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Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) patients are given calcium channel blockers (CCBs) to prevent brain vessel vasospasm. We hypothesized that preinjury antihypertensive use may protect against vasospasm. It remains unclear whether the timing of in-hospital CCB initiation affects the vasospasm risk in this population., Methods: This retrospective cohort study included aSAH patients (≥18 y/o) at a Comprehensive Stroke Center (1/18-11/21). Patients taking prehospital antihypertensives [CCBs, Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin II receptor blockers (ARBs)] were compared to those who were not. Results were stratified by patients receiving vasospasm prophylaxis ('in-hospital CCBs') ≤1.2 h of arrival vs. >1.2 h from arrival. Outcomes included vasospasm, hospital length of stay (LOS), and mortality., Results: Of 251 patients, 18% were taking prehospital antihypertensives. Patients were comparable in baseline characteristics. There was no difference in the rate of vasospasm when compared by prehospital antihypertensive use. For those on prehospital antihypertensives, the time to in-hospital CCBs was significantly longer for patients who developed vasospasm than for those who did not (1.2 vs. 4.9 h, respectively, p = 0.02). For those on prehospital antihypertensives, receipt of in-hospital CCBs within 1.2 h of arrival was associated with a significantly lower vasospasm rate (6% vs. 39%, p = 0.03) and LOS (14 vs. 20 d, p = 0.01) when compared to receiving in-hospital CCBs > 1.2 h of arrival, respectively. The mortality rate (50% vs. 26%, p = 0.06) was statistically similar between groups, respectively. These results were not observed among patients who were not on prehospital antihypertensives. The timing to in-hospital CCB initiation had no effect on vasospasm (p = 0.23), death (p = 0.08), or LOS (p = 0.31) for patients not on prehospital antihypertensives., Conclusions: Enhancing the efficiency of in-hospital CCB initiation for patients on prehospital antihypertensives may decrease the occurrence of vasospasm and lead to a shorter LOS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The prior trials investigating triple-H therapy for preventing delayed cerebral ischemia (DCI) enrolled patients with aneurysmal subarachnoid hemorrhage (aSAH) who underwent early aneurysm therapy within 3 days. However, surgical clipping might be performed during 4-7 days that high incidence cerebral vasospasm is likely. We examined effects of hypervolemia-augmented blood pressure (HV-ABP) protocol on DCI prevention when clipping was delayed., Methods: The study enrolled aSAH patients hospitalized during 2013-2019 who underwent clipping 4-7 days after rupture in a university hospital in Thailand. DCI and secondary outcomes were compared among patients who achieved the HV-ABP protocol (3-5 L/day fluid intake and 140-180 mmHg systolic blood pressure maintained for 72 hours postoperatively) and those who did not. The intervention-outcome associations were estimated using logistic regression for the whole group and a patient subgroup with similar propensity scores (PS) for protocol achievement., Results: One hundred seventy-seven aSAH patients were clipped 4-7 days after rupture; 97 patients (54.8%) achieved the HV-ABP protocol, while 80 patients (45.2%) did not. One hundred twenty-two patients with one-to-one PS matching reduced the originally unequal patient characteristics. The observed DCI was lower in patients with protocol-achieved (8.3%) than in their nonachieved counterparts (22.5%). This resulted in an association with the HV-ABP intervention with adjusted odds ratios of 0.201 (95% confidence interval, 0.066-0.613) in the whole sample and 0.228 (0.065-0.794) in the PS-matched subsample. No statistically significant differences in the secondary outcomes were found., Conclusions: Achieving the targets recommended in the HV-ABP protocol was associated with reducing the DCI incidence in patients with aSAH who underwent delayed clipping., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background: Magnesium sulfate (MgSO 4 ) is a potential neuroprotective agent for patients with aneurysmal subarachnoid hemorrhage (SAH). We analyzed the effect of early application of intraoperative intravenous MgSO 4 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) MgSO 4 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 MgSO 4 within 24 hours after aneurysmal SAH onset. Favorable functional outcome was more likely in the MgSO 4 group after 12 months of follow-up., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the effectiveness of ventriculo-cisternal irrigation (VCI) in preventing vasospasms and delayed cerebral infarction (DCI) by washing out subarachnoid clots earlier after aneurysm surgery., Methods: We retrospectively identified 340 subarachnoid hemorrhage (SAH) patients with ruptured intracranial aneurysms treated with postoperative VCI at our institution between December 2010 and January 2020. As VCI therapy, a ventricular drain/cisternal drain was placed during aneurysm surgery, and lactated Ringer's solution was used for irrigation until day 4 of SAH, followed by intracranial pressure control at 5-10 cmH 2 O until day 14., Results: The median age was 65 years (interquartile range 52-75), with 236 female patients (69%). The World Federation of Neurosurgical Societies grade distribution was as follows: grade I or II, 175 patients (51%); grade III or IV, 84 (25%); and grade V, 81 (24%). With VCI management in all patients, total vasospasm occurred in 162 patients (48%), although the DCI incidence was low (23 patients [6.8%]). Major drainage-related complications were observed in five patients (1.5%). Early surgery, performed on SAH day 0 or 1, was identified as a preventive factor against DCI occurrence (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.07-0.67; P = 0.008), while additional surgery (4.76, 1.62-13.98; P = 0.005) and dyslipidemia (3.27, 1.24-8.63; P = 0.017) were associated with DCI occurrence., Conclusion: Managing vasospasms with VCI after SAH is considered a safe and effective method to prevent DCI. Early surgery after SAH may be associated with a decreased risk of DCI with VCI therapy., (© 2023. The Author(s).)

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is of the most serious emergencies in neurosurgical practice and continues to be associated with high morbidity and mortality. Beyond securing the ruptured aneurysm to prevent a rebleed, physicians continue to be concerned about potential complications such as cerebral vasospasm-delayed cerebral ischemia (DCI), an area where management remains highly variable. This study aimed at reviewing the most recent literature and assessing any up-to-date schemes for treating the most common aSAH neurological complications in adults that can be applied in daily clinical practice towards optimising outcomes., Methods: A systematic review was performed according to PRISMA guidelines on the management of aSAH neurological complications in adults. The literature surveyed was between 2016 and 2022 inclusive, using the Pubmed search engine. Comparisons between the methods suggested by existing therapeutic algorithms were discussed., Results: Six stepwise algorithms assisting the decision-making for treating cerebral vasospasm-DCI were recognised and compared. No algorithm was found for the management of any other neurological complications of aSAH. Despite differences in the algorithms, induced hypertension and endovascular therapy were common treatments in all approaches. Controversy in the therapeutic process of these complications surrounds not only the variability of methods but also their optimal application towards clinical outcome optimisation., Conclusions: A universal approach to managing aSAH complications is lacking. Despite advances in the techniques to secure a ruptured aneurysm, there persist a high rate of neurological deficit and mortality, and several unanswered questions. More research is required towards stratification of current treatment algorithms as per the quality of their evidence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This research was undertaken as partial fulfillment of the requirements for the MSc Surgical Sciences at the University of Edinburgh. Dissertation for MSc Degree 2022., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Clazosentan has been studied to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).This meta-analysis of randomized controlled trials updates the current knowledge regarding the efficacy and safety of clazosentan compared with placebo after aSAH., Methods: Databases were systematically searched for randomized controlled trials directly comparing the use of clazosentan and placebo for the treatment of cerebral vasospasm after aSAH. Additional eligibility criteria were the report of any of the outcomes of interest (vasospasm, morbidity, functional outcome, or mortality). The primary outcome was vasospasm-related delayed cerebral ischemia (DCI). The analyses were stratified by clazosentan dosage (low or high dose) and aneurysm treatment modality (clipping or coiling). The Cochrane RoB-2 tool was used for studies quality assessment., Results: Six studies comprising 7 clinical trials were included, involving 2778 patients. Clazosentan decreased the risk of vasospasm-related DCI (risk ratio [RR] 0.56, 95% CI 0.38-0.81) and delayed ischemic neurological deficit (RR 0.63, 95% 0.50-0.80). Angiographic vasospasm (RR 0.54, 95% CI 0.47-0.61) was also decreased. Functional outcomes (favorable Glasgow Outcome Scale, RR 0.99, 95% CI 0.79-1.24) and death (RR 1.03, 95% CI 0.71-1.49) did not change. Meanwhile, adverse events were increased by clazosentan (RR 1.54, 95% CI 1.35-1.76)., Conclusion: Clazosentan decreased vasospasm-related DCI and angiographic vasospasm but did not improve functional outcomes or mortality. Adverse events were increased by clazosentan., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background/importance: Delayed cerebral ischemia (DCI) is the second-leading cause of death and disability in patients with aneurysmal subarachnoid hemorrhage (aSAH), and is associated with cerebral arterial vasospasm (CAV). Current treatments for CAV are expensive, invasive, and have limited efficacy. Cervical sympathetic block (CSB) is an underappreciated, but potentially highly effective therapy for CAV., Objective: To provide a comprehensive review of the preclinical and human literature pertinent to CSB in the context of CAV., Evidence Review: This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. We conducted a literature search using Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science until February 2022, to identify abstracts, conference proceedings, and full-text papers pertinent to cervical sympathectomy and CAV in animal/adult patients., Findings: We included six human and six experimental studies. Human studies were mostly prospective observational, except one retrospective and one randomized clinical trial, and used various imaging modalities to measure changes in arterial diameter after the block. Studies that used digital subtraction angiography showed an improvement in cerebral perfusion without change in vessel diameter. Transcranial Doppler studies found an approximately 15% statistically significant decrease in velocities consistent with arterial vasodilatation. Overall, the results suggest an increase in cerebral arterial diameter and neurological improvement in patients receiving a CSB. Animal studies demonstrate that sympathetic system ablation vasodilates cerebral vasculature and decreases the incidence of symptomatic vasospasm., Conclusions: This scoping review suggests that CSB may be a viable option for treatment and prevention of CAV/DCI in patients with aSAH, although the included studies were heterogeneous, mostly observational, and with a small sample size. Further research is needed to standardize the technique and prove its effectiveness to treat patients suffering of CAV/DCI after aSAH., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning-induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10- to 14-week-old male wild-type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane-induced changes in iNOS expression were measured. N-(3-(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1-way ANOVA and 2-way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P <0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N-(3-(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild-type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N-(3-(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Conclusions Isoflurane conditioning-induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH.

Cerebral vasospasm remains the most frequent and devastating complication after subarachnoid aneurysmal hemorrhage because of secondary cerebral ischemia and its sequelae. The underlying pathophysiology involves vasodilator peptide release (such as CGRP) and nitric oxide depletion at the level of the precapillary sphincters of the cerebral (internal carotid artery network) and dural (external carotid artery network) arteries, which are both innervated by craniofacial autonomic afferents and tightly connected to the trigeminal nerve and trigemino-cervical nucleus complex. We hypothesized that trigeminal nerve modulation could influence the cerebral flow of this vascular network through a sympatholytic effect and decrease the occurrence of vasospasm and its consequences. We conducted a prospective double-blind, randomized controlled pilot trial to compare the effect of 10 days of transcutaneous electrical trigeminal nerve stimulation vs. sham stimulation on cerebral infarction occurrence at 3 months. Sixty patients treated for aneurysmal SAH (World Federation of Neurosurgical Societies scale between 1 and 4) were included. We compared the radiological incidence of delayed cerebral ischemia (DCI) on magnetic resonance imaging (MRI) at 3 months in moderate and severe vasospasm patients receiving trigeminal nerve stimulation (TNS group) vs. sham stimulation (sham group). Our primary endpoint (the infarction rate at the 3-month follow-up) did not significantly differ between the two groups ( p = 0.99). Vasospasm-related infarctions were present in seven patients (23%) in the TNS group and eight patients (27%) in the sham group. Ultimately, we were not able to show that TNS can decrease the rate of cerebral infarction secondary to vasospasm occurrence. As a result, it would be premature to promote trigeminal system neurostimulation in this context. This concept should be the subject of further research.

Rationale: Aneurysmal subarachnoid hemorrhage (SAH) has high morbidity and mortality. While the primary injury results from the initial bleeding cannot currently be influenced, secondary injury through vasospasm and delayed cerebral ischemia worsens outcome and might be a target for interventions to improve outcome. To date, beside the aneurysm treatment to prevent re-bleeding and the administration of oral nimodipine, there is no therapy available, so novel treatment concepts are needed. Evidence suggests that inflammation contributes to delayed cerebral ischemia and poor outcome in SAH. Some studies suggest a beneficial effect of anti-inflammatory glucocorticoids, but there are no data from randomized controlled trials examining the efficacy of glucocorticoids. Therefore, current guidelines do not recommend the use of glucocorticoids in SAH., Aim: The Fight INflammation to Improve outcome after aneurysmal Subarachnoid HEmorRhage (FINISHER) trial aims to determine whether dexamethasone improves outcome in a clinically relevant endpoint in SAH patients., Methods and Design: FINISHER is a multicenter, prospective, randomized, double-blinded, placebo-controlled clinical phase III trial which is testing the outcome and safety of anti-inflammatory treatment with dexamethasone in SAH patients., Sample Size Estimates: In all, 334 patients will be randomized to either dexamethasone or placebo within 48 h after SAH. The dexamethasone dose is 8 mg tds for days 1-7 and then 8 mg od for days 8-21., Study Outcome: The primary outcome is the modified Rankin Scale (mRS) at 6 months, which is dichotomized to favorable (mRS 0-3) versus unfavorable (mRS 4-6)., Discussion: The results of this study will provide the first phase III evidence as to whether dexamethasone improves outcome in SAH.

Background: Cerebral vasospasm is one of the frequent complications that can occur following subarachnoid hemorrhage (SAH). With new protocols in the management of SAH, the combined risk of death and long-term disability have been reduced by about 10% compared with the past., Objective: This work aims to report the latest updates on the vasospasm developing after the SAH in patients in the ICU department. In this short review, we reviewed the latest scientific findings on the mechanisms of vasospasm, and in addition, we considered it necessary to review the literature to report the tools for early diagnosis of vasospasm and the best treatment strategies to prevent the negative outcome in patients admitted to ICU., Aim: The aim of this narrative review is to report the main characteristics of vasospasm, new diagnostic methods, and, especially, more effective treatment of vasospasm., Materials and Methods: The peer-reviewed articles analyzed were selected from PubMed, Google scholar, Embase, and Scopus databases published in the previous 20 years using the keywords "vasospasm", "vasospasm diagnosis", "vasospasm and SAH", "vasospasm treatment", and nontraumatic brain injury. Among the 78 papers identified, 43 articles were selected; after the title - abstract examination and removing the duplicates, only 31 articles were examined., Results: Vasospasm can be classified according to clinical (asymptomatic vs. symptomatic) and diagnostic (angiographic vs. ultrasound) methods. Various procedures such as TCD and CT perfusion are used for early diagnosis and close monitoring of this condition. The treatment of vasospasm consists of both prevention (nimodipine, statitis, and magnesium sulphate) and active treatment (mainly endovascular)., Conclusion: As the review shows, vasospasm is a complication of SAH, a complication that is difficult to recognize early and treat with the best outcome. However, with the equipment we have, it has been possible to improve the outcome, even if it is still not ideal, in patients who develop vasospasm. Several studies are in the final stages to improve the outcome of this unfortunately frequent condition., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Delayed cerebral vasospasms after subarachnoid hemorrhage (SAH) are a risk factor for poor prognosis after successful treatment of ruptured intracranial aneurysms. Different strategies to remove clots from the subarachnoid space and prevent vasospasms have different outcomes. Intrathecal urokinase infusion therapy combined with endovascular treatment (EVT) can reduce the incidence of symptomatic vasospasms. To analyze the relationship between symptomatic vasospasms and residual SAHs after urokinase infusion therapy, we retrospectively reviewed the records of 348 consecutive patients managed with EVT and intrathecal urokinase infusion therapy for aneurysmal SAH at our institution between 2010 and 2021. Among them, 163 patients met the study criteria and were classified into two groups according to the presence of residual SAH in the cisterns, Sylvian fissures, and frontal interhemispheric fissure. The incidence of symptomatic vasospasms and the clinical outcomes were assessed. In total, eight (5.0%) patients developed symptomatic vasospasms. Patients with symptomatic vasospasms had a significantly higher incidence of residual SAH in the Sylvian or frontal interhemispheric fissures than those without (P <.0001). No patient with SAHs resolved by urokinase infusion therapy developed symptomatic vasospasms. However, the two groups did not differ significantly in terms of modified Rankin scale scores at discharge. Treatment with intrathecal urokinase infusion after EVT for aneurysmal SAH can substantially reduce the risk of clinically evident vasospasms.

Introduction: Stellate ganglion block has been reported to expand cerebral vessels and alleviate vasospasm after aneurysmal subarachnoid hemorrhage. However, the causal relationship between early stellate ganglion block and cerebral vasospasm prevention has not yet been established. The purpose of this study was to explore the effectiveness and safety of early stellate ganglion block as a preventive treatment for cerebral vasospasm and delayed cerebral ischemia., Methods/design: This is a single-center, prospective, randomized, controlled, blinded endpoint assessment superiority trial. A total of 228 patients will be randomized within 48 h of aneurysmal subarachnoid hemorrhage onset in a 1:1 ratio into two groups, one group receiving an additional e-SGB and the other group receiving only a camouflaging action before anesthesia induction in the operating room. The primary outcome is the incidence of symptomatic vasospasm within 14 days after aSAH. Further safety and efficacy parameters include the incidence of radiographic vasospasm, new cerebral infarction, postoperative delirium, and complications up to 90 days after surgery; postoperative cerebral hemodynamics; Mini-Mental State Examination score; modified Rankin scale score; and all-cause mortality up to 90 days after surgery., Discussion: This is a randomized controlled trial to explore the effectiveness and safety of early stellate ganglion block as a preventive treatment to reduce cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. If the results are positive, it may provide a new direction for the prevention and treatment of cerebral vasospasm and delayed cerebral ischemia., Trial Registration: The study was registered on Clincaltrials.gov on December 13, 2020 (NCT04691271)., (© 2022. The Author(s).)

Background: Cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of high morbidity and mortality, for which there is no consistently effective treatment. Cervical spinal cord stimulation (cSCS) has been shown to induce vasodilatation and improve peripheral and cerebral blood flow in both animal and human studies. This pilot study was performed to assess the clinical effect and long-term results of cSCS treatment in aSAH patients., Methods: This was the first IRB- and US FDA-approved prospective non-randomized non-controlled study comprising of 12 aSAH patients (8 women, 4 men, age range 34-62 years) treated between May and November 2008. All patients underwent up to 2 weeks of cSCS with a single percutaneously implanted 8-contact electrode. Neurological outcomes at discharge and follow-up of up to 13 years and mortality/complications rates were analyzed., Results: All 12 aSAH patients underwent cSCS electrode implantation immediately after securing the aneurysm. Patients were stimulated for 10-14 consecutive days starting within 3 days of aneurysm rupture. Angiographic vasospasm occurred in six patients; two patients developed new vasospasm-related neurological symptoms; both recovered completely by discharge time. One patient died from unrelated multi-system failure; the rest were followed up clinically (average, 7.5 years; range, 12-151 months) and angiographically (average, 6.5 years; range, 36-125 months). No delayed ischemic neurological deficits/strokes and no cSCS-related adverse effects were observed., Conclusions: Our short- and long-term data suggest that cSCS is feasible and safe for patients in the acute aSAH settings. Small size of the patient cohort and lack of control do not allow us to conclude whether cSCS is able to prevent cerebral vasospasm, decrease its severity, and improve clinical outcomes in aSAH patients. However, our findings support further clinical trials and development of cSCS as a new concept to prevent and treat cerebral vasospasm., Clinicaltrials: gov NCT00766844, posted on 10/06/2008., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Angiographic treatment of asymptomatic cerebral vasospasm (CVS) in aneurysmal subarachnoid hemorrhage remains controversial. We sought to investigate its relationship with the development of delayed cerebral ischemia., Methods: Consecutive patients admitted between July 2017 and June 2019, with a diagnosis of aneurysmal subarachnoid hemorrhage, were retrospectively analyzed. The rate of development of delayed cerebral ischemia was compared between a group of patients who underwent cerebral angiography for asymptomatic CVS and those who did not. The Mann-Whitney U test or χ 2 test was used to compare the 2 groups., Results: Thirty-seven of the 94 patients with aneurysmal subarachnoid hemorrhage were screened for CVS, of whom 16 (43%) had moderate-severe vasospasm. When patients who underwent therapeutic cerebral angiography were compared with those who did not and after adjusting for sex, age, and grade of subarachnoid hemorrhage, treatment was not found to be significantly associated with delayed cerebral ischemia (hazard ratio = 0.82, 95% confidence interval: 0.19-3.52, P = 0.79). We found that the median length of stay in the intensive care unit and hospital increased significantly with the severity of CVS (P < 0.001)., Conclusions: Cerebral angiography has a low rate of detecting moderate-severe CVS in asymptomatic patients. Moreover, there was no statistically significant difference in the rate of delayed cerebral ischemia between asymptomatic patients treated versus those not treated for CVS. There was significant association between the severity of CVS and the intensive care unit and hospital length of stay. More studies are needed to evaluate the utility of treating asymptomatic CVS in high-grade aneurysmal subarachnoid hemorrhage., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Posterior cerebral blood flow is regulated by the basilar arteries (BAs). Vasospasm of BAs can occur after subarachnoid hemorrhage (SAH). Superior cervical sympathetic ganglia (SCG) fibers have a vasoconstrictor effect on the BA. We aimed to investigate the relationship between the degenerated neuron density of the SCG and the severity of BA vasospasm after experimental SAH., Methods: Twenty-four rabbits were used. Five were used as the control group, and 5 were used as the sham group. Experimental SAHs were performed in the remaining 14 animals (study group) by injecting homologous blood into the cisterna magna. After 3 weeks of injection, neuron densities of SCG and the severity of BA vasospasm index values (VSI) were examined histopathologically and compared statistically., Results: The mean VSI was 0.669 ± 0.1129 in the control group, 0.981 ± 0.159 in the sham group, and 1.512 ± 0.298 in the study group. The mean degenerated neuronal density of SCG was 436 ± 79/mm 3 in severe vasospasm (n = 3), 841 ± 101/mm 3 in moderate vasospasm (n = 4), and 1.921 ± 849/mm 3 in the less vasospasm detected animals (n = 6)., Conclusions: This study shows an inverse relationship between the degenerated neuronal density in the SCG and VSI values. This finding indicates a diminished sympathetic input from the SCG, resulting in a beneficial effect (the felix culpa) by dilating the lumen diameter of the BA, so SCG degeneration after SAH protects the BA spasm., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To perform an updated meta-analysis to comprehensively assess the efficacy and safety of cilostazol in preventing aneurysmal subarachnoid hemorrhage (SAH)-related secondary complications., Methods: Electronic databases of PubMed, the Cochrane library, CNKI and Wanfang were searched on August 2021. Pooled odds ratio (OR) and standardized mean difference (SMD) were calculated for dichotomous and continuous outcomes, respectively., Results: A total of 14 studies [comprising 18,726 aneurysmal SAH patients (6654 in the cilostazol group and 12,072 in the control group)] performed in Japan or China were included. Compared with the control group, cilostazol treatment significantly reduced the median cerebral artery (SMD = -0.49; p < 0.001), improved the therapeutic efficacy (OR = 2.37; p = 0.009), decreased the incidence of symptomatic vasospasm/delayed cerebral ischemia (OR = 0.42; p < 0.001), severe angiographic vasospasm (OR = 0.54; p < 0.001), new cerebral infarction (OR = 0.33; p < 0.001), poor outcomes (OR = 0.86; p = 0.001), mortality (OR = 0.62; p < 0.001) and increased the incidence of no or mild angiographic vasospasm (OR = 1.94; p = 0.004), but did not induce more adverse events (OR = 1.08; p = 0.871). The mechanism of cilostazol treatment was to inhibit the production of tenascin-C (SMD = -1.46; p < 0.001). These results were hardly changed by subgroup analysis., Conclusion: This meta-analysis indicates cilostazol may be an effective and safe drug for aneurysmal SAH patients. However, further trials involving other world populations are required to demonstrate the generalization of treatment effects of cilostazol., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Preventing delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) remains an important therapeutic target. Preconditioning stimulates multiple endogenous protective mechanisms and may be a suitable treatment for DCI following SAH. We here compare remote limb conditioning with resveratrol conditioning in a clinically relevant SAH model., Methods: We produced a SAH in 39 male Sprague Dawley rats using a single injection model. Animals were randomized to four groups: repetitive limb conditioning with a blood pressure cuff, sham conditioning, intraperitoneal resveratrol (10 mg/kg) or intraperitoneal vehicle administered at 24, 48 and 72 h after SAH. On day 4 neurological and behavioral scores were obtained, and animals were euthanized. The cross-sectional area of the basilar artery was measured at the vertebrobasilar junction, and at the mid and distal segments. Hippocampal cells were counted in both hemispheres and normalized per mm length. We compared true limb preconditioning with sham conditioning and resveratrol with vehicle preconditioning., Results: The cross-sectional area of the mid-basilar artery in the true limb preconditioning group was significantly larger by 43% ( p = 0.03) when compared with the sham preconditioning group. No differences in the cross-sectional area were found in the resveratrol-treated group when compared to the vehicle-treated group. We found no differences in the neuro score, behavioral score, and in mean hippocampal neuron counts between the groups., Conclusion: We found beneficial vascular effects of remote limb preconditioning on SAH-induced basilar artery vasoconstriction. Our findings support further studies of limb preconditioning as a potential treatment after SAH.

Introduction: Cerebral vasospasm (CVS) is the leading cause of mortality and morbidity following aneurysmal subarachnoid haemorrhage (aSAH). One of the recently implicated underlying mechanisms of CVS is inflammatory cascades. Specific feasibility objectives include determining the ability to recruit 30 participants over 24 months while at least 75% of them comply with at least 75% of the study protocol and being able to follow 85% of them for 3 months after discharge., Methods and Analysis: This is a feasibility study for a randomised controlled trial. Eligible participants are adult patients who are 18 years of age and older with an aSAH confirmed by a brain CT scan, and CT angiography, or magnetic resonance angiography, or digital subtraction angiography who admitted to the emergency department within 12 hours of the ictus. Eligible subjects will be randomised 1:1 for the administration of either ibuprofen or a placebo, while both groups will concomitantly be treated by the standard of care for 2 weeks. Care givers, patients, outcome assessors and data analysts will be blinded. This will be the first study to investigate the preventive effects of a short-acting non-steroidal anti-inflammatory drug on CVS and the key expected outcome of this pilot study is the feasibility and safety assessment of the administration of ibuprofen in patients with aSAH. The objectives of the definitive trial would be to assess the effect of ibuprofen relative to placebo on mortality, CVS, delayed cerebral ischaemia, and level of disability at 3-month follow-up., Ethics and Dissemination: This study is approved by Mashhad University of Medical Sciences ethical committee (IR.MUMS.MEDICAL.REC.1398.225). Results from the study will be submitted for publication regardless of whether or not there are significant findings., Trial Registration Number: ISRCTN14611625., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To compare the efficacy of two different concepts of cisternal therapy-PREVENTIVE fibrinolysis plus on-demand spasmolysis versus RESCUE spasmolysis-for the prevention of cerebral vasospasm (CVS) and delayed cerebral infarction (DCI) in patients with aneurysmal subarachnoid haemorrhage (aSAH)., Methods: Retrospective analysis of 84 aSAH patients selected for cisternal therapy for DCI prevention. 66 high-risk patients received PREVENTIVE cisternal therapy to enhance blood clearance. Either stereotactic catheter ventriculocisternostomy (STX-VCS) or intraoperative placement of a cisterno-ventriculostomy catheter (CVC), followed by fibrinolytic cisternal lavage using urokinase was performed. In case of vasospasm, nimodipine was applied intrathecally. 22 low-risk patients who developed CVS against expectations were selected for STX-VCS as RESCUE intervention for cisternal spasmolysis with nimodipine. Rates of DCI and mean flow velocities of daily transcranial Doppler (TCD) ultrasonographies were evaluated., Results: Despite a higher prespecified DCI risk, patients selected for PREVENTIVE intervention primarily aiming at blood clearance had a lower DCI rate compared with patients selected for intrathecal spasmolysis as a RESCUE therapy (11.3% vs 18.2%). After intrathecal treatment onset, CVS (TCD>160 cm/s) occurred in 45% of patients with PREVENTIVE and 77% of patients with RESCUE therapy (p=0.013). A stronger response of CVS to intrathecal nimodipine was observed in patients with PREVENTIVE intervention as the mean CVS duration after start of intrathecal nimodipine was 3.2 days compared with 5.8 days in patients with RESCUE therapy (p=0.026)., Conclusions: PREVENTIVE cisternal therapy directed at blood clearance is more effective for the prevention of CVS and delayed infarction compared with cisternal RESCUE spasmolysis., Trial Registration Number: DRKS00016532., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Clazosentan (PIVLAZ ™ ) is a small molecule, endothelin (ET) A receptor-selective antagonist being developed by Idorsia Pharmaceuticals. ET A receptor inhibition by clazosentan decreases ET-related cerebral vasospasm, which may occur after an aneurysmal subarachnoid haemorrhage. Clazosentan has been approved in Japan for use in the prevention of cerebral vasospasm, vasospasm-related cerebral infarction and cerebral ischaemic symptoms after aneurysmal subarachnoid haemorrhage, following the results from the JapicCTI163369 and JapicCTI163368 phase III trials. This article summarises the milestones in the development of clazosentan leading to this first approval in this indication., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Poor patient outcomes after aneurysmal subarachnoid hemorrhage (SAH) occur due to a multifactorial process, mainly involving cerebral inflammation (CI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia, followed by neurodegeneration. CI is mainly triggered by enhanced synthesis of serotonin (5-HT), prostaglandin F2alpha (PGF2a), and cytokines such as interleukins. Levosimendan (LV), a calcium-channel sensitizer, has already displayed anti-inflammatory effects in patients with severe heart failure. Therefore, we wanted to elucidate its potential anti-inflammatory role on the cerebral vasculature after SAH., Methods: Experimental SAH was induced by using an experimental double-hemorrhage model. Sprague Dawley rats were harvested on day 3 and day 5 after the ictus. The basilar artery was used for isometric investigations of the muscular media tone. Vessel segments were either preincubated with LV or without, with precontraction performed with 5-HT or PGF2a followed by application of acetylcholine (ACh) or LV., Results: After preincubation with LV 10 -4 M and 5-HT precontraction, ACh triggered a strong vasorelaxation in sham segments (LV 10 -4 M, E max 65%; LV 10 -5 M, E max 48%; no LV, E max 53%). Interestingly, SAH D3 (LV 10 -4 , E max 76%) and D5 (LV 10 -4 , E max 79%) segments showed greater vasorelaxation compared with sham. An LV series after PGF2a precontraction showed significantly enhanced relaxation in the sham (P=0.004) and SAH groups (P=0.0008) compared with solvent control vessels., Conclusions: LV application after SAH seems to beneficially influence DCVS by antagonizing 5-HT- and PGF2a-triggered vasoconstriction. Considering this spasmolytic effect, LV might have a role in the treatment of SAH, additionally in selected patients suffering takotsubo cardiomyopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Clazosentan has been investigated globally for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The authors evaluated its effects on vasospasm-related morbidity and all-cause mortality following aSAH in Japanese patients., Methods: Two similar double-blind, placebo-controlled phase 3 studies were conducted in 57 Japanese centers in patients with aSAH, after aneurysms were secured by endovascular coiling in one study and surgical clipping in the other. In each study, patients were randomly administered intravenous clazosentan (10 mg/hr) or placebo (1:1) starting within 48 hours of aSAH and for up to 15 days after aSAH. Stratified randomization based on World Federation of Neurosurgical Societies grade was performed using a centralized interactive web response system. Vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH, including new cerebral infarcts and delayed ischemic neurological deficits as well as all-cause mortality, were the first primary endpoint in each study. The second primary endpoint was all-cause morbidity (new cerebral infarct or delayed ischemic neurological deficit from any causes) and all-cause mortality (all-cause morbidity/mortality) within 6 weeks post-aSAH. The incidence of individual components of the primary morbidity/mortality endpoints within 6 weeks and patient outcome at 12 weeks post-aSAH (including the modified Rankin Scale scores) were also evaluated. The above analyses were also performed in the population pooled from both studies., Results: In each study, 221 patients were randomized and 220 were included in the full analysis set of the primary analysis (109 in each clazosentan group, 111 in each placebo group). Clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling (from 28.8% to 13.6%; relative risk reduction 53%; 95% CI 17%-73%) and after clipping (from 39.6% to 16.2%; relative risk reduction 59%; 95% CI 33%-75%). All-cause morbidity/mortality and poor outcome (dichotomized modified Rankin Scale scores) were significantly reduced by clazosentan after preplanned study pooling. Treatment-emergent adverse events were similar to those reported previously., Conclusions: Clazosentan significantly reduced the combined incidence of vasospasm-related morbidity and all-cause mortality post-aSAH with no unexpected safety findings. Clinical trial registration nos.: JapicCTI-163368 and JapicCTI-163369 (https://www.clinicaltrials.jp).

Objective: Cerebral vasospasm and the resulting infarction remain the most devastating complications of aneurysmal subarachnoid hemorrhage (aSAH). Limited treatment options are available, with nimodipine as the only approved prophylactic medication. In addition to its anticoagulant properties, heparin also has a pleiotropic and anti-inflammatory effect that could be beneficial in vasospasm. In this study, the authors sought to evaluate the efficacy and safety of heparin in the treatment of aSAH., Methods: The PubMed, EBSCOhost, Europe PMC, and Cochrane Central databases were searched to find studies including patients with aSAH who were treated with intravenous unfractionated heparin (UFH) after an aneurysm-securing procedure. Studies that did not include a comparison with UFH or low-molecular-weight heparin in deep vein thrombosis prophylactic doses were excluded. The primary outcome was cerebral vasospasm, and the secondary outcomes were cerebral infarction, clinical deterioration caused by delayed cerebral ischemia, bleeding complications, and thromboembolism complications., Results: Overall, 5 nonrandomized studies were included; 4 studies evaluated the safety and 3 studies evaluated the efficacy of intravenous heparin. From the analysis of 3 studies with a total of 895 patients, administration of intravenous UFH for > 48 hours was related to a significantly lower rate of cerebral infarction (OR 0.44, 95% CI 0.25-0.79). No significant association was found with other efficacy outcomes. Regarding cognitive outcome, one study found a significant improvement in Montreal Cognitive Assessment scores; however, the functional outcome as indicated by the modified Rankin Scale score was not improved by heparin administration. From the analysis of 4 studies with 1099 patients, no significant increases in bleeding and other complications were found., Conclusions: Administration of intravenous UFH for more than 48 hours reduced the rate of cerebral infarction with a good safety profile. This result supports the ongoing clinical trial.

Cerebral vasospasm occurs within 4 to 14 days from the onset of aneurysmal subarachnoid hemorrhage (aSAH) in 40 to 70% of patients. Of patients with cerebral vasospasm, 17 to 40% experience delayed ischemic neurological deficits and about half of them develop cerebral infarction. Although the mechanism of the onset of cerebral vasospasm has not been fully elucidated, one of mechanisms is considered that after the onset of aSAH, the level of endothelin, a potent and sustained vasoconstriction substance, increases by production induced by oxyhemoglobin and release from erythrocytes and thus cerebral vasospasm develops via endothelin (ET) A receptor. PIVLAZ I.V. Infusion liquid 150 mg (clazosentan sodium) is an endothelin receptor antagonist with a binding affinity for ET A receptor approximately 1,000 times higher than that for ET B receptor. In the clinical study, the incidence of cerebral vasospasm-related morbidity and all-cause mortality was significantly decreased by clazosentan compared with the placebo. The marketing approval was obtained for the indication of "Prevention of cerebral vasospasm, and vasospasm-related cerebral infarction and cerebral ischemic symptoms after aSAH securing" in January 2022. It is expected to contribute to reducing the risk of sequela and improving quality of life in patients with aSAH.

Background and Purpose: Microthrombosis could play a role in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Tirofiban has shown promising results in reducing delayed cerebral ischemia in retrospective studies. However, the safety of using tirofiban in aneurysmal subarachnoid hemorrhage is not rigorously established., Methods: A phase 1/2a double-blinded randomized controlled trial (2:1 randomization) to assess the safety of a 7-day intravenous infusion of tirofiban compared with placebo, in patients with aneurysmal subarachnoid hemorrhage treated with ventriculostomy placed in the operative room and coiling was conducted. The primary end point was any intracranial hemorrhage during the hospital stay. The secondary end points were: incidence of radiographic and clinical vasospasm, incidence of delayed cerebral ischemia, and incidence of cerebral ischemic changes noted on magnetic resonance imaging or computed tomography., Results: Eighteen patients received intravenous tirofiban and 12 received placebo. There was no difference in baseline characteristics except for higher male proportions in the tirofiban group. There was no difference in death, in development of new or change in existing intracranial hemorrhages, in thrombocytopenia, and need for shunts in the two arms. However, the tirofiban arm had a lower incidence of delayed cerebral ischemia compared with placebo (6% [1/18] versus 33% [4/12]; P =0.04), and less radiographic vasospasm as detected by catheter angiogram or computed tomography angiography ( P =0.01) and computed tomography perfusion ( P =0.01)., Conclusions: The above preliminary results support proceeding with further testing of the safety and efficacy of 7-day intravenous infusion of tirofiban in a pragmatic (placing external ventricular drain by the bedside), multicenter setting, and using a larger population. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03691727.

Spontaneous subarachnoid haemorrhage is characterized by extravasation of blood into the subarachnoid space without a preceding trauma. The leading cause is a ruptured intracranial aneurysm. Serious neurologic complications can occur, such as rebleeding, cerebral vasospasm and delayed cerebral ischemia. Subarachnoid haemorrhage is a serious condition with a high mortality rate and those who survive often suffer long-term consequences. Prevention of rebleeding by aneurysm repair is essential and guidelines recommend this procedure should be done as soon as possible or within 72 hours. Management requires intensive care with emphasis on accurate blood pressure control, maintaining normal fluid and electrolyte balance and monitoring the level of consciousness. All patients should be treated with the calcium channel blocker nimodipine to reduce the risk of vasospasm and delayed cerebral ischemia which are among the most serious complications of subarachnoid haemorrhage.

Objectives: A paucity of treatments to prevent delayed cerebral ischemia (DCI) has stymied recovery after aneurysmal subarachnoid hemorrhage (aSAH). Nicardipine has long been recognized as a potent cerebrovascular vasodilator with a history off-label use to prevent vasospasm and DCI. Multiple centers have developed nicardipine prolonged release implants (NPRI) that are directly applied during clip ligation to locally deliver nicardipine throughout the vasospasm window. Here we perform a systematic review and meta-analysis to assess whether NPRI confers protection against DCI and improves functional outcomes after aSAH., Materials and Methods: A systematic search of PubMed, Ovid Embase, and Cochrane databases was performed for studies reporting the use of NPRI after aSAH published after January 1, 1980. We included all studies assessing the association of NPRI with DCI and or functional outcomes. Findings from studies with control arms were analyzed using a random effects model. A separate network meta-analysis was performed, including controlled NPRI studies, single-arm NPRI reports, and the control-arms of modern aSAH randomized clinical trials as additional comparators., Results: The search identified 214 unique citations. Three studies with 284 patients met criteria for the random effects model. The pooled summary odds ratio for the association of NPRI and DCI was 0.21 (95% CI 0.09-0.49, p = 0.0002) with no difference in functional outcomes (OR 1.80, 95% CI 0.63 - 5.16, p = 0.28). 10 studies of 866 patients met criteria for the network meta-analysis. The pooled summary odds ratio for the association of NPRI and DCI was 0.30 (95% CI 0.13-0.89,p = 0.017) with a trend towards improved functional outcomes (OR 1.68, 0.63 - 4.13 95% CI, p = 0.101)., Conclusions: In these meta-analyses, NPRI decreases the incidence of DCI with a non-significant trend towards improvement in functional outcomes. Randomized trials on the role of intrathecal calcium channel blockers are warranted to evaluate these observations in a prospective manner., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Cerebral vasospasm (CVS) and delayed ischemic neurological deficits (DIND) are a common cause of morbidity following aneurysmal subarachnoid hemorrhage (SAH). Statins have been shown to decrease CVS. The objective of this article was to ascertain the effect of statins on functional outcome and mortality following aneurysmal SAH by performing meta-analysis., Methods: A comprehensive search of different databases was performed to retrieve randomized controlled trials. Meta-analysis with subgroup analysis and metaregression was done. Trial sequential analysis (TSA) was performed to determine if the cumulative sample size was appropriately powered for the obtained pooled effect values and to avoid random error., Results: Twelve articles were selected for meta-analysis. Pooled OR for the change in favorable outcome, mortality, CVS, DIND and elevated transaminases was 1.07 (p = 0.55), 0.78 (p = 0.17), 0.58 (p = 0.0004), 0.54 (p = 0.0293) and 0.68 (p = 0.1774) respectively. Further, subgroup analysis and metaregression showed that the use of different statin or dose did not result in significant variation in results in the parameters studied. TSA showed that more trials and patients are required to reach to a definitive conclusion regarding any effect on statins on functional outcome and mortality as the current studies neither reached the level of confidence nor crossed the futility boundary., Conclusion: Use of statins in patients with aneurysmal SAH resulted in marginal but non-significant favorable impact on functional outcome and mortality. TSA showed that more studies are required to get conclusive evidence in this regard., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Cerebral vasospasm is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). Many drugs have been tried to mitigate cerebral vasospasm and delayed cerebral ischemia. Cilostazol, a selective inhibitor of phosphodiesterase 3, is a promising agent in preventing cerebral vasospasm and delayed cerebral ischemia after aSAH. The objective of this article was to ascertain the effect of cilostazol on cerebral vasospasm after aSAH by performing meta-analysis and trial sequential analysis., Methods: A systematic search of the literature was performed, and all the eligible randomized controlled trials were included in the meta-analysis and trial sequential analysis., Results: A total of 454 articles were identified using the search criteria. Six articles were selected for systematic review and the 4 randomized controlled trials were included in the meta-analysis. The pooled odds ratio for symptomatic vasospasm, new-onset infarct, and angiographic vasospasm was 0.35 (95% confidence interval [CI], 0.21-0.59; P < 0.0001), 0.38 (95% CI, 0.21-0.66; P = 0.0007) and 0.49 (95% CI, 0.31-0.80; P = 0.004), respectively. The pooled risk ratio for unfavorable outcome was 0.52 (95% CI, 0.37-0.74; P = 0.0003)., Conclusions: Cilostazol decreases the prevalence of symptomatic vasospasm, new-onset infarct, and angiographic vasospasm when administered after aSAH. Trial sequential analysis increased the precision of our results because the defined thresholds of effect were met by the available studies. However, further studies involving patients from other geographic areas are required to confirm the generalization of the results., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.

Purpose of Review: Delayed cerebral ischaemia (DCI) complicates the clinical course of patients with subarachnoid haemorrhage (SAH) in 20--30% and substantially worsens outcome. In this review, we describe a multimodal diagnostic approach based on underlying mechanisms of DCI and provide treatment options with a special focus on the most recently published literature., Recent Findings: Symptomatic vasospasm refers to clinical deterioration in the presence of vasospasm whereas DCI constitutes multiple causes. Pathophysiologic mechanisms underlying DCI range beyond large vessel vasospasm from neuroinflammation, to microthromboembolism, impaired cerebral autoregulation, cortical spreading depolarizations and many others. The current definition of DCI can be challenged by these mechanisms. We propose a pragmatic approach using a combination of clinical examination, cerebral ultrasonography, neuroimaging modalities and multimodal neuromonitoring to trigger therapeutic interventions in the presence of DCI. In addition to prophylactic nimodipine and management principles to improve oxygen delivery and decrease the brain metabolic demand, other specific interventions include permissive hypertension, intra-arterial application of calcium channel blockers and in selected patients angioplasty., Summary: The complex pathophysiology underlying DCI urges for a multimodal diagnostic approach triggering targeted interventions. Novel treatment concepts still have to be proven in large trials., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cerebral vasospasm is a major source of morbidity and mortality following aneurysm rupture and has limited treatment options., Objective: To evaluate the role of programmed death-1 (PD-1) in cerebral vasospasm., Methods: Endovascular internal carotid artery perforation (ICAp) was used to induce cerebral vasospasm in mice. To evaluate the therapeutic potential of targeting PD-1, programmed death ligand-1 (PD-L1) was administered 1 h after ICAp and vasospasm was measured histologically at the level of the ICA bifurcation bilaterally. PD-1 expressing immune cell populations were evaluated by flow cytometry. To correlate these findings to patients and evaluate the potential of PD-1 as a biomarker, monocytes were isolated from the peripheral blood and analyzed by flow cytometry in a cohort of patients with ruptured cerebral aneurysms. The daily frequency of PD-1+ monocytes in the peripheral blood was correlated to transcranial Doppler velocities as well as clinical and radiographic vasospasm., Results: We found that PD-L1 administration prevented cerebral vasospasm by inhibiting ingress of activated Ly6c+ and CCR2+ monocytes into the brain. Human correlative studies confirmed the presence of PD-1+ monocytes in the peripheral blood of patients with ruptured aneurysms and the frequency of these cells corresponded with cerebral blood flow velocities and clinical vasospasm., Conclusion: Our results identify PD-1+ monocytes as mediators of cerebral vasospasm and support PD-1 agonism as a novel therapeutic strategy., (© Congress of Neurological Surgeons 2020.)

Objective: The aim of this study is to determine protective/modulatory effects of betanin in a femoral artery vasospasm model in rats. Materials and Methods: Sprague-Dawley rats were divided into three groups. Group 1: sham (n = 7), group 2: vasospasm model only (n = 7), group 3: postoperative betanin treatment in the vasospasm model (n = 7). 100 mg/kg betanin was administered orally to group 3 for 7 days, postoperatively. Peripheral blood malondialdehyde (MDA) and nitric oxide (NO) levels were measured for the quantification of oxidative stress, lumen diameter and wall thickness of femoral artery segments were determined to assess vasodilator effects of betanin. Results: Femoral artery vasospasm formation significantly increased both MDA (13.54 ± 3.09 mmol/mL) and NO levels (0.61 ± 0.06 µmol/mL) relative to the sham (9.07 ± 1.09 and 0.48 ± 0.1, respectively). Upon betanin administration, both MDA and NO approached baseline levels (9.95 ± 0.92 and 0.5 ± 0.06, respectively). Pathological examination of lumen diameter and wall thickness of the femoral arteries also revealed that betanin administration resulted in significant increase in lumen diameter when compared to vasospasm group (614.15 ± 245.77 versus 117.40 ± 46.19 µm) and decrease in wall thickness (64.68 ± 14.13 versus 96.73 ± 9.20 µm). Conclusion: Betanin was shown to have protective effect against oxidative stress in a peripheral artery vasospasm model in rats. It may also have a role in mitigating maladaptive changes in arterial structure, as shown in pathological examination.

Background and Purpose: Poor-grade subarachnoid hemorrhage still has a poor prognosis. This randomized controlled clinical trial evaluated intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy in patients with poor-grade subarachnoid hemorrhage., Methods: Thirty-seven patients with poor-grade subarachnoid hemorrhage were randomized to Mg+H 2 , Mg, and control groups. Mg and Mg+H 2 groups received intracisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days. Mg+H 2 group also received intravenous hydrogen-rich solution infusion for 14 days. Primary outcome measures were occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures were modified Rankin Scale and Karnofsky performance status at 3 and 12 months, Barthel index at 12 months, and serum and cerebrospinal fluid malondialdehyde and neuron-specific enolase., Results: Serum neuron-specific enolase levels were significantly lower in the Mg+H 2 group from days 3 to 14 than in the control group. Cerebrospinal fluid neuron-specific enolase levels were also significantly lower in the Mg+H 2 group from days 3 to 7 than in the control group. Incidences of cerebral vasospasm and delayed cerebral ischemia were significantly higher in the control group than in other groups. Modified Rankin Scale and Karnofsky performance status did not significantly differ between the three groups at 3 months. Modified Rankin Scale scores 0 to 2 were more common in the Mg and Mg+H 2 groups at 1 year. Barthel index was higher in the Mg+H 2 group than in the control group., Conclusions: Intracisternal magnesium sulfate infusion started immediately after surgery reduces the incidence of cerebral vasospasm and delayed cerebral ischemia and improves clinical outcomes without complications in patients with poor-grade subarachnoid hemorrhage. Intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy decreases serum malondialdehyde and neuron-specific enolase and improves Barthel index, indicating hydrogen has additional effects. Registration: URL: https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000014696.

Objectives: To investigate the efficacy of acupuncture in preventing cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) and explore its underlying mechanism. Design: A randomized, double-blinded, and placebo-controlled trial. Setting/Location: Subjects were recruited from Kyung Hee University Hospital at Gangdong, Seoul, Korea Subjects: A total of 50 patients admitted with acute SAH. Interventions: The study group received acupuncture treatments ( n  = 25), while the control group underwent mock transcutaneous electrical nerve stimulation and sham acupuncture ( n  = 25) six times/week for 2 weeks. Outcome measures: The primary outcome was the incidence of delayed ischemic neurologic deficit (DIND), and secondary measurements included angiographic vasospasm, vasospasm-related infarction, modified Rankin Scale score, and plasma nitric oxide (NO) and endothelin-1 (ET-1) levels. Results: The study group treated with acupuncture showed a lower incidence of DIND (9.1%) than the control group (20.8%); however, this difference in the incidence of DIND was not statistically significant. The study group demonstrated better clinical outcomes, especially in functional recovery. Significant alterations in plasma NO and ET-1 levels after the 2-week intervention were observed only in the study group. Conclusions: Their study shows that acupuncture treatment improved functional recovery after SAH and could potentially prevent cerebral vasospasm. These effects could be attributed to the recovery of endothelial dysfunction by acupuncture through modulating the plasma NO and ET-1 levels. The study protocol has been registered on www.clinicaltrials.gov (NCT02275949).

Delayed cerebral ischemia (DCI) is the leading cause of mortality and disability in patients who survived the initial bleed of subarachnoid hemorrhage. Currently available guidelines are based on expert opinions derived from small observational studies due to the lack of randomized controlled trials. In this review, we will review some of the available literature and describe our local protocols for prophylaxis, risk stratification, monitoring in patients at risk, including multimodal invasive monitoring, and interventions measures in patients with DCI. These protocols are largely in line with the current guidelines but are deemed to evolve as ongoing and future trials provide stronger evidence to support interventions.

Background and Purpose: Vasospasm and delayed cerebral ischemia (DCI) contribute significantly to the morbidity/mortality associated with aneurysmal subarachnoid hemorrhage (SAH). While considerable research effort has focused on preventing or reversing vasospasm, SAH-induced brain injury occurs in response to a multitude of concomitantly acting pathophysiologic mechanisms. In this regard, the pleiotropic epigenetic responses to conditioning-based therapeutics may provide an ideal SAH therapeutic strategy. We previously documented the ability of hypoxic preconditioning (PC) to attenuate vasospasm and neurological deficits after SAH, in a manner that depends on the activity of endothelial nitric oxide synthase. The present study was undertaken to elucidate whether the NAD-dependent protein deacetylase sirtuin isoform SIRT1 is an upstream mediator of hypoxic PC-induced protection, and to assess the efficacy of the SIRT1-activating polyphenol Resveratrol as a pharmacologic preconditioning therapy., Methods: Wild-type C57BL/6J mice were utilized in the study and subjected to normoxia or hypoxic PC. Surgical procedures included induction of SAH via endovascular perforation or sham surgery. Multiple endpoints were assessed including cerebral vasospasm, neurobehavioral deficits, SIRT1 expression via quantitative real-time PCR for mRNA, and western blot for protein quantification. Pharmacological agents utilized in the study include EX-527 (SIRT1 inhibitor), and Resveratrol (SIRT1 activator)., Results: Hypoxic PC leads to rapid and sustained increase in cerebral SIRT1 mRNA and protein expression. SIRT1 inhibition blocks the protective effects of hypoxic PC on vasospasm and neurological deficits. Resveratrol pretreatment dose-dependently abrogates vasospasm and attenuates neurological deficits following SAH - beneficial effects that were similarly blocked by pharmacologic inhibition of SIRT1., Conclusion: SIRT1 mediates hypoxic preconditioning-induced protection against neurovascular dysfunction after SAH. Resveratrol mimics this neurovascular protection, at least in part, via SIRT1. Activation of SIRT1 is a promising, novel, pleiotropic therapeutic strategy to combat DCI after SAH., (Copyright © 2020. Published by Elsevier Inc.)

Background: There has not been any effective prophylaxis for delayed cerebral ischemia delayed cerebral ischemia (DCI) since the introduction of nimodipine. Platelet inhibition may reduce the risk by preventing the formation of microthrombi. Tirofiban has been used as a single monotherapy bridge given its safety profile and controlled platelet inhibition., Objective: To assess the risk of DCI in aneurysmal subarachnoid hemorrhages (aSAH) patients treated with the tirofiban protocol., Methods: aSAH patients between December 2010 and March 2019 who were treated with stent assisted coiling or flow-diverting device were started on a continuous tirofiban infusion protocol and were compared with patients who underwent coil embolization without antiplatelet therapy. Safety analysis was performed to assess DCI, hemorrhagic, and ischemic events., Results: A total of 21 patients were included in the tirofiban series and 81 in the control group. There was no statistical difference in age, gender, Hunt-Hess grade, and Fisher scale between the 2 groups except for a higher Fisher grade II in the tirofiban group. Multivariate analysis revealed tirofiban to reduce the risk of vasospasm by 72 percent (OR .28, P = .03), without affecting the risk of hemorrhagic complications (OR = 0.50, P = .26). Tirofiban reduced the risk of symptomatic stroke endovascular procedure but it did not reach significance (P = .06). DCI, older age, and postprocedural symptomatic stroke were significant predictors of mortality. Tirofiban reduced the mortality risk, but this association was not statistically significant., Conclusion: The tirofiban protocol in aSAH patients reduces the risk of DCI without conferring additional risks. This supports previous findings were antiplatelet therapy reduced DCI in human and animal models., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Objective: To develop a nicardipine prolonged-release implant (NPRI) to prevent cerebral vasospasm in patients with subarachnoid hemorrhage in 1999, which may be used during craniotomy, and report the results of our recent 12-year single critical care center experience., Methods: Of 432 patients with aneurysmal subarachnoid hemorrhage treated between 2007 and 2019, 291 were enrolled. 97 Patients were aged >70 years (33%), 194 were female (67%), 138 were World Federation of Neurological Societies grades 1, 2, and 3 (47%), 218 were Fisher group 3 (75%), and 243 had an anterior circulation aneurysm (84%). Using a propensity score matching method for these five factors, the severity of cerebral vasospasm, occurrence of delayed cerebral infarction, and modified Rankin Scale (mRS) score at discharge were analyzed., Results: One hundred patients each with or without NPRI were selected, and the ratios of coil/clip were 0/100 and 88/12, respectively. Cerebral vasospasm and delayed cerebral infarction were both significantly less common in the NPRI group (p=0.004, OR=0.412 (95% CI 0.223 to 0.760) and p=0.005, OR=0.272 (95% CI 0.103 to 0.714, respectively); a significant difference was seen in the mRS score at discharge by Fisher's exact test (p=0.0025). A mRS score of 6 (dead) was less common in the group with NPRI, and mRS scores of 0 and 1 were also less common. No side effects were seen., Conclusions: NPRIs significantly reduced the occurrence of cerebral vasospasm and delayed cerebral infraction without any side effects. The NPRI and non-NPRI groups showed different patterns of short-term outcomes in the single critical care center, which might have been due to selection bias and patient characteristics. Differences in outcomes may become clear in comparisons with patients treated by craniotomy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)