Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia.

The clinical management of aneurysmal subarachnoid hemorrhage (SAH)-associated vasospasm remains a challenge in neurosurgical practice, with its prevention and treatment having a major impact on neurological outcome. While considered a mainstay, nimodipine is burdened by some non-negligible limitations that make it still a suboptimal candidate of pharmacotherapy for SAH. This narrative review aims to provide an update on the pharmacodynamics, pharmacokinetics, overall evidence, and strength of recommendation of nimodipine alternative drugs for aneurysmal SAH-associated vasospasm and delayed cerebral ischemia. A PRISMA literature search was performed in the PubMed/Medline, Web of Science, ClinicalTrials.gov, and PubChem databases using a combination of the MeSH terms "medical therapy," "management," "cerebral vasospasm," "subarachnoid hemorrhage," and "delayed cerebral ischemia." Collected articles were reviewed for typology and relevance prior to final inclusion. A total of 346 articles were initially collected. The identification, screening, eligibility, and inclusion process resulted in the selection of 59 studies. Nicardipine and cilostazol, which have longer half-lives than nimodipine, had robust evidence of efficacy and safety. Eicosapentaenoic acid, dapsone and clazosentan showed a good balance between effectiveness and favorable pharmacokinetics. Combinations between different drug classes have been studied to a very limited extent. Nicardipine, cilostazol, Rho-kinase inhibitors, and clazosentan proved their better pharmacokinetic profiles compared with nimodipine without prejudice with effective and safe neuroprotective role. However, the number of trials conducted is significantly lower than for nimodipine. Aneurysmal SAH-associated vasospasm remains an area of ongoing preclinical and clinical research where the search for new drugs or associations is critical.

[Reversible cerebral vasoconstriction syndrome. Recurrence of thunderclap headaches after treatment with corticosteroids]. / Síndrome de vasoconstricción cerebral reversible. Recurrencia de cefaleas en trueno tras tratamiento con corticoides.

INTRODUCTION: Reversible cerebral vasoconstriction syndrome is a clinicoradiological entity with a self-limiting course that manifests with recurrent episodes of thunderclap headache, and is associated with certain triggers. Recurrence is very rare, and the pathophysiology is thought to be related to altered autoregulation of the cerebrovascular tone. We present a clinical case that raises questions about possible recurrences and triggers. CASE REPORT: A 44-year-old woman with a history of multiple sclerosis treated with interferon beta-1b who had four episodes of thunderclap headache while resting, after completing a course of corticosteroids due to a flare-up of optic neuritis. Three years earlier, the patient had presented several episodes of explosive-onset headache during a self-limited period of one month, only occurring during sexual intercourse. In the year prior to our assessment, she had suffered three thunderclap headaches with similar characteristics, but they were triggered only by intense physical exercise. She had not consulted a physician about these events. A cranial computed tomography scan was performed after the administration of contrast media and a cerebral arteriography, which were consistent with cerebral vasoconstriction syndrome, and its reversibility was confirmed three months later. CONCLUSIONS: Reversible cerebral vasoconstriction syndrome shares a phenotypic expression with primary exertion headaches. It is associated with drugs with vasoactive effects, including interferons, and corticosteroids are associated with a worse prognosis, and such their administration should be avoided.

TITLE: Síndrome de vasoconstricción cerebral reversible. Recurrencia de cefaleas en trueno tras tratamiento con corticoides.Introducción. El síndrome de vasoconstricción cerebral reversible es una entidad clinicorradiológica de curso autolimitado que se manifiesta con episodios de cefalea en trueno recurrentes y que se asocia a determinados desencadenantes. La recidiva es muy poco frecuente y la fisiopatología se cree que está en relación con la alteración de la autorregulación del tono vascular cerebral. Presentamos un caso clínico que plantea cuestiones sobre posibles recurrencias y desencadenantes. Caso clínico. Mujer de 44 años con antecedente de esclerosis múltiple en tratamiento con interferón beta-1b que consultó por cuatro episodios de cefalea en trueno en reposo, tras finalizar un ciclo de corticoides por un brote de neuritis óptica. Tres años antes, la paciente había presentado varios episodios de cefalea de inicio explosivo durante un período autolimitado de un mes, únicamente producidos en el contexto de relaciones sexuales. El año previo a nuestra valoración padeció en tres ocasiones cefalea en trueno de características similares, pero exclusivamente desencadenadas con el ejercicio físico intenso. No había consultado por estos eventos. Se realizó una tomografía computarizada craneal tras la administración de contraste y una arteriografía cerebral, que fueron compatibles con síndrome de vasoconstricción cerebral, y se confirmó su reversibilidad tres meses después. Conclusiones. El síndrome de vasoconstricción cerebral reversible comparte expresión fenotípica con el grupo de cefaleas primarias por esfuerzo físico. Se asocia a fármacos con efectos vasoactivos, entre los que se encuentran los interferones, y los corticoides se asocian a un peor pronóstico, por lo que es importante evitar su administración.

CT perfusion-guided administration of IV milrinone is associated with a reduction in delayed cerebral infarction after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) is a singular pathological entity necessitating early diagnostic approaches and both prophylactic and curative interventions. This retrospective before-after study investigates the effects of a management strategy integrating perfusion computed tomography (CTP), vigilant clinical monitoring and standardized systemic administration of milrinone on the occurrence of delayed cerebral infarction (DCIn). The "before" period included 277 patients, and the "after" one 453. There was a higher prevalence of Modified Fisher score III/IV and more frequent diagnosis of vasospasm in the "after" period. Conversely, the occurrence of DCIn was reduced with the "after" management strategy (adjusted OR 0.48, 95% CI [0.26; 0.84]). Notably, delayed ischemic neurologic deficits were less prevalent at the time of vasospasm diagnosis (24 vs 11%, p = 0.001 ), suggesting that CTP facilitated early detection. In patients diagnosed with vasospasm, intravenous milrinone was more frequently administered (80 vs 54%, p < 0.001 ) and associated with superior hemodynamics. The present study from a large cohort of aSAH patients suggests, for one part, the interest of CTP in early diagnosis of vasospasm and DCI, and for the other the efficacy of CT perfusion-guided systemic administration of milrinone in both preventing and treating DCIn.

Early Hydrogen-Oxygen Gas Mixture Inhalation in Patients with Aneurysmal Subarachnoid Hemorrhage (HOMA): study protocol for a randomized controlled trial.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurosurgical emergency with a high mortality rate. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) are delayed products of early brain injury (EBI), which may constitute the principal determinant of an unfavorable patient prognosis. Consequently, the mitigation of DCI and CVS assumes paramount significance in the pursuit of enhanced patient outcomes. However, except for oral nimodipine, there is no effective therapy available in the current guideline. Hence, the exigency arises to proffer novel treatment paradigms. The diversity of hydrogen therapeutic targets has been largely reported in basic research, unveiling its latent capacity to ameliorate EBI in aSAH patients. METHODS: Early Hydrogen-Oxygen Gas Mixture Inhalation in Patients with Aneurysmal Subarachnoid Hemorrhage (HOMA), a single-center, prospective, open-labeled, randomized controlled clinical trial, endeavors to evaluate the efficacy and safety of hydrogen-oxygen gas mixture inhalation therapy in aSAH patients. A cohort of 206 patients will be randomized to either hydrogen-oxygen gas mixture inhalation group (8 h per day, 3 L/min, hydrogen concentration of 67%, oxygen concentration of 33%) or oxygen inhalation group (8 h per day, 3 L/min, oxygen concentration of 33%) within 72 h after aSAH and treated for 7 days in the ICU ward. The primary outcomes are the incidence of DCI and CVS during hospitalization. DISCUSSION: The HOMA aims to evaluate the effectiveness of hydrogen-oxygen gas mixture inhalation therapy in preventing DCI or CVS and improving outcomes in aSAH patients. Notably, this is the first large-scale trial of hydrogen therapy in aSAH patients. Given that the Chinese population represents a significant portion of the global population and the increasing incidence of stroke due to aging, optimizing patient care is vital. Given the current challenges in aSAH patient outcomes, initiating more prospective clinical trials is essential. Recent research has shown hydrogen's therapeutic potential, aligning with EBI in aSAH, driving our exploration of hydrogen therapy's mechanisms in post-aneurysm rupture damage. ETHICS AND DISSEMINATION: The protocol for the HOMA study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (KY 2022-020-02). All results of the present study will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION: ClinicalTrials.gov NCT05282836. Registered on March 16, 2022.

Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

Impact of thyroid hormone replacement therapy on the course and functional outcome of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Thyroid hormones were reported to exert neuroprotective effects after ischemic stroke by reducing the burden of brain injury and promoting post-ischemic brain remodeling. OBJECTIVE: We aimed to analyze the value of thyroid hormone replacement therapy (THRT) due to pre-existing hypothyroidism on the clinical course and outcome of aneurysmal subarachnoid hemorrhage (SAH). METHODS: SAH individuals treated between January 2003 and June 2016 were included. Data on baseline characteristics of patients and SAH, adverse events and functional outcome of SAH were recorded. Study endpoints were cerebral infarction, in-hospital mortality and unfavorable outcome at 6 months. Associations were adjusted for outcome-relevant confounders. RESULTS: 109 (11%) of 995 individuals had THRT before SAH. Risk of intracranial pressure- or vasospasm-related cerebrovascular events was inversely associated with presence of THRT (p = 0.047). In multivariate analysis, THRT was independently associated with lower risk of cerebral infarction (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI] = 0.41-0.99, p = 0.045) and unfavorable outcome (aOR = 0.50, 95% CI = 0.28-0.89, p = 0.018), but not with in-hospital mortality (aOR = 0.69, 95% CI = 0.38-1.26, p = 0.227). CONCLUSION: SAH patients with THRT show lower burden of ischemia-relevant cerebrovascular events and more favorable outcome. Further experimental and clinical studies are required to confirm our results and elaborate the mechanistic background of the effect of THRT on course and outcome of SAH.

Effect of Intrathecal Eugenol on Cerebral Vasospasm in an Experimental Subarachnoid Hemorrhage Model.

BACKGROUND: Eugenol has various curative properties. It affects the dilatation of cerebral arteries through voltage-dependent Ca2+ channel inhibition. This study is the first to explore the impact of eugenol on neuroprotection and vasospasm in an experimental subarachnoid hemorrhage (SAH) model. METHODS: Twenty-four adult male Sprague-Dawley rats were indiscriminately separated into 3 groups: the control group (n = 8), the SAH group (n = 8), and the eugenol group (n = 8). A double-bleeding method was used. The eugenol group received intracisternal eugenol (Sigma-Aldrich, St. Louis, MO, USA) at 30 µg/20 µl after induction of SAH. On the day 7, all groups were euthanized. Measurements were taken for basilar artery wall thickness, lumen diameter, serum endothelin-1 (ET-1), and caspase-3 levels. RESULTS: The eugenol group exhibited significantly lower wall thickness, ET-1, oxidative stress index, and caspase-3 levels compared to the SAH group. In comparison to the control group, the eugenol group showed a higher oxidative stress index along with higher ET-1 and caspase-3 levels, but these differences were not statistically significant. Wall thickness was significantly higher in the eugenol group than in the control group. CONCLUSIONS: This study represents the first literature exploration of intrathecal eugenol's impact on vasospasm induced after experimental SAH. Administration of intrathecal eugenol demonstrates a positive effect on the treatment of experimental vasospasm as well as on the reduction of oxidative stress and apoptosis.

Systemic tolerance of intravenous milrinone administration for cerebral vasospasm secondary to non-traumatic subarachnoid hemorrhage.

PURPOSE: Delayed cerebral ischemia (DCI) is a severe subarachnoid hemorrhage (SAH) complication, closely related to cerebral vasospasm (CVS). CVS treatment frequently comprises intravenous milrinone, an inotropic and vasodilatory drug. Our objective is to describe milrinone's hemodynamic, respiratory and renal effects when administrated as treatment for CVS. METHODS: Retrospective single-center observational study of patients receiving intravenous milrinone for CVS with systemic hemodynamics, oxygenation, renal disorders monitoring. We described these parameters' evolution before and after milrinone initiation (day - 1, baseline, day 1 and day 2), studied treatment cessation causes and assessed neurological outcome at 3-6 months. RESULTS: Ninety-one patients were included. Milrinone initiation led to cardiac output increase (4.5 L/min [3.4-5.2] at baseline vs 6.6 L/min [5.2-7.7] at day 2, p < 0.001), Mean Arterial Pressure decrease (101 mmHg [94-110] at baseline vs 95 mmHg [85-102] at day 2, p = 0.001) norepinephrine treatment requirement increase (32% of patients before milrinone start vs 58% at day 1, p = 0.002) and slight PaO2/FiO2 ratio deterioration (401 [333-406] at baseline vs 348 [307-357] at day 2, p = 0.016). Milrinone was interrupted in 8% of patients. 55% had a favorable outcome. CONCLUSION: Intravenous milrinone for CVS treatment seems associated with significant impact on systemic hemodynamics leading sometimes to treatment discontinuation.

Therapeutic Potential of Natural Compounds in Subarachnoid Haemorrhage.

Subarachnoid hemorrhage (SAH) is a common and fatal cerebrovascular disease with high morbidity, mortality and very poor prognosis worldwide. SAH can induce a complex series of pathophysiological processes, and the main factors affecting its prognosis are early brain injury (EBI) and delayed cerebral ischemia (DCI). The pathophysiological features of EBI mainly include intense neuroinflammation, oxidative stress, neuronal cell death, mitochondrial dysfunction and brain edema, while DCI is characterized by delayed onset ischemic neurological deficits and cerebral vasospasm (CVS). Despite much exploration in people to improve the prognostic outcome of SAH, effective treatment strategies are still lacking. In recent years, numerous studies have shown that natural compounds of plant origin have unique neuro- and vascular protective effects in EBI and DCI after SAH and long-term neurological deficits, which mainly include inhibition of inflammatory response, reduction of oxidative stress, anti-apoptosis, and improvement of blood-brain barrier and cerebral vasospasm. The aim of this paper is to systematically explore the processes of neuroinflammation, oxidative stress, and apoptosis in SAH, and to summarize natural compounds as potential targets for improving the prognosis of SAH and their related mechanisms of action for future therapies.

Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan.

Subarachnoid hemorrhage often leads to poor outcomes owing to vasospasm, even after successful aneurysm treatment. Clazosentan, an endothelin receptor inhibitor, has been proven to be an effective treatment for vasospasms in a Japanese randomized controlled trial. However, its efficacy in older patients (≥ 75 years old) and those with World Federation of Neurosurgical Societies (WFNS) grade V has not been demonstrated. We retrospectively evaluated the efficacy of clazosentan in older patients and those with WFNS grade V, using real-world data. Patients with subarachnoid hemorrhage treated before and after the introduction of clazosentan were retrospectively evaluated. The patients were categorized into two groups (clazosentan era versus pre-clazosentan era), in which vasospasm management and outcomes were compared. Vasospasms were managed with fasudil hydrochloride-based (pre-clazosentan era) or clazosentan-based treatment (clazosentan era). Seventy-eight patients were included in this study: the clazosentan era (n = 32) and pre-clazosentan era (n = 46). Overall, clazosentan significantly reduced clinical vasospasms (clazosentan era: 31.3% versus pre-clazosentan era: 60.9%, p = 0.01), delayed cerebral ischemia (DCI) (9.4% versus 39.1%, p = 0.004), and vasospasm-related morbidity and mortality (M/M) (3.1% versus 19.6%, p = 0.03). In subgroup analysis of older patients or those with WFNS grade V, no significant difference was observed in clinical outcomes, although both DCI and vasospasm-related M/M were lower in the clazosentan era. Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment.

Immediate angiographic control after intra-arterial nimodipine administration underestimates the vasodilatory effect.

Intra-arterial nimodipine administration is a widely used rescue therapy for cerebral vasospasm. Although it is known that its effect sets in with delay, there is little evidence in current literature. Our aim was to prove that the maximal vasodilatory effect is underestimated in direct angiographic controls. We reviewed all cases of intra-arterial nimodipine treatment for subarachnoid hemorrhage-related cerebral vasospasm between January 2021 and December 2022. Inclusion criteria were availability of digital subtraction angiography runs before and after nimodipine administration and a delayed run for the most affected vessel at the end of the procedure to decide on further escalation of therapy. We evaluated nimodipine dose, timing of administration and vessel diameters. Delayed runs were performed in 32 cases (19 patients) with a mean delay of 37.6 (± 16.6) min after nimodipine administration and a mean total nimodipine dose of 4.7 (± 1.2) mg. Vessel dilation was more pronounced in delayed vs. immediate controls, with greater changes in spastic vessel segments (n = 31: 113.5 (± 78.5%) vs. 32.2% (± 27.9%), p < 0.0001) vs. non-spastic vessel segments (n = 32: 23.1% (± 13.5%) vs. 13.3% (± 10.7%), p < 0.0001). In conclusion intra-arterially administered nimodipine seems to exert a delayed vasodilatory effect, which should be considered before escalation of therapy.

Early Intravenous Magnesium Sulfate and Its Impact on Cerebral Vasospasm as well as Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Retrospective Matched Case-Control Analysis.

BACKGROUND: Magnesium sulfate (MgSO4) is a potential neuroprotective agent for patients with aneurysmal subarachnoid hemorrhage (SAH). We analyzed the effect of early application of intraoperative intravenous MgSO4 and compared cerebral vasospasm (CV), delayed cerebral ischemia (DCI), and neurological outcome in 2 patient cohorts. METHODS: A retrospective matched-pair analysis from patients at a single center in Germany was performed without (group A) and with (group B) MgSO4 application <24 hours after diagnosis. Pairs were matched according to the known risk factors for DCI and CV (age, Fisher grade, smoking, severity of SAH). Incidence of CV and DCI and neurological outcome using the modified Rankin Scale score 3 and 12 months after SAH were recorded. RESULTS: The inclusion criteria were met by 196 patients. After risk stratification, 48 patients were included in the final analysis (age 54.2 ± 8.1 years; 30 women and 18 men) and were assigned to group A (n = 24) or group B (n = 24). CV occurred less frequently in group B (33%) than in group A (46%). Likewise, DCI was present in 13% in group B compared with 42% in group A. After 12 months, 22 patients in group B had a favorable functional outcome (modified Rankin Scale score 0-3) compared with 15 patients in group A. CONCLUSIONS: In this study, the incidence of CV and DCI was lower in patients receiving intravenous MgSO4 within 24 hours after aneurysmal SAH onset. Favorable functional outcome was more likely in the MgSO4 group after 12 months of follow-up.

Risks of nimodipine dose reduction during the high-risk period for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Nimodipine dose reduction is recommended in case of high vasopressor demand after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to assess potential adverse effects of nimodipine reduction during the high-risk period for delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) between days 5 and 10 after hemorrhage. Demographic and clinical data as well as daily nimodipine dose of aSAH patients admitted between 2010 and 2019 were retrospectively analyzed. Univariable and multivariable regression analyses were performed to identify factors associated with DCI, angiographic CVS, DCI-related infarction, and unfavorable outcome. A total of 205 patients were included. Nimodipine dose reduction occurred in 108 (53%) patients ('nimodipine reduction group'), while 97 patients (47%) received the full dose ('no nimodipine reduction group'), Patients in the 'nimodipine reduction group' had significant worse WFNS and Fisher grades and developed significantly more often DCI and angiographic CVS. DCI-related infarction and unfavorable outcome were also significantly increased in the 'nimodipine reduction group.' 'Reduced nimodipine dose' was the only independent predictor for the occurrence of DCI and angiographic CVS in multivariable regression analysis. 'Poor WFNS grade' and 'reduced nimodipine dose' were identified as independent risk factors for DCI-related infarction while 'older age,' 'poor WFNS grade,' and 'reduced nimodipine dose' were associated with unfavorable outcome at 3 months after discharge. Nimodipine dose reduction during the high-risk period of DCI and CVS between days 5 and 10 after hemorrhage might abrogate the positive prognostic effects of nimodipine and should be critically evaluated.

Dexamethasone Addition Impairs the Therapeutic Effects of Nimodipine for Subarachnoid Hemorrhage: An Experimental Animal Study.

AIM: To evaluate the effects of the combination of nimodipine and dexamethasone in subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: In this study, 35 female adult Wistar Albino rats were randomly assigned to four groups: Sham (n=8), SAH with no treatment (n=9), SAH with nimodipine (n=9, oral gavage, 12 mg/kg, BID) treatment, and SAH with combined therapy with nimodipine and dexamethasone (n=9, intraperitoneally, 1mg/kg, BID). The "cisterna magna double injection of autologous blood" model was used. The animals were euthanized 5 days after the first injection. RESULTS: Of the total, five rats died before euthanasia. The SAH+Nontreatment group showed the worst score in neurological examinations, and the most severe histopathological findings were noted in terms of vasospasm. The SAH+Nimodipine group showed the best neurological score and the closest histopathological results to those of the Sham group, whereas adding dexamethasone to nimodipine treatment (the SAH+Nimodipine+Dexamethasone group) worsened the neurological and histopathological outcomes. CONCLUSION: We thus concluded that the therapeutic effects of nimodipine were impaired when combined with dexamethasone. We thus hypothesized that dexamethasone possibly induces the CYP3A4-enzyme that metabolizes nimodipine. However, it should be noted that our results are based on laboratory findings obtained on a small sample, therefore further studies with drug-drug interaction on a larger sample size through CYP3A4-enzyme and clinical confirmation are warranted.

Pharmacological Prevention of Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH) include early brain injury and delayed neurologic deterioration, which may result from delayed cerebral ischemia (DCI). Complex pathophysiological mechanisms underlie DCI, which often includes angiographic vasospasm (aVSP) of cerebral arteries. METHODS: Despite the study of many pharmacological therapies for the prevention of DCI in aSAH, nimodipine-a dihydropyridine calcium channel blocker-remains the only drug recommended universally in this patient population. A common theme in the research of preventative therapies is the use of promising drugs that have been shown to reduce the occurrence of aVSP but ultimately did not improve functional outcomes in large, randomized studies. An example of this is the endothelin antagonist clazosentan, although this agent was recently approved in Japan. RESULTS: The use of the only approved drug, nimodipine, is limited in practice by hypotension. The administration of nimodipine and its counterpart nicardipine by alternative routes, such as intrathecally or formulated as prolonged release implants, continues to be a rational area of study. Additional agents approved in other parts of the world include fasudil and tirilazad. CONCLUSIONS: We provide a brief overview of agents currently being studied for prevention of aVSP and DCI after aSAH. Future studies may need to identify subpopulations of patients who can benefit from these drugs and perhaps redefine acceptable outcomes to demonstrate impact.

Effect of Intrathecal Urokinase Infusion on Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Vasospasm following an aneurysmal subarachnoid hemorrhage (SAH) causes serious neurological complications, despite surgical clipping of the aneurysm. Intrathecal urokinase (UK) infusion has been shown to effectively prevent symptomatic vasospasm in patients who have undergone endovascular obliteration of the ruptured aneurysms. OBJECTIVE: To investigate whether intrathecal UK infusion can prevent symptomatic vasospasm in patients undergoing surgical or endovascular treatment. METHODS: A total of 90 patients with severe aneurysmal SAH were enrolled and assigned to a surgical neck clipping (n = 56) or an endovascular coil embolization (n = 34) groups. After treatment, UK infusion from the lumbar drain was repeated in 32 patients in the surgical neck clipping group (group B) and all in the endovascular coil embolization group (group C) until complete resolution of the SAH was observed on computed tomography. The remaining 24 of the surgical neck clipping group, without UK infusion, were assigned to group A. RESULTS: Symptomatic vasospasm occurred in 7 (29.2%) patients in group A, 2 (6.3%) in group B, and none in group C (group A vs. group B [P = 0.02]; group B vs. group C [P = 0.14]). Excellent clinical outcomes (modified Rankin score, 0 or 1) were observed in 37.5%, 59.4%, and 76.5% of patients in group A, B, and C, respectively (group A vs. group B [P = 0.11]). CONCLUSION: Clearance of SAH via intrathecal UK infusion significantly reduced symptomatic vasospasm in patients in both UK groups, resulting in better clinical outcomes.

Ferroptosis as a Therapeutic Target in Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a cerebrovascular disorder with significant mortality and morbidity. Neural injury in SAH is mediated through a variety of pathophysiological processes. Currently available treatments are either nonspecific in targeting the basic pathophysiological mechanisms that result in neural damage in SAH, or merely focus on vasospasm. Ferroptosis is a type of programmed iron dependent cell death, which has received attention due to its possible role in neural injury in SAH. Herein, we review how intracellular iron overload mediates the production of reactive free radicals and lipid peroxidation through a variety of biochemical pathways in SAH. This in turn results in induction of ferroptosis, as well as exacerbation of vasospasm. We also discuss several therapeutic agents that have been shown to inhibit ferroptosis through targeting different steps of the process. Such agents have proven effective in ameliorating vasospasm, neural damage, and neurobehavioral outcomes in animal models of SAH. Human studies to test the safety and efficacy of intrathecal or parenteral administration of the inhibitors of ferroptosis in improving outcomes of SAH patients are warranted. There are currently a few ongoing clinical trials pursuing this therapeutic concept, the results of which will be critical to determine the value of ferroptosis as a novel therapeutic target in SAH.

Stellate Ganglion Block in Subarachnoid Hemorrhage: A Promising Protective Measure Against Vasospasm?

BACKGROUND: Stellate ganglion block (SGB) may have protective effects in patients at risk of vasospasm following subarachnoid hemorrhage (SAH) due to reduced sympathetic activity. However, the safety and clinical outcomes of SGB in this scenario are not definitively known. The objective was to evaluate the safety, clinical outcomes, and cerebral blood flow velocity in patients submitted to SGB or cervical sympathectomy with SAH. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a systematic review and meta-analysis of studies investigating SGB or cervical sympathectomy use in SAH were conducted. PubMed, Cochrane Library, and Embase were evaluated. Patients with mRS from 0 to 2, GOS from 4 to 5, or symptom resolution were considered favorable clinical outcomes. Related mortality was defined as death by vasospasm or delayed cerebral ischemia. RESULTS: The analysis included 8 studies comprising 182 patients. Only 2 studies employed SGB prophylactically. The results revealed favorable outcomes in 52% of patients (95% CI: 37%-65%). The overall incidence of complications was 2% (95% CI: 0% -26%). The mortality rate was 13% (95% CI: 7%-21%), with a vasospasm-related mortality rate of 11% (95% CI: 2%-20%). A decrease of cerebral blood flow velocity was reported in 4 studies. CONCLUSIONS: The notable reduction in cerebral blood flow velocity following SGB, alongside positive outcomes and a low occurrence of mortality and complications, highlights its significance as a therapeutic intervention for vasospasm following SAH. While the number of studies evaluating SGB as a preventive measure is limited, the promising results emphasize the importance of future research.