uuid:d477e187-2a1e-45bc-9a80-559ccec2f148 ## Contents ### Page 1 # European Stroke Organisation (ESO), EuropeanAssociation of Neurosurgical Societies (EANS) andEuropean Society for Minimally Invasive NeurologicalTherapy (ESMINT) guideline on aneurysmal subarachnoid haemorrhage Mervyn D. I. Vergouwen, ![ORCID Logo]() , Anna Ramos-Pachon ![ORCID Logo]() , Elena-Oana Terecoasa, ![ORCID Logo]() , Nicola Willett ![ORCID Logo]() , Elisa Cuadrado-Godia ![ORCID Logo]() , Thomas Gaberel, ![ORCID Logo]() , Elke Ruth Gizewski ![ORCID Logo]() , Raimund Helbok, ![ORCID Logo]() , Leonard Ho ![ORCID Logo]() , Michael Hugelshofer ![ORCID Logo]() , Miikka Korja ![ORCID Logo]() , Torstein R. Meling ![ORCID Logo]() , Marios-Nikos Psychogios ![ORCID Logo]() , Gabriel J. E. Rinkel, ![ORCID Logo]() , Christian A. Taschner ![ORCID Logo]() , Peter Vajkoczy ![ORCID Logo]() , Nima Etminan ![ORCID Logo]() Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain Department of Neurology, University Emergency Hospital Bucharest, Bucharest, Romania Carol Davila University of Medicine and Pharmacy, Bucharest, Romania Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany Department of Neurology, Hospital del Mar, Universitat Pompeu Fabra, Barcelona, Spain Department of Neurosurgery, University Hospital of Caen, Caen, France PhIND – Physiopathology and Imaging of Neurological Disorders, Inserm U1237, Institut Blood and Brain at Caen-Normandie, Cyceron, UNICAEN, Normandie University, Caen, France Department of Radiology, Medical University Innsbruck, Innsbruck, Austria Department of Neurology, Kepler University Hospital, Johannes Kepler University Linz, Linz, Austria Clinical Research Institute for Neurosciences, Kepler University Hospital and Johannes K epler University Linz, Linz, Austria European Stroke Organisation, Basel, Switzerland Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland Department of Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland Department of Neurosurgery, The National Hospital, Rigshospitalet, Copenhagen, Denmark Diagnostic and Interventional Neuroradiology, Clinic of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland Department of Neuroradiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Department of Neurosurgery, Charite Universitätsmedizin Berlin, Berlin, Germany Corresponding author: Mervyn D.I. Vergouwen, Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands () Abstract Aneurysmal subarachnoid haemorrhage (aSAH) results from the rupture of an intracranial aneurysm. The case-fatality afteraSAH is approximately 40% and those who survive often have functional, cognitive or emotional sequelae. We preparedguidelines according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology,using data from meta-analyses, randomised trials, prospective observational and case–control studies, prospective registrieswith external validation and single-arm cohort studies with > 50 patients with aSAH. Based on high levels of evidence, werecommend oral administration of nimodipine and regular coiling over clipping if both aneurysm treatment options areequally suitable in patients who are in good clinical condition, and recommend against the routine use of antifibrinolytic drugsprior to aneurysm treatment and against the use of tirilazad, statins, magnesium sulphate or endothelin receptor antagonists.Because of lower levels of evidence, no evidence-based recommendations can be made for the prophylactic use of antiplateletdrugs or external lumbar drainage, hypertension induction, treatment of the ruptured aneurysm with endovascular devices other than coils or endovascular treatment of vasospasm. We formulated 37 expert-consensus statements, which include, among others, the suggestions to treat aSAH patients in a dedicated neuro-ICU or high care unit in a centre that treats at least ### Page 2 70 patients with aSAH per year or at least 35 patients with aSAH per year in geographically remote areas, and to treat theruptured aneurysm within 24 h after ictus provided that the most dedicated team of experts is available. These guidelines present up-to-date recommendations and expert-consensus statements on key aspects in the management of aSAH patients. Keywords assessment, clipping, coiling, delayed cerebral ischaemia, endovascular repair, grading of recommendations, guideline, hydrocephalus,management, medical management, rebleeding, subarachnoid haemorrhage, systematic review # Plain language summary Intracranial aneurysms are abnormal outpouchings in the walls of intracranial arteries. They are present in approximately 3%of adults and are more common in women than in men. If an aneurysm ruptures, it causes a bleeding into the space betweenthe brain and its surrounding membranes, known as aneurysmal subarachnoid haemorrhage. This type of stroke often occursat a relatively young age: about half of affected patients are under 50 years old, and roughly two-thirds are women. Outcomesafter aneurysmal subarachnoid haemorrhage are often poor. Approximately 40% of the patients die within 3 months, andamong those who survive long term, outcomes vary widely. Roughly one-third of all patients regain independence in daily activities, while another group survives with some level of disability. Among survivors, cognitive and emotional problems are very common, including memory impairment, reduced concentration, fatigue and depression. Most survivors do not return to their pre-haemorrhage level of functioning. How well someone recovers after aneurysmal subarachnoid haemorrhage depends on how severe the bleeding is and oncomplications that may happen especially in the first 2 weeks after the bleeding. The most feared complications are rebleedingof the ruptured aneurysm (occurring in approximately 40% of the patients if the ruptured aneurysm remains untreated),reduced blood flow to the brain (which can cause symptoms in approximately 20% of patients) and a build-up of fluid in thebrain (in approximately 25% of patients). Hospital care is mainly focused on preventing these complications, finding them early if they occur, and treating them. The ultimate goal is to improve recovery and long-term physical, cognitive and emotional functioning. This guideline provides recommendations based on high-quality studies from the medical literature, and opinions fromexperts if high-quality studies are lacking. The recommendations and expert opinions address when an aneurysm shouldbe treated, which aneurysm treatment methods are best, and which drugs can help lower the risk of complications duringhospital care. It also describes diagnostic methods that help physicians identify the cause of clinical deterioration and outlinesthe management of complications. In addition, it gives guidance on the appropriate hospital and specialist setting, taking into account patient volume and experience and on the timing of follow-up brain scans after aneurysm treatment. Based on a high level of scientific evidence, this guideline recommends that patients with aneurysmal subarachnoid haem- orrhage should not receive antifibrinolytic drugs to reduce the risk of rebleeding, as they do not decrease the risk of pooroutcome. In patients who are awake or only mildly drowsy, with at most mild neurological deficits, coiling without adjunctivedevices is preferred over microsurgical clipping to treat the ruptured aneurysm in situations where both treatment options are equally suitable. All patients should receive oral nimodipine, a drug that reduces the risk of brain damage, but not other drugs such as statins, magnesium sulphate or endothelin receptor antagonists. Based on the opinion from experts, this guideline suggests that lowering blood pressure before the aneurysm is treated mayhelp reduce the risk of rebleeding of the aneurysm in patients with very high blood pressure, but it remains unclear whether ornot it decreases the risk of poor outcome. Blood pressure lowering should be performed slowly and in a controlled manner, ie,without undershoot, and with short-acting medications. The ruptured aneurysm should ideally be treated within 24 h, whenpossible, and by an experienced physician who treats at least 30 intracranial aneurysms (either ruptured or unruptured) peryear. Treatment decisions should always be made by a multidisciplinary team (composed of at least 1 neurosurgeon and 1neurointerventionalist) to consider the different aneurysm treatment options, and decide on the safest method, and the mosteffective and durable treatment outcome. For aneurysms that cannot be treated by regular coiling, ie, without adjunctivedevices, there are no high-quality data showing that more novel endovascular techniques and devices (such as stent-assistedcoiling, flow diverting stents or intra-saccular devices) decrease the risk of poor outcome compared to regular coiling. If apatient worsens due to reduced blood flow in the brain, raising blood pressure may be considered, but only after the aneurysmis secured and fluid administration has failed. Endovascular drug treatments may be used in patients with a critically reducedblood flow to the brain due to severe narrowing of the brain arteries, but treatments that widen the arteries by the use of inflatable balloons should only be considered as a last-line rescue treatment after careful multidisciplinary discussion of the potential risks and uncertain benefits. The current data are insufficient to support the use of temporary stents. Brain scans (CT and CT-perfusion) are useful when a patient’s condition worsens or cannot be assessed clinically. Routine invasive brain monitoring, EEG and complex monitoring systems are not recommended because benefits are unclear. If fluid builds up in the brain (hydrocephalus), drainage is recommended when there is a reduced level of consciousness. The type of drainage ### Page 3 depends on the results of brain imaging and the presence of blood in the ventricles. Long-term fluid drainage devices shouldbe used in patients with chronic hydrocephalus when temporary drainage is no longer safe. Patients should be treated in aspecialised neuro-ICU in centres that treat at least 70 patients with aneurysmal subarachnoid haemorrhage per year, or at least 35 in remote areas. After hospital discharge, follow-up brain scans can be made to investigate whether or not reopening of the aneurysm occursafter treatment. Follow-up imaging is only indicated as long as re-treatment of the aneurysm remains an option, and in the following situations that depend on type of aneurysm treatment:• Patients treated with coils should have follow-up imaging at least once at or after 12 months after aneurysm treatment.• Patients treated with clips usually do not need long-term follow-up imaging if imaging within 6 months after treatment shows that the aneurysm is completely occluded.• Patients with partially occluded aneurysms or those who are treated with newer devices, such as intrasaccular devices or flow-diverting stents, need long-term follow-up.• Patients who are at high risk of developing new aneurysms, such as those with a young age, positive family history foraneurysmal subarachnoid haemorrhage or autosomal dominant polycystic kidney disease, should have scans every 5 years to check for new aneurysms. - • Patients treated with coils should have follow-up imaging at least once at or after 12 months after aneurysm treatment. - • Patients treated with clips usually do not need long-term follow-up imaging if imaging within 6 months after treatment shows that the aneurysm is completely occluded. - • Patients with partially occluded aneurysms or those who are treated with newer devices, such as intrasaccular devices or flow-diverting stents, need long-term follow-up. - • Patients who are at high risk of developing new aneurysms, such as those with a young age, positive family history foraneurysmal subarachnoid haemorrhage or autosomal dominant polycystic kidney disease, should have scans every 5 years to check for new aneurysms. Admit or immediately transfer the patient to a dedicated neuro-ICU or high care unit in a centre that treats at least 70 patients with aSAH per year, or at least 35 patients with aSAH per year in geographically remote areas. . If regular coiling is not feasible, the multidisciplinary team should discuss the safety, effectiveness, and durability of microsurgical and alternative endovascular options to determine the preferred treatment strategy.Key recommendations/suggestions of the GuidelineDo not routinely administrate antifibrinolytic drugs prior to treatment of the ruptured aneurysm Discuss all patients with aSAH in an interdisciplinary manner, with at least one neurosurgeon and one neuro-interventionalist Treat the ruptured aneurysm by regular coiling in patients who are in good clinical condition (WFNS I-III) and who have an aneurysm of either the anterior or posterior circulation that can be treated by either regular coiling (i.e. without adjunctive devices) or microsurgical clipping. Stent-assisted coiling should be reserved for selected cases where other treatment options are not feasible. Flow-diversion should be reserved as a last-line treatment option for ruptured aneurysms. Have the ruptured aneurysm treated by a neurosurgeon or neurointerventionalist who performs the treatment of choice in more than 30 patients with aneurysms (ruptured and unruptured) per year. Treat the ruptured aneurysm within 24 hours after ictus, provided that the most dedicated team of experts is available. Administer oral nimodipine for the prevention of delayed cerebral ischaemia and decrease the risk of poor functional outcome. Perform head CT in combination with CT-perfusion in case of clinical deterioration. Do not perform routine DSA to screen for macrovascular vasospasm Perform radiological follow-up of the treated aneurysm beyond 6 months after aneurysm treatment in patients who have neck remnants or partially occluded aneurysms (irrespective of type of aneurysm treatment) as long as a potential re-treatment remains an option. In case of treatment with endovascular devices other than coils, perform radiological follow-up until at least five years after treatment as long as a potential re-treatment remains an option, regardless of the degree of occlusion, to ensure adequate long-term occlusion. ### Page 4 # Graphical Abstract # Table of Contents Abstract Plain language summary Graphical Abstract Introduction Methods Composition and approval of the Module Working Group Development and approval of clinical questions Literature search Data analysis Evaluation of the quality of evidence and formulation of recommendations Drafting of the document, revision and approval Results Topic 1. Medical (non-)invasive treatment to decrease the risk of rebleeding and poor functional outcome PICO 1a PICO 1b PICO 2 Topic 3. Aneurysm treatment modality PICO 3a PICO 3b PICO 4 Topic 5. Treatment of delayed cerebral ischaemia PICO 5a PICO 5b Topic 6. Neuroimaging and neuromonitoring PICO 6a PICO 6b ### Page 5 PICO 7 PICO 8 Topic 9. Centre volume and number/volume of neurosurgeon and neurointerventionalist PICO 9a PICO 9b PICO 10 Discussion References # Introduction Aneurysmal subarachnoid haemorrhage (aSAH) results from therupture of an intracranial aneurysm. The median age of patients with aSAH is 52 years and most patients are women. Although theglobal incidence of aSAH has declined from 10.2 (95% CI, 8.4–12.5)per 100,000 person-years in 1980 to 6.1 (95% CI, 4.9–7.5) in 2010,the overall disease burden remains substantial, in part becauseof the relatively young age of affected patients. Subarachnoidhaemorrhage resulted in approximately 350,000 deaths and more than 10 million disability-adjusted life years globally in 2021. The most important determinants of poor functional outcomeafter aSAH are the effects of the initial bleeding, rebleeding of theruptured aneurysm, delayed cerebral ischaemia (DCI) and hydro- cephalus. During hospitalisation, the management of patientswith aSAH is focused on the prevention and treatment of compli- cations resulting from aSAH to reduce the risk of death, disabilityand cognitive and emotional consequences. Since the publica- tion of the European Stroke Organisation (ESO) guidelines for themanagement of intracranial aneurysms and subarachnoid haem- orrhage in 2013, new data have been reported regarding the diag- nosis, prevention and treatment of aSAH-related complications and radiological follow-up of treated aneurysms. These include,with varying levels of evidence, the use of antifibrinolytic drugs,novel treatment options for treatment of the ruptured aneurysm, use of lumbar drains and endovascular treatment of vasospasm. The aim of this guideline is to provide contemporary evidence- based recommendations and expert-consensus statementsto guide neurosurgeons, neurologists, neurointensivists and(interventional) radiologists in the clinical management ofpatients with aSAH at the emergency room, during hospital admission and during follow-up, to reduce the risk of case-fatality and long-term disability. # Methods ## Composition and approval of the Module Working Group This guideline was initiated by the ESO. Two chairpersons(M.D.I.V. and N.E.) were selected to assemble and coordinatethe Guideline Module Working Group (MWG). The initial workinggroup consisted of 12 experts, 1 of whom withdrew during theguideline development process because of other obligations (G.C.,see Acknowledgements). Later, 2 delegates were invited to join onbehalf of the European Association of Neurosurgical Societies(EANS; T.R.M.) and the European Society for Minimally InvasiveNeurological Therapy (ESMINT, C.A.T.). Thus, the final groupcontained 13 experts. The ESO Guideline Board and Executive Committee reviewed the intellectual and financial disclosures of all MWG members and approved the composition of the group. The full details of all MWG members and their disclosures are included in the. The MWG was supported by 5 non-votingmembers (A.R.-P., E.-O.T., N.W., L.H., S.T. [see Acknowledgements]). ## Development and approval of clinical questions This guideline was prepared according to the ESO standardoperating procedures (SOP), which are based on the Gradingof Recommendations, Assessment, Development and Evaluations (GRADE) framework. The MWG developed a list of topics and cor- responding questions of greatest clinical interest. Questions wereformatted using the PICO approach (Population, Intervention,Comparator and Outcome). We decided on 10 topics for which weformulated 15 PICO questions, which were reviewed by 2 external reviewers as well as members of the ESO Guideline board and Executive Committee. We considered separate outcomes for the different PICOs dueto the different nature of the underlying research questions. Usingthe Delphi method, the members of the MWG voted in a closed bal- lot to identify which outcomes were of highest priority, accordingto the GRADE methodology using a 9-point scale (7–9: critical; 4–6: important; 1–3: of limited importance). The final recommenda- tions are based on those outcomes that have been rated as critical according to the GRADE approach. Results of the outcome ratings for each PICO question are shown in. ## Literature search For each PICO question, search terms were developed by the MWGand guideline methodologist. Where a validated search strategywas available, this was used or adapted. Where there was a recentrelevant systematic review on the question of interest, the cor- responding search strategy and results were used and updated as necessary. Search strategies are described in. The search was performed by the ESO Guideline methodolo- gist. The following databases were searched: PubMed, Medline,Cochrane from inception to July 2023. An update search was per- formed in May 2025. Reference lists of review articles, the authors’personal reference libraries and previous guidelines were also searched for additional relevant records. Search results were loaded into the web-based Covidence plat- form (Health Innovation, Melbourne, Australia) for assessment bythe MWG. Per PICO question, 2 MWG members formed a “PICOgroup.” The PICO groups consisted of: PICO 1 M.D.I.V., G.C. (see Acknowledgement); PICO 2 M.K., R.H.; PICO 3 P.V., G.J.E.R.; PICO 4 ### Page 6 E.C.-G., N.E.; PICO 5 M.-N.P., P.V.; PICO 6 M.H., E.R.G.; PICO 7 T.G.,M.H.; PICO 8 R.H., T.G.; PICO 9 G.J.E.R., N.E. and PICO 10 E.R.G.,M.-N.P. The MWG members were supported by 3 junior members(A.R.-P., E.-O.T., N.W.) who independently screened (2 per PICO) thetitles and abstracts of publications registered in Covidence andthen assessed the full text of studies to determine the potential relevance. All disagreements were resolved by discussion between the 2 reviewers and the PICO leads. We included studies on acute aneurysmal SAH in humans,in which at least 90% of the evaluated aneurysms had to besaccular. We included studies with the following designs: (1)meta-analyses of studies mentioned under 2–6; (2) RCTs; (3)prospective observational/cohort studies; (4) prospective case–control studies; (5) prospective registry studies with externalvalidation; (6) single-arm cohort studies including > 50 patients.We excluded the following studies: (1) studies that did notreport death, functional outcome or any clinical outcome ofinterest to be assessed according to PICO questions; (2) registrystudies based on hospital codings/health insurance systemswithout external validation; (3) studies reporting on aneurysms associated with arteriovenous malformations or in populations with specific diseases (such as collagen disorders, moyamoya disease or syndrome, dwarfism or autoimmune disorders); (4) studies reporting on ruptured iatrogenic aneurysms or iatrogenic rupture of aneurysms during thrombectomy; (5) studies in which patients with ruptured aneurysms could not be distinguished from those with only unruptured aneurysms. ## Primary outcome For all PICOs, the primary outcome measure was poor functionaloutcome, which was defined as a mRS score of 3–6. In studieswhere a Glasgow Outcome Scale (GOS) score was reported, a GOS 1–3 was used as an equivalent measure. ## SAH grading In the literature on aSAH, different scales are used for describingthe clinical condition on admission, such as the Hunt&Hess scaleand World Federation of Neurosurgical Societies (WFNS) scale.We used the rating scales as described in the cited manuscript. TheHunt&Hess and WFNS scales are explained in. ## Data analysis L.H. performed data extraction and analysis. In cases where rele- vant data were not reported in an eligible study, the correspond- ing author was contacted by the PICO leader. In the case of noresponse, one of the guideline chairs also contacted the corre- sponding author. If no answer was received, data were considered as missing. Where feasible, we conducted fixed-effects meta-analyses,estimating heterogeneity using the REML method, provided nosubstantial heterogeneity was detected. Results are presented aseffect estimates with corresponding 95% CIs. Heterogeneity was assessed using theχ2 test and quantified with the I2 statistic.When I2 exceeded 50%, a random-effects model was applied.We also calculated 95% prediction intervals to account forTable 1 Scales used to describe the clinical condition of an aSAH patienton admission.Hunt&Hess WFNS Glasgow Coma Scale score Motor deficit 1 Asymptomatic or mild headache and slight neck stiffness 15 No2 Moderate–severe headache, neck stiffness, no neurological deficit except cranial nerve palsy 13-14 No3 Drowsiness, confusion, or mild focal neurological deficit 13-14 Yes4 Stupor, moderate–severe hemiparesis, early decerebrate rigidity, autonomic disturbance 7-12 ± Deficit5 Deep coma, decerebrate rigidity, moribund appearance 3-6 ± DeficitAbbreviation: aSAH = aneurysmal subarachnoid haemorrhage; WFNS = WorldFederation of Neurosurgical Societies.between-study variability. Results are displayed using forest plots. All analyses were performed in R using the meta package. ## Evaluation of the quality of evidence andformulation of recommendations The risk of bias of each included randomised trial was assessed with the Cochrane RoB2 tool. As recommended, the evidencesynthesis did not use a quality “score” threshold but classifiedoverall risk of bias at the study level and then in the aggregate. The results of data analysis were imported into the GRADEproGuideline Development Tool (McMaster University, 2015; devel- oped by Evidence Prime, Inc.). For each PICO question and eachoutcome, the following were considered: risk of bias based onthe type of available evidence (randomised or observationalstudies); considerations on inconsistency of results; indirectnessof evidence, imprecision of results and other possible bias. LHgenerated the GRADE evidence profiles/summary of findingstables, which MWG members used to prepare “Evidence-based recommendations,” based on the GRADE approach. The direction, strength and formulation of the recommendations were deter- mined according to the GRADE evidence profiles and the ESO-SOP ()., The phrasing of the recommendations was exten- sively discussed between all MWG members until consensus was reached. Finally, expert consensus-statements were added wheneverthe PICO group considered that there was insufficient evidenceavailable to provide evidence-based recommendations and wherepractical guidance is needed for routine clinical practice. Expertconsensus statements were modified using the Delphi methoduntil consensus was reached regarding the phrasing of thestatement. The expert consensus statements were then sent to all MWG-members for anonymous voting. According to the ESO SOP for guidelines, only those consensus statements that reached amajority of votes are reported in the guideline. Importantly, theseexpert consensus statements should not be regarded as evidence- based recommendations, since they only reflect the opinion of the writing group. ### Page 7 ## Drafting of the document, revision andapproval Each PICO question was addressed in distinct sections, in linewith the updated ESO SOP. First, the “Analysis of current evi- dence” section summarised current pathophysiological consider- ations followed by a summary and discussion of the results ofthe identified RCTs and other studies. Second, “Additional infor- mation” was added when more details on the studies referred toin the first section were needed to provide information on keysubgroup analyses of the included studies, on ongoing or futureRCTs, and on other studies which can provide important clinicalguidance on the topic. Third, an “Expert consensus statement” paragraph was added whenever the MWG considered that insuf- ficient evidence was available to provide evidence-based recom- mendations for situations in which practical guidance is needed for everyday clinical practice. The Guideline document was reviewed by all MWG membersand modified using a Delphi approach until a consensus wasreached. The final submitted document was peer-reviewed by2 external reviewers, 2 members of the ESO Guideline Board and 1 member of the Executive Committee. # Results An overview of the risk of bias assessments of the included trials is shown in. The GRADE evidence profiles thatinformed the evidence-based recommendations are shown in. ## Topic 1. Medical (non-)invasive treatmentto decrease the risk of rebleeding and poor functional outcome ## PICO 1a In adult patients with aneurysmal subarachnoid haemorrhage(aSAH), does treatment with antifibrinolytic drugs compared tono antifibrinolytic drugs decrease the risk of poor functional out- come?Evidence-based Recommendations StrengthIn adult patients with aSAH, we recommend against routine administration of antifibrinolytic drugs prior to treatment of the ruptured aneurysm to decrease the risk of poor functional outcome.⊕⊕⊕ ↓↓Quality of evidence ### Analysis of current evidence We identified 12 RCTs comparing treatment with antifibrinolyticdrugs vs no antifibrinolytic drugs, and 1 recent Cochrane review.– Eleven RCTs– studied the effect of tranexamicacid, and 1 trial the effect of epsilon amino-caproic acid onaneurysm rebleeding or functional outcome. Ten RCTs wereperformed in an era during which aneurysm treatment waspostponed to the post-delayed cerebral ischaemia (DCI) period. Inthose trials, the effect of long-term treatment with antifibrinolytic drugs was studied. The 2 most recent RCTs studied the effect of ### Page 8 Figure 1 Effect (odds ratio) of antifibrinolytic drugs compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.Figure 2 Effect (odds ratio) of antifibrinolytic drugs compared with control on case-fatality in adults with aneurysmal subarachnoid haemorrhage.Figure 3 Effect (odds ratio) of antifibrinolytic drugs compared with control on rebleeding in adults with aneurysmal subarachnoid haemorrhage.short-term treatment. ![For image description, please refer to the figure legend and surrounding text.]() ![For image description, please refer to the figure legend and surrounding text.]() ![For image description, please refer to the figure legend and surrounding text.]() , The largest RCT also included patients with non-aneurysmal SAH. From that trial, we extracted data onpatients with aneurysmal SAH. Pooled analyses of all available RCTs showed that treatmentwith antifibrinolytic drugs does not decrease the risk of poor functional outcome (odds ratio [OR]: 1.03; 95 CI, 0.86–1.23;) or case-fatality (OR: 0.96; 95% CI, 0.81–1.15;),despite a decreased risk of rebleeding (risk ratio [RR]: 0.56; 95% CI, 0.37–0.83;). The discrepancy between a reduced riskof rebleeding and a neutral effect on outcome has been explainedas resulting from a higher risk of ischaemic complications andhydrocephalus in patients treated with antifibrinolytic drugs, or impeded recovery from ischaemic injury. The 2 most recent RCTs were performed in an era thatreflects current clinical practice with early aneurysm treatmentand both microsurgical and endovascular aneurysm treatment options., Only the Ultra-early tranexamic acid after subarach- noid haemorrhage (ULTRA) trial was adequately powered to detecta potential effect on clinical outcome. In ULTRA, tranexamic acidwas started in the initial hospital directly after head CT confirmeda diagnosis of SAH. The median time between ictus and CT diagnosis was 93 min, and the time between ictus and the start of ### Page 9 tranexamic acid was 185 min. Treatment of the ruptured aneurysmoccurred after a median time of 14 h after CT diagnosis. In the955 participants with SAH, tranexamic acid had no statisticallysignificant effect on rebleeding (OR: 0.71; 95% CI, 0.48–1.04) anddid not decrease the odds of poor functional outcome (OR: 1.16; 95% CI, 0.89–1.50) or case-fatality (OR: 1.15; 95% CI, 0.86–1.54) in the whole study population. Similar results were found in the subgroup of 813 patients withaneurysmal SAH. Although a statistically significant reduction inrebleeding was observed (OR: 0.66; 95% CI, 0.44–0.99), no effecton poor functional outcome (OR: 1.08; 95% CI, 0.82–1.43) or case- fatality (OR: 1.11; 95% CI, 0.82–1.51) was found. Short-term treat- ment with tranexamic acid did not increase the risk of DCI (OR: 0.99; 95% CI, 0.72–1.36) or hydrocephalus (OR: 1.23; 95% CI,0.93–1.63). In conclusion, the ULTRA trial provided strong evi- dence that very early and very short-lasting antifibrinolytic ther- apy does not decrease the risk of poor functional outcome in patients with aSAH. ### Additional information After publication of the ULTRA trial, several studies wereperformed to investigate the effect of tranexamic acid in certainsubgroups. Patients with a good clinical condition on admissionand men treated with tranexamic acid had worse functional outcomes compared to those not treated with tranexamic acid.No effect on outcome was observed in patients with a poor clinicalcondition on admission and in women. Although the start oftranexamic acid > 6 h after ictus was associated with a reduced risk of rebleeding, it did not result in better outcomes. ## PICO 1b In adult patients with aSAH, does treatment with antihypertensivedrugs compared to no antihypertensive drugs decrease the risk ofpoor functional outcome? In adult patients with aSAH and systolic blood pressures higher than 160-180 mm Hg persisting after installment of analgesics, oral nimodipine and urinary catheter prior to aneurysm treatment, we suggest considering blood pressure lowering drugs to lower systolic blood pressure to around 160 mm Hg to reduce the risk of rebleeding. Vote: 11/13 If it is decided to give blood pressure lowering drugs, we suggest continuous infusion of short-acting drugs, e.g. labetalol, and avoiding diuretic drugs to maintain normovolemia. Care should be taken to ensure that the blood pressure reduction is gradual, with systolic blood pressure reduced cautiously over time (corresponding to no more than a 10% reduction in mean arterial pressure within the first 2 hours) to decrease the risk of DCI. Vote: 11/13Expert consensus statements: ### Analysis of current evidence We did not identify any RCTs during the last 4 decades investigat- ing the effect of antihypertensive drugs with the primary aim ofdecreasing the risk of rebleeding of the ruptured aneurysm and thereby improving outcome. ### Additional information Several observational studies investigated the relationshipbetween antihypertensive drug treatment and the risk of rebleeding.– One study showed that blood pressure treatmentmay decrease the risk of rebleeding, but not poor outcome,potentially as a result of an increased risk of cerebral infarction.A study without a control group found that the incidence ofrebleeding was low (3.1%) after the implementation of a strategyof intensive systolic blood pressure reduction (target 120 ± 20 mm Hg). Another study found that after the implementation of ablood pressure management protocol (systolic blood pressuretarget of 160 mm Hg), the incidence of in-hospital rebleedingdeclined from 6.7% to 2.8% (OR: 0.4; 95% CI, 0.10–1.63) and the incidence of DCI from 44.2% to 7.7% (OR: 0.10; 95% CI, 0.04–0.23). A recent study compared the incidence of in- hospital rebleeding between a hospital with a policy of aggressiveblood pressure lowering (systolic blood pressure target beforeaneurysm treatment ≤ 140 mm Hg) vs a hospital with a moreliberal blood pressure approach, and found a trend (adjustedHR 0.66 [95% CI, 0.23–1.92]) towards a lower incidence ofrebleeding in the hospital with a more aggressive blood pressure lowering strategy. However, there were differences in risk factors for rebleeding between the 2 centres, which introduced major bias. ## PICO 2 In adult patients with aSAH, does early aneurysm occlusion com- pared to no early aneurysm occlusion decrease the risk of poor functional outcome?Expert consensus statementIn adult patients with aSAH, we suggest treatment of the ruptured aneurysm within 24 hours after ictus. The timing should be optimized to ensure that the most dedicated team of experts is available when needed. Vote: 13/13 ### Analysis of current evidence We identified only one small RCT that assessed the timing of aneurysm treatment. The study was conducted in the pre- coiling era and included 211 good-grade (Hunt and Hess gradesI–III) aSAH patients (aged 16 to 65 years) admitted to a singlehospital between 1985 and 1987. Patients with intracerebralhaematomas, decreased level of consciousness or severeneurological deficits were excluded. All included patients hadanterior circulation aneurysms, and patients were randomlyassigned to early (0–3 days), intermediate (4–7 days) or late (8 days and later) surgical clipping. Sixteen patients never underwent aneurysm surgery due to severe deterioration or death before ### Page 10 the planned surgery. Delayed cerebral ischaemia and rebleedingwere the main causes of preoperative deterioration. None of thepatients received antifibrinolytic agents or hypertensive drugtreatment, while intramuscular betamethasone 4 mg 4 timesdaily was routinely given. Of the 211 patients, 159 randomlyreceived either intravenous followed by oral nimodipine orplacebo treatment up to 21 days. The 3-month case-fatality rateswere not different between early, intermediate and late surgerygroups (case-fatality rates of 6%, 6% and 13%, respectively).Using a 3-point outcome scale (independent, dependent, death),92% of the early surgery group patients were independent at 3months, 79% in the intermediate group and 80% in the late surgerygroup. However, dependency was significantly higher in theintermediate surgery group (11 patients, 16%) in comparison tothe early surgery group (2 patients, 3%). In summary, early surgery within 3 days after bleeding in comparison to delayed surgery did not lead to higher case-fatality. A comparison between early and intermediate surgery groups (late surgery group excluded) suggested that 3-month functional outcome was better for patients operated early. During the endovascular treatment era (since the early 1990s),no randomised trial has addressed the effect of timing of aneurysm occlusion on outcome of SAH patients. ### Additional information Due to the paucity of high-quality studies, recent (publishedwithin the last 10 years) meta-analyses were reviewed as support- ing information. These meta-analyses generally include lowerquality studies, which have inherent selection and treatmentbiases. In a meta-analysis including 16 observational studiesof endovascular aneurysm occlusion, treatment within 24 hreduced the odds for poor outcome in comparison to patients treated at > 1 day, but not when compared to 24–72 h. Anothermeta-analysis of surgical patients included the only published randomised trial, 1 prospective and 12 retrospective studies for quantitative analyses. Early surgery, defined as surgery within 3 days, was associated with better outcomes irrespective ofthe clinical condition on admission and a higher survival rate.Similarly, in a third meta-analysis published in 2017, aneurysmtreatment within 48 h was compared to treatment between 48 h and 7 days, and to delayed (>7 days) treatment of poor-grade SAH patients. The meta-analysis included all published studies(even small case series) between 1990 and 2014 that reported onsurgical or endovascular treatment for poor-grade SAH patients.A total of 26 studies with 1255 patients assessed outcomes by treatment timing. Based on these highly miscellaneous data,the authors concluded that poor-grade SAH patients treatedwithin 48 h had the highest rates of good neurological outcome(61% compared to 40% for treatment between 48 h and 7 days, and 37% for delayed treatment). In another meta-analysisincluding also only poor-grade SAH patients (14 articles, 1111patients), aneurysm treatment within < 24 h from symptom onset,clipping or coiling, was not associated with a decreased risk ofpoor functional outcome when compared to delayed (>24 h) treatment. The results between studies were inconsistent anddepended on statistical methods used. It is estimated that treatment < 1 day results in, at most, a 0.3%reduction in the incidence of rebleeding as the rebleeding inci- dence depends strongly on the admission delay; most rebleedsoccur before hospital admission or at the emergency room. Interms of poor outcome, it has been estimated that emergencyaneurysm occlusion (within 4 h from admission, not from ictus) can reduce poor outcome due to rebleeding only in 0.4% (95% CI, 0.2–1.1) of patients. In other words, 250 SAH patients wouldhave to be treated within 4 h from admission to prevent one poor outcome due to rebleeding. ## Topic 3. Aneurysm treatment modality ## PICO 3a In adult patients with aSAH, does any type of endovascularaneurysm occlusion compared to neurosurgical aneurysmocclusion decrease the risk of poor functional outcome?Evidence-based Recommendations Quality of evidence StrengthIn adult patients with aSAH in good clinical condition (WFNS I-III) with aneurysms of either the anterior or posterior circulation that can be treated by either regular coiling (i.e. without adjunctive devices) or neurosurgical clipping, we recommend regular coiling as the preferred strategy to decrease the risk of a poor functional outcome.⊕⊕⊕⊕ ↑↑Expert consensus statements1. We suggest that all patients with aSAH are discussed in an interdisciplinary manner, with at least one neurosurgeon and one neuro-interventionalist. Vote: 13/13 2. In adult patients with aSAH, we suggest that the team discuss which modality would result in the best clinical outcome of the specific patient, with the safest and optimal occlusion of the specific aneurysm. Vote: 13/13 3. In adult patients with aSAH younger than 45 years of age, we suggest that the better long-term protection from clipping compared to coiling is taken into consideration for choosing the treatment modality of the aneurysm. Vote: 12/13 4. In adult patients with aSAH admitted in a poor clinical condition (defined as GCS < 13), we suggest a multidisciplinary approach to decide on type and timing of aneurysm treatment taking into account the (presumed) cause of the poor clinical condition. Vote: 13/13 5. In adult patients with aSAH and a poor or worsening clinical condition from a space-occupying intracerebral or subdural haematoma, we suggest immediate surgery for aneurysm clipping and haematoma removal. Vote: 11/13 ### Analysis of current evidence A Cochrane systematic review included 4 randomised clinical tri- als involving 2458 participants that compared neurosurgical clip- ping vs endovascular coiling. The evidence in this Cochranereview comes mainly from the largest of these 4 trials (Interna- tional Subarachnoid Haemorrhage Trial [ISAT]: 2143 participants).Most patients were in good clinical condition (WFNS I–III) and had an aneurysm on the anterior circulation. At 1 year after SAH, ### Page 11 Figure 4 Effect (odds ratio) of endovascular coiling compared with neurosurgical clipping on 12-month poor functional outcome with aneurysmalsubarachnoid haemorrhage.Figure 5 Effect (odds ratio) of endovascular coiling compared with neurosurgical clipping on 12-month poor functional outcome with aneurysmalsubarachnoid haemorrhage (worst-case scenario).the OR of poor outcome (death or dependency) for endovascu- lar coiling vs neurosurgical clipping was 0.69 (95% CI, 0.58–0.83; ![For image description, please refer to the figure legend and surrounding text.]() ![For image description, please refer to the figure legend and surrounding text.]() ), with an absolute risk reduction of poor outcome of 7%(95% CI, 4%–11%). The better outcome after coiling was substan- tiated in the worst-case-scenario analysis in which all patients lostto follow-up after coiling were given a poor outcome and thoselost to follow-up after clipping a good outcome. In this worst- case scenario, the OR for poor outcome for endovascular coiling vs neurosurgical clipping was 0.74 (95% CI, 0.62–0.88;),and the absolute risk reduction was 6% (95% CI, 2%–10%). Inthe subgroup of patients with a posterior circulation aneurysm (2trials, 69 participants), the OR for poor outcome was 0.27 (95% CI, 0.09–0.82;) and the absolute decrease in risk of pooroutcome was 27% (95% CI, 6%–48%). The data from this review therefore show that coiling is associ- ated with better clinical outcomes for patients in good clinical con- dition with ruptured aneurysms of either the anterior or posteriorcirculation that are suitable for both neurosurgical clipping andendovascular coiling. This review provides evidence of the benefitof regular endovascular coiling only, because no randomised trialswere included on balloon- or stent-assisted coiling or for other endovascular procedures, such as intrasaccular devices or flow- diverting stents. Patients with middle cerebral artery (MCA) aneurysms wereunderrepresented in this review, and for patients with aSAH inpoor clinical condition, the review found no reliable randomisedevidence comparing the potential harms and benefits of endovas- cular coiling vs neurosurgical clipping. It must also be noted thatmost patients admitted to the participating hospitals at time ofenrolment of the randomised trial have been treated outside thetrial. The results from these trials can therefore, as for any other trial, only be extrapolated to patients fulfilling the inclusion and exclusion criteria of these trials. The overarching inclusion crite- rion in all these trials was equipoise for both treatment options. Long-term follow-up was available for ISAT, but not for the othertrials included in the review. At 10 years, the OR of poor outcomefor endovascular coiling vs neurosurgical clipping was 0.70 (95% CI, 0.56–0.88;). ### Additional information One other controlled trial has been performed to compare neu- rosurgical clipping and endovascular treatment: the Barrow Rup- tured Aneurysm Trial (BRAT). The BRAT was a single-centre clinical trial excluded from theCochrane review due to major methodological limitations. It wasnot truly randomised (patients were allocated alternately), theprotocol was unpublished and the trial was unregistered. Patientswithout aneurysms or with aneurysms unsuitable for 1 treatmentwere included, and 30% did not receive their assigned treatment,causing group imbalance. Missing outcomes (10%–15%) were excluded at 1 year, no intention-to-treat analyses were done after 3 years and subgroup analyses were not prespecified, leading to a very high risk of bias. At 1 year, patients assigned to coiling had better outcomes thanthose assigned to clipping. However, at 3, 6 and 10 years no out- come differences were found. At 10 years, complete obliterationoccurred in 93% of clipped vs 22% of coiled aneurysms, with rebleeding in 2/83 coiled patients and none of the 175 clipped patients. ### Page 12 For patients in good or moderate clinical condition (WFNS I–III)with aneurysms of either the anterior or posterior circulation thatcan be treated by either regular coiling or neurosurgical clipping,we have good evidence that coiling is associated with better clin- ical outcomes. The results of the trials cannot be generalised tothe whole population of patients with ruptured aneurysms andto all endovascular and microsurgical techniques available today.For patients in a poor clinical condition and for those with ananeurysm that cannot be treated by regular coiling, there is noreliable randomised evidence comparing the potential harms and benefits of endovascular coiling vs neurosurgical clipping. In the following, we list patient populations where decisions have to be made on less robust data, based on an individual, interdisciplinary decision-making process. We here provide the data underlying our expert consensus statement. Patients in poor condition Patients with space-occupying haematomas were not includedinto the listed trials. This is still a patient population where thepriority for microsurgical evacuation of the haematoma is thedriver for the decision to rapidly operate these patients and clip the aneurysm in the same setting. Age Patients of lower age might be considered differently. Althoughthe trials included in the Cochrane review did not specify sub- groups according to age, it has been argued that the advantage ofcoil embolisation over clip ligation cannot be assumed for patients< 40 years old. In this age range the difference in the safety ofthe 2 procedures is small, and the better long-term protectionfrom aSAH afforded by clip placement may give this treatment an advantage in life expectancy for patients < 45 years of age. Complex aneurysm morphology Patients harbouring aneurysms of complex anatomy are under- represented in the trials. The role of the aneurysm anatomy as adriver of decision making thus remains unclear. The current evi- dence fails to show superiority for any treatment modality in thecase of aneurysms > 10 mm, broad necked aneurysms (usuallydefined as neck width ≥ 4 mm or dome-to-neck ratio < 2), branch- ing vessels arising from the aneurysm neck, fusiform aneurysms, blister aneurysms, etc. Similarly, the complexity of the aneurysm anatomy does not support the preferential use of endovascular implants other than coils over microsurgical clipping. Finally, the results obtained in the trials are limited tointerdisciplinary neurovascular centres where treating physicianshave sufficient experience in the treatment of these patients during the whole complex course following subarachnoid haemorrhage. ## PICO 3b In adult patients with aSAH, does any type of endovascularaneurysm treatment other than coiling compared to coiling ofthe ruptured aneurysm decrease the risk of poor functional outcome? ### Analysis of current evidence The trials included in the Cochrane review and BRATcompared endovascular coiling vs neurosurgical clipping. SinceExpert consensus statements1. Given the limited comparative evidence available, we suggest that in adult patients with subarachnoid haemorrhage from a ruptured aneurysm which cannot be treated with regular coiling, the multidisciplinary team discusses the safety, effectiveness, and durability of microsurgical and alternative endovascular options to determine the preferred treatment strategy. Vote: 12/13 2. In adult patients with aSAH, we suggest stent-assisted coiling in selected cases where other treatment options are not feasible. Vote: 13/13 3. In adult patients with aSAH, we suggest to reserve flow diversion as a last-line treatment option. Vote: 12/13the implementation of coils, advanced endovascular devices, suchas balloon-assisted coiling, stent-assisted coiling, flow divertingstents and intrasaccular devices, have been introduced with theaim to treat ruptured aneurysms not suited for regular coiling,eg, wide-neck aneurysms. These newer devices have enabledthe endovascular repair of more complex aneurysms, but thesedevices also differ with respect to immediate and long-termocclusion rates as well as risks of complications, compared to coiling or microsurgical clipping. So far, only one trial has been initiated to test the superiority of endovascular management of patients with ruptured aneurysms, in which all endovascular means were included: The ISAT-2. International Subarachnoid Haemorrhage Trial-2 was arandomised trial comparing any endovascular vs microsurgicaltreatment of ruptured intracranial aneurysms, focusing onthose excluded from previous trials. The trial was stopped after10 years because of slow recruitment when 270 of the 1896planned patients had been enrolled. In total, 133 patients wererandomised to microsurgical aneurysm treatment and 130 toendovascular treatment. Seven patients were excluded. Thistrial differed from the previous trials in the type of endovasculartreatment, which was most often balloon-assisted coiling (83%).The other patients were treated with stents or flow-diverters.Moreover, 40% of the ruptured aneurysms were on the MCA,an anatomical location that was underrepresented in theprevious Cochrane review. In the intention-to-treat analysis, poor outcome had occurred in 35 (27%) of 130 endovascular patients and in 40 (30%) of 133 surgical patients (RR: 0.90; 95% CI, 0.61–1.31). Residual aneurysms at 1 year were less frequent with microsurgery (10/118 [8%, 95% CI, 5%–15%]) than EVT (22/109 [20%, 95% CI, 14%–29%]). Because the trial was terminated prematurely, it lacked statistical power to rule in or out statistically significant results. Thus, for endovascular ### Page 13 procedures other than coiling, there is no reliable evidence fromrandomised trials comparing these treatments vs neurosurgical clipping. ### Additional information Stent-assisted coiling Evidence supporting stent-assisted coiling for ruptured intracra- nial aneurysms remains limited and heterogeneous. A system- atic review on 17 retrospective case series published before 2010 totalling 339 patients highlighted substantial variability acrosspublished case series. The pooled results suggested higher rates ofcomplications than with regular coiling, with clinically significantintracranial haemorrhagic complications in 8% and clinically sig- nificant thromboembolic events in 6% of patients. In a subsequent systematic review and meta-analysis on 8 retrospective cohortstudies with 1408 ruptured intracranial aneurysms treated before2016, ischaemic complications occurred more often in the stent- assisted group (16.6% vs 11.0%; RR: 1.75; 95% CI, 1.3–2.36), as didhaemorrhagic complications (10.3% vs 5.7%; RR: 1.6; 95% CI, 1.09–2.35), compared to regular coiling. More recent prospective multi- centre registry data provide additional insight into contemporarypractice. A Chinese prospective registry study reporting on 278 patients with aneurysmal SAH from wide-neck aneurysms treated with stent-assisted coiling between 2020 and 2023 found clini- cally relevant thromboembolic complications in 11.5% of patientsand clinically relevant haemorrhagic complications in 4.7%. In conclusion, there is no good controlled evidence on stent- assisted coiling compared to regular coiling, and the observationalstudies suggest a high risk of complications. Balloon-assisted coiling In contrast to stent-assisted coiling, balloon remodelling doesnot involve permanent intravascular implants and does notrequire antiplatelet therapy. A meta-analysis on studies published between 1997 and 2006 reported no statistically significantdifferences in procedural complications between balloon-assistedand regular-unassisted coiling. However, the meta-analysis wascriticised for its methodology and the exclusion of articles reporting higher complication rates.– A French prospective,multicentre observational study on 768 patients treated fromNovember 2006 to September 2008 (CLARITY) reported asignificantly higher rate of adequate angiographic occlusionwith balloon-assisted coiling (94.9%), compared with regularcoiling (88.7%) (P = .017), while overall rate of treatment-relatedcomplications, with or without clinical manifestations, was similarin both treatment groups (17.4% with coil embolisation and 16.9%with remodelling). Thus, good comparative and recent data onballoon-assisted coiling vs regular coiling are lacking. The few available data suggest that balloon remodelling has a safety profile comparable to regular coiling. Flow diversion Flowdiverting stents were designed for treatment of complexaneurysms, such as wide-necked sidewall aneurysms or bloodblister–like aneurysms. However, they are increasingly usedfor other indications, eg, bifurcation aneurysms. The use offlowdiverting stents in patients with aSAH remains controversial,because they require stent deployment in the acute phase, oftenwithout adequate antiplatelet preparation, which increases therisk of thromboembolic complications. In addition, mandatorydual antiplatelet therapy increases the risk of haemorrhagiccomplications during necessary neurosurgical interventions(eg, external ventricular drain [EVD] placement). Because flowdiversion does not immediately exclude the aneurysm fromthe circulation, there is a persistent risk of early rebleeding in the acute period. A meta-analysis including 20 studies (17 retrospective) published before 2018 evaluating 223 patients with acutely ruptured intracranial aneurysms treated with flow- diverter stents found that the risk of rebleeding after treatment was 4%, all occurring within 72 h after treatment. The overallrisk of treatment complications was 17.8%, with the majority being ischaemic complications. No studies are available in which the use of flowdiverting stentsare compared to regular coiling (without additional stent) or tosurgical clipping in patients with ruptured aneurysms. Observa- tional studies suggest that the use of flow diversion in recently ruptured aneurysms is associated with a high risk of ischaemic and haemorrhagic complications. Intrasaccular devices Although intrasaccular devices (also known as endosaccular flowdisruptors) were specifically designed for treatment of wide-necksaccular aneurysms, there use has expanded to other indications. A meta-analysis of 16 studies published before 2024 comparedthe Woven EndoBridge (WEB) with either stent-assisted coiling orregular coiling, and included both studies with unruptured andruptured intracranial aneurysms. The total risk of complicationswas approximately 6.5% in patients treated with WEB, comparedwith 14% in patients treated with stent-assisted coiling and 12%in regular coiling. The rates of adequate and complete occlusionduring follow-up were similar in the 3 treatment groups, althoughpatients treated with WEB had a shorter follow-up duration. The CLARYS study was a prospective multicentre study conducted in 13 European centres that enrolled 60 patients with a ruptured aneurysm in the anterior or posterior circulation. Twenty-threeperiprocedural complications occurred in 18 patients and resolvedwithout sequelae in 16 patients. Two of these complications wereattributed to the procedure and/or the use of the WEB, leadingto a procedure/device-related intraoperative complication rate of3.3%. WEB-related 1-month and 1-year morbidity and mortalitywere 0%. At 1 year, 19/46 aneurysms (41.3%) were completely occluded (Raymond-Roy grade I), 21/46 (45.7%) had a residual neck and 6/46 (13.0%) had residual aneurysm filling. Six patients(13%) underwent target aneurysm re-treatment within 1 year. Cur- rently, there are no prospective long-term (>10 years) follow-upstudies available with large numbers of patients and independent core lab assessments. ## PICO 4 In adult patients with aSAH, does any type of pharmacological orinterventional treatment aiming to reduce the risk of DCI com- pared to no such treatment decrease the risk of poor functional outcome? ### Analysis of current evidence We systematically reviewed the literature for RCTs evaluatingpharmacological and interventional strategies for DCI prevention. ### Page 14 Evidence-based Recommendations Quality of evidence StrengthIn adult patients with aSAH, we recommend prophylactic treatment with oral nimodipine to decrease the risk of poor functional outcome.⊕⊕⊕⊕ ↑↑Evidence-based Recommendations Quality of evidence StrengthIn adult patients with aSAH, we do not recommend prophylactic treatment with either tirilazad, statins, magnesium sulfate, or endothelin receptor antagonists to decrease the risk of poor functional outcome.⊕⊕⊕ ↓↓Evidence-based Recommendations Quality of evidence StrengthIn adult patients with aSAH, no recommendation can be made on prophylactic treatment with antiplatelet drugs or lumbar drainage to decrease the risk of poor functional outcome until further data from RCTs are available.⊕⊕ -Only strategies investigated in at least 3 RCTs were included.In the first paragraph, we present the available evidence for calcium antagonists. Following the publication of the BRANT trial and several other RCTs, oral nimodipine became thestandard of care for preventing DCI in Europe, consistent with the recommendations from previous ESO guidelines. Therefore, thesubsequent paragraphs on other treatment strategies analysedonly those RCTs in which patients received nimodipine as astandard of care. Pharmacological and interventional strategieswere categorised based on their mechanism of action, with some categories containing a single drug and others encompassing multiple drugs with similar pharmacodynamic properties. Treatment protocols varied considerably across studies,particularly regarding dosing regimens and duration of therapy.In trials with multiple intervention arms (eg, different dosages),all intervention groups were aggregated and compared againstthe control group. To maintain methodological consistency, only intention-to-treat analyses from RCTs were considered. Since the current definition of DCI was standardised in 2010,earlier studies employed surrogate measures such as delayedischaemic neurological deficits or symptomatic vasospasm.For this analysis, these outcomes were consolidated under the broader definition of DCI to enable pooling of studies. ### Calcium antagonists Calcium antagonists can induce vasodilation by inhibitingcalcium influx into vascular smooth muscle. Therefore, calciumantagonists have been investigated for the prevention of DCI afteraSAH. For our analysis, we included 7 RCTs comparing oral or intravenous (IV) nimodipine to placebo,,– as well as onetrial comparing nicardipine with placebo, involving a total of2276 patients. Trials comparing different doses of nicardipine orIV nimodipine were excluded. We also reviewed 3 meta-analyses, including 1 Cochrane review,– but no additional data wereretrieved from these meta-analyses. Overall, treatment with calcium antagonists was associatedwith a reduction in poor functional outcome (OR: 0.75; 95% CI, 0.61–0.93;) and cerebral infarction (OR: 0.58; 95% CI, 0.35–0.95;), but not of case-fatality (OR: 0.82; 95% CI, 0.66–1.02;). The positive effect of calcium antagonistson poor functional outcome was driven by trials investigatingthe effect of oral nimodipine, which showed a reduction in poor functional outcome (OR: 0.56; 95% CI, 0.40–0.76;), butnot of case-fatality (OR: 0.74; 95% CI, 0.53–1.02;). ACochrane review similarly reported no overall associationbetween nimodipine treatment and case-fatality, although astatistically significant reduction was observed after excludingstudies of lower methodological quality (RR: 0.82; 95% CI, 0.67–0.99). Collectively, these results indicate continued uncertainty regarding nimodipine’s efficacy in reducing case-fatality. ### Tirilazad Tirilazad inhibits lipid peroxidation and scavenges free radicals,thereby protecting cell membranes from oxidative damage. Inexperimental SAH models, tirilazad improved cerebral blood flow (CBF), reduced angiographic vasospasm and decreased infarct volume. The potential protective effect of tirilazad was evaluated inpatients with aSAH in 1 phase 2 trial and 4 phase 3 RCTsconducted between 1995 and 1999, including almost 4000 patients.,– Additionally, a Cochrane review published in 2010 further analysed its efficacy and safety, but no additionaldata were retrieved. Our meta-analysis showed that tirilazad does not reduce poorfunctional outcome (OR: 0.97; 95% CI, 0.84–1.12;), or case- fatality (OR: 0.68; 95% CI, 0.42–1.09;). Tirilazad reducedthe incidence of DCI (OR: 0.80; 95% CI, 0.70–0.93;), butnot cerebral infarction (OR: 0.96; 95% CI, 0.58–1.58;). ### Statins Statins not only decrease cholesterol levels but also have anti- inflammatory and antioxidant properties, improve endothelialfunction via increased nitric oxide (NO) production and reduce endothelin-1 (ET-1) levels. Since many of these pathwaysare probably involved in the pathogenesis of DCI, statinshave been extensively investigated in aSAH patients for DCI prevention. We identified 10 RCTs conducted between 2005 and 2020,–which included a total of 1575 patients. In 6 out of 10 stud- ies, nimodipine was administered as standard care to all patients.,,,,, Of these 6 studies, 4 investigated simvas- tatin,,,, 1 investigated atorvastatin, and 1 pravastatin.Four trials were phase 2 studies,,, and 3 trials hadfewer than 50 participants.,, We also reviewed 7 meta- analyses– to double-check whether all available RCTs wereincluded in the current PICO, and to check whether or notadditional data were presented in the existing reviews. However, no additional data were identified. Overall, statin treatment did not reduce the incidence of poorfunctional outcome (OR: 1.09; 95% CI, 0.86–1.38;), case- fatality (OR: 1.25; 95% CI, 0.85–1.83;) or DCI (OR: 1.00;95% CI, 0.33–3.07;). Cerebral infarction was not anal- ysed in the included studies. ### Magnesium sulphate Magnesium sulphate exerts pleiotropic effects, including calciumchannel blockade, enhanced nitric oxide production, inhibitionof NMDA receptors, reduction of inflammatory mediators andantioxidant properties. Its role as a preventive treatment for DCI has been evaluated in 13 RCTs– conducted between2002 and 2018, involving a total of 2944 patients. Each RCT ### Page 15 Figure 6 Effect (odds ratio) of calcium antagonists compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.Figure 7 Effect (odds ratio) of tirilazad compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.Figure 8 Effect (odds ratio) of statins on compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.used a different dosing regimen and treatment duration. Nine trials ![For image description, please refer to the figure legend and surrounding text.]() ![For image description, please refer to the figure legend and surrounding text.]() ![For image description, please refer to the figure legend and surrounding text.]() –,,– evaluated magnesium sulphate as an adjunctto nimodipine, comparing it with placebo plus nimodipine andtherefore were included in the analysis. Seven meta-analyses were also reviewed–; however, no additional data were identified. Magnesium sulphate did not decrease the risk of poor func- tional outcome (OR: 0.94; 95% CI, 0.78–1.12;) or reducecase-fatality (OR: 0.81; 95% CI, 0.42–1.57;). Although itwas not associated with a decreased risk of DCI (OR: 0.52; 95% CI, 0.19–1.42;), magnesium sulphate was associated witha lower risk of cerebral infarction (OR: 0.30; 95% CI, 0.14–0.62; ### Page 16 Figure 9 Effect (odds ratio) of magnesium sulphate compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.Figure 10 Effect (odds ratio) of ETRAs compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.Abbreviation: ETRAs = endothelin receptor antagonists. ![For image description, please refer to the figure legend and surrounding text.]() ![For image description, please refer to the figure legend and surrounding text.]() ). Of note, infarct outcomes were assessed in only 165 patients. ### Endothelin receptor antagonists (ETRAs) Endothelin receptor antagonists (ETRAs) block the effects of ET- 1, which is a protein with strong vasoconstrictive properties pro- duced by endothelial cells after subarachnoid haemorrhage. Our search identified 8 RCTs,– 1 Cochrane review, and7 other meta-analyses.– Five trials comprising 2957 patientsbetween 2000 and 2024 included nimodipine as a standard of care–,, and were thus included in our analyses. Fourtrials analysed the effect of clazosentan,,,, which is aselective endothelin A receptor antagonist, and 1 trial the effect ofTAK-044, which is a non-selective antagonist of both endothelinA and B receptors. ETRAs did not reduce poor functional outcome (OR: 1.12; 95% CI, 0.94–1.33;) or case-fatality (OR: 1.07; 95% CI, 0.69– 1.65;), although they reduced the risk of DCI (OR: 0.63; 95% CI, 0.48–0.82;). Moreover, ETRAs did not reducethe overall risk of cerebral infarction (OR: 0.77; 95% CI, 0.49–1.20;). ### Antiplatelet drugs It has been hypothesised that microthrombosis contributes tothe pathogenesis of DCI. Therefore, the effect of antiplateletdrugs has been extensively investigated in patients with aSAH.The following antiplatelet drugs were investigated: cilostazol (4 RCTs, 405 patients),– acetylsalicylic acid (2 RCTs, 211patients),, dipyridamole (1 RCT, 348 patients), tirofiban(1 RCT, 30 patients), E5880 (1 RCT, 68 patients), cataclotx (1RCT, 24 patients) and OKY-046 (1 RCT, 256 patients). Of them, only 3 trials,, including 241 patients usednimodipine as the standard of care and were included in the meta- analysis. Two trials, were phase 2 and 1 trial was phase3. Two trials investigated acetylsalicylic acid, and 1 trialinvestigated tirofiban. We also identified 1 Cochrane reviewand 5 additional meta-analyses, but these did not yield further data.– Overall, antiplatelet therapy did not reduce the risk of poorfunctional outcome (OR: 0.67; 95% CI, 0.33–1.34;) orreduce case-fatality (OR: 1.05; 95% CI, 0.42–2.59;). Fur- thermore, antiplatelet treatment did not reduce the risk of DCI (OR: 0.72; 95% CI, 0.15–3.49;) or cerebral infarction (OR:0.50; 95% CI, 0.06–4.38;). ### Lumbar drainage Lumbar drainage (LD) has been investigated as a potentialstrategy to prevent DCI by facilitating cerebrospinal fluid (CSF) removal and cisternal bloodclot wash-out downstream.Our analysis included 3 RCTs comprising 557 patients.–A further meta-analysis yielded no additional data. Of the3 RCTs, 1 reported functional outcome using means andmedians of GOS scores at 1- and 3-month follow-up, instead ofproportions of patients with poor outcome. The correspondingauthor was contacted multiple times for more information butdid not respond. Therefore, that trial could not be included in the meta-analysis. Instead, the results of that trial are reported separately. ### Page 17 Figure 11 Effect (odds ratio) of antiplatelet drugs compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.Figure 12 Effect (odds ratio) of LD compared with control on poor functional outcome in adults with aneurysmal subarachnoid haemorrhage.Abbreviation: LD = lumbar drainage.The methodology was similar between the 2 trials includedin the pooled analysis, with lumbar CSF drained at a rate of 5–10 mL/h for an average duration of 4–5 days. The procedures weresafe, with a low risk of complications, primarily minor infections or mechanical issues. Serious complications (such as infection, rebleeding or herniation) were very uncommon (<2%). ![For image description, please refer to the figure legend and surrounding text.]() ![For image description, please refer to the figure legend and surrounding text.]() , Lumbar drainage did not reduce the risk of poor functionaloutcome at 3–6 months (OR: 0.78; 95% CI, 0.43–1.44;)or overall case-fatality (OR: 0.75; 95% CI, 0.43–1.31;).However, it was associated with a lower risk of DCI (OR: 0.41; 95% CI, 0.24–0.70;) and cerebral infarction (OR: 0.55; 95% CI, 0.38–0.79;). An additional study not included inthe meta-analysis reported higher GOS scores at both 1 and 3months in patients treated with LD compared to controls (median5 [IQR: 1–5] vs 4 [IQR: 1–5], P = .04). Based on the currently available evidence, which includes 2RCTs with conflicting results and a third positive study the resultsof which could not be included in the pooled analysis, no recom- mendation can be made for or against the use of LD to decrease the risk of poor functional outcome after aSAH. Further research is needed to provide conclusive evidence. ## Topic 5. Treatment of delayed cerebral ischaemia ## PICO 5a In adult patients with aSAH and clinical deterioration due to DCI,does hypertension induction compared to no hypertension induc- tion decrease the risk of poor functional outcome? ### Analysis of current evidence The only randomised-controlled study performed on the effectsof induced hypertension in aSAH patients with DCI showed noreduction in poor outcome (adjusted RR for poor outcome 1.0Evidence-based Recommendations Quality of evidence StrengthIn adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, no recommendation can be made on hypertension induction to decrease the risk of poor functional outcome.⊕⊕ -Expert consensus statementIn adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, we suggest considering induced hypertension, provided that the ruptured aneurysm is treated and after standard therapy has proven insufficient. Clinical contraindications and potential complications of induced hypertension should be considered. Vote: 11/13[95% CI, 0.6–1.8]) and a possibly higher rate of serious adverseevents in the intervention group (RR: 2.0; 95% CI, 0.9–5.0). It mustbe noted that the trial was prematurely stopped after 41 out of 240 patients (17%) were enrolled. Therefore, there was insufficient power to draw a final conclusion on the role of induced hyper- tension in aSAH patients with DCI. Of note, although the meanarterial pressure was on average 12 mm Hg higher in patients in thehypertension induction group compared to those in the controlgroup, no statistically significant difference in cerebral perfusion was observed. ### Additional information We retrieved additional information on the effects of inducedhypertension in adult patients with aSAH and clinicaldeterioration due to DCI. In a retrospective study conducted in3 academic hospitals in the Netherlands between 2006 and 2015,479 (29%) of 1647 enrolled patients had clinical deteriorationdue to DCI. In this cohort, hypertension induction reduced the odds to develop DCI-related cerebral infarction (adjusted hazard ratio [HR], 0.59; 95% CI, 0.35–0.99) and a strong effect of induced ### Page 18 hypertension was observed on the prevention of poor outcome(adjusted OR: 0.27; 95% CI, 0.14–0.55), suggesting induced hypertension might be reasonable in selected patients. Anotherretrospective study from the Netherlands, that included patientsadmitted between 2015 and 2019, compared 2 centres usinghypertension induction in patients with DCI with 1 centre not using this strategy. Two authors, blinded to the patients’ hospital andtreatment given, independently evaluated whether neurologicalstatus on days 1 and 5 after DCI onset had improved, remainedstable or worsened compared with the status at DCI onset, basedon Glasgow Coma Scale (GCS) scores and physicians’ neurologicalassessments documented in the medical records. Discrepancieswere resolved by a third blinded author. Although at day 1 afterDCI more patients in the hypertension induction group hadclinical improvement compared to those without hypertension induction (adjusted RR [aRR]: 1.63 [95% CI, 1.17–2.27]), there was no difference in clinical improvement between the groups at day 5 after DCI (aRR: 1.04 [95% CI, 0.84–1.29]) and no difference in functional outcome (RR: 1.24 [95% CI, 0.81–1.90]). ## PICO 5b In adult patients with aSAH and clinical deterioration due toDCI, does endovascular treatment of vasospasm compared tono endovascular treatment decrease the risk of poor functional outcome?Evidence-based Recommendations Quality of evidence StrengthIn adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, no recommendation can be made on endovascular treatment of vasospasm to decrease the risk of poor functional outcome.⊕⊕ -Expert consensus statements1. In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia in combination with refractory and severe vasospasm, we suggest considering intraarterial pharmacological treatment as a rescue therapy in selected patients to decrease the risk of poor functional outcome. Vote: 11/13 2. In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia in combination with refractory severe vasospasm, the current evidence is insufficient to support the routine use of mechanical vasodilatation with balloon angioplasty. In selected cases, this approach may be considered as a last-line rescue treatment after careful multidisciplinary discussion of the potential risks and uncertain benefits. Vote: 12/13 3. In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia in combination with refractory severe vasospasm, the current data are insufficient to support the use of mechanical vasodilatation with temporary deployment of retrievable stents to decrease the risk of poor functional outcome. Vote: 13/13 ### Analysis of current evidence Endovascular treatment of vasospasm in aSAH—such as intra- arterial pharmacological therapy and mechanical vasodilatationusing balloon angioplasty or temporary deployment of aretrievable stent—has been explored in clinical studies as apotential strategy to treat DCI. Two RCTs on the effects of endovascular treatment of vasospasm in aSAH patients with DCI have been completed to date., An RCT in 3 Germancentres was stopped prematurely for safety reasons after aprespecified interim analysis, when 36 out of the planned 92 patients were randomised. Eighteen patients were randomisedto endovascular treatment and 18 to the control arm. Twopatients in the intervention arm did not receive endovasculartreatment and were not included in the analysis. Of the 16 patientswho underwent endovascular treatment, 5 patients received 1treatment, 7 patients 2 treatments, 2 patients 3 treatments, 1patient 4 treatments and 1 patient 5 treatments. The majorityof procedures (29/34) consisted of intra-arterial nimodipineand 4/34 procedures were done by balloon angioplasty. Fiveout of 34 (15%) endovascular treatment procedures resulted inmajor treatment complications (2 dissections, 3 infarctions). Noeffect on the primary endpoint (incidence of new infarct lesionsmeasured on diffusion weighted MR images) was observed.Patients randomised to the control arm had a better clinicaloutcome at 6 months than patients randomised to endovasculartreatment of vasospasm (mRS 2 ± 1.5 vs 4 ± 1.8; P = .004).The study did not demonstrate a clinical benefit and reportedworse functional outcomes in the invasive group. Since the trial was likely underpowered due to early termination and a smaller-than-planned sample size, a potential benefit of invasive diagnostic and endovascular treatment cannot be definitively excluded. In addition, variability in vasospasm severity may have limited the generalisability of the findings. The second trial was a single-centre RCT from Thailand with 68 patients, of whom 36 patients were randomised to a single endovascular treatment session with intra-arterial nimodipine and 32 patients to the control arm. The results showed apositive effect on motor improvement at discharge (58% inthe intervention arm and 22% in the control group; P = .002),but no effect on functional outcome (measured with the mRS)at discharge or at 6 months. Although the trial suggested apotential short-term benefit of endovascular treatment for vasospasm, the small sample size and single-centre design limit the robustness and generalisability of the findings. These limitations reduce the certainty of the evidence derived from this study. In a pooled analysis of the 2 trials, endovascular treatment ofvasospasm in aSAH patients with DCI did not reduce the risk of poor functional outcome (OR: 2.33; 95% CI, 1.05–5.18;)or case-fatality (OR: 2.93; 95% CI, 0.58–14.90;). ### Additional information We identified one systematic review focussing mainly on intra- arterial pharmacological treatment and balloon angioplasty.In addition, we included data from 2 observational studiesevaluating temporary stent-retriever deployment as a novelstrategy for mechanical vasodilatation. A systematic review and meta-analysis of 7 non-randomised, predominantlyretrospective cohort studies (517 patients) compared endovas- cular therapy (intra-arterial pharmacological treatment with orwithout balloon angioplasty) with the standard treatment for vasospasm after aSAH. Endovascular therapy, mainly intra-arterial ### Page 19 Figure 13 Effect (odds ratio) of endovascular treatment of vasospasm compared with control on poor functional outcome in adults with aneurysmalsubarachnoid haemorrhage with DCI. Abbreviation: DCI = delayed cerebral ischemia.pharmacological treatment, was associated with a decreasedrisk of in-hospital mortality (RR: 0.49; 95% CI [0.29–0.83]), butnot of functional outcome at discharge (RR: 0.99; 95% CI [0.68–1.45]) or at follow-up (RR: 1.09; 95% CI [0.86–1.39]), or of major cerebral infarction on CT at discharge (RR: 0.79; 95% CI [0.34– 1.84]), compared to standard of care. ![For image description, please refer to the figure legend and surrounding text.]() Only limited data are available on balloon angioplasty. Amulticentre retrospective cohort study from 3 US academiccentres evaluated the safety and efficacy of non-compliant balloon angioplasty for vasospasm after aSAH. Fifty-twopatients were included who had new focal or global neurologicdeficits resulting from DCI in combination with moderateor severe angiographic vasospasm. In total, 165 angioplastyprocedures were performed. The study did not include a controlgroup. The main outcomes were angiographic improvementof vasospasm, delayed cerebral infarction on CT or MRI andfunctional outcome (mRS). Angiographic improvement occurredin 97% of treated vessels, and clinical symptoms improved in78.8% of patients. Cerebral infarction developed in 46.2% ofpatients, and 61.5% achieved favourable functional outcome(mRS 0–2) at follow-up. No procedure-related complicationswere reported. The authors concluded that non-compliantballoon angioplasty appears safe and effective in improving angiographic vasospasm in patients with medically refractory vasospasm. However, in the absence of a control group, no conclusion can be made on the effect on functional outcome. A single-centre retrospective observational study evaluated the effect of distal balloon angioplasty for vasospasm after aSAH. The study included 392 patients treated between2012 and 2017. Between 2012 and 2015, 160 patients receivedproximal balloon angioplasty, if needed followed by intra-arterialpharmacological therapy for distal vasospasm. From 2015 to2017, 232 patients received proximal balloon angioplasty, ifneeded followed by distal balloon angioplasty. The primaryendpoint was delayed cerebral infarction occurring in theterritory of a previously treated vessel. Distal balloon angioplastywas associated with lower rates of post-angioplasty delayedcerebral infarction (2.2% vs 7.5%) and fewer repeat angioplastyprocedures (8% vs 19%). However, overall delayed cerebralinfarction, mortality and favourable functional outcome didnot differ significantly between treatment periods. Procedure- related complications were uncommon, with angioplasty-related infarction in ∼ 2.5% and symptomatic intracranial haemorrhage in ∼ 0.7%–1.3%. The authors concluded that distal balloon angioplasty may reduce angiographic recurrence of vasospasm and post-angioplasty infarction but did not demonstrate a clear clinical benefit. Finally, temporary deployment of retrievable stents has beenreported in small observational series as a mechanical approachfor vasospasm treatment. However, since the available studieswere limited to small uncontrolled cohorts, none of the studies adhered to the inclusion criteria for this guideline. In conclusion, the available evidence for endovasculartreatment of vasospasm is predominantly observational andretrospective. Adequately powered, randomised controlledclinical trials with predefined clinical endpoints are urgentlyneeded to answer the question whether endovascular treatment of vasospasm in patients with DCI is safe and decreases the risk of poor functional outcome after aSAH. ## Topic 6. Neuroimaging andneuromonitoring ## PICO 6a In adult patients with aSAH, does any type of neuroimaging com- pared to regular neurological examination decrease the risk of poor functional outcome?Expert consensus statements1. In adult patients with aSAH and clinical deterioration, we suggest plain head CT in combination with CT-Perfusion (CTP) imaging to detect the cause of deterioration. Vote: 11/13 2. In adult patients with aSAH who are neurologically not assessable but at high risk for DCI, we suggest plain head CT and CTP at least once between day 4 and 14. Vote: 10/13 3. In adult patients with aSAH, we do not suggest a routine DSA for screening of macrovascular vasospasm. Vote: 13/13 ### Analysis of current evidence The literature search yielded no randomised trials or otherwisecontrolled studies, but only uncontrolled observational studies, which are discussed in the additional information section. ### Page 20 ### Additional information Angiography Anatomical imaging of cerebral arteries with DSA provides thehighest spatial resolution for brain arteries and serves as the gold standard for the assessment of macrovascular diameter. How- ever, due to the invasiveness and inherent procedural risks of DSA,CTA is often used as an alternative for detection of macrovascu- lar spasm. In a meta-analysis comparing CTA with DSA, CTAhad a sensitivity of 79.6% (95% CI, 74.9%–83.8%) and specificityof 93.1% (95% CI, 91.7%–94.3%). However, although there is a strong association between macrovascular spasm and DCI,,a causal relationship is increasingly questioned. Other hypothesesfor the pathogenesis of DCI include microthrombosis, microcircu- latory spasm, cortical spreading ischaemia and impaired cerebralautoregulation. In addition, clinical trials showed that treatmentstrategies that reduce macrovascular spasm do not decrease the risk of poor functional outcome, which questions the usefulness of detecting angiographic vasospasm., Perfusion imaging Imaging of brain perfusion may detect tissue at risk for irreversibleischaemic damage and guide therapeutic interventions.Due to its practicability and favourable risk/benefit profile foraSAH patients, CTP measurement evolved as the most used perfusion imaging modality.– CTP combines informationabout macro- and microvascular blood flow and may distinguishbetween reversible hypoperfusion and irreversible ischaemia.Quantitative image analyses with calculation of CBF, cerebralblood volume, mean transit time (MTT), time to peak and timeto drain have been used to investigate impaired brain perfusionin aSAH patients. Increase in MTT has repeatedly been reported to accurately predict DCI before irreversible ischaemia occurs.In a prospective cohort of 64 aSAH patients with quantitativeCTP at day 3, MTT predicted DCI with a sensitivity of 95%(95% CI, 83%–99%) and a negative predictive value of 96% (95% CI, 87%–99%) indicating very high diagnostic accuracy as screening tool for DCI., In a meta-analysis of 570 patients,a decrease of CBF (pooled mean difference− 11.9 mL/100 gper minute [95% CI,−15.2 to−8.6]) and an increase in MTT(pooled mean difference 1.5 s [CI, 0.9–2.2]) during the high-riskphase (days 4–14 after ictus) was associated with DCI. However,absolute values of quantitative CTP parameters vary between different CT scanners and analysis algorithms. Therefore,measuring perfusion by CTP needs standardisation to definegeneralisable absolute perfusion thresholds after aSAH in future studies. Magnetic resonance imaging (MRI) Although MRI is a sensitive modality for the early detection ofcerebral ischaemia, its feasibility in the routine management ofpatients with aSAH during the high-risk period for DCI is limitedby both patient-related and logistical factors. Many patients withaSAH are restless or have a decreased level of consciousness andtherefore unable to lie still, which makes an MRI scan impossible.Furthermore, having a patient on the respiratory machine forabout 20 min and monitoring that patient in the MR suite ischallenging and often undesirable. In addition, when ischaemiclesions are detected on MRI, it is often difficult to determinewhether these findings are attributable to DCI, acute ischaemic events (resulting from the acute aneurysm rupture) or procedure- related ischaemia. Collectively, these considerations limit the utility of MRI as a diagnostic tool in routine clinical practice. Emerging technologies, such as bedside ultra-low-field portable MRI systems and further reductions in acquisition time, may help to address some of these limitations in the future. ## PICO 6b In adult patients with aSAH, does any type of neuromonitoringcompared to regular neurological examination decrease the riskof poor functional outcome?Expert consensus statements1. In adult patients with aSAH, no suggestion can be given on the use of TCD monitoring. Vote: 10/13 2. In adult patients with aSAH and radiological hydrocephalus who are neurologically not assessable, we suggest ICP monitoring via EVD if an EVD is in place. Vote: 13/13 3. In adult patients with aSAH without radiological hydrocephalus who are neurologically not assessable, no suggestion can be given on ICP monitoring. Vote: 11/13 4. In adult patients with aSAH who are neurologically not assessable, we do not suggest invasive multimodal neuromonitoring with continuous measurement of partial pressure of brain tissue oxygen (PbtO2) and/or microdialysis due to the uncertain risk/benefit ratio of these modalities. Vote: 10/13 5. In adult patients with aSAH who are neurologically not assessable, we do not suggest the routine use of continuous EEG monitoring. Vote: 13/13 ### Analysis of current evidence The literature search yielded no randomised trials or otherwisecontrolled studies, but only uncontrolled observational studies, which are discussed in the additional information section. ### Additional information Transcranial Doppler TCD Transcranial Doppler is widely used for routine monitoring ofarterial blood flow velocities as an indirect measure to detectlarge artery vasospasm after aSAH. The non-invasive nature andbedside availability of TCD offer advantages over other imaging modalities for vasospasm monitoring. However, as discussed ### Page 21 above, there is ongoing debate about the clinical relevanceof macrovascular spasm and elevated blood flow velocities in cerebral arteries measured by TCD., A meta-analysis of 15studies comparing TCD with DSA for detection of angiographicvasospasm in the middle cerebral artery reported a pooledsensitivity of 66.7% (95% CI, 55.9–75.9) and specificity of 89.5%(95% CI, 80.3–94.7). An estimated vasospasm incidence of 70%in aSAH patients results in a positive predictive value of 93.7%and negative predictive value of 53.4%. Due to even lowernegative predictive values for all other cerebral arteries, TCDdoes not reliably exclude the presence of vasospasm. The limited diagnostic accuracy of TCD, and the fact that most patients with large artery vasospasm do not have clinical deterioration due to DCI undermines its usefulness as a reliable screening tool in the monitoring of aSAH patients. Continuous EEG In unconscious patients, subtle neurological changes caused byfocal cerebral ischaemia are often difficult to recognise. Continu- ous EEG (cEEG) may partially compensate for missing functionalinformation. cEEG can be used for monitoring seizure activity and brain function in critically ill patients with altered mental status. In aSAH patients, seizure activity in cEEG has beenreported in up to 19% of patients, which may contribute to worse clinical outcome. In addition to seizure detection, cEEG datacan be analysed to define patterns of DCI-related pathologicalelectric activity of the brain. For example, a decreased alpha to delta ratio is associated with DCI. In a prospective study of 227consecutive aSAH patients, 103 were eligible for quantitative EEGanalyses. In this cohort, cEEG predicted DCI with a sensitivity of91% (95% CI, 81%–98%) and specificity of 83% (95% CI, 71%–93%)in low-risk patients, and a sensitivity of 95% (95% CI, 87%–99%) and specificity of 77% (95% CI, 36%–99%) in high-risk patients.However, the identified EEG patterns for DCI prediction anddiagnosis need further validation in independent cohortsof aSAH patients with standardised definitions. In addition,clinical trials are needed to investigate whether therapeuticinterventions based on cEEG findings decrease the risk of poorfunctional outcome in aSAH patients, to justify the high resource requirements for around-the-clock real-time data acquisition and interpretation. Invasive neuromonitoring probes Parenchymal monitoring probes can be used to obtain additionalphysiological data in neurologically unassessable aSAH patients,eg, ICP, regional CBF and the metabolic status of the brain.Intracranial pressure elevations are common and have beenreported in up to 80% of poor grade aSAH patients. Inunconscious patients with radiographic signs of hydrocephalus,ICP can be reliably monitored via an EVD (also see PICO 7).However, there is uncertainty about the risk/benefit profile of EVDinsertion for ICP monitoring in aSAH patients without radiographic hydrocephalus. Parenchymal ICP probes are considered less invasive andcommonly used for this indication. The SYNAPSE-ICU studywas an international, prospective observational cohort study of2395 patients with acute brain injury, of whom 521 (22%) had SAH,, which aimed to explore practice variation in ICPmonitoring variation to prioritise uncertainties in the clinicalmanagement of critical care patients with acute brain injuryand support further collaborative prospective studies. The studyshowed that SAH patients with ICP monitoring received moreaggressive therapy treatments compared to patients without ICPmonitoring. Intracranial pressure monitoring was associated witha reduction in poor functional outcome (OR: 0.14; 95% CI, 0.02– 0.53) and case-fatality (HR: 0.25; 95% CI, 0.13–0.49) in SAH patients in a poor clinical condition, but not in those with 2 reactive pupils. Combined probes allow for continuous measurement of braintissue oxygen pressure (PtbO2 ) and ICP. This, in combination withsystemic blood pressure measurements, may provide information about cerebral autoregulation. Brain tissue oxygen pressuremonitoring has been reported to be sensitive in detection ofmetabolic cerebral compromise even in the absence of elevated ICP. In addition, microdialysis with quantification of interstitialmetabolites, such as lactate and pyruvate, have been reported todetect metabolic derangements in situations without impaired PtbO 2 . Treatment paradigms for poor grade aSAH patientsbased on an extended definition of DCI integrating multimodalneuromonitoring data (ICP, PtbO2 , microdialysis) have beenreported to increase 12 months favourable neurological outcome in a cohort of 55 consecutive poor grade aSAH patients.However, due to the very limited sample size of reported neu- romonitoring studies in aSAH patients, inconsistent definitionsof DCI across studies, the lack of validated clinically relevantthresholds and limited therapeutic options, there is uncertaintyabout the risk/benefit profile of invasive monitoring methods.In addition, invasive multimodal neuromonitoring is inherently limited by providing only regional information around the site of implantation and a lack of data from clinical good grade aSAH patients. ## PICO 7 In adult patients with aSAH, does treatment of hydrocephalus(either by EVD, ventriculoperitoneal [VP]-shunt or LD) comparedto no treatment of hydrocephalus decrease the risk of poor func- tional outcome? ### Analysis of current evidence External ventricular drain There are no RCTs comparing the placement of an EVD with theabsence of an EVD in aSAH patients with hydrocephalus. Further- more, there are no prospective observational studies meeting the inclusion criteria. Lumbar drain There are 4 RCTs that meet the predefined inclusion crite- ria.–, All identified RCTs evaluate the effects of LDplacement in addition to an EVD in patients with impairedconsciousness, or as a standalone procedure in conscious patients without acute hydrocephalus. The primary goal of LD placement ### Page 22 Expert consensus statements1. In adult patients with aSAH who present with radiological hydrocephalus and a decreased level of consciousness, we suggest CSF drainage. Vote: 13/13 2. In adult patients with aSAH who present with obstructive hydrocephalus and a decreased level of consciousness, we suggest EVD placement. Vote: 13/13 3. In adult patients with aSAH who present with communicating hydrocephalus and a decreased level of consciousness, we suggest LD or repeated LPs as the strategy of first choice for CSF drainage. Vote: 11/13 4. In adult patients with aSAH who present with radiological hydrocephalus and a normal level of consciousness, we do not suggest CSF drainage. Vote: 12/13 5. In adult patients with aSAH who come at a point at which prolonged CSF drainage (by EVD, LD or repeated LPs) carries a higher risk of severe complications than placement of a permanent CSF diversion, we suggest permanent CSF diversion. Vote: 13/13 6. In adult patients with aSAH who present with symptomatic chronic hydrocephalus, we suggest permanent CSF diversion. Vote: 13/13in these studies was the prevention of DCI and thus potentially adecreased risk of poor functional outcome. Therefore, the resultsof these studies are presented in PICO 4, which addresses the prevention of DCI. There are no RCTs comparing the placement of an LD and theabsence of an LD in aSAH patients with hydrocephalus to decreasethe risk of poor functional outcome or case-fatality. In addition,there are no prospective observational studies meeting the inclu- sion criteria. Lumbar puncture There are no RCTs comparing the effect of LP with no LP in aSAHpatients with hydrocephalus. Nor are there any prospective obser- vational studies meeting the inclusion criteria. Internal ventricular drain There are no RCTs comparing the placement of a VP shunt withno VP shunt in aSAH patients with chronic hydrocephalus. Nor arethere any prospective observational studies meeting the inclusion criteria. ### Additional information EVD in acute hydrocephalus after aSAH The placement of an EVD in patients with acute hydrocephalusfollowing aSAH, whether obstructive or communicating, is com- mon practice in nearly all centres treating aSAH patients. Externalventricular drain allows rapid control of acute hydrocephalus andICP, and thereby is often considered a lifesaving treatment. In caseof obstructive hydrocephalus or significant mass effect it is the only treatment possible, since LD or LP in these situations can lead to death by brain herniation. However, although commonlyperformed, EVD also has specific risks: brain haemorrhage alongthe catheter tract, catheter malposition, mechanical brain injurywith putative long-term effect on motor function, cognition and risk of seizures, as well as catheter-related infection., In addi- tion, there is a debate regarding the indications for EVD placement,which can be clinical (decreased level of consciousness) and/or radiological (ventricular enlargement). Therefore, the risk/ben- efit ratio of EVD insertion must be weighed and alternatives con- sidered. LD and LP in acute hydrocephalus after aSAH In case of acute and communicating hydrocephalus, a LD or LPcan also be used instead of an EVD.– Placement of an LDor performance of an LP probably carries a lower risk of compli- cations than the placement of an EVD. However, CSF diversionby means of a LD or LP in case of obstructive hydrocephalus orsignificant cerebral oedema poses a risk of tonsillar herniation and thus death, and is therefore contraindicated in these situations. Regarding the LD, an observational study without control groupreported no complications related to LD insertion (infection, brainherniation, over drainage) in 28 Fisher III aSAH patients. Inanother study, 229 Fisher III aSAH patients without obstructivehydrocephalus had an LD inserted, and the rate of CSF infection was 0.4%, which may be lower than that observed with EVD.One study in aSAH patients with symptomatic hydrocephalus ret- rospectively compared 56 patients with an EVD and 21 patientswith a LD. The decision to treat with EVD or LD depended onthe surgeon on call. Overall drain complications were 32.0% inpatients with EVD and 9.5% in patients with LD. External ventric- ular drain vs LD complications consisted of haemorrhage (1.8% vs 0%), infection (7.1 vs 0%), clogged drain (25% vs 0%), dislodge- ment of drain (1.8% vs 4.6%) and replacement of drain (16% vs 4.8%). No case of cerebellar tonsillar herniation occurred. Regarding LP, in an observational study, 17 patients with symp- tomatic communicating hydrocephalus were treated by serial LPs.None had CSF infection or tonsillar herniation, and none required EVD insertion. In a recent study, 86 patients with aSAH andacute symptomatic hydrocephalus were treated with LP as initialtreatment. Seventy patients (81%) showed initial improvementafter initial LP, 39 (45%) improved with LP only and 41 (48%)needed continuous drainage by LD or EVD. Thus, LD or EVD insertion could be avoided in approximately half of the patients. The rate of complications related to LP was not explicitly reported. Timing of CSF drainage in acute hydrocephalus after aSAH Cerebrospinal fluid drainage in aSAH patients before occlusion ofthe ruptured aneurysm may modify aneurysm transmural pres- sure, which may increase the risk of aneurysmal rebleeding. This question has been investigated in several observational studies. Regarding EVD, a meta-analysis of observational studiesreported rebleeding among 106/960 patients (11%) treatedwith EVD, vs 250/2711 patients without EVD (9.2%; OR: 1.60, 95% CI, 0.82–3.22). However, several confounding factorslimit the interpretation of these findings, particularly the ### Page 23 time interval between ictus, EVD placement, rebleeding andaneurysm treatment. Another study compared 3 matched patientgroups: those with hydrocephalus treated with EVD, those with hydrocephalus without EVD and those without hydrocephalus (n = 34 per group). The mean time from ictus to CSF drainagewas 12 h, and drainage continued for an average of 6.3 days priorto aneurysm treatment. Rebleeding rates were similar acrossgroups, occurring in 7/34 patients in both hydrocephalus groupsand in 6/34 patients in the group without hydrocephalus. Thesefindings suggest that early EVD placement with prolonged CSFdrainage does not appear to increase the risk of rebleeding.Although EVD itself may not increase rebleeding risk, another study with 194 patients suggested that not EVD by itself, but rather the volume and timing of CSF drainage (60 mL of CSF drained in 6 h) may increase the risk of rebleeding. This observationindicates that the risk may be related to both the volume and timing of CSF drainage. Regarding LD, in a retrospective study, rebleeding occurred in11/324 (3.4%) patients with LD and in 2/51 (3.9%) patients without LD. Permanent CSF shunt in aSAH There are no high-quality studies evaluating the benefit of plac- ing a permanent shunt in chronic hydrocephalus following aSAH.Insertion of permanent shunt is proposed when the EVD or LD can- not be removed, or in case of symptomatic chronic hydrocephalus. When an external drain has been inserted (EVD or LD), theremoval of this drain usually relies on a clamping attempt withclinical and radiological assessment. The duration of externaldrainage that necessitates the placement of an internal shuntis unknown, as well as the number of failures of drain closure indicating the insertion of a permanent CSF shunt. Of note, the longer the EVD is inserted, the higher the risk of catheter-related infection is. Chronic hydrocephalus after aSAH may also become clinicallymanifest after the removal of the external drain, several weeks after discharge. A retrospective study that included 39 patientsprovides controlled data. Patients presenting with gait ataxia,cognitive disturbance and urinary incontinence had enlargedventricles and normal CSF opening pressure on LP. Patientswith high CSF opening pressure were excluded. Of the remainingparticipants, 24 received a VP shunt and 15 did not receive a VP shunt. At 1 and 6 months, Barthel index scores (39 vs 47) and Mini Mental Status (18 vs 19) were improved in the VP shunt group. ## PICO 8 In adult patients with aSAH, does treatment on a dedicated neuro- ICU or high care unit compared to a general ICU or high care unitdecrease the risk of poor functional outcome? ### Expert consensus statementIn adult patients with aSAH, we suggest admission and management in a dedicated neuro-ICU or high care unit to decrease the risk of poor functional outcome. Vote: 13/13 ### Analysis of current evidence No RCTs directly compare the effects of dedicated neuro-ICU orhigh care units with general ICU or high care units on outcomes in patients with aSAH. ### Additional information Dedicated neuro-ICU or high care unit vs general-ICU or high care unit Several observational studies have compared outcomes betweenaSAH patients managed in a neuro-ICU vs a historical cohort in a general ICU.– There are 5 studies suggesting abenefit of dedicated neuro-ICU on functional outcomes in aSAH patients.– A Japanese retrospective study compared 83aSAH patients admitted to an intensive care unit (ICU) managedby general intensivists between 2001 and 2006 (historical controlgroup) to 151 aSAH patients admitted to an ICU managed by neurointensivists between 2007 and 2014. Patients admitted tothe unit led by neurointensivists had better outcomes at hospitaldischarge in univariate analysis (discharge mRS 0–2; 58.3% vs41.0%; P = .01). Of note, an independent effect on outcomes(mRS 0–2) was only seen in a subgroup of good-grade aSAH patients (Hunt and Kosnik grades I and II) (OR: 4.54 [95% CI, 1.08–22.17]; P = .045), but not in patients with a poor clinical condition on admission. A single-centre North American studyfound that implementation of a neurointensivist-led team wasassociated with a higher chance of being discharged home(141/386 [36.5%] vs 80/317 [25.2%]; P < .001), and a lower chanceof being discharged to a rehabilitation facility (25.2% vs 36.5%) without a difference in mortality (25.4% vs 26.8%) and discharge to nursing care (5.7% vs 5.4%). The cohort of the ICU managedby a neurointensivist team consisted of 386 SAH patients admittedbetween 1998 and 2002 and were compared to a historical controlgroup of 317 aSAH patients admitted between 1995 and 1998.Improved discharge disposition was seen in subgroups of patientswith admission Hunt and Hess grades I and II and grade III,but not for aSAH admission grades IV and V. In a single centreretrospective North American study the implementation of aneurointensivist co-management approach in a neurosurgical ICU(296 aSAH patients admitted between 2005 and 2007 compared toa historical control group of 216 aSAH patients admitted between2003 and 2005) did not show an effect on hospital mortality (18.2%after vs 13.4% before [P = .14]), although there was a statistically significant decrease of mean length of ICU stay (from 12.4 days to 10.9 days, P = .02) and of the need for VP shunts (23.0% vs 11.5% [P = .001]). In a single-centre North-American study including 363 SAHpatients among a mixed cohort of 2096 stroke patients, avail- ability of a neurocritical care specialist, but not a specialised neurocritical care units was associated with improved discharge ### Page 24 disposition, lower in-hospital mortality (48/259 [18.5%] vs 33/104[31.7%]; P = .006), or withdrawal of care, and lower mortalityat 3 months (52/259 [20.1%] vs 33/104 [31.7%]; P = .018) and 12 months (54/259 [20.8%] vs 35/104 [33.7%]; P = .01) specifically in aSAH patients. When the trained neurointensivist left theunit and was not replaced, a greater rate of in-hospital mortalityor discharge to hospice (OR: 2.206 [95% CI, 1.062–4.584]; P = .034),overall worsened discharge disposition (OR: 2.455 [95% CI, 1.165–5.177]; P = .018) and shorter ICU LOS (OR: 0.459 [95% CI, 0.229– 0.917]; P = .028) was observed. In a European study, the effect of the implementation of a neur- ocritical care protocol was studied among microsurgically clippedaSAH patients (n = 198, admitted between 1999 and 2003) com- pared to historical controls (n = 150, 1993–1994). The latter groupincluded a significantly higher percentage of severe aSAH patients(WFNS grades IV and V) compared to the historical group (47.0% vs15.3%, P < .0001) and WFNS grade V patients were not treated in the historical control group. While overall outcomes were simi- lar, the study showed significant improvement for the most severecases. In the historical group, all patients with WFNS grade V diedor survived in a vegetative state, as they were not treated withaneurysm surgery. In contrast, 35.1% of WFNS grade V patients inthe latter group (20 out of 57 patients) achieved a good functional outcome. The authors concluded that specialised neurocritical care is particularly beneficial for patients with high-grade aSAH. Contrarily, a German study included 755 aSAH patients (456 in aneurosurgical ICU, 2005–2013 vs 299 in a general ICU, 1990–2005),found that the type of ICU was neither associated with dischargeGOS nor 6-month GOS (OR: 1.45 [95% CI, 0.53–3.95]) for long-term outcome. In a North-American study the implementation of aneurointensivist team (n = 108 aSAH patients admitted between1998 and 2000) was neither associated with NICU mortality (HR1.39 [95% CI, 0.67–2.88]) nor in-hospital mortality (HR 1.48 [95% CI, 0.65–3.34]). However, NICU and hospital length of stay were significantly reduced (HR 1.60 [95% CI, 1.13–2.26] and HR 1.43 [95% CI, 1.01–2.03]). Due to limitations in study design—primarily retrospectiveobservational studies with historical control groups—alongwith changes in clinical care over time, variations in pre- hospital management and differences in the timing of aneurysmtreatment, the impact of specialised neurocritical care on patient outcomes is likely multifactorial.– Higher levels of evidencecan only be achieved through prospective randomised trials. ## Topic 9. Centre volume andnumber/volume of neurosurgeon and neurointerventionalist ## PICO 9a In adult patients with aSAH, does treatment in a high-volumecentre compared to a low-volume centre decrease the risk of poor functional outcome? ### Expert consensus statementWe suggest that all patients with spontaneous SAH are admitted or immediately transferred to centres that treat at least 70 patients with aSAH per year, or at least 35 patients with aSAH per year in remote areas where access is limited. Vote: 12/13 ### Analysis of current evidence The literature search found no randomised or otherwise con- trolled trials, but only retrospective or registry-based studies, which are discussed in the additional information section. ### Additional information We found 2 systematic reviews analysing studies on the relation- ship between hospital case volume and in-hospital mortality. The first review included studies published up to 2012 assessingthe relationship between hospital caseload and in-hospitalmortality for patients undergoing treatment after aneurysmal subarachnoid haemorrhage. This review included 4 studies,describing 36,600 patients. The quality of studies was graded aslow in 3 and very low in 1. A meta-analysis using a random effectsmodel showed a decrease in hospital mortality (OR: 0.77 [95%CI, 0.60–0.97]) in high-volume hospitals treating SAH patients.Removal of the study with very low quality increased the effectsize (OR: 0.68 [95% CI, 0.56–0.84]). The definition of hospitalvolume differed among studies. In one study, low volume wasdefined as 9 or fewer patients per year, whereas in another, itwas defined as fewer than 30 patients per year. Similarly, one study defined high volume as more than 20 patients annually, and another defined it as more than 50 patients a year. Apart from the non-uniform cut-off values for low- or high-volume centres, there was also uncertainty about the case-mix between centres, and no adjustment for baseline characteristics was not performed. The second systematic review included studies that reportedin-hospital mortality in SAH patients and provided an adjustedOR or core data on baseline characteristics, such as age, sex and co-morbidities, to calculate an adjusted OR. The 5 includedstudies were published between 2002 and 2019; 4 were of highmethodological quality according to the Newcastle–Ottawa Scale,and the fifth had a moderate quality. Three studies came fromAsia, and 2 from Europe and the United States. In total, the 5 stud- ies enrolled 46,186 patients. Crude in-hospital mortality rangedfrom 7.0% to 40%. High hospital case volume was associated withreduced in-hospital mortality (OR: 0.53; 95% CI, 0.42–0.68). Thisassociation was found in each included study separately, and wasconsistent in subgroups divided according to geographical region, treatment modality (surgical vs endovascular), proportion of sur- gical patients, sample size and annualised case volume grouping. ### Page 25 Studies dichotomised the annualised case volumes, or dividedthese into tertiles or quartiles, with the highest categories startingat 19, 30, 70 or 100 patients per year. For one study, the cut-offs were not reported. We also found one study that did not use in-hospital data foroutcome assessment, but mortality at 1 year after SAH. This studywas based on registries of Denmark, Norway and Sweden, andincluded 5773 SAH patients and 1807 patients with unruptured aneurysms admitted between 2002 and 2010 in 15 neurosurgi- cal centres. It used population-based death registries for out- come assessment in patients with SAH and unruptured intracra- nial aneurysms. For case volume load, the centres were dividedinto 3 tertiles (with < 36 patients per year in the lowest tertileand > 63 in the highest tertile). One-year mortality in patientswith aSAH was slightly higher with increasing case load (HR per10-patient increase, 1.04; 95% CI, 1.00–1.07) after adjusting forseveral baseline factors, but not SAH severity. One of the potentialexplanations for these discrepant results that the authors pro- vide is that, in these Scandinavian countries, all treatments ofintracranial aneurysms are performed at academic hospitals byspecialised cerebrovascular surgeons and interventional neuro- radiologists. In contrast to the somewhat worse outcome afterSAH in high volume centres, however, there was a trend towards better outcome for treatment of unruptured aneurysms in high volume centres in this study, which is not in line with this potential explanation. Others have argued that the worse outcome in high- volume centres is explained by selection bias, with high-volume centres accepting patients in poor clinical condition more often, and thus at higher risk of poor outcome. In conclusion, there is high consistency between studiesregarding a positive relationship between hospital caseloadand in-hospital outcomes. Also, throughout the range of criteriafor high-volume centres, there is consistency regarding highcase volume and in-hospital favourable outcomes. This relation remains even if the cut-off for high volume is based on high caseloads, such as 70 or even 100 patients per year. In the absence of RCTs and given the improbability that suchtrials will be conducted on this topic, there is an urgent needfor prospective comparative effectiveness studies to evaluatewhether patients admitted to high-volume centres experiencebetter outcomes than those treated at low-volume centres. In addition, these studies should aim to determine the optimal volume threshold for defining a centre as high-volume. ## PICO 9b In adult patients with aSAH, does aneurysm treatment by a high- volume neurosurgeon or neurointerventionalist, compared to alow-volume neurosurgeon or neurointerventionalist, decrease the risk of poor functional outcome? ### Expert consensus statementIn adult patients with aSAH, we suggest that aneurysms are repaired by neurosurgeons or neurointerventionalists who perform the treatment of choice in more than 30 patients with aneurysms (ruptured and unruptured) per year. Vote: 12/13 ### Analysis of current evidence The literature search found no controlled studies. ### Additional information For several common procedures, such as carotid endarterectomy,coronary artery bypass grafting, valve replacement and abdomi- nal aortic aneurysm repair, surgeon specialisation is an importantpredictor of operative mortality independent of volume in that specific procedure. The literature search revealed no such dataon intracranial aneurysm repair. We found one study that investigated the association betweenthe neurosurgeon’s scientific productivity and clinical outcomes following microsurgical clipping of ruptured aneurysms. Thestudy was a post-hoc analysis of 3307 patients from 162 centres in21 countries, who had undergone clipping of ruptured intracranialaneurysms by 147 neurosurgeons and who had participated indrug trials between 1990 and 1997. In this single study, patientsunder the care of neurosurgeons with higher H-indices had betterfunctional outcomes (P = 0.01) compared to neurosurgeons withlower H-indices, without any statistically significant difference in mortality. Neither the total number of publications nor possession of a graduate degree had an impact on outcomes. In the ESO guidelines on unruptured intracranial aneurysms itwas suggested to repair unruptured intracranial aneurysms only incentres performing the proposed treatment in > 30 patients with(ruptured or unruptured) aneurysms per year per neurosurgeon or neurointerventionalist. ## PICO 10 In adult patients with aSAH, does radiological follow-up beyond6 months after aneurysm treatment, compared to a maximumradiological follow-up duration of 6 months, decrease the risk of poor functional outcome?Evidence-based Recommendations Quality of evidence StrengthIn adult patients with aSAH, no recommendation can be made on radiological follow-up beyond 6 months after microsurgical or endovascular aneurysm treatment to decrease the risk of poor functional outcome.⊕ - ### Analysis of current evidence There are no completed RCTs or prospective cohort studiesinvestigating whether radiological follow-up beyond 6 monthsin adult patients with aSAH decreases the risk of poor functional ### Page 26 Expert consensus statements:1. In adult patients with aSAH who are treated with coils and adequate occlusion within 6 months, we suggest at least one additional radiological follow-up at or beyond 12 months after aneurysm repair to investigate potential aneurysm recanalization, as long as a potential re-treatment remains an option. Vote: 13/13 2. In adult patients with aSAH who are treated with microsurgical clipping and adequate occlusion within 6 months, we do not suggest further radiological follow-up to investigate potential aneurysm recanalization. Vote: 11/13 3. In adult patients with aSAH who have neck remnants or partially occluded aneurysms (irrespective of type of aneurysm treatment), we suggest radiological follow-up beyond 6 months after aneurysm treatment as long as a potential re-treatment remains an option. Vote: 13/13 4. In adult patients with aSAH who are treated with endovascular devices other than coils, we suggest radiological follow-up at least five years after treatment, regardless of the degree of occlusion, to ensure adequate long-term occlusion and as long as a potential re-treatment remains an option. Vote: 11/13 5. In adult patients with aSAH, we suggest radiological follow-up beyond 6 months after aneurysm treatment in order to evaluate for de novo aneurysms at 5-year intervals as long as a potential treatment remains an option, in those with a high-risk profile (such as young age, positive family history for aSAH, autosomal dominant polycystic kidney disease). Vote: 12/13outcome, compared to radiological follow-up only until 6 monthsafter aneurysm treatment. ### Additional information In the current literature, relevant studies are limited to theassessment of radiological follow-up beyond 6 months afteraneurysm treatment in adult patients with aSAH. There areno studies available addressing radiological follow-up within 6 months after aneurysm treatment for comparison. Recanalisation Recanalisation of a treated aneurysm can occur at different stageswith everything beyond 6 months being labelled as late recanal- isation. Data on late recanalisation stem from non-randomised,uncontrolled studies, which show high heterogeneity in follow- up duration, follow-up modality, definition of recanalisation and rupture status of the aneurysm, limiting the generalisability of the studies. A study enrolling 435 aSAH survivors after clipping, with atotal follow-up time of 5681 patient-years found a probabilityof 0.7% of re-occurrence within 10 years for patients without aresidual neck immediately after treatment, compared to 13.9% in patients with a neck remnant. These results were confirmed bya recent meta-analysis including 1167 patients (463 with rupturedaneurysms) treated first line with the smart coil device, whichshowed a late recanalisation rate of 10% (95% CI, 6%–17%).For the WEB device, late recanalisation rates of 11% and 11.5% were reported,, while for flow-diverters, rates of adequateocclusion were higher at 12 months compared to 6 months and ranged between 77% and 92%.– A WEB database studyevaluating 763 patients, of whom 230 had treatment of a rupturedintracranial aneurysm, found an occlusion rate of 65.1% during amean follow-up duration of 17.7 months, with 7.3% of the patients requiring re-treatment. On multivariate analysis, independentfactors negatively correlated with complete aneurysm occlusionat the last follow-up were being a former smoker(OR: 0.5; 95% CI,0.3–0.8), maximal aneurysm diameter (OR: 0.8; 95% CI, 0.7–0.8) and the presence of an aneurysm wall branch (OR: 0.4; 95% CI, 0.28–0.73). Recurrent SAH The best available evidence on long-term risk of recurrent aSAH(either from the target aneurysm, another aneurysm at baselineor from a de novo aneurysm after aSAH) comes from the ISAT trialwhich followed the UK cohort for 18 years. In this cohort, the risk ofrecurrent aSAH between 30 days and 1 year was 0.6% in the coilinggroup and 0.4% in the clipping group; between 1 and 5 years, itwas 0.021% and 0.006% and after 5 years, it was 0.5% and 0.3%,respectively. For the target aneurysm, the risk of recurrent aSAH was 1.6% in the coiling group and 0.5% in the clipping group sug- gesting a very limited clinical impact of prolonged surveillance.It may be that these numbers are an underestimation, since re- treatment may have prevented recurrent aSAH. In the long-termfollow-up study, no data on follow-up imaging and re-treatmentwere available. On the other hand, in the era that ISAT was per- formed, re-treatment was rarely conducted. We retrieved additional data from uncontrolled cohort studies.One study reported on 1001 patients with aSAH treated with coilor clip in 9 high-volume centres in the United States from 1996 to 1998. During a mean follow-up of 4 years, 19 post-proceduralre-ruptures occurred. This study suggests a strong correlation ofre-rupture risk and initial occlusion rate with higher rate of re- rupture in initially incompletely occluded aneurysms (overall risk:1.1% for complete occlusion, 2.9% for 91%–99% occlusion, 5.9%for 70%–90%, 17.6% for < 70%; P < .0001 in univariate and mul- tivariable analysis). In addition, long-term follow-up data (mean73.7 months) from a single-centre study including 570 patients with coil embolisation after aSAH suggests a rate of late re-rupture (defined as > 30 days after treatment) of 1.6%, which is in line with the ISAT data. De novo aneurysm formation De novo aneurysm formation is a second reason for extendedfollow-up. Studies on this topic are limited by incomplete follow- up, varying imaging modalities and a lack of standardisationin timing of imaging. This limits our understanding of the truerates of recurrence and/or re-rupture, particularly with the use ofnewer endovascular devices. A meta-analysis from 2018 includingpatients with and without SAH reported the overall incidence ofde novo aneurysm formation of 2% (95% CI, 2%–3%) over a mean follow-up time of 8.3 years. If a de novo aneurysm was found, 11.2% were detected in the first 5 years, and the majority (88.8%) after more than 5 years. This study did not find a statisticallysignificant difference in rates of de novo aneurysm formationbetween patients who had ruptured aneurysms and those withunruptured aneurysms. A recent meta-analysis including 9351patients from 19 cohort studies published between 1993 and 2021 found that during a follow-up period of 2.5–18.5 years, 304 (3.25%) patients developed a de novo aneurysm. Mainrisk factors were age < 60 years (RR: 1.41; 95% CI, 1.25–1.58),female sex (RR: 1.63; 95% CI, 1.27–2.08), smoking history (RR: 1.37; 95% CI, 1.07–1.80), family history of IAs (RR: 2.30; 95% CI, ### Page 27 1.32–4.00) and multiple IAs at initial diagnosis (RR: 1.69; 95% CI,1.11–2.58). In this paper a prediction model from those studieswas developed. This prediction model showed an increasing riskfor de novo aneurysms with an increasing risk score resulting ina 25% risk at scores of 16–23. Another study supported these riskfactors and found that stage 3 or greater chronic kidney disease in patients with autosomal dominant polycystic kidney disease as an additional risk factor for de novo aneurysms. Different follow-up modalities must be used for microsurgicalor endovascular therapy. As clips result in severe artefacts onMRI, only DSA or CTA are suitable for detecting recanalisation ora growing aneurysm remnant at the treated location. MRA is only useful for the detection of new aneurysms at other locations not affected by clip-related artefacts. In conclusion, these data indicate that (progressive) recanal- isation and recurrent SAH of a treated aneurysm or de novoaneurysm may occur beyond 6 months after aneurysm treatment.However, a beneficial effect of radiological follow-up beyond6 months after aneurysm treatment on outcome has not beenestablished. Most aneurysms with recanalisation will not ruptureduring a patient’s lifetime, while re-treatment carries a riskof complications that may affect outcome. It remains unclear whether the beneficial effect on prevention of recurrent aSAH outweighs the risk of complications from re-treatment. # Discussion We used the GRADE methodology to develop evidence-basedrecommendations and formulated expert consensus statementsin areas of uncertainty to assist physicians in decision-makingregarding patients with aSAH. All 15 evidence-based recommen- dations and 37 expert consensus statements are summarised in. Full consensus among the voting MWG members wasobtained on 16 expert consensus statements, and a majorityagreed on the other 21 statements. This ESO/EANS/ESMINTguideline on aSAH expands upon previous guidelines from the European Stroke Organisation (2013), American Heart Associ- ation/American Stroke Association (2023), and NeurocriticalCare Society (2023). The 2013 ESO guideline addressed themanagement of both unruptured intracranial aneurysms andsubarachnoid haemorrhage. In 2022, the ESO guideline was updated for unruptured intracranial aneurysms. Only a few evidence-based recommendations in this guidelineare supported by high-level evidence. These include the use oforal nimodipine (PICO 4) and treatment of the ruptured aneurysmby regular coiling when both regular coiling and microsurgicalclipping are equally suitable in patients who are in a good clin- ical condition (PICO 3). In addition, there were evidence-basedrecommendations with a moderate level of evidence against giv- ing antifibrinolytic drugs (PICO 1), tirilazad, statins, magnesiumsulphate, or ETRAs (all PICO 4). There was a low level of evi- dence for the routine use of lumbar drains (PICO 4). Although3 RCTs were performed investigating the effect of LD, we couldonly include data from 2 RCTs in a pooled analysis on functionaloutcome and concluded that no recommendation could be madeon the routine use of lumbar drains until more RCT data becomeavailable. Also for PICO 5, there was a low-level of evidence. This is particularly noteworthy given the widespread clinical use of rescue therapy (induced hypertension or endovascular treatment of vasospasm) in patients who develop DCI. Similarly, there was a very low-level of evidence for the use of endovascular techniques and devices other than regular coiling for the treatment of the ruptured aneurysm, despite their widespread use. In areas where more guidance was needed, expert consensus statements were developed to support clinical decision-making in routine practice. One of the major differences from the previous ESO guideline isthat we now address the use of balloon-assisted coiling, intrasac- cular devices, stent-assisted coiling and flow-diverting stents forthe treatment of the ruptured aneurysm. Although the ISAT trialdemonstrated that regular coiling is superior to microsurgicalclipping for (small neck) ruptured aneurysms that are equallysuitable for both approaches, it is often assumed that advancedendovascular techniques offer a similar advantage over microsur- gical clipping. However, this assumption has not been confirmedin an RCT. Studies in unruptured intracranial aneurysms showthat stent-assisted coiling and flowdiverting stents are associated with a higher risk of treatment complications compared to regular coiling. The ISAT-2 trial compared any endovascular treatment(>80% treated by balloon-assisted coiling) with microsurgicaltreatment of the ruptured intracranial aneurysm, but the trialwas prematurely terminated because of poor enrolment and was therefore underpowered to draw strong conclusions. The literature on endovascular treatment options for intracra- nial aneurysms primarily consists of case series or registries, mostof which are retrospective or sponsored by industry, and thefew comparative studies mostly have a non-randomised design.The only randomised comparison was severely underpoweredbecause it was stopped prematurely when only 14% of thepatients needed were included. The available studies also haveother methodological flaws. In a systematic review of 1356 studies with 410,993 patients, key outcomes were rarely clearly defined and were often incompletely reported. A definitionfor safety was provided in only 2% of studies, and only 0.1%specified a complication, mortality or morbidity rate below whicha procedure would qualify as safe. Definitions of effectivenesswere similarly uncommon: only 2% addressed this outcome at theaneurysm level, and none defined a threshold for ineffectiveness.Another review evaluating flow-diverting stents for unrupturedintracranial aneurysms reported industry involvement or conflicts of interest in 7 of 13 studies, highlighting the potential for bias in the published outcomes. We recommend investigator-initiatedRCTs in which the safety, efficacy and durability of new devicesare compared with existing treatment options, with predefinedoutcomes that are assessed by independent outcome assessors without industry involvement. In the absence of high-level evidence for the use of advancedendovascular treatments in situations where regular coiling of theruptured aneurysm is not possible, we formulated expert consen- sus statements in which it was suggested to have an interdisci- plinary discussion on the safety, effectiveness and durability ofthe microsurgical and endovascular options other than regularcoiling to decide upon the preferred strategy. If regular coiling isnot possible, we suggest that the multidisciplinary team discussesthe safety, effectiveness and durability of microsurgical and alter- native endovascular options to determine the preferred treatmentstrategy, given the limited comparative evidence available. Stent- assisted coiling has a less favourable safety profile in patients with a ruptured aneurysm, so we suggest that this treatment is only per- formed if other treatment options are not feasible. Flow diversion also has a less favourable safety profile and often does not result in ### Page 28 Table 3 Synoptic table of all recommendations and expert consensus statements.Recommendation Expert consensus statementPICO 1a: In adult patients with aSAH, does treatment with antifibrinolytic drugs compared to no antifibrinolytic drugs decrease the risk of poor functional outcome? 1. In adult patients with aSAH and systolic blood pressures higher than 160-180 mm Hg persisting after installment of analgesics, oral nimodipine and urinary catheter prior to aneurysm treatment, we suggest considering blood pressure lowering drugs to lower systolic blood pressure to around 160 mm Hg to reduce the risk of rebleeding. 2. If it is decided to give blood pressure lowering drugs, we suggest continuous infusion of short-acting drugs, e.g. labetalol, and avoiding diuretic drugs to maintain normovolemia. Care should be taken to ensure that the blood pressure reduction is gradual, with systolic blood pressure reduced cautiously over time (corresponding to no more than a 10% reduction in mean arterial pressure within the first 2 hours) to decrease the risk of DCI. In adult patients with aSAH, no recommendation can be made on the administration of blood pressure lowering drugs prior to treatment of the ruptured aneurysm to decrease the risk of poor functional outcome. Quality of evidence: Very lowStrength of recommendation:-⊕In adult patients with aSAH,we recommend against routine administration of antifibrinolytic drugs prior to treatment of the ruptured a aneurysm to decrease the risk of poor functional outcome. Strength of recommendation: StrongQuality of evidence: Moderate ⊕⊕⊕against interventionIn adult patients with aSAH, no recommendation can be made on treating the ruptured aneurysm as early as possible to decrease the risk of poor functional outcome. Quality of evidence: Very low ⊕⊕Strength of recommendation: -↑↑↑↑PICO 2: In adult patients with aSAH, does early aneurysm occlusion compared to no early aneurysm occlusion decrease the risk of poor functional outcome? In adult patients with aSAH, we suggest treatment of the ruptured aneurysm within 24 hours after ictus. The timing should be optimized to ensure a that the most dedicated team of experts is available when needed. PICO 1b: In adult patients with aSAH, does treatment with antihypertensive drugs compared to no antihypertensive drugs decrease the risk of poor functional outcome?⊕⊕⊕⊕ ### Page 29 Table 3 Continued.In adult patients with aSAH in good clinical condition (WFNS I-III) with aneurysms of either the anterior or posterior circulation that can be treated by either regular coiling (i.e. without adjunctive devices) or neurosurgical clipping, we recommend regular coiling as the preferred strategy to decrease the risk of poor functional outcome. Quality of evidence: High ⊕⊕⊕⊕Strength of recommendation: Strong for intervention ↑↑PICO 3b: In adult patients with aSAH, does any type of endovascular aneurysm treatment other than coiling compared to coiling of the ruptured aneurysm decrease the risk of poor functional outcome? PICO 3a: In adult patients with aSAH, does any type of endovascular aneurysm occlusion compared to neurosurgical aneurysm occlusion decrease the risk of poor functional outcome? 1. We suggest that all patients with aSAH are discussed in a an interdisciplinary manner, with at least one neurosurgeon and one neuro-interventionalist. 2. In adult patients with aSAH, we suggest the team discuss which modality would result in the best clinical outcome of the specific patient, with the safest and optimal occlusion of the specific aneurysm. 3. In adult patients with aSAH younger than 45 years of age, we suggest that the better long-term protection from clipping compared to coiling is taken into consideration for choosing the treatment modality of the aneurysm. 4. In adult patients with aSAH admitted in a poor clinical condition (defined as GCS < 13), we suggest a multidisciplinary approach to decide on type and timing of aneurysm treatment taking into account the (presumed) cause of the poor clinical condition. 5. In adult patients with aSAH and a poor or worsening clinical condition from a space-occupying intracerebral or subdural haematoma, we suggest immediate surgery for aneurysm clipping and haematoma removal. In adult patients with aSAH, no recommendation can be made on the use of endovascular treatment options other than regular coiling for treatment of the ruptured aneurysm to decrease the risk of poor functional outcome. Quality of evidence: Very low ⊕Strength of recommendation: - 1. Given the limited comparative evidence available, we suggest that in adult patients with subarachnoid haemorrhage from a ruptured aneurysm which cannot be treated with regular coiling, the multidisciplinary team safety, effectiveness, and durability of microsurgical and alternative endovascular options to determine the preferred treatment strategy. 2. In adult patients with aSAH, we suggest stent-assisted coiling in selected cases where other treatment options are not feasible. 3. In adult patients with aSAH, we suggest to reserve flow diversion as a last-line treatment option. ### Page 30 Table 3 Continued.PICO 4: In adult patients with aSAH, does any type of medical treatment aiming to reduce the risk of delayed cerebral ischaemia (DCI) compared to no such treatment decrease the risk of poor functional outcome? In adult patients with aSAH, no recommendation can be made on prophylactic treatment with antiplatelet drugs or lumbar drainage to decrease the risk of poor functional outcome until further data from RCT are available. Quality of evidence: Low ⊕⊕ ⊕Strength of recommendation: - In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, no recommendation can be made on hypertension induction to decrease the risk of poor functional outcome. Quality of evidence: Low ⊕⊕Strength of recommendation: - In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, we suggest considering induced hypertension, provided that the ruptured aneurysm is treated and after standard therapy has proven insufficient. Clinical contraindications and potential complications of induced hypertension should be considered. In adult patients with aSAH, we recommend prophylactic treatment with oral nimodipine to decrease the risk of poor functional outcome. Quality of evidence: High ⊕⊕⊕⊕Strength of recommendation: Strong for intervention ↑↑In adult patients with aSAH, we do not recommend prophylactic treatment with either tirilazad, statins, magnesium sulfate, or endothelin receptor antagonists to decrease the risk of poor functional outcome. Quality of evidence: Moderate ⊕⊕⊕Strength of recommendation: Strong against intervention↑↑PICO 5a: In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, does hypertension induction compared to no hypertension induction decrease the risk of poor functional outcome? ### Page 31 Table 3 Continued.In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, no recommendation can be made on endovascular treatment of vasospasm to decrease the risk of poor functional outcome. Quality of evidence: Low ⊕⊕⊕Strength of recommendation - PICO 6a: In adult patients with aSAH, does any type of neuroimaging compared to regular neurological examination decrease the risk of poor functional outcome? In adult patients with aSAH, no recommendation can be made on neuroimaging to decrease the risk of poor functional outcome. Quality of evidence: Very low ⊕Strength of recommendation: - 1. In adult patients with aSAH and clinical deterioration, we suggest plain head CT in combination with CT-Perfusion (CTP) imaging to detect the cause of deterioration. 2. In adult patients with aSAH who are neurologically not assessable but at high risk for DCI, we suggest plain head CT and CTP at least once between day 4 and 14. 3. In adult patients with aSAH, we do not suggest a routine DSA for screening of macrovascular vasospasm. 1. In adult patients with aSAH and clinical deterioration due to delayed cerebral schaemia in combination with refractory and severe vasospasm, we suggest considering intra-arterial pharmacological treatment as a rescue therapy in selected patients to decrease the risk of poor functional outcome. 2. In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia in combination with refractory severe vasospasm, the current evidence is insufficient to support the routine use of mechanical vasodilatation with balloon angioplasty. In selected cases, this approach may be considered as a last-line rescue treatment after careful multidisciplinary discussion of the potential risks and uncertain benefits. 3. In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia in combination with refractory severe vasospasm, the current data are insufficient to support the use of mechanical vasodilatation with temporary deployment of retrievable stents to of poor functional outcome. PICO 5b: In adult patients with aSAH and clinical deterioration due to delayed cerebral ischaemia, does endovascular treatment of vasospasm compared to no endovascular treatment decrease the risk of poor functional outcome? ### Page 32 Table 3 Continued.PICO 6b: In adult patients with aSAH, does any type of neuromonitoring compared to regular neurological examination decrease the risk of poor functional outcome? In adult patients with aSAH, no recommendation can be made on neuromonitoring to decrease the risk of poor functional outcome. Quality of evidence: Very low ⊕⊕Strength of recommendation: - 1. In adult patients with aSAH, no suggestion can be given on the use of TCD monitoring. 2. In adult patients with aSAH and radiological hydrocephalus who are neurologically not assessable, we suggest ICP monitoring via EVD if an EVD is in place. 3. In adult patients with aSAH without radiological hydrocephalus who are neurologically not assessable, no suggestion can be given on ICP monitoring. 4. In adult patients with aSAH who are neurologically not assessable, we do not suggest invasive multimodal neuromonitoring with continuous measurement of partial pressure of brain tissue oxygen (PbtO2) and/or microdialysis due to the uncertain risk/benefit ratio of these modalities. 5. In adult patients with aSAH who are neurologically not assessable, we do not suggest the routine use of continuous EEG monitoring. In adult patients with aSAH and hydrocephalus, no recommendation can be made on CSF diversion strategies to decrease the risk of poor functional outcome. Quality of evidence: Very low ⊕Strength of recommendation: - 1. In adult patients with aSAH who present with radiological hydrocephalus and a decreased level of consciousness, we suggest CSF drainage. 2. In adult patients with aSAH who present with obstructive hydrocephalus and a decreased level of consciousness, we suggest EVD placement. 3. In adult patients with aSAH who present with communicating hydrocephalus and a decreased level of consciousness, we suggest LD or repeated LPs as the strategy of first choice for CSF drainage. PICO 7: In adult patients with aSAH, does treatment of hydrocephalus (either by EVD, VP-shunt or lumbar drainage) compared to no treatment of hydrocephalus decrease the risk of poor functional outcome? ### Page 33 Table 3 Continued.4. In adult patients with aSAH who present with radiological hydrocephalus and a normal level of consciousness, we do not suggest CSF drainage. 5. In adult patients with aSAH who come at a point at which prolonged CSF drainage (by EVD, LD or repeated LPs) carries a higher risk of severe complications than placement of a permanent CSF diversion, we suggest permanent CSF diversion. 6. In adult patients with aSAH who present with symptomatic chronic hydrocephalus, we suggest permanent CSF diversion. PICO 8: In adult patients with aSAH, does treatment on a dedicated neuro-ICU or high care unit compared to a general ICU or high care unit decrease the risk of poor functional outcome? In adult patients with aSAH, no recommendation can be made on admission to a dedicated neuro-ICU or high care unit to decrease the risk of poor Quality of evidence: Very low ⊕⊕Strength of recommendation: - In adult patients with aSAH, we suggest admission and management in a dedicated neuro-ICU or high care unit to decrease the risk of poor functional outcome. PICO 9a: In adult patients with aSAH, does treatment in a high-volume centre compared to a low-volume centre decrease the risk of poor functional outcome? In adult patients with aSAH, no recommendation can be made on admission/transfer to a high- volume centre to decrease the risk of poor functional outcome. Quality of evidence: Very low ⊕Strength of recommendation: - We suggest that all patients with spontaneous SAH are admitted or immediately transferred to centres that treat at least 70 patients with aSAH per year, or at least 35 patients with aSAH per year in remote areas where access is limited. In adult patients with aSAH, no recommendation can be made on case-volume per neurosurgeon and neurointerventionalist to decrease the risk of poor functional outcome. In adult patients with aSAH, we suggest that aneurysms are repaired by neurosurgeons or neurointerventionalists who perform the treatment of choice in more than 30 patients with aneurysms (ruptured and unruptured) per year. PICO 9b: In adult patients with aSAH, does aneurysm treatment by a high-volume neurosurgeon or neurointerventionalistcompared to a low-volume neurosurgeon or neurointerventionalist decrease the risk of poor functional outcome? Quality of evidence: Very low ⊕⊕Strength of recommendation: - ### Page 34 Table 3 Continued.In adult patients with aSAH, no recommendation can be made on radiological follow-up beyond 6 months after microsurgical or endovascular aneurysm treatment to decrease the risk of poor functional outcome. Quality of evidence: Very low ⊕⊕Strength of recommendation: - 1. In adult patients with aSAH who are treated with coils and adequate occlusion within 6 months, we suggest at least one additional radiological follow-up at or beyond 12 months after aneurysm repair to investigate potential aneurysm recanalization, as long as a potential re-treatment remains an option. 2. In adult patients with aSAH who were treated with clip reconstruction and adequate occlusion within 6 months, we do not suggest further radiological follow-up to investigate potential aneurysm recanalization. 3. In adult patients with aSAH who have neck remnants or partially occluded aneurysms (irrespective of type of aneurysm treatment), we suggest radiological follow-up beyond 6 months after aneurysm treatment as long as a potential re-treatment remains an option. 4. In adult patients with aSAH who are treated with endovascular devices other than coils, we suggest radiological follow-up at least five years after treatment, regardless of the degree of occlusion, to ensure adequate long-term occlusion and as long as a potential re-treatment remains an option. 5. In adult patients with aSAH, we suggest radiological follow-up beyond 6 months after aneurysm treatment in order to evaluate for de novo aneurysms at 5-year intervals as long as a potential treatment remains an option, in those with a high-risk profile (such as young age, positive family history for aSAH, autosomal dominant polycystic kidney disease). PICO 10: In adult patients with aSAH, does a radiological follow-up beyond 6 months after aneurysm treatment compared to a maximum radiological follow-up duration of 6 months decrease the risk of poor functional outcome?Abbreviations: aSAH = aneurysmal subarachnoid haemorrhage; CSF = cerebrospinal fluid; CTP = CT perfusion; DCI = delayed cerebral ischaemia; DSA = digitalsubtraction angiography; EEG = electroencephalogram; EVD = external ventricular drain; GCS = Glasgow Coma Scale; ICP = intracranial pressure; ICU = intensive careunit; LD = lumbar drainage; LP = lumbar puncture; MAP = mean arterial pressure; PbtO 2 = partial pressure of brain tissue oxygen; PICO = population, intervention,comparator and outcome; TCD = transcranial Doppler; VP-shunt = ventriculoperitoneal shunt; WFNS = World Federation of Neurosurgical Societies.immediate aneurysm occlusion, which may lead to rebleeding ofthe ruptured aneurysm in the first few days. Therefore, we suggestto reserve flow diversion as a last-line treatment option. Another important difference to the 2013 ESO guideline isthe expert consensus statement on the timing of aneurysmtreatment. The 2013 guideline suggested treating the rupturedaneurysm “as early as logistically and technically possible toreduce the risk of rebleeding; if possible, it should be aimed to intervene at least within 72 h after onset of first symptoms.” This was based on a small randomised trial, which showed atrend towards better outcomes in patients operated within 3 daysafter the bleeding. The current ESO/EANS/ESMINT guidelinesuggests “treatment of the ruptured aneurysm within 24 hoursafter ictus; the timing should be optimised to ensure that themost dedicated team of experts is available when needed.”Nevertheless, the timing of aneurysm treatment remains a topicof debate. Although ultra-early aneurysm treatment within 24 hor even emergency aneurysm treatment within 6 h after ictus mayreduce the risk of rebleeding, it may be that such early aneurysm treatment, or related general anesthaesia, increases the extent of early brain injury and the risk of DCI, thereby offsetting the beneficial effect on rebleeding. However, the current literatureon aneurysm treatment within 24 h after ictus only consists oflow-quality observational studies. A randomised trial is requiredto determine the optimal timing of aneurysm treatment within the 72-h window, if deemed ethically acceptable. Also, since the publication of the 2013 ESO guidelines, theresults of 3 randomised trials on rescue therapy in patients with DCI have been published.,, The RCTs on hypertensioninduction and intra-arterial nimodipine showed no effect onfunctional outcome, while the other RCT on endovascular treatment of vasospasm showed worse outcomes in those treated ### Page 35 endovascularly compared with those receiving hypertensioninduction. However, each of these trials included less than 70patients and were thus underpowered to draw strong conclusionsand to formulate evidence-based recommendations. Althoughsome people may feel that it is unethical to include patients withDCI in an RCT to investigate the effect of rescue therapy, and thuswithhold rescue therapy in the control arm of the trial, the resultsof the 3 available RCTs show that new trials on this topic are urgently needed. This ESO/EANS/ESMINT guideline committee on aSAH endorses the conduct of future RCTs to definitively assess the effects of hypertension induction or endovascular treatment of vasospasm in patients with aSAH who develop DCI. We also need to address certain limitations. First, for mostPICOs, no data from RCTs were available to develop evidence- based recommendations based on high-level evidence. Forthe expert consensus statements, we often used data fromobservational studies, which were at high risk of bias. Second,the proposed minimum volumes for centres (70 aSAH patientsper year, or 35 per year for centres in remote areas) and for interventionalists (30 procedures per year, in either ruptured or unruptured aneurysms) may appear high. However, they are consistent with the growing body of evidence demon- strating improved outcomes with higher aneurysm treatment volumes.– The majority (12/13 votes) of the MWG agreed thatcentralised and specialised care is necessary for improving patientoutcomes. In conclusion, this guideline offers up-to-date, evidence-basedrecommendations and expert consensus statements for the man- agement of patients with aSAH. Given that the majority of PICOsare supported by low-level, very low-level or no evidence, westrongly encourage the conduct of RCTs or well-designed prospec- tive comparative studies focusing on clinically relevant outcomes related to the diagnosis, prevention and treatment of complica- tions following aSAH. # Acknowledgements# Acknowledgements The authors would like to thank the ESO staff, Yvonne Brüchert,for excellent administrative support, the Chair and Co-chair ofthe ESO Guidelines Board, Georgios Tsivgoulis and Diana Aguiarde Sousa, for their support during the conduct of the guidelineproject, Professor Giuseppe Citerio for his help with PICO 1 until he had to step down because of other obligations, and Sofia Tsokani for her help with the meta-analyses and generation of forestplots. # Author contributions All PICO leaders and the guideline chairs were involved in writingthe first draft of the manuscript. L.H. conducted the statisticalanalyses. All authors reviewed and edited the manuscript and approved the final version of the manuscript. # Supplemental material is available at European Stroke Journalonline. # Conflicts of interest All authors have completed a declaration of competing interestsand details are available in. # Funding Funding for the development of these guidelines was providedby the European Stroke Organisation, Basel, Switzerland. Theauthors did not receive financial support for the development, writing and/or publication of this guideline. # Ethical approval Ethical approval was not necessary for the work described in this article. # References Etminan N, Chang H-S, Hackenberg K, et al. Worldwide inci- dence of aneurysmal subarachnoid hemorrhage accordingto region, time period, blood pressure, and smoking preva- lence in the population: a systematic review and meta- analysis. JAMA Neurol. 2019;76:588-597. 2. Collaborators GGSHRF. Global, regional, and national bur- den of nontraumatic subarachnoid hemorrhage: the globalburden of disease study 2021. JAMA Neurol. 2025;82:765-787. Collaborators GGSHRF Roos YBWEM, de Haan RJ, Beenen LFM, Groen RJM, AlbrechtKW, Vermeulen M. Complications and outcome in patientswith aneurysmal subarachnoid haemorrhage: a prospectivehospital based cohort study in the Netherlands. J Neurol Neurosurg Psychiatry. 2000;68:337-341. Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, RinkelG. European Stroke Organisation guidelines for the manage- ment of intracranial aneurysms and subarachnoid haemor- rhage. Cerebrovasc Dis. 2013;35:93-112. Steiner T, Dichgans M, Norrving B, et al. European StrokeOrganisation (ESO) standard operating procedure forthe preparation and publishing of guidelines. Eur Stroke J. 2021;6:CXXII-CXXXIV. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knot- tnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011; 64:380-382. Vergouwen MD, Etminan N, Ilodigwe D, Macdonald RL. Lowerincidence of cerebral infarction correlates with improvedfunctional outcome after aneurysmal subarachnoid hemor- rhage. J Cereb Blood Flow Metab. 2011;31:1545-1553. Hunt WE, Hess RM. Surgical risk as related to time of inter- vention in the repair of intracranial aneurysms. J Neurosurg. 1968;28:14-20. Report of World Federation of Neurological Surgeons Com- mittee on a Universal Subarachnoid Hemorrhage Grad- ### Page 36 ing Scale. J Neurosurg. 1988;68:989-990. Balduzzi S, Rücker G, Schwarzer G. How to perform ameta-analysis with R: a practical tutorial. BMJ Mental Health. 2019;22:153-160. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revisedtool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. Harrison JK, Reid J, Quinn TJ, Shenkin SD. Using qualityassessment tools to critically appraise ageing research: a guide for clinicians. Age Ageing. 2016;46:359-365. Girvin JP. The use of antifibrinolytic agents in the pre- operative treatment of ruptured intracranial aneurysms.Trans Am Neurol Assoc. 1973;98:150-152. Roos Y. Antifibrinolytic treatment in subarachnoid hemor- rhage: a randomized placebo-controlled trial. STAR Study Group. Neurology. 2000;54:77-82. Chandra B. Treatment of subarachnoid hemorrhage fromruptured intracranial aneurysm with tranexamic acid: a double-blind clinical trial. Ann Neurol. 1978;3:502-504. Chowdhary UM, Sayed K. Prevention of early recurrence ofaneurysmal subarchnoid haemorrhage by tranexamic acid:a controlled clinical trial. Vasc Surg. 1986;20:8-13. Fodstad H, Forssell Å, Liliequist B, Schannong M. Antifibri- nolysis with tranexamic acid in aneurysmal subarachnoidhemorrhage: a consecutive controlled clinical trial. Neuro- surgery. 1981;8:158-165. Kaste M, Ramsay M. Tranexamic acid in subarachnoid hem- orrhage. A double-blind study. Stroke. 1979;10:519-522. Maurice-Williams RS. Prolonged antifibrinolysis: an effectivenon-surgical treatment for ruptured intracranial aneurysms?Br Med J. 1978;1:945-947. Hillman J, Fridriksson S, Nilsson O, Yu Z, Säveland H, Jakob- sson K-E. Immediate administration of tranexamic acid andreduced incidence of early rebleeding after aneurysmal sub- arachnoid hemorrhage: a prospective randomized study.J Neurosurg. 2002;97:771-778. Tsementzis SA, Hitchcock ER, Meyer CH. Benefits and risksof antifibrinolytic therapy in the management of rupturedintracranial aneurysms. A double-blind placebo-controlled study. Acta Neurochir. 1990;102:1-10. Vermeulen M, Lindsay KW, Murray GD, et al. Antifibrinolytictreatment in subarachnoid hemorrhage. New Engl J Med. 1984;311:432-437. Post R, Germans MR, Tjerkstra MA, et al. Ultra-early tranex- amic acid after subarachnoid haemorrhage (ULTRA): a ran- domised controlled trial. Lancet. 2021;397:112-118. van Rossum J, Wintzen AR, Endtz LJ, Schoen JHR, deJonge H. Effect of tranexamic acid on rebleeding after sub- arachnoid hemorrhage: a double-blind controlled clinical trial. Ann Neurol. 1977;2:242-245. Germans MR, Dronkers WJ, Baharoglu MI, et al. Antifibri- nolytic therapy for aneurysmal subarachnoid haemorrhage.Cochrane Database Syst Rev. 2022;11:CD001245. Tjerkstra MA, Post R, Germans MR, et al. Tranexamicacid after aneurysmal subarachnoid hemorrhage. Neu- rology. 2022;99:e2605-e2614. Tjerkstra MA, Post R, Germans MR, et al. Ultra-early andshort-term tranexamic acid treatment in patients with good- and poor-grade aneurysmal subarachnoid hemorrhage.Neurology. 2024;102:e209169. Germans MR, Tjerkstra MA, Post R, et al. Impact of timeto start of tranexamic acid treatment on rebleed riskand outcome in aneurysmal subarachnoid hemorrhage.Eur Stroke J. 2024;9:658-666. Wijdicks EFM, Vermeulen M, Murray GD, Hijdra A, vanGijn J. The effects of treating hypertension following aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg. 1990;92:111-117. Oheda M, Inamasu J, Moriya S, et al. Early rebleeding inpatients with subarachnoid haemorrhage under intensive blood pressure management. J Clin Neurosci. 2015;22:1338- 1342. Duangthongphon P, Souwong B, Munkong W, KitkhuandeeA. Results of a preventive rebleeding protocol in patientswith ruptured cerebral aneurysm: a retrospective cohort study. Asian J Neurosurg. 2019;14:748-753. Calviere L, Gathier CS, Rafiq M, et al. Rebleeding afteraneurysmal subarachnoid hemorrhage in two centers usingdifferent blood pressure management strategies. Front Neurol. 2022;13:836268. Öhman J, Heiskanen O. Timing of operation for rup- tured supratentorial aneurysms: a prospective randomized study. J Neurosurg. 1989;70:55-60. Rawal S, Alcaide-Leon P, Macdonald RL, et al. Meta-analysisof timing of endovascular aneurysm treatment in subarach- noid haemorrhage: inconsistent results of early treatment within 1 day. J Neurol Neurosurg Psychiatry. 2017;88:241- 248. Yao Z, Hu X, Ma L, You C, He M. Timing of surgery for aneurys- mal subarachnoid hemorrhage: a systematic review andmeta-analysis. Int J Surg. 2017;48:266-274. Zhao B, Rabinstein A, Murad MH, Lanzino G, Panni P,Brinjikji W. Surgical and endovascular treatment of poor- grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg Sci. 2017;61:403-415. ### Page 37 Han Y, Ye F, Long X, et al. Ultra-early treatment for poor- grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. World Neurosurg. 2018;115:e160- e171. Linzey JR, Williamson C, Rajajee V, Sheehan K, ThompsonBG, Pandey AS. Twenty-four–hour emergency interventionversus early intervention in aneurysmal subarachnoid hem- orrhage. J Neurosurg. 2018;128:1297-1303. Tack RW, Vergouwen MD, van der Schaaf I, van der ZwanA, Rinkel GJ, Lindgren AE. Preventable poor outcome fromrebleeding by emergency aneurysm occlusion in patients with aneurysmal subarachnoid haemorrhage. Eur Stroke J. 2019;4:240-246. Lindgren A, Vergouwen MDI, van der Schaaf I, et al.Endovascular coiling versus neurosurgical clipping for peo- ple with aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2018;8:CD003085. McDougall CG, Spetzler RF, Zabramski JM, et al. The barrowruptured aneurysm trial: clinical article. J Neurosurg. 2012; 116:135-144. Mitchell P, Kerr R, Mendelow AD, Molyneux A. Could laterebleeding overturn the superiority of cranial aneurysm coilembolization over clip ligation seen in the international sub- arachnoid aneurysm trial? J Neurosurg. 2008;108:437-442. Darsaut TE, Lecaros N, Comby P-O, et al. A randomized trialcomparing endovascular and surgical management of rup- tured intracranial aneurysms excluded from previous trials.J Neurosurg. 2025;142:1794-1802. Bodily KD, Cloft HJ, Lanzino G, Fiorella DJ, White PM, KallmesDF. Stent-assisted coiling in acutely ruptured intracranialaneurysms: a qualitative, systematic review of the litera- ture. Am J Neuroradiol. 2011;32:1232-1236. Zhang X, Zuo Q, Tang H, et al. Stent assisted coiling ver- sus non-stent assisted coiling for the management of rup- tured intracranial aneurysms: a meta-analysis and system- atic review. J Neurointerv Surg. 2019;11:489-496. Li G, Ding S, Wang J, et al. The safety and efficacy of stent- assisted coiling for acutely ruptured cerebral aneurysms:a multicenter prospective registry study (SAVE). Int J Surg. 2025;111:3876-3885. Shapiro M, Babb J, Becske T, Nelson PK. Safety and effi- cacy of adjunctive balloon remodeling during endovasculartreatment of intracranial aneurysms: a literature review. Am J Neuroradiol. 2008;29:1777-1781. Sluzewski M, van Rooij WJ. Is the risk of balloon assistanceunderinflated? Am J Neuroradiol. 2008;29:1782. Henkes H, Fischer S, Weber W, et al. Endovascular coil occlu- sion of 1811 intracranial aneurysms: early angiographic andclinical results. Neurosurgery. 2004;54:268-285. Sluzewski M, Van Rooij WJ, Beute GN, Nijssen PC. Balloon- assisted coil embolization of intracranial aneurysms: inci- dence, complications, and angiography results. J Neu- rosurg. 2006;105:396-399. Pierot L, Cognard C, Anxionnat R, Ricolfi F. Remodelingtechnique for endovascular treatment of ruptured intracra- nial aneurysms had a higher rate of adequate postopera- tive occlusion than did conventional coil embolization with comparable safety. Radiology. 2011;258:546-553. Cagnazzo F, di Carlo DT, Cappucci M, Lefevre P-H, CostalatV, Perrini P. Acutely ruptured intracranial aneurysms treatedwith flow-diverter stents: a systematic review and meta- analysis. Am J Neuroradiol. 2018;39:1669-1675. Maroufi SF, Fallahi MS, Waqas M, Levy EI. Comparisonbetween Woven EndoBridge and coiling with and withoutstent assistance for intracranial bifurcation and wide-neckaneurysms: a comprehensive systematic review and meta- analysis. J Neurosurg. 2024;141:1026-1039. Spelle L, Herbreteau D, Caroff J, et al. CLinical Assessmentof WEB device in Ruptured aneurYSms (CLARYS): results of1-month and 1-year assessment of rebleeding protection and clinical safety in a multicenter study. J Neurointerv Surg. 2022;14:807-814. Spelle L, Herbreteau D, Caroff J, et al. CLinical Assessmentof WEB device in Ruptured aneurYSms (CLARYS): 12-monthangiographic results of a multicenter study. J Neurointerv Surg. 2023;15:650-654. Pickard JD, Murray GD, Illingworth R, et al. Effect of oralnimodipine on cerebral infarction and outcome after sub- arachnoid haemorrhage: British aneurysm nimodipine trial.Br Med J. 1989;298:636-642. Vergouwen MDI, Vermeulen M, van Gijn J, et al. Definitionof delayed cerebral ischemia after aneurysmal subarachnoidhemorrhage as an outcome event in clinical trials and obser- vational studies. Stroke. 2010;41:2391-2395. Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M,Viars P. Prevention of vasospasm in subarachnoid haemor- rhage. A controlled study with nimodipine. Acta Neurochir. 1986;82:110-114. Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm—acontrolled trial of nimodipine in patients with subarachnoidhemorrhage. New Engl J Med. 1983;308:619-624. Mee E, Dorrance D, Lowe D, Neil-Dwyer G. Controlledstudy of nimodipine in aneurysm patients treated early after subarachnoid hemorrhage. Neurosurgery. 1988;22: 484-491. Öhman J, Heiskanen O. Effect of nimodipine on the outcomeof patients after aneurysmal subarachnoid hemorrhage andsurgery. J Neurosurg. 1988;69:683-686. ### Page 38 Petruk KC, West M, Mohr G, et al. Nimodipine treat- ment in poor-grade aneurysm patients: results of a mul- ticenter double-blind placebo-controlled trial. J Neuro- surg. 1988;68:505-517. Öhman J, Servo A, Heiskanen O. Long-term effects ofnimodipine on cerebral infarcts and outcome after aneurys- mal subarachnoid hemorrhage and surgery. J Neurosurg. 1991;74:8-13. Haley EC, Kassell NF, Torner JC, Truskowski LL, German- son TP. A randomized trial of two doses of nicardipinein aneurysmal subarachnoid hemorrhage: a report of the cooperative aneurysm study. J Neurosurg. 1994;80:788-796. Barker FG, Ogilvy CS. Efficacy of prophylactic nimodipinefor delayed ischemic deficit after subarachnoid hemorrhage:a metaanalysis. J Neurosurg. 1996;84:405-414. Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calciumantagonists for aneurysmal subarachnoid haemorrhage.Cochrane Database Syst Rev. 2007;3:CD000277. Guang Jian L, Jie L, Li Ping Z, et al. Meta-analysis of theeffectiveness and safety of prophylactic use of nimodipinein patients with an aneurysmal subarachnoid haemorrhage.CNS Neurol Disord Drug Targets. 2011;10:834-844. Kassell NF, Haley EC, Apperson-Hansen C, Alves WM. Ran- domized, double-blind, vehicle-controlled trial of tirilazadmesylate in patients with aneurysmal subarachnoid hem- orrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg. 1996;84:221-228. Haley EC, Kassell NF, Alves WM, Weir BKA, Hansen CA.Phase II trial of tirilazad in aneurysmal subarachnoid hemor- rhage: a report of the cooperative aneurysm study. J Neuro- surg. 1995;82:786-790. Haley EC, Kassell NF, Apperson-Hansen C, Maile MH, AlvesWM. A randomized, double-blind, vehicle-controlled trial oftirilazad mesylate in patients with aneurysmal subarachnoidhemorrhage: a cooperative study in North America. J Neuro- surg. 1997;86:467-474. Lanzino G, Kassell NF, Dorsch NWC, et al. Double-blind,randomized, vehicle-controlled study of high-dose tirilazadmesylate in women with aneurysmal subarachnoid hemor- rhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg. 1999;90:1011-1017. Lanzino G, Kassell NF. Double-blind, randomized, vehicle- controlled study of high-dose tirilazad mesylate in womenwith aneurysmal subarachnoid hemorrhage. Part II. A coop- erative study in North America. J Neurosurg. 1999;90:1018- 1024. Zhang S, Wang L, Liu M, Wu B. Tirilazad for aneurysmalsubarachnoid haemorrhage. Cochrane Database Syst Rev. 2010;2:CD006778. Hisada T, Ayaori M, Ohrui N, et al. Statin inhibits hypoxia- induced endothelin-1 via accelerated degradation ofHIF-1 α in vascular smooth muscle cells. Cardiovasc Res. 2012;95:251-259. Chen JLM, Zhu X, Chen L, et al. Atorvastatin reduces cerebralvasospasm and infarction after aneurysmal subarachnoidhemorrhage in elderly Chinese adults. Aging (Albany NY). 2020;12:2939-2951. Lynch JR, Wang H, McGirt MJ, et al. Simvastatin reducesvasospasm after aneurysmal subarachnoid hemorrhage.Stroke. 2005;36:2024-2026. Tseng M-Y, Czosnyka M, Richards H, Pickard JD, KirkpatrickPJ. Effects of acute treatment with pravastatin on cerebralvasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage.Stroke. 2005;36:1627-1632. Chou SH-Y, Smith EE, Badjatia N, et al. A randomized,double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke. 2008;39:2891-2893. Naraoka M, Matsuda N, Shimamura N, et al. Long-actingstatin for aneurysmal subarachnoid hemorrhage: a ran- domized, double-blind, placebo-controlled trial. J Cereb Blood Flow Metab. 2018;38:1190-1198. Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, MurrayGD. Simvastatin in aneurysmal subarachnoid haemorrhage(STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13:666-675. Wong GKC, Wong A, Zee BCY, et al. Cognitive outcome inacute simvastatin treatment for aneurysmal subarachnoid hemorrhage: a propensity matched analysis. J Neurol Sci. 2015;358:58-61. Diringer MN, Dhar R, Scalfani M, et al. Effect of high-dosesimvastatin on cerebral blood flow and static autoregulationin subarachnoid hemorrhage. Neurocrit Care. 2016;25:56-63. Vergouwen MD, Meijers JC, Geskus RB, et al. Biologic effectsof simvastatin in patients with aneurysmal subarachnoidhemorrhage: a double-blind, placebo-controlled random- ized trial. J Cereb Blood Flow Metab. 2009;29:1444-1453. Garg K, Sinha S, Kale SS, et al. Role of simvastatin in pre- vention of vasospasm and improving functional outcomeafter aneurysmal sub-arachnoid hemorrhage: a prospective,randomized, double-blind, placebo-controlled pilot trial.Br J Neurosurg. 2013;27:181-186. Sillberg VAH, Wells GA, Perry JJ. Do statins improveoutcomes and reduce the incidence of vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2008;39:2622-2626. Bohara S, Gaonkar VB, Garg K, et al. Effect of statins onfunctional outcome and mortality following aneurysmal ### Page 39 subarachnoid hemorrhage—results of a meta-analysis,metaregression and trial sequential analysis. Clin Neurol Neurosurg. 2021;207:106787. Liu H, Xu X. Effect of simvastatin in patients with aneurysmalsubarachnoid hemorrhage: a systematic review and meta- analysis. Am J Emerg Med. 2017;35:1940-1945. Akhigbe T, Zolnourian A, Bulters D. Cholesterol-reducingagents for treatment of aneurysmal subarachnoid hem- orrhage: systematic review and meta-analysis of random- ized controlled trials. World Neurosurg. 2017;101:476-485. Shen J, Huang K-Y, Zhu Y, et al. Effect of statin treatmenton vasospasm-related morbidity and functional outcomein patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2017; 127:291-301. Shen J, Shen J, Zhu K, Zhou H, Tian H, Yu G. Efficacyof statins in cerebral vasospasm, mortality, and delayedcerebral ischemia in patients with aneurysmal subarachnoidhemorrhage: a systematic review and meta-analysis of randomized controlled trials. World Neurosurg. 2019; 131:e65-e73. Vergouwen MDI, de Haan RJ, Vermeulen M, Roos YBWEM.Effect of statin treatment on vasospasm, delayed cere- bral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2010;41: e47-e52. Kunze E, Lilla N, Stetter C, Ernestus R-I, Westermaier T.Magnesium protects in episodes of critical perfusion after aneurysmal SAH. Transl Neurosci. 2018;9:99-105. Wong GKC, Chan MTV, Boet R, Poon WS, Gin T. Intra- venous magnesium sulfate after aneurysmal subarachnoidhemorrhage: a prospective randomized pilot study. J Neuro- surg Anesthesiol. 2006;18:142-148. Muroi C, Terzic A, Fortunati M, Yonekawa Y, Keller E. Magne- sium sulfate in the management of patients with aneurys- mal subarachnoid hemorrhage: a randomized, placebo- controlled, dose-adapted trial. Surg Neurol. 2008;69:33-39. Westermaier T, Stetter C, Vince GH, et al. Prophylactic intra- venous magnesium sulfate for treatment of aneurysmal sub- arachnoid hemorrhage: a randomized, placebo-controlled, clinical study. Crit Care Med. 2010;38:1284-1290. Leijenaar JF, Mees SMD, Algra A, Van Den Bergh WM, RinkelGJE. Effect of magnesium treatment and glucose levels ondelayed cerebral ischemia in patients with subarachnoidhemorrhage: a substudy of the magnesium in aneurys- mal subarachnoid haemorrhage trial (MASH-II). Int J Stroke. 2015;10:108-112. Veyna RS, Seyfried D, Burke DG, et al. Magnesium sul- fate therapy after aneurysmal subarachnoid hemorrhage.J Neurosurg. 2002;96:510-514. van den Bergh WM. Magnesium sulfate in aneurysmal sub- arachnoid hemorrhage. Stroke. 2005;36:1011-1015. Schmid-Elsaesser R, Kunz M, Zausinger S, PruecknerS, Briegel J, Steiger H-J. Intravenous magnesiumversus nimodipine in the treatment of patients with aneurysmal subarachnoid hemorrhage: a randomized study. Neurosurgery. 2006;58:1054-1065. Mees SMD, Algra A, Vandertop WP, et al. Magnesium foraneurysmal subarachnoid haemorrhage (MASH-2): a ran- domised placebo-controlled trial. Lancet. 2012;380:44-49. Akdemir H, Kulakszoğlu EO, Tucer B, Menkü A, PostalcL, Günald Ö. Magnesium sulfate therapy for cerebralvasospasm after aneurysmal subarachnoid hemorrhage.Neurosurg Q. 2009;19:35-39. Wong GKC, Poon WS, Chan MTV, et al. Intravenous mag- nesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH). Stroke. 2010;41:921-926. Bradford CM, Finfer S, O’Connor A, et al. A randomisedcontrolled trial of induced hypermagnesaemia following aneurysmal subarachnoid haemorrhage. Crit Care Resusc. 2013;15:119-125. Ma L, Liu W-G, Zhang J-M, Chen G, Fan J, Sheng H-S.Magnesium sulphate in the management of patients withaneurysmal subarachnoid haemorrhage: a meta-analysis of prospective controlled trials. Brain Inj. 2010;24:730-735. Dorhout Mees SM, Algra A, Wong GKC, et al. Early mag- nesium treatment after aneurysmal subarachnoid hemor- rhage. Stroke. 2015;46:3190-3193. Reddy D, Fallah A, Petropoulos J-A, Farrokhyar F, MacdonaldRL, Jichici D. Prophylactic magnesium sulfate for aneurys- mal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care. 2014;21:356-364. Zhao X-D, Zhou Y-T, Zhang X, Zhuang Z, Shi J-X. A meta anal- ysis of treating subarachnoid hemorrhage with magnesiumsulfate. J Clin Neurosci. 2009;16:1394-1397. Golan E, Vasquez DN, Ferguson ND, Adhikari NKJ, ScalesDC. Prophylactic magnesium for improving neurologic out- come after aneurysmal subarachnoid hemorrhage: system- atic review and meta-analysis. J Crit Care. 2013;28:173-181. Wong GKC, Boet R, Poon WS, et al. Intravenousmagnesium sulphate for aneurysmal subarachnoidhemorrhage: an updated systemic review and meta-analysis. Crit Care. 2011;15:R52. Wong GK, Chan MT, Gin T, Poon WS. Intravenous magnesiumsulfate after aneurysmal subarachnoid hemorrhage: currentstatus. Acta Neurochir Suppl. 2011;110(Pt 2):169-73. Macdonald RL, Higashida RT, Keller E, et al. Randomized trialof clazosentan in patients with aneurysmal subarachnoidhemorrhage undergoing endovascular coiling. Stroke. 2012;43:1463-1469. ### Page 40 Shaw MDM, Vermeulen M, Murray GD, Pickard JD, Bell BA,Teasdale GM. An efficacy and safety study of the ETA/Breceptor antagonist TAK-044 in subarachnoid hemorrhage.J Neurosurg. 2000;93:992-997. Macdonald RL, Higashida RT, Keller E, et al. Clazosentan,an endothelin receptor antagonist, in patients withaneurysmal subarachnoid haemorrhage undergoingsurgical clipping: a randomised, double-blind, placebo- controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011;10:618-625. Fujimura M, Joo J-Y, Kim J-S, Hatta M, Yokoyama Y,Tominaga T. Preventive effect of clazosentan againstcerebral vasospasm after clipping surgery for aneurysmalsubarachnoid hemorrhage in Japanese and Korean patients.Cerebrovasc Dis. 2017;44:59-67. Endo H, Hagihara Y, Kimura N, et al. Effects of clazosen- tan on cerebral vasospasm–related morbidity and all-causemortality after aneurysmal subarachnoid hemorrhage: two randomized phase 3 trials in Japanese patients. J Neu- rosurg. 2022;137:1707-1717. Vajkoczy P, Meyer B, Weidauer S, et al. Clazosentan (AXV- 034343), a selective endothelin a receptor antagonist, inthe prevention of cerebral vasospasm following severeaneurysmal subarachnoid hemorrhage: results of a random- ized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg. 2005;103:9-17. Macdonald RL, Kassell NF, Mayer S, et al. Clazosentan toovercome neurological ischemia and infarction occurringafter subarachnoid hemorrhage (CONSCIOUS-1). Stroke. 2008;39:3015-3021. Mayer SA, Bruder N, Citerio G, et al. REACT: a random- ized trial to assess the efficacy and safety of clazosentanfor preventing clinical deterioration due to delayed cere- bral ischemia after aneurysmal subarachnoid hemorrhage.J Neurosurg. 2025;142:98-109. Guo J, Shi Z, Yang K, Tian JH, Jiang L. Endothelin recep- tor antagonists for subarachnoid hemorrhage. Cochrane Database Syst Rev. 2012;9:CD008354. Song J, Xue Y-Q, Wang Y-J, Xu P, Sun D-K, Chen W. Anupdate on the efficacy and safety profile of clazosentan incerebral vasospasm after aneurysmal subarachnoid hem- orrhage: a meta-analysis. World Neurosurg. 2019;123:e235- e244. Rong W-L, Xiao X, Zhao J-L, Yang X-W, Hu Z-L, Li M-H. Differ- ent doses of clazosentan for aneurismal subarachnoid hem- orrhage: a meta-analysis of randomized controlled trials.Am J Ther. 2018;25:e652-e660. Wang X, Li YM, Li WQ, Huang CG, Lu YC, Hou LJ. Effect ofclazosentan in patients with aneurysmal subarachnoid hem- orrhage: a meta-analysis of randomized controlled trials.PLoS One. 2012;7:e47778. Kramer A, Fletcher J. Do endothelin-receptor antagonistsprevent delayed neurological deficits and poor outcomesafter aneurysmal subarachnoid hemorrhage? Stroke. 2009;40:3403-3406. Ma J, Huang S, Ma L, Liu Y, Li H, You C. Endothelin-receptorantagonists for aneurysmal subarachnoid hemorrhage: anupdated meta-analysis of randomized controlled trials. Crit Care. 2012;16:R198. Shen J, Pan J-W, Fan Z-X, Xiong X-X, Zhan R-Y. Dissociationof vasospasm-related morbidity and outcomes in patientswith aneurysmal subarachnoid hemorrhage treated withclazosentan: a meta-analysis of randomized controlled tri- als: a review. J Neurosurg. 2013;119:180-189. Vergouwen MDI, Algra A, Rinkel GJE. Endothelin receptorantagonists for aneurysmal subarachnoid hemorrhage.Stroke. 2012;43:2671-2676. Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, RoosYB. Microthrombosis after aneurysmal subarachnoid hem- orrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab. 2008;28:1761-1770.. Suzuki S, Sayama T, Nakamura T, et al. Cilostazol improvesoutcome after subarachnoid hemorrhage: a preliminary report. Cerebrovasc Dis. 2011;32:89-93. Senbokuya N, Kinouchi H, Kanemaru K, et al. Effects ofcilostazol on cerebral vasospasm after aneurysmal sub- arachnoid hemorrhage: a multicenter prospective, random- ized, open-label blinded end point trial: clinical article. J Neurosurg. 2013;118:121-130. Sugimoto K, Nomura S, Shirao S, et al. Cilostazol decreasesduration of spreading depolarization and spreadingischemia after aneurysmal subarachnoid hemorrhage.Ann Neurol. 2018;84:873-885. Matsuda N, Naraoka M, Ohkuma H, et al. Effect of cilostazolon cerebral vasospasm and outcome in patients withaneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled trial. Cerebrovasc Dis. 2016;42:97-105. van den Bergh WM, MASH Study Group. Randomizedcontrolled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage. Stroke. 2006;37:2326-2330. MASH Study Group Hop JW, Rinkel GJE, Algra A, van der Sprenkel JWB, vanGijn J. Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage. Neurology. 2000;54:872-878. Shaw MDM, Foy PM, Conway M, et al. Dipyridamole andpostoperative ischemic deficits in aneurysmal subarachnoid hemorrhage. J Neurosurg. 1985;63:699-703. Zanaty M, Allan L, Samaniego EA, et al. Phase 1/2a trial of ISPASM. Stroke. 2021;52:3750-3758. Hirashima Y, Endo S, Nukui H, Kobayashi N, Takaku A. Effectof a platelet-activating factor receptor antagonist, E5880, ### Page 41 on cerebral vasospasm after aneurysmal subarachnoidhemorrhage—open clinical trial to investigate efficacy and safety. Neurol Med Chir. 2001;41:165-176. Tokiyoshi K, Ohnishi T, Nii Y. Efficacy and toxicity of throm- boxane synthetase inhibitor for cerebral vasospasm after subarachnoid hemorrhage. Surg Neurol. 1991;36:112-118. Suzuki S, Sano K, Handa H, et al. Clinical study of OKY-046, athromboxane synthetase inhibitor, in prevention of cerebralvasospasms and delayed cerebral ischaemic symptoms aftersubarachnoid haemorrhage due to aneurysmal rupture: a randomized double-blind study. Neurol Res. 1989;11:79-88. Dorhout Mees S, van den Bergh WM, Algra A, Rinkel GJE.Antiplatelet therapy for aneurysmal subarachnoid haem- orrhage. Cochrane Database Syst Rev. 2007;4:CD006184. Chen H, Luo W, Cai X, Cai J. Cilostazol administration for sub- arachnoid hemorrhage: a meta-analysis of randomized con- trolled trials. Clin Neuropharmacol. 2022;45:111-116. Saber H, Desai A, Palla M, Mohamed W, Seraji-BozorgzadN, Ibrahim M. Efficacy of cilostazol in prevention ofdelayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a meta-analysis. J Stroke Cerebrovasc Dis. 2018; 27:2979-2985. Bohara S, Garg K, Singh Rajpal PM, Kasliwal M. Role of cilosta- zol in prevention of vasospasm after aneurysmal subarach- noid hemorrhage—a systematic review, meta-analysis, andtrial sequential analysis. World Neurosurg. 2021;150:161- 170. Dorhout Mees SM, Rinkel GJE, Hop JW, Algra A, van GijnJ. Antiplatelet therapy in aneurysmal subarachnoid hemor- rhage. Stroke. 2003;34:2285-2289. Liu J, He J, Chen X, et al. Cilostazol for aneurysmal subarach- noid hemorrhage: an updated systematic review and meta- analysis. Cerebrovasc Dis. 2022;51:138-148. Blackburn SL, Grande AW, Swisher CB, Hauck EF,Jagadeesan B, Provencio JJ. Prospective trial ofcerebrospinal fluid filtration after aneurysmal subarachnoidhemorrhage via lumbar catheter (PILLAR). Stroke. 2019;50:2558-2561. Al-Tamimi YZ, Bhargava D, Feltbower RG, et al. Lumbardrainage of cerebrospinal fluid after aneurysmal subarach- noid hemorrhage. Stroke. 2012;43:677-682. Wolf S, Mielke D, Barner C, et al. Effectiveness of lumbarcerebrospinal fluid drain among patients with aneurysmalsubarachnoid hemorrhage: a randomized clinical trial.JAMA Neurol. 2023;80:833-842. Borkar S, Singh M, Kale S, et al. Spinal cerebrospinal fluiddrainage for prevention of vasospasm in aneurysmal sub- arachnoid hemorrhage: a prospective, randomized con- trolled study. Asian J Neurosurg. 2018;13:238-246. Grossen AA, Ernst GL, Bauer AM. Update on intrathecal man- agement of cerebral vasospasm: a systematic review andmeta-analysis. Neurosurg Focus. 2022;52:E10. Gathier CS, van den Bergh WM, van der Jagt M, et al.Induced hypertension for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Stroke. 2018;49:76- 83. Gathier CS, Dankbaar JW, van der Jagt M, et al. Effects ofinduced hypertension on cerebral perfusion in delayedcerebral ischemia after aneurysmal subarachnoid hemorrhage. Stroke. 2015;46:3277-3281. Haegens NM, Gathier CS, Horn J, Coert BA, Verbaan D, vanden Bergh WM. Induced hypertension in preventing cerebralinfarction in delayed cerebral ischemia after subarachnoid hemorrhage. Stroke. 2018;49:2630-2636. Tjerkstra MA, Müller MCA, Coert BA, et al. Clinicalresponse following hypertension induction for clinicaldelayed cerebral ischemia following subarachnoidhemorrhage: A retrospective, multicenter, cohort study.Eur J Neurol. 2023;30:2278-2287. Vatter H, Güresir E, König R, et al. Invasive Diagnosticand Therapeutic Management of Cerebral VasoSpasm afterAneurysmal Subarachnoid Hemorrhage (IMCVS)—a phase 2 randomized controlled trial. J Clin Med. 2022;11:6197. Yindeedej V, Nimmannitya P, Noiphithak R, Punyarat P, Tan- tongtip D. Clinical outcome in cerebral vasospasm patientstreated with and without intra-arterial nimodipine infusion.J Neurol Surg A Cent Eur Neurosurg. 2021;83:420-426. Ma Y-H, Shang R, Li S-H, Wang T, Lin S, Zhang C-W. Efficacyof endovascular therapy for cerebral vasospasm followinganeurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Front Neurol. 2024;15:1360511. Patel AS, Griessenauer CJ, Gupta R, et al. Safety and effi- cacy of noncompliant balloon angioplasty for the treatmentof subarachnoid hemorrhage–induced vasospasm: a multi- center study. World Neurosurg. 2017;98:189-197. Labeyrie M-A, Gaugain S, Boulouis G, et al. Distal balloonangioplasty of cerebral vasospasm decreases the risk ofdelayed cerebral infarction. Am J Neuroradiol. 2019;40:1342- 1348. Chaudhary SR, Ko N, Dillon WP, et al. Prospective evaluationof multidetector-row CT angiography for the diagnosis ofvasospasm following subarachnoid hemorrhage: a compar- ison with digital subtraction angiography. Cerebrovasc Dis. 2007;25:144-150. Greenberg ED, Gold R, Reichman M, et al. Diagnosticaccuracy of CT angiography and CT perfusion forcerebral vasospasm: a meta-analysis. Am J Neuroradiol. 2010;31:1853-1860. Vergouwen MDI, Ilodigwe D, Macdonald RL. Cerebralinfarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent ### Page 42 effects. Stroke. 2011;42:924-929. Dankbaar JW, Rijsdijk M, van der Schaaf IC, Velthuis BK,Wermer MJH, Rinkel GJE. Relationship between vasospasm,cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology. 2009;51:813-819. Cremers CHP, Vos PC, van der Schaaf IC, et al. CT perfusionduring delayed cerebral ischemia after subarachnoid hemor- rhage: distinction between reversible ischemia and ischemiaprogressing to infarction. Neuroradiology. 2015;57:897-902. Hofmann BB, Fischer I, Donaldson DM, et al. Evaluation ofMTT heterogeneity of perfusion CT imaging in the early braininjury phase: an insight into aSAH pathopysiology. Brain Sci. 2023;13:824. Rijsdijk M, van der Schaaf IC, Velthuis BK, Wermer MJ, RinkelGJE. Global and focal cerebral perfusion after aneurysmalsubarachnoid hemorrhage in relation with delayed cerebral ischemia. Neuroradiology. 2008;50:813-820. Mir DIA, Gupta A, Dunning A, et al. CT perfusion for detectionof delayed cerebral ischemia in aneurysmal subarachnoidhemorrhage: a systematic review and meta-analysis. Am J Neuroradiol. 2014;35:866-871. Murphy A, Lee T-Y, Marotta TR, et al. Prospectivemulticenter study of changes in MTT after aneurysmalSAH and relationship to delayed cerebral ischemia inpatients with good- and poor-grade admission status. Am J Neuroradiol. 2018;39:2027-2033. Malinova V, Tsogkas I, Behme D, Rohde V, Psychogios MN,Mielke D. Defining cutoff values for early prediction ofdelayed cerebral ischemia after subarachnoid hemorrhage by CT perfusion. Neurosurg Rev. 2020;43:581-587. Tsolaki V, Aravantinou-Fatorou A, Georgakopoulou VE, et al.Early diagnosis of cerebral vasospasm associated with cere- bral ischemia following subarachnoid hemorrhage: evalu- ation of computed tomography perfusion and transcranial doppler as accurate methods. Med Int (Lond). 2022;2:34. Lolli VE, Guenego A, Sadeghi N, et al. CT perfusion imagingin aneurysmal subarachnoid hemorrhage. State of the art.Front Radiol. 2024;4:1445676. Majewska P, Hara S, Gulati S, Solheim O. Associationbetween transcranial Doppler vasospasm and functionaloutcome after subarachnoid hemorrhage. Brain Circ. 2021;7:271-276. Kumar G, Shahripour RB, Harrigan MR. Vasospasm on tran- scranial Doppler is predictive of delayed cerebral ischemiain aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2016;124:1257-1264. Mastantuono J-M, Combescure C, Elia N, Tramèr MR,Lysakowski C. Transcranial Doppler in the diagnosis ofcerebral vasospasm: an updated meta-analysis. Crit Care Med. 2018;46:1665-1672. Francoeur CL, Mayer SA. Management of delayed cere- bral ischemia after subarachnoid hemorrhage. Crit Care. 2016;20:277. Herman ST, Abend NS, Bleck TP, et al. Consensus statementon continuous EEG in critically ill adults and children, partI: indications. J Clin Neurophysiol. 2015;32:87-95. Guo Y, Fang S, Wang J, Wang C, Zhao J, Gai Y. Continuous EEGdetection of DCI and seizures following aSAH: a systematicreview. Br J Neurosurg. 2020;34:543-548. Rosenthal ES, Biswal S, Zafar SF, et al. Continuous electroen- cephalography predicts delayed cerebral ischemia after sub- arachnoid hemorrhage: a prospective study of diagnosticaccuracy. Ann Neurol. 2018;83:958-969. Zoerle T, Lombardo A, Colombo A, et al. Intracranial pressureafter subarachnoid hemorrhage∗. Crit Care Med. 2015;43: 168-176. Addis A, Baggiani M, Citerio G. Intracranial pressure moni- toring and management in aneurysmal subarachnoid hem- orrhage. Neurocrit Care. 2023;39:59-69. Robba C, Graziano F, Rebora P, et al. Intracranial pressuremonitoring in patients with acute brain injury in the inten- sive care unit (SYNAPSE-ICU): an international, prospective observational cohort study. Lancet Neurol. 2021;20:548-558. Baggiani M, Graziano F, Rebora P, et al. Intracranial pres- sure monitoring practice, treatment, and effect on out- come in aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2023;38:741-751. Jaeger M, Soehle M, Schuhmann MU, MeixensbergerJ. Clinical significance of impaired cerebrovascularautoregulation after severe aneurysmal subarachnoid hemorrhage. Stroke. 2012;43:2097-2101. Chen HI, Stiefel MF, Oddo M, et al. Detection of cere- bral compromise with multimodality monitoring in patients with subarachnoid hemorrhage. Neurosurgery. 2011;69:53- 63. Veldeman M, Albanna W, Weiss M, et al. Invasiveneuromonitoring with an extended definition ofdelayed cerebral ischemia is associated with improved outcome after poor-grade subarachnoid hemorrhage.J Neurosurg. 2021;134:1527-1534. Hänggi D, Liersch J, Turowski B, Yong M, Steiger H-J. Theeffect of lumboventricular lavage and simultaneous low- frequency head-motion therapy after severe subarachnoidhemorrhage: results of a single center prospective phase II trial. J Neurosurg. 2008;108:1192-1199. Gower DJ, Baker AL, Bell WO, Ball MR. Contraindications tolumbar puncture as defined by computed cranial tomog- raphy. J Neurol Neurosurg Psychiatry. 1987;50:1071-1074. ### Page 43 Mahto N, Owodunni OP, Okakpu U, et al. Postproceduralcomplications of external ventricular drains: a meta-analysisevaluating the absolute risk of hemorrhages, infections, andrevisions. World Neurosurg. 2023;171:41-64. Bales JW, Bonow RH, Buckley RT, Barber J, Temkin N,Chesnut RM. Primary external ventricular drainage catheterversus intraparenchymal ICP monitoring: outcome analy- sis. Neurocrit Care. 2019;31:11-21. Hasan D, Vermeulen M, Wijdicks EF, Hijdra A, van GijnJ. Management problems in acute hydrocephalus after subarachnoid hemorrhage. Stroke. 1989;20:747-753. Jeong JH, Kim JW, Choi DH. Safety and effectiveness oflumbar cerebrospinal fluid drainage to prevent delayed cere- bral ischemia after Fisher grade 3 subarachnoid hemorrhagewith minimal intraventricular hemorrhage. Neurochirurgie. 2020;66:225-231. Kim DY, Cho Y-H, Kim S, et al. Feasibility of prompt lumbardrainage in patients with aneurysmal subarachnoid hemor- rhage. World Neurosurg. 2023;175:e1032-e1040. Tack RWP, Lindgren A, Vergouwen MDI, van der Zwan A,van der Schaaf I, Rinkel GJE. Lumbar puncture for treatingacute hydrocephalus after aneurysmal subarachnoid haem- orrhage. J Neurol Sci. 2023;446:120566. Hasan D, Lindsay KW, Vermeulen M. Treatment of acutehydrocephalus after subarachnoid hemorrhage with serial lumbar puncture. Stroke. 1991;22:190-194. Chao K, Martin D, Tsouvalas C, Wiginton J, Torres F, NguyenN. Comparison of safety of lumbar drain versus externalventricular drain in symptomatic hydrocephalus follow- ing aneurysmal subarachnoid hemorrhage. Interv Neuro- radiol. 2024;15910199241276676. Yang C, Zhang Z, Liao R, Li Y. Relationship betweenpreoperative external ventricular drainage and preoperativerebleeding in aneurysmal subarachnoid hemorrhage: a meta-analysis. Clin Neurol Neurosurg. 2023;224:107563. Hellingman CA, van den Bergh WM, Beijer IS, et al. Riskof rebleeding after treatment of acute hydrocephalusin patients with aneurysmal subarachnoid hemorrhage.Stroke. 2007;38:96-99. van Lieshout JH, Pumplün I, Fischer I, et al. Volume ofcerebrospinal fluid drainage as a predictor for pretreatment aneurysmal rebleeding. J Neurosurg. 2018;128:1778-1784. Terakado T, Ito Y, Hirata K, et al. Efficacy and safety of lum- bar drainage before endovascular treatment for ruptured intracranial aneurysms. J Neuroendovasc Ther. 2024;18:29- 36. Camacho EF, Boszczowski Í, Basso M, et al. Infection rateand risk factors associated with infections related to external ventricular drain. Infection. 2011;39:47-51. Walcott BP, Iorgulescu JB, Stapleton CJ, Kamel H. Inci- dence, timing, and predictors of delayed shunting for hydro- cephalus after aneurysmal subarachnoid hemorrhage. Neu- rocrit Care. 2015;23:54-58. Yu H, Yang M, Zhan X, Zhu Y, Shen J, Zhan R. Ventriculoperi- toneal shunt placement in poor-grade patients with chronicnormal pressure hydrocephalus after aneurysmal subarach- noid haemorrhage. Brain Inj. 2016;30:74-78. Egawa S, Hifumi T, Kawakita K, et al. Impactof neurointensivist-managed intensive care unitimplementation on patient outcomes after aneurysmal subarachnoid hemorrhage. J Crit Care. 2016;32:52-55. Samuels O, Webb A, Culler S, Martin K, Barrow D. Impactof a dedicated neurocritical care team in treating patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2011;14:334-340. Josephson SA, Douglas VC, Lawton MT, English JD, SmithWS, Ko NU. Improvement in intensive care unit outcomesin patients with subarachnoid hemorrhage after initia- tion of neurointensivist co-management: clinical article. J Neurosurg. 2010;112:626-630. Knopf L, Staff I, Gomes J, McCullough L. Impact of a neuroin- tensivist on outcomes in critically ill stroke patients. Neuro- crit Care. 2012;16:63-71. Lerch C, Yonekawa Y, Murol C, Bjeljac M, Keller E. Spe- cialized neurocritical care, severity grade, and outcome ofpatients with aneurysman subarachnoid hemorrhage. Neur- ocrit Care. 2006;5:85-92. Mielke D, Malinova V, Moerer O, Suntheim P, Voit M, RohdeV. Does the subspecialty of an intensive care unit (ICU) hasan impact on outcome in patients suffering from aneurysmal subarachnoid hemorrhage? Neurosurg Rev. 2019;42:147- 153. Varelas PN, Schultz L, Conti M, Spanaki M, GenarrelliT, Hacein-Bey L. The impact of a neuro-intensivist onpatients with stroke admitted to a neurosciences intensive care unit. Neurocrit Care. 2008;9:293-299. Boogaarts HD, van Amerongen MJ, de Vries J, et al.Caseload as a factor for outcome in aneurysmal subarach- noid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2013;120:605-611. Huang JY, Lin HY, Wei QQ, et al. Relationship between annu- alized case volume and in-hospital motality in subarach- noid hemorrhage: a systematic review and meta-analysis.Medicine (Baltimore). 2021;100:e27852. Lindekleiv H, Mathiesen EB, Forde OH, Wilsgaard T, Inge- brigtsen T. Hospital volume and 1-year mortality after treat- ment of intracranial aneurysms: a study based on patient ### Page 44 registries in Scandinavia. J Neurosurg. 2015;123:631-637. Rochat P, Hauerberg J, Kelsen J, Eskesen V, Poulsgaard L,Brennum J. Letter to the editor: low mortality in aneurysm treatment by cream skimming. J Neurosurg. 2016;124:1546- 1547. Sahni NR, Dalton M, Cutler DM, Birkmeyer JD, Chandra A.Surgeon specialization and operative mortality in United States: retrospective analysis. BMJ. 2016;354:i3571. Alotaibi NM, Ibrahim GM, Wang J, et al. Neurosurgeonacademic impact is associated with clinical outcomes after clipping of ruptured intracranial aneurysms. PLoS One. 2017;12:e0181521. Etminan N, de Sousa DA, Tiseo C, et al. European StrokeOrganisation (ESO) guidelines on management of unrup- tured intracranial aneurysms. Eur Stroke J. 2022;7:LXXXI-CVI. Han HJ, Lee W, Kim J, et al. Incidence rate and pre- dictors of recurrent aneurysms after clipping: long-termfollow-up study of survivors of subarachnoid hemorrhage.Neurosurg Rev. 2022;45:3209-3217. Habibi MA, Mirjnani MS, Zafari R, et al. The safety and effi- ciency of SMART coil for brain aneurysm: a systematic review and meta-analysis. Neuroradiol J. 2025;38:401-415. Zhang S-M, Liu L-X, Ren P-W, Xie X-D, Miao J.Effectiveness, safety and risk factors of Woven EndoBridgedevice in the treatment of wide-neck intracranial aneurysms: systematic review and meta-analysis. World Neurosurg. 2020;136:e1-e23. El Naamani K, Mastorakos P, Adeeb N, et al. Long-termfollow-up of cerebral aneurysms completely occluded at 6months after intervention with the Woven EndoBridge (WEB)device: a retrospective multicenter observational study.Transl Stroke Res. 2024;15:591-598. Hohenstatt S, Ulfert C, Herweh C, et al. Long-termfollow-up after aneurysm treatment with the flowredirection endoluminal device (FRED) flow diverter.Clin Neuroradiol. 2024;34:181-188. Roy JM, El Naamani K, Amaravadi C, et al. Long-term safetyand efficacy of the FRED X flow diverter for intracranialaneurysms: a multicenter study of 154 patients. J Neu- rosurg. 2025;143:232-242. Khanafer A, Lobsien D, Sirakov A, et al. Flow diversionwith hydrophilic polymer coating with prasugrel as singleantiplatelet therapy in the treatment of acutely rupturedintracranial aneurysms: a multicenter case series, compli- cation and occlusion rates. J Neurointerv Surg. 2025;17:870- 877. Mastorakos P, Naamani KE, Adeeb N, et al. Predictors ofaneurysm obliteration in patients treated with the WEBdevice: results of a multicenter retrospective study. Am J Neuroradiol. 2024;45:906-911. Molyneux AJ, Birks J, Clarke A, Sneade M, Kerr RSC. The dura- bility of endovascular coiling versus neurosurgical clippingof ruptured cerebral aneurysms: 18 year follow-up of theUK cohort of the international subarachnoid aneurysm trial (ISAT). Lancet. 2015;385:691-697. Johnston SC, Dowd CF, Higashida RT, et al. Predictorsof rehemorrhage after treatment of ruptured intracra- nial aneurysms. Stroke. 2008;39:120-125. Plowman RS, Clarke A, Clarke M, Byrne JV. Sixteen- year single-surgeon experience with coil embolizationfor ruptured intracranial aneurysms: recurrence rates and incidence of late rebleeding: clinical article. J Neurosurg. 2011;114:863-874. Giordan E, Lanzino G, Rangel-Castilla L, Murad MH, BrinjikjiW. Risk of de novo aneurysm formation in patients with aprior diagnosis of ruptured or unruptured aneurysm: sys- tematic review and meta-analysis. J Neurosurg. 2018;131:14- 24. Tan J, Song R, Su J, et al. Establishment and multicenterexternal validation of a risk prediction model for de novointracranial aneurysms based on a systematic review and meta-analysis of 19 cohorts. J Neurosurg. 2024;140:783-791. Nguyen BA, Halpin B, Olson V, et al. Risk factors for unrup- tured intracranial aneurysms in asymptomatic patientswith autosomal dominant polycystic kidney disease: whoneeds screening? A systematic review and meta-analysis. J Neurosurg. 2025;143:220-231. Hoh BL, Ko NU, Amin-Hanjani S, et al. 2023 Guideline forthe management of patients with aneurysmal subarachnoidhemorrhage: a guideline from the American Heart Asso- ciation/American Stroke Association. Stroke. 2023;54:e314- e370. Treggiari MM, Rabinstein AA, Busl KM, et al. Guidelines for theneurocritical care management of aneurysmal subarach- noid hemorrhage. Neurocrit Care. 2023;39:1-28. Molyneux A. International Subarachnoid Aneurysm Trial(ISAT) of neurosurgical clipping versus endovascular coilingin 2143 patients with ruptured intracranial aneurysms: a ran- domised trial. Lancet. 2002;360:1267-1274. Algra AM, Lindgren A, Vergouwen MDI, et al. Proceduralclinical complications, case-fatality risks, and risk factorsin endovascular and neurosurgical treatment of unrup- tured intracranial aneurysms: a systematic review and meta-analysis. JAMA Neurol. 2019;76:282-293. Volovici V, Verploegh IS, Satoer D, et al. Outcomesassociated with intracranial aneurysm treatments reportedas safe, effective, or durable: a systematic review and meta-analysis. JAMA Netw Open. 2023;6:e2331798-e. ### Page 45 Wenz F, Wiedemann T, Rinkel GJE, Etminan N. Flow divertertreatment for saccular unruptured intracranial aneurysms: asystematic review focussing on study quality and initial out- comes. Eur Stroke J. 2026;11:23969873251370992.. Vergouwen MD, Germans MR, Post R, et al. Aneurysm treat- ment within 6 h versus 6–24 h after rupture in patients with subarachnoid hemorrhage. Eur Stroke J. 2023;8:802-807. Lindgren A, Burt S, Bragan Turner E, et al. Hospital case- volume is associated with case-fatality after aneurysmal subarachnoid hemorrhage. Int J Stroke. 2019;14:282-289. McNeill L, English SW, Borg N, Matta BF, Menon DK. Effectsof institutional caseload of subarachnoid hemorrhage on mortality. Stroke. 2013;44:647-652. Ryu B-G, Lee SU, Shim HS, et al. Clinical outcomes ofcoil embolization for unruptured intracranial aneurysmscategorized by region and hospital size : a nationwide cohort study in Korea. J Korean Neurosurg Soc. 2023;66:690-702. © The Author(s) 2026. Published by Oxford University Press on behalf of the European Stroke Organisation. 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