Article published online: 2023-02-06

https://doi.org/10.1590/0004-282X-ANP-2022-S101
CEREBROVASCULAR DISEASE

Updates on aneurysmal subarachnoid

hemorrhage: is there anything really new?
Atualizações em hemorragia subaracnóidea aneurismática: há algo realmente novo?
Thire Baggio Machado MARAZZI1, Pedro Vitale MENDES2

ABSTRACT
Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe disease, with systemic involvement and complex diagnosis and
treatment. Since the current guidelines were published by the AHA/ASA, Neurocritical Care Society and the European Stroke Organization
in 2012-2013,there has been an evolution in the comprehension of SAH-associated brain injury and its multiple underlying mechanisms. As
a result, several clinical and translational trials were developed or are underway. Objective: The aim of this article is to review some updates
in the diagnosis and treatment of neurological complications of SAH. Methods: A review of PubMed (May, 2010 to February, 2022) was
performed. Data was summarized. Results: Content of five meta-analyses, nine review articles and 23 new clinical trials, including pilots,
were summarized. Conclusions: Advances in the comprehension of pathophysiology and improvements in critical care have been reflected in
the reduction of mortality in SAH. However, despite the number of publications, the only treatments shown to be effective in adequate, well-
controlled clinical trials are nimodipine and repair of the ruptured aneurysm. Thus, doubts about the optimal management of SAH still persist.
Keywords: Subarachnoid Hemorrhage; Aneurysm; Vasospasm, Intracranial.

RESUMO
Antecedentes: Hemorragia subaracnóide aneurismática (HSAa) é uma doença grave, com envolvimento sistêmico, complexo diagnóstico e
tratamento. Desde a publicação dos atuais protocolos de conduta pela AHA/ASA, Neurocritical Care Society e European Stroke Organization de
2012-2013, houve evolução na compreensão da lesão cerebral associada à HSA e seus múltiplos mecanismos subjacentes. Como resultado,
muitos trabalhos clínicos e translacionais foram desenvolvidos ou estão em andamento. Objetivos: O objetivo deste artigo é revisar algumas
das atualizações no diagnóstico e tratamento de complicações neurológicas de HSA. Métodos: Revisão de Pubmed (Maio de 2010 a Fevereiro
de 2022) foi realizada. Dados foram sintetizados. Resultados: O conteúdo de 5 metanálises, 9 artigos de revisão e 23 novos estudos clínicos,
incluindo pilotos, foram sumarizados. Conclusões: Avanços na compreensão da fisiopatologia e melhorias no cuidado crítico têm se refletido
na redução da mortalidade em HSA. Entretanto, apesar do volume de publicações, os únicos tratamentos que se mostraram efetivos com
testes clínicos bem controlados são o uso de nimodipino e o tratamento dos aneurisma rotos. Assim, dúvidas acerca do manejo ideal em
HSA ainda persistem.
Palavras-chave: Hemorragia Subaracnóidea; Aneurisma;Vasoespasmo Intracraniano.

GENERAL CONSIDERATIONS 50% at the time of aneurysmal rupture and with 30-day mor-
tality up to 45%) and extensive long-term morbidity (a third
Aneurysmatic Subarachnoid Hemorrhage (aSAH) is a of survivors require full care, and a third are not able to return
complex disease and a relevant health problem. In terms to work)4. And lastly, it is estimated that the global aSAH case-
of epidemiology, concepts should be highlighted: incidence fatality rate has decreased by 17% to 50% in the last 30 years as
varies greatly among countries. It is estimated at 2-16 per a result of improving diagnostic accuracy, surgical techniques,
100,000 per annum worldwide1, while Finland is the country critical care support, cardiovascular risk prevention measures
with the highest incidence, with 22.7 per 100,000 per annum2. and adherence to guideline recommendations5.
Furthermore, aSAH affects a relatively young population, with International guidelines are periodically updated with
a peak of around 50 years-old3, causing higher mortality (about recommendations on screening, diagnosis, treatment and a

Universidade de São Paulo, Departamento de Neurologia, São Paulo SP, Brazil.

1

Universidade de São Paulo, Departamento de Emergências Clínicas, São Paulo SP, Brazil.
2

TBMM  http://orcid.org/0000-0002-2613-490X; PVM  http://orcid.org/0000-0002-2613-490X; 0000-0002-6062-9105

Correspondence: Thire Baggio Machado Marazzi; Email: thire.marazzi@fm.usp.br.
Conflict of interest: There is no conflict of interest to declare.
Authors’ contributions: The authors contributed equally to the manuscript.
Received on March 13, 2022; Accepted on April 29, 2022.

80
comprehensive pathophysiological review. However, the last Box 1. The Ottawa SAH Rule*.
publication was by the AHA/ASA, Neurocritical Care Society,
and the European Stroke Organization dated 2012-20133,6,7. This Inclusion: patients older than 15 y with new severe nontraumatic
article was developed by summarizing some recent studies headache reaching maximum intensity within 1h.
(five meta-analyses, nine review articles and 23 clinical trials)
Not for patients with new neurologic deficits, previous aneurysms,
and their results as to diagnosis and treatment of aSAH neu-
SAH, brain tumors, or history of recurrent headaches (≥3 episodes
rological complications.
over the course of ≥6 mo).

UP-TO-DATE IN DIAGNOSIS Investigate if ≥1 high-risk variables present:

1. Age ≥40 y
In approximately 70% of patients with aSAH the clinical 2. Neck pain or stiffness
manifestation was a sudden headache. In order to help clini- 3. Witnessed loss of consciousness
cians with diagnostic decisions in the emergency department 4. Onset during exertion
the Ottawa SAH rules were developed. A cohort comprising 5. Thunderclap headache (instantly peaking pain)
2131 patients with a headache peaking within an hour and no 6. Limited neck flexion on examination
neurologic deficits was analyzed8. Ottawa SAH rules (Box 1)
considered patients high-risk if one or more variables were
Adaptated of Perry JJ, Stiell IG, Sivilotti ML, et al. Clinical decision rules to
present from some clinical and epidemiological criterias8. This rule out subarachnoid hemorrhage for acute headache. JAMA 2013; 310:
tool, in practice, has reduced the total number of lumbar punc- 1248–558.
* Ottawa SHA rules was a clinical decision tool.
tures9 in low-risk patients. The sensitivity was 100% (95% CI,
97.2%-100.0%) and specificity was 15.3% (95% CI, 13.8%-16.9%)8. method. Alternatives are CT angiography (CTA), with a pooled
sensitivity of 97% and specificity of 91%12, and magnetic reso-
IMAGING nance angiography (MRA). In meta-analysis12, MRA and CTA
showed the same sensitivity as contrast-enhanced MR angi-
The imaging method recommended and most used for ography (CEMRA) or Time-of-Flight MR angiography (TOF)
the diagnosis of SAH is the non contrast head Computed technique. Nevertheless, some considerations must be made:
Tomography (CT). It is an easy-to-perform test with high sen- MRA has higher rates of false-positives and false-negatives (espe-
sitivity (93% to 100%) in the first six hours of symptoms9. The cially lesions <3 mm and located at the skull base and middle
sensitivity of this method progressively reduces in the days cerebral artery)12 and MRA has low accuracy in aneurysm neck
following the ictus, when other modalities, such as cranial size determination13. New techniques have been developed to
Magnetic Resonance Imaging (MRI), become more sensitive. reduce coil artifacts and increase the already high sensitivity
MRI is an imaging method that can be used from the hyper- to residual aneurysm screening. One such technique was the
acute to the chronic phase10, requiring an adequate choice of sequence non-contrast enhanced zero echo time (zTE)14.
sequence for analysis. More than two days after the ictus, the In recent years, MRI vessel wall assessment techniques
most used sequence is gradient recalled echo (GRE), reported in have been studied to predict expansion and aneurysmal rup-
some studies with a sensitivity of 94% (95% for CT)10. Meanwhile, ture, and to localize each high-risk in patients with multiple
in subacute and chronic phases (4-15 days), the most sensitive aneurysms15. Both qualitative and quantitative, automatic or
sequences are susceptibility-weighted imaging (SWI) and fluid semi-automatic methods of evaluating wall enhancement have
attenuated inversion recovery (FLAIR), sensitivities: 100% for been published, all with good predictive ability and good repro-
FLAIR, 50% for CT, 30% for GRE10. ducibility15,16. There are still few studies showing a pathophysi-
Generally, physicians prefer CT because of availability, lower ological and radiological correlation associated with increased
costs and time and simpler MRI image acquisition in critically local vessel wall enhancement.
ill patients. However, MRI images provide a superior assessment
of brain parenchyma and can be useful to predict unfavorable UP-TO-DATES IN COMPREHENSIVE
outcomes. De Marchis et al.11, even established that for every PATHOPHYSIOLOGY
10ml of DWI or FLAIR lesion volume, there was an outcome
loss similar to 1 addition in Hunt Hess grade [OR 2.01 (95% (CI) SAH-associated brain injury (SAHBI) is still not completely
1.10–3.68; p=0.02)]. Other studies using functional outcomes understood despite medical advances made over the past
by Rankin scale, cognitive test and Glasgow Outcome Scale three decades.
have been described in a recent review10. Previously, the SAHBI was didactically divided into early and
For the etiological diagnosis of SAH and programming an delayed phases9. All studies focused on preventing and treating
aneurysmal surgical approach, digital subtraction catheter the most severe complications of each one. Management of
angiography (DSA) with 3-dimensional reconstructions remains unruptured aneurysms, reduction of risk factors, timing and
the gold standard. However, it remains an invasive and risky surgical treatment techniques, treatment of rebleeding and

Marazzi TBM, et al. Updates on aneurysmal subarachnoid hemorrhage. 81

 hydrocephalus were the focus of early brain injury (EBI) trials. TIMING AND TREATMENT FOR ANEURYSM REPAIR
Meanwhile, in the delayed phase, prevention and treatment of
vasospasm (VSP) were used in order to reduce delayed cere- Guidelines suggest repairing the aneurysm “as early as fea-
bral ischemia (DCI). sible”(3), but it was still unclear whether ultra-early treatment
(<24h) improves outcomes compared with early treatment (24-
As bench studies identified inflammatory mechanisms as
72h). Discordant results have been published in retrospective
precursors of DCI, some translational trials began to be devel-
studies and the three largest23–25 were reviewed in meta-analy-
oped. However, although the results demonstrated a reduction
sis26. Patients treated within 24 hours showed poor functional
in large arteries VSP occurrence, there was no difference in
(OR 1.46 [0.47-2.9]) and mortality (OR 1.80 [0.88-3.67]) out-
functional outcome, e.g. clinical trials using the endothelin-1 comes, when compared with those treated between 24 and 72
(ET-1) receptor antagonist clazosentan17. These results moti- hours. This data should be critically evaluated: one (the largest
vated a shift in the focus of investigation from aSAH severe sample) showed poor outcomes in treatment within 24 hours
complications to the underlying mechanisms and the cascade and all are retrospective, some non-randomized, most treated
triggered at the time of aneurysmal rupture and consequently with coil. Thus, more studies are needed.
downstream.
The current concept of pathophysiology of SAHBI is mul- EARLY BRAIN INJURY
tiphasic, complex and multifactorial, with a cascade of events
that are all interrelated and that permeate all stages of the dis- Intravenous glibenclamide, a SUR1 inhibitor glyburide, has
been shown to be safe and effective in reducing cerebral edema
ease9,18,19. Considered aSAH phases are a continuum in which
in patients with large cerebral infarct in pilot studies27. Some
all events contribute to outcome.
studies are underway with the use of the drug in patients with
Some supracited underlying mechanisms already studied
aSAH, including the Brazilian GASH trial28. Therefore, at the
were neuroinflammation, microthrombosis, cortical spreading moment, there is no evidence to support its use.
depolarizations, disrupted integrity of the blood-brain barrier,
microvascular dysfunction, sympathoadrenal activation and DCI PREVENTION
endothelial cell dysfunction. Many reviews on advances in each
of these mechanisms and their promising fields of investiga-
Strategies
tion have been published recently18–20.
Although prophylactic hypertension and hypervolemia are
not recommended under current guidelines3,6,7, there are a few
UP-TO-DATE IN NEUROLOGICAL MANAGEMENT randomized controlled trials comparing the volume and pres-
sure management strategies. Recently, a German group per-
aSAH is a disease with severe neurological and systemic formed Randomized Controlled Trial (RCT)29 with 108 patients
manifestations. Below are detailed some therapeutic and moni- comparing goal-directed hemodynamic therapy (GDHT) versus
toring strategies for only neurological complications. standard therapy. Transpulmonary thermodilution monitor-
ing was used to calculate global end-diastolic index, cardiac
REBLEEDING index and extravascular lung water index. According to an
institutional goal protocol, fluids and vasoactive drugs could
At least ten randomized studies between 1982 and 2012 be used and titulated in accordance with clinical response or
evaluated the use of oral or intravenous antifibrinolytic drugs the occurrence of side effects. The results showed that GDHT
(tranexamic acid, epsilon amino-caproic acid) for SAH early reduced the rate of DCI (odds ratio: 0.324; 95% CI 0.11–0.86; p =
rebleeding prevention21. The results showed a reduced risk of 0.021), with a better functional outcome (GOS=5) three months
rebleeding by about 35%, but no improvement in clinical out- after discharge, although it did not change the mortality rate
comes. In addition, an increase in DCI was observed. Due to when compared with the control group.
these two independent effects, current international guidelines
Pharmacological therapies
differ in their recommendations about the use of antifibrinol-
Many pharmacological therapies have been tested for the
ytic drugs. To clarify this doubt, “Ultra-early Tranexamic Acid
prevention of EBI and DCI. However, most publication designs
After SAH” (ULTRA) was developed and published in 202122.
are retrospective studies or pilot trials. We summarize some
Four hundred and eighty patients received ultra-early (at diag- of them and two RCTs in Table 1.
nosis) short-term tranexamic acid treatment (bolus 1g plus
1g each 8h, maximum doses 4g). No improvement in clinical RCT findings
outcome at six months was shown. Therefore, there is no evi- Previously, the guidelines already included results from
dence for current use. RCTs with the use of the magnesium sulfate (MASH II)30

82 Arq Neuropsiquiatr 2022;80(5 Suppl. 1):80-87

and endothelin-1 (ET-1) receptor antagonist clazosentan
Emerging therapies
(CONSCIOUS 1 and 2)17 claiming no clinical benefit. After
Cilostazol, a selective phosphodiesterase-3 inhibitor with
publication of the current guidelines, no new RCTs showed dis-
vasodilating and antiplatelet action, has been shown to be a
cordant results of MASH II over intravenous magnesium use.
promising and safe enteral drug.
Recently, the use of clazosentanhas become a subject of study:
A meta-analysis published in 201837 evaluated the use of
the REACT trial is being developed with different clazosentan
Cilostazol in four RCTs and a prospective cohort, in a total of
doses and it is proposed to identify the subgroups of patients
543 patients. The result was decreased risk of symptomatic vaso-
who would benefit (ClinicalTrials.gov Identifier: NCT03585270)
spasm (0.31, 95% CI 0.20 to 0.48; P < 0.001), cerebral infarction
from prevention of neurologic worsening by DCI.
(0.32, 95% CI 0.20 to 0.52; P < 0.001) and poor outcome (0.40,
Among the newly-published RCTs, two were more promi-
95% CI 0.25 to 0.62; P < 0.001). No serious adverse effects were
nent: the use of oral simvastatin (STASH trial)31 and intrathecal
related with a dose of 100mg oral BID for 2 weeks. These stud-
use of nimodipine (NEWTON2 trial)32, both lacking favorable
ies however, included only those from the Japanese popula-
results in clinical outcome.
tion. Most trials must be performed with another population.
Therefore, unfortunately, no additional drug therapy has
Another promising therapy is continuous infusion unfrac-
been suggested in high-quality studies.
tionated heparin, the use of which was associated with a reduc-
tion in rescue therapy necessity in severe vasospasm and DCI
Therapies remain controversial incidence, and improved cognitive outcomes38,39. In these, the
The use of intraventricular fibrinolytic therapy had already dose used was started at 8 U/kg/h 12 hours after surgery, pro-
been evaluated in meta-analyses in 200433showing benefits in gressing in 36 hours to 10 U/kg/h (Maryland Protocol). The
reducing DCI and morbidity. However, the quality of the nine pathophysiological explanation is complex, as heparin has
studies included, with only one randomized, was considered broad effects: antifibrinolytic and anti-inflammatory effects,
low or moderate. Despite the limitations, the ASH treatment reduction of free radicals, interaction with hemoglobin-free
Japanese guideline34 incorporated the therapy into its recommen- complex and activation endothelial.
dations. We found two subsequent published studies (Table 1), An RCT is underway for large-scale evaluation of effects
only one with a primary functional outcome35,36. In this study, and safety: Randomizing Aneurysmal Subarachnoid Heparin
the intraventricular fibrinolytic therapy had no benefits36. Heparin Assay (ASTROH)40.

Table1. Clinical trials of delayed cerebral ischemia therapeutics.

Study Study type Agent Biological Background Result
STASH (Simvastatin in Aneurysmal RCT Simvastatin 40 mg/d Complex and multiple No differences for
Subarachnoid Hemorrhage)31 orally for 21 days mechanism. Success long-term or short-term
phase II trials with others outcome
statins
NEWTON2 (Study of EG-1962 RCT Microparticle Oral nimodipine Trial stopped early due to
Compared to Standard of Care formulation of 600mg improves clinical high rate of vasospasm
Oral Nimodipine in Adults With nimodipine. Application outcome, no reduction and DCI
Aneurysmal Subarachnoid intratecal radiologic VSP
Hemorrhage)32
Intraventricular Tissue Pilot trial Dose 2 mg 12/12h Amount of intracranial TPA as a potent clot
Plasminogen Activator in Phase II intraventricular tissue hemorrhage directly clearance accelerator.
Subarachnoid Hemorrhage plasminogen activator associated with worse No clinical outcome
Patients: A Prospective, (TPA) clinical outcome. assessment
Randomized, Placebo Controlled
Pilot Trial35
Prospective, randomized, open- Prospective 5 mg of rt-PA was diluted Amount of intracranial No reduction of delayed
label phase II trial on concomitant randomized in 2 mL of NaCl and given hemorrhage directly cerebral ischemia or
intraventricular fibrinolysis and Phase II as an intraventricular associated with worse poor functional outcome
low-frequency rotation after severe bolus every 12 hours clinical outcome.
subarachnoid hemorrhage36
Low-dose intravenous heparin Controlled Low-dose intravenous Microthrombotic Reduction in the
infusion in patients with retrospectively heparin infusion:8 U/kg/ mechanisms in occurrence of DCI
aneurysmal subarachnoid hr progressing over 36 intracranial vasculature and vasospasm in the
hemorrhage: a preliminary hours to 10 U/kg/hr shown to be associated intervention group. No
assessment39 with DCI in bench study increase in bleeding.
RCT: Randomized Clinical Trial; DCI: Delayed Cerebral Ischemia; VSP: vasospam.

Marazzi TBM, et al. Updates on aneurysmal subarachnoid hemorrhage. 83

 separated 55 studies using different doses and types ( fasudil,
Rescue therapies
nimodipine, nicardipine,papaverine verapamil) of intra-arte-
In the treatment of established DCI, some rescue thera-
rial vasodilators. The control group included patients without
pies are recommended. In this context however, no treatment
endovascular treatment or arterial balloon. Despite differences
was supported by a high-quality clinical trial and the impact
of complications remains unmeasured. All recommendations in outcome results with each vasodilator, all robustly reduced
were based on observational, retrospective, uncontrolled case the severity of vasospasm but without neurological response.
series or institutional protocols. This study did not include milrinone as a vasodilator.
Induction of arterial hypertension is the first treatment rec- Milrinone is a selective inhibitor of the phosphodiesterase
ommended by many guidelines in this scenario3,6,7. In 2018, the III isoenzyme with a vasodilatador and inotropic effect, which
RCT41 compared functional outcome by Rankin scale among has been used as a rescue therapy after failure of induced hyper-
patients with and without induction of arterial hypertension tension in some specialized services in the world4,43, although
three hours after onset of clinical symptoms. Hypertension was it is not cited in current guidelines. Milrinone can be used as a
performed with norepinephrine or fluids, and was progressively continuous intravenous infusion (IV), intra-arterial (IA) bolus,
increased until clinical improvement or MAP > 130 mmHg or or a combination of both (IVIA). Studies evaluating therapeu-
SBP > 230, while the control maintained MAP around 80. tic modalities do not show differences in safety and outcome
The study was paused with 41 participants due to slow between intravenous or associated therapy44. In 2016, a meta-
recruitment and adverse effects. The adjusted risk ratio for analysis found 24 studies using milrinone IV, IA, IVIA, all with
poor outcome was 1.0 (95% confidence interval, 0.6–1.8) and low quality of evidence45. Unfortunately, the only RCT was dis-
the risk ratio for serious adverse events 2.1 (95% confidence continued in 2017 due to lack of suitable subjects46.
interval, 0.9–5.0) was reported. Specifically, the intravenous milrinone infusion protocol
Endovascular treatments with arterial balloon and intra- (initiation dose, continuous infusion dose, velocity of incre-
arterial vasodilator infusions, commonly used after hypertension ment and withdrawal and treatment time) is based on service
induction due to favorable results in retrospective studies and experiences, the most widespread being the Montreal Protocol
case series, are not yet supported by RCT results. Venkatraman42 (Figure 1)43. There is still a lack of studies that evaluate the

Algorithm adaptation of milrinone using Montreal Protocol. CVC: Central Venous Pressure; BP: Blood Pressure; MAP: Median Arterial Pressure.
Figure 1. Adaptation of Montreal Protocol.

84 Arq Neuropsiquiatr 2022;80(5 Suppl. 1):80-87

comparison of safety and benefit between intravenous infusion OTHER FREQUENT NEUROLOGICAL COMPLICATIONS
protocols from different institutions.
Recently, a retrospective study47 with 40 patients showed Despite the prevalence of seizures in SAH, no randomized
clinical trials with new antiepileptic drugs for primary or sec-
benefits without side effects with high doses of IV milrinone.
ondary prophylaxis have been published.
In this study, 18 patients received boluses of up to 8mg IV with In conclusion, advances in the comprehension of pathophys-
continuous infusion of up to 2.75 mcg/kg/min (maximum iology and improvements in critical care have been reflected
cumulative daily 230mg). in the reduction of mortality in SAH. However, despite the
Other inotropic therapies have been shown to be effec- number of publications, the only treatments shown to be effec-
tive in reversing vasospasm. In a few comparative studies48,49, tive in adequate, well-controlled clinical trials are nimodipine
the benefit of using dobutamine outweighs that of milrinone and repair of the ruptured aneurysm. Thus, doubts about the
optimal management of SAH still persist.
in refractory patients.The risks and precautions are the same
with both drugs: hypotension is the main complication and ACKNOWLEDGEMENTS
the use of a cardiac output monitor is the main additional care. We thank Edward James Hutchings for English language
For both drugs, high quality studies are needed. support.

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