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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 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.

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: 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.)

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.

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.

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.

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.

Objective: To compare the effect of two prophylactic euvolemic fluid strategy regimens on the incidence of cerebral vasospasm and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH)., Methods: Ninety-six patients with a basal intravenous intake of 15 mL/kg/day of Ringer's lactate solution were included, and an additional 15 to 50 mL/kg/day Ringer's lactate (RL-group) or hydroxyethyl starch 130/0.4 solution (HES-group) was administered to maintain the targeted mean arterial pressure. The primary end point was the occurrence of cerebral vasospasm during the first 14 days. The secondary end points were case fatality, Barthel's index, and Glasgow Outcome Scores (GOS) at 30 days after SAH., Results: Cerebral vasospasm developed in 42 patients (43.7%), and nine of these events were severe. The vasospasm rate among the RL- and HES-based groups was 25/48 and 17/48, respectively. For the secondary endpoint, four patients (4%) died by the end of follow-up (two in each group). Unfavorable outcome cases were not different in the RL and HES groups (9 vs. 14, respectively). There was no difference between the Barthel's scores at 30 days between the two groups., Conclusions: Using starches in a prophylactic treatment strategy in aneurysmal SAH in not supported by the study.The trial was registered at Clinicaltrials.gov under the number NCT02064075.

Aim of the Study: Among subarachnoid haemorrhage (SAH) patients, delayed cerebral injury (DCI) and infarction are the most important causes of death and major disability. Cerebral vasospasm (cVS) and DCI remain the major cause of death and disability. Thymoquinone (TQ) is the substance most responsible for the biological activity of nigella sativa (NS) and is useful in the treatment of ischaemic and neurodegenerative diseases, oxidative stress, inflammatory events, cardiovascular and neurological diseases. We conducted an experimental study aimed to investigate the preventive and corrective effects of TQ., Materials and Methods: 24 Sprague-Dawley rats were randomly divided into three groups. The first was the control group which was a sham surgery group. The second group was the SAH group where the double haemorrage SAH protocol was used to induce vasospasm. The third group was the SAH+TQ group, where cVS was induced by the SAH protocol and the animals received oral 2 cc thymoquinone solution for seven days at a dose of 10 mg/kg, after the induction of SAH. The rats were euthanised seven days after the first procedure. The degree of cerebral vasospasm was evaluated by measuring the basilar artery luminal area and arterial wall thickness. Apoptosis was measured by the western blot method at brainstem neural tissue. Oxidative stress was measured by the Erel Method. Endothelin-1 was measured with ELISA analysis at blood. Statistical analysis was performed., Results: Endothelin-1 values were found to be statistically significantly lower in the control and SAH+TQ groups compared to the SAH group (P < 0.001). Mean lumen area values were significantly higher in the control and SAH+TQ groups than in the SAH group (P < 0.001). In the control and SAH+TQ groups, wall thickness values decreased significantly compared to the SAH group (P < 0.001). OSI values were significantly lower in the control and SAH+TQ groups than in the SAH group (P < 0.001). Apoptosis was significantly lower in the control and SAH+TQ groups than in the SAH group (P < 0.001)., Conclusion: Our results show that post-SAH TQ inhibits/improves DCI and cVS with positive effects on oxidative stress, apoptosis, ET-1, lumen area, and vessel wall thickness, probably due to its anti-ischaemic, antispasmodic, antioxidant, anti-inflammatory, anti-apoptotic and neuroprotective effects.

Background and Purpose- Clazosentan, an endothelin receptor antagonist, has been shown to reduce angiographic vasospasm and vasospasm-related morbidity after aneurysmal subarachnoid hemorrhage (SAH), although no effect on long-term functional outcome has been demonstrated. Thick clot on initial computed tomography is associated with an increased risk of vasospasm and delayed cerebral ischemia. In this post hoc analysis, we hypothesized that use of clazosentan in this subpopulation would provide stronger benefit. Methods- We analyzed SAH patients enrolled in the CONSCIOUS-2 and CONSCIOUS-3 studies (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) and compared the effects of clazosentan 5 mg/h, 15 mg/h, and placebo starting the day after aneurysm repair. The analysis was performed separately based on the presence or absence of thick (≥4 mm) and diffuse (≥3 cisterns) SAH on admission computed tomography. The primary composite end point was all-cause mortality and vasospasm-related morbidity at 6 weeks, and the main secondary end point was the extended Glasgow Outcome Scale at 3 months, adjusted for admission clinical grade. Results- Of 1718 randomized patients, 919 (53%) had thick and diffuse SAH. The primary composite end point in this group occurred in 36% of placebo-treated patients (n=294), 30% patients treated with clazosentan 5 mg/h (n=514; relative risk, 0.82; 95% CI, 0.67-0.99), and 19% patients treated with clazosentan 15 mg/h (n=111; relative risk, 0.54; 95% CI, 0.36-0.80). Despite this, death or poor functional outcome (Glasgow Outcome Scale ≤4) occurred in 33% of placebo-treated patients, 34% of patients treated with clazosentan 5 mg/h (relative risk 1.02; 95% CI, 0.84-1.23), and 35% of patients treated with clazosentan 15 mg/h (relative risk 1.14; 95% CI, 0.88-1.48). Conclusions- In an enriched population with thick and diffuse SAH, clazosentan at a dose of 5 and 15 mg/h was able to significantly reduce vasospasm-related morbidity in a dose-dependent manner. The absence of an effect on long-term functional status likely reflects the complexity and multiplicity of factors that contribute to poor outcome after SAH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00558311; NCT00940095.

Graft stenosis and occlusion remain formidable complications in cerebral revascularization procedures, which can lead to significant morbidity and mortality. Graft vasospasm can result in early postoperative graft stenosis and occlusion and is believed to be at least partially mediated through adrenergic pathways. Despite various published treatment protocols, there is no single effective spasmolytic agent. Multiple factors, including anatomical and physiological variability in revascularization conduits, patient age, and comorbidities, have been associated with graft vasospasm pathogenesis and response to spasmolytics. The ideal spasmolytic agent thus likely needs to target multiple pathways to exert a generalizable therapeutic effect. Botulinum toxin (BTX)-A is a powerful neurotoxin widely used in clinical practice for the treatment of a variety of spastic conditions. Although its commonly described paradigm of cholinergic neural transmission blockade has been widely accepted, evidence for other mechanisms of action including inhibition of adrenergic transmission have been described in animal studies. Recently, the first pilot study demonstrating clinical use of BTX-A for cerebral revascularization graft spasm prevention has been reported. In this review, the mechanistic basis and potential future clinical role of BTX-A in graft vasospasm prevention is discussed.

Background: Aneurysmal subarachnoid hemorrhage is an important cause of premature death and disability worldwide. Magnesium sulphate is shown to have a neuroprotective effect and it reverses cerebral vasospasm. Milrinone is also used in the treatment of cerebral vasospasm. The aim of the present study was to compare the effect of prophylactic magnesium sulphate and milrinone on the incidence of cerebral vasospasm after subarachnoid hemorrhage., Methods: The study included 90 patients with aneurysmal subarachnoid hemorrhage classified randomly (by simple randomization) into two groups: magnesium sulphate was given as an infusion of 500mg.day -1 without loading dose for 21 days. Group B: milrinone was given as an infusion of 0.5μg.kg -1 .min -1 without loading dose for 21 days. The cerebral vasospasm was diagnosed by mean cerebral blood flow velocity in the involved cerebral artery (mean flow velocity≥120cm.s -1 ), neurological deterioration by Glasgow coma scale, or angiography (the decrease in diameter of the involved cerebral artery >25%)., Results: The mean cerebral blood flow velocity decreased significantly in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p<0.001). The incidence of cerebral vasospasm decreased significantly with magnesium compared to milrinone (p=0.007). The Glasgow coma scale significantly improved in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p=0.036, p=0.012, p=0.016, respectively). The incidence of hypotension was higher with milrinone than magnesium (p=0.012)., Conclusions: The incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage was significantly lower and Glasgow coma scale significantly better with magnesium when compared to milrinone. Milrinone was associated with a higher incidence of hypotension and requirement for dopamine and norepinephrine when compared to magnesium., (Copyright © 2018 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.)

Objective: Subarachnoid haemorrhage (SAH) accounts for 3% of all strokes, and is associated with significant morbidity and mortality. There is growing evidence implicating apolipoprotein E (apoE) in mediating adaptive anti-inflammatory and neuroprotective responses following ischaemic and traumatic brain injury. In the current study, we test the efficacy of a small apoE mimetic peptide, CN-105 in a murine model of SAH., Methods: Mice subjected to SAH received repeated intravenous injections of CN-105 every 12 hours for 3 days, with the first dose given 2 hours after injury. Daily functional outcomes were assessed by rotarod and neurological severity score. Haemorrhage grade and cerebral vascular diameters were measured at 5 days post-SAH. Cerebral microgliosis, neuronal degeneration and survival were analysed at 5 and 35 days post-SAH, respectively., Results: CN-105 reduces histological evidence of inflammation, reduces vasospasm and neuronal injury and is associated with improved long-term behavioural outcomes in a murine model of SAH., Conclusions: Given its favourable pharmacokinetic profile, central nervous system penetration and demonstration of clinical safety, CN-105 represents an attractive therapeutic candidate for treatment of brain injury associated with SAH., Competing Interests: Competing interests: DTL is an officer of Aegis CN, LLC, which supplied study drug. Aegis had no editorial control over study design, execution or the writing of this manuscript. DTL and BJK are coinventors of the Duke-held patent for CN-105.

Introduction/Purpose To achieve aneurysm occlusion, flow diverters (FDs) must be accurately sized to maximize coverage over the neck and induce thrombosis. Catheterization for diagnostic angiography can cause vasospasm that may affect vessel measurements. This study evaluates impacts of intra-arterial infusion of a calcium channel blocker (CCB) on angiographic measurements in patients treated with FDs to determine effects on final diameter of the FD and subsequent occlusion. Materials and methods Pre-treatment measurements were recorded for diameter of the distal and proximal landing zones and maximum and minimum diameters between these segments. Post-treatment measurements of the stent following deployment were recorded at these locations. When CCB was infused, post-infusion pre-treatment measurements were recorded. Rates of occlusion were noted for all patients. T-tests were performed to assess for differences in pre- and post-treatment measurements and rates of occlusion between groups with and without CCB infusion. Results Twenty-eight FDs were deployed to treat 25 aneurysms in 24 patients. CCB infusion was performed prior to deployment of 12 (42.9%) devices. No significant difference was noted between groups for pre- and post-treatment measurement changes. Confirmed aneurysm occlusion was more likely to occur in the CCB infusion group (88.9% vs. 36.4%, p = 0.009). Conclusion Optimization of device sizing is important to increase FD density over the aneurysm neck and promote thrombosis. To improve measurement accuracy, CCB infusion can reduce effects of mild vasospasm. Subsequent aneurysm occlusion was more likely to occur following FD treatment when device size selection was based on measurements performed following CCB infusion.

Intracranial aneurysms (IAs) that undergo rupture causing subarachnoid hemorrhage (SAH), are common in young patients with coarctation of the aorta (CoA), but rarer in middle-aged and elderly patients. The pathogenesis of IAs associated with CoA remains unclear. We report the case of a 50-year-old woman who presented with SAH. On evaluation, six IAs were distributed among the anterior communicating artery (ACoA) (ruptured), distal segments of both anterior cerebral arteries (ACA), the left internal carotid artery (ICA), the bifurcation of the left middle cerebral artery (MCA)/MCA early branch, and the inferior trunk of the left MCA. CoA was also diagnosed. The ruptured ACoA IA, and two other unruptured IAs, were successfully clipped during emergency surgery. Postoperative intensive care was instituted to avoid cerebral vasospasm and renal or spinal cord ischemia. During the same hospitalization, the remaining three IAs were clipped at a second surgery. She was discharged with slight cognitive impairment eighty days after admission. Subsequently, she underwent elective treatment for the CoA. According to the literature, IAs associated with CoA have a higher tendency to involve the ACoA than IAs without CoA. Moreover, adult CoA patients tend to have multiple IAs, considered to be due to hypertension associated with CoA, as well as genetic predisposition. In CoA patients, ruptured IAs should be treated as early as possible before correction of the CoA. Close postoperative observation with management of cerebral vasospasm, renal or spinal cord ischemia, and respiratory compromise in the perioperative period is vital.

Subarachnoid hemorrhage is a stroke subtype with particularly bad outcome. Recent findings suggest that constrictions of pial arterioles occurring early after hemorrhage may be responsible for cerebral ischemia and - subsequently - unfavorable outcome after subarachnoid hemorrhage. Since we recently hypothesized that the lack of nitric oxide may cause post-hemorrhagic microvasospasms, our aim was to investigate whether inhaled nitric oxide, a treatment paradigm selectively delivering nitric oxide to ischemic microvessels, is able to dilate post-hemorrhagic microvasospasms; thereby improving outcome after experimental subarachnoid hemorrhage. C57BL/6 mice were subjected to experimental SAH. Three hours after subarachnoid hemorrhage pial artery spasms were quantified by intravital microscopy, then mice received inhaled nitric oxide or vehicle. For induction of large artery spasms mice received an intracisternal injection of autologous blood. Inhaled nitric oxide significantly reduced number and severity of subarachnoid hemorrhage-induced post-hemorrhage microvasospasms while only having limited effect on large artery spasms. This resulted in less brain-edema-formation, less hippocampal neuronal loss, lack of mortality, and significantly improved neurological outcome after subarachnoid hemorrhage. This suggests that spasms of pial arterioles play a major role for the outcome after subarachnoid hemorrhage and that lack of nitric oxide is an important mechanism of post-hemorrhagic microvascular dysfunction. Reversing microvascular dysfunction by inhaled nitric oxide might be a promising treatment strategy for subarachnoid hemorrhage., (© The Author(s) 2015.)

Objective: To review our experience in surgical management of proximal anterior cerebral artery (A1) aneurysms in 23 patients., Methods: Between January, 2004 and December, 2014, 23 patients (1.6%) with A1 aneurysms diagnosed by CTA or DSA were treated surgically. The "3H" therapy was adopted for postoperative prevention of cerebrovascular spasm. All the patients were followed up and examined with cerebrovascular CTA at 6, 12, 48 and 60 months after the operation with their Glasgow Outcome Scale score recorded., Results: The patients consisted of 15 men and 8 women with an age range of 16 to 72 years (mean 51.3 years). The average diameter of the aneurysms was 5.8 mm, ranging from 3.2 to 9.7 mm. Twenty-two saccular aneurysms were found in these patients; 21 patients presented with SAH and two had vascular malformation. All the A1 aneurysms were managed through the pterional approach, and the mean postoperative Glasgow Outcome Scale score was 4.8., Conclusion: Thorough analysis of the angiographic data is essential for the diagnosis and treatment of A1 aneurysms. Preservation of the perforators and prevention of aneurysm rupture are critical during the surgery. Full exposure of the Sylvian fissure and temporary occlusion of the parent artery ensures safe and effective dissection of A1 aneurysms.

BACKGROUND Delayed cerebral vasospasm (DCVS) following aneurismal subarachnoid hemorrhage (SAH) is a leading cause of poor prognosis and death in SAH patients. Effective management to reduce DCVS is needed. A prospective controlled trial was conducted to determine if massive cerebrospinal fluid (CSF) replacement (CR) could reduce DCVS occurrence and improve the clinical outcome after aneurysmal SAH treated with endovascular coiling. MATERIAL AND METHODS Patients treated with endovascular coiling after aneurysmal SAH were randomly divided into a control group receiving regular therapy alone (C group, n=42) and a CSF replacement group receiving an additional massive CSF replacement with saline (CR group, n=45). CSF examination, head CT, DCVS occurrence, cerebral infarction incidence, Glasgow Outcome Scale prognostic score, and 1-month mortality were recorded. RESULTS The occurrence of DCVS was 30.9% in the C group and 4.4% in the CR group (P<0.005). The cerebral infarction incidences in the C and CR groups were 19.0% and 2.2% (P<0.05), respectively, 1 month after the treatments. Mortality was not significantly different between the 2 groups during the follow-up period. CONCLUSIONS Massive CR after embolization surgery for aneurysmal SAH can significantly reduce DCVS occurrence and effectively improve the outcomes.

Background and Purpose: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH., Methods: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI., Results: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32)., Conclusions: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH., (© 2015 American Heart Association, Inc.)

Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant.

Mechanically-induced vasospasm often occurs during guiding catheter insertion, occasionally preventing catheter advancement to the desired location. Delicate manipulation would be impossible without the proper positioning of guiding catheters, and vasospasm-induced cerebral hypoperfusion may cause thrombotic complications. From June 2012 to December 2013, we prospectively analyzed 150 endovascular treatment cases, excluding acute cases, for the frequency of vasospasm, risk factors, and countermeasures. The associated risk factors such as the Japanese-style State-Trait Anxiety Inventory (STAI) score; anatomy and devices; and the efficacies of warm compresses, intra-arterial lidocaine/nicardipine, and tranquilizers were analyzed. Groups 1, 2, and 3 comprised 50 patients each with controls, tranquilizer administration, and prophylactic warm compresses/intra-arterial drug injection, respectively. Moderate or severe vasospasm was seen in approximately 40% patients in each group; however, severe vasospasm was absent in Group 3. Mild vasospasm-induced cerebral infarction occurred in one patient each in Groups 1 and 2. Vasospasm during diagnostic angiography [odds ratio (OR) = 10.63; P = 0.01], many ≥ 30° vessel curves [OR = 4.21; P = 0.01], and the high STAI score [OR = 1.84; P = 0.01] were risk factors for severe vasospasm. Although the relationship between anxiety and sympathetic tone remained unclear, tranquilizer administration relieved vasospasm. Warm compresses and the intra-arterial drug infusion were also useful for relieving vasospasm. Prophylactic measures such as a tranquilizer and warm compresses are expected to alleviate vasospasm; in addition, countermeasures such as the intra-arterial injection of lidocaine/nicardipine are effective.

Background and Purpose: Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome in patients with subarachnoid hemorrhage. In this trial, we investigated the therapeutic potential of prostacyclin, an endogen substance with known effect on vascular tone and blood flow regulation, on factors related to DIND., Methods: This trial is a single-center, randomized, blinded, clinical, pilot trial with 3 arms. Ninety patients were randomized to continuous infusion of prostacyclin 1 ng/kg per minute, prostacyclin 2 ng/kg per minute, or placebo. The intervention was initiated day 5 after subarachnoid hemorrhage and discontinued day 10. Primary outcome was the difference in change from baseline in global cerebral blood flow. Secondary outcome measures were occurrence of DIND, angiographic vasospasm, and clinical outcome at 3 months., Results: No statistically significant difference in change of global cerebral blood flow was found between the intervention groups. The observed incidence of DIND and angiographic vasospasm was markedly higher in the placebo group, although this difference was not statistically significant. No statistically significant differences in safety parameters or clinical outcome were found between the 3 groups., Conclusions: Administration of prostacyclin to patients with subarachnoid hemorrhage may be safe and feasible. Global cerebral blood flow after subarachnoid hemorrhage is not markedly affected by administration of prostacyclin in the tested dose range. It may be possible that the observed reduction in the point estimates of DIND and vasospasm in the prostacyclin groups represents an effect of prostacyclin as this trial was not powered to investigate the effect of prostacyclin on these outcomes., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT01447095., (© 2014 American Heart Association, Inc.)

Aneurysmal subarachnoid hemorrhage (aSAH) is a serious and debilitating condition that leads to the development of many complications, which are followed by mortality and morbidity. As anesthesiologists, we may require to manage aSAH at various settings such as in the perioperative period or in a nonoperative setting such as the neuroradiology suite for diagnostic and therapeutic interventions. Therefore, it is important to understand the pathophysiology of aSAH and anesthetic management for operations and interventions. For decades, early brain injury and cerebral vasospasm have played major roles in the outcome following aSAH. The purpose of this article is to review recent advances and future perspectives in the treatment of aSAH, early brain injury, and cerebral vasospasm., (Copyright © 2014. Published by Elsevier B.V.)

Aneurysmal subarachnoid hemorrhage (aSAH)-induced cerebral vasospasm and delayed ischemic neurological deficit (DIND) are the major causes of morbidity and mortality in patients with aSAH. The effects of statins-use for patients with aSAH remain controversial. Here,a total of 249 patients from six randomized controlled trials(RCTs) were subjected to meta-analysis. No significant decrease was found in the incidence of vasospasm(RR, 0.80; 95% CI, 0.54-1.17), with substantial heterogeneity (I(2) = 49%, P = 0.08), which was verified by the further sensitivity analysis and subgroup meta-analysis. Furthermore, no significant difference was presented in the incidence of poor neurological outcome(RR, 0.94; 95% CI, 0.77-1.16), and potential side effects(RR, 2.49; 95% CI, 0.75-8.33). Nevertheless, significant difference was reported in the occurrence of DIND(RR, 0.58; 95% CI, 0.37-0.92) and mortality(RR, 0.30; 95% CI, 0.14-0.64). At present, although statins-use in the patients with aSAH should not be considered standard care at present, statins-use may have the potential effects in the prevention of mortality in patients with aSAH.

These are evidence based guidelines for the management of medical complications in patients following aneurysmal subarachnoid hemorrhage, developed and endorsed by the Croatian Society of Neurovascular Disorders, Croatian Society of Neurology including Section for Neurocritical Care, Croatian Neurosurgical Society, Croatian Society for Difficult Airway Management and Croatian Medical Association. They consist of recommendations for best monitoring, medical treatment and interventions based on the literature, evaluation of the results of large international clinical trials, and collective experience of the authors.

Background and Purpose: Predictors of outcome after aneurysmal subarachnoid hemorrhage have been determined previously through hypothesis-driven methods that often exclude putative covariates and require a priori knowledge of potential confounders. Here, we apply a data-driven approach, principal component analysis, to identify baseline patient phenotypes that may predict neurological outcomes., Methods: Principal component analysis was performed on 120 subjects enrolled in a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Correlation matrices were created using a combination of Pearson, polyserial, and polychoric regressions among 46 variables. Scores of significant components (with eigenvalues>1) were included in multivariate logistic regression models with incidence of severe angiographic vasospasm, delayed ischemic neurological deficit, and long-term outcome as outcomes of interest., Results: Sixteen significant principal components accounting for 74.6% of the variance were identified. A single component dominated by the patients' initial hemodynamic status, World Federation of Neurosurgical Societies score, neurological injury, and initial neutrophil/leukocyte counts was significantly associated with poor outcome. Two additional components were associated with angiographic vasospasm, of which one was also associated with delayed ischemic neurological deficit. The first was dominated by the aneurysm-securing procedure, subarachnoid clot clearance, and intracerebral hemorrhage, whereas the second had high contributions from markers of anemia and albumin levels., Conclusions: Principal component analysis, a data-driven approach, identified patient phenotypes that are associated with worse neurological outcomes. Such data reduction methods may provide a better approximation of unique patient phenotypes and may inform clinical care as well as patient recruitment into clinical trials., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00111085.

Aim: The aim of this study was to investigate the effect of copper, which is the cofactor and regulator of the superoxide dysmutase enzyme, on preventing experimental peripheral vasospasm in rats through antioxidative mechanisms., Material and Methods: Twenty-four female Wistar-Albino rats were divided into 3 groups: group 1 (n=8), control group; group 2 (n=8), vasospasm group; and group 3 (n=8), vasospasm + copper treatment group. Morphometric measurements of wall thickness and lumen diameter of femoral arteries were performed., Results: Statistical comparison of groups 1 and 2, regarding thickness of vascular walls, revealed a significant increase in group 2 (p=0.037) and regarding lumen diameters, revealed a significant decrease in group 2 (p=0.043). Comparison of diameters of the vascular lumen of groups 1 and 3 showed no significant difference (p=0.19), whereas the comparison of the thicknesses of the vascular walls displayed a significant increase in group 3 (p=0.028). Comparison of groups 2 and 3 regarding diameter of vascular lumens showed a significant decrease in group 2 (p=0.042), whereas group 3 displayed a significant decrease, in terms of thickness of the vascular walls (p=0.029)., Conclusion: This study showed quantitatively that copper could prevent the development of experimental peripheral vasospasm in rats.

Purpose: The triple-H therapy is widely used for cerebral vasospasm (CV) prevention and treatment in patients after subarachnoid haemorrhage (SAH). However, this practice is based on low level evidence. Aim of this study was to evaluate errors in fluid administration, fluid balance monitoring and bedside charts completeness during a trial of triple-H therapy., Materials and Methods: An audit of the SAH patient charts was performed. A total of 508 fluid measurements were performed in 41 patients (6 with delayed cerebral ischaemia; DCI) during 14 days of observation., Results: Underestimating for intravenous drugs was the most frequent error (80.6%; 112), resulting in a false positive fluid balance in 2.4% of estimations. In 38.6% of the negative fluid balance cases, the physicians did not order additional fluids for the next 24h. In spite of that, the fluid intake was significantly increased after DCI diagnosis. The mean and median intake values were 3.5 and 3.8l/24h respectively, although 40% of the fluid balances were negative. The positive to negative fluid balance ratio was decreasing in the course of the 14 day observation., Conclusions: This study revealed inconsistencies in the fluid orders as well as mistakes in the fluid monitoring, which illustrates the difficulties of fluid therapy and reinforces the need for strong evidence-based guidelines for hypervolemic therapy in SAH., (Copyright © 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Object: The effect on clinical outcomes of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in patients over 80 years who underwent coil embolization was evaluated., Methods: Forty-four cases were reviewed and divided into two groups according to patient age: Group A, 79 years or younger, and Group B, 80 or older. Patient characteristics, prevalence of symptomatic vasospasm, modified Rankin Scale (mRS) scores at discharge and frequency of symptomatic vasospasm in patients with mRS scores of 3-6 were analyzed., Results: Thirty-two (73%) of the 44 cases were categorized as Group A and 12 (27%) as Group B. Group B had a significantly higher prevalence of symptomatic vasospasm compared to Group A (P=0.0040). mRS scores at discharge were significantly higher in Group B than in Group A (P=0.0494). Among cases with mRS scores of 3-6, there was a significantly higher frequency of symptomatic vasospasm in Group B than in Group A (P=0.0223)., Conclusions: In our cohort of aneurysmal SAH patients treated by coil embolization, patients over 80 years of age were more likely to suffer symptomatic vasospasm, which significantly correlated with worse clinical outcomes, than those 79 years and under.

Delayed complications of subarachnoid hemorrhage (SAH) such as angiographic vasospasm, cortical spreading ischemia, microcirculatory dysfunction, and microthrombosis are reported in both patients and animal models of SAH. We demonstrated previously that SAH is associated with increased oxidative stress in the brain parenchyma, and that this correlates with dysfunction of endothelial nitric oxide synthase (eNOS) (homodimeric uncoupling). Uncoupling of eNOS exacerbated oxidative stress and enhanced nitric oxide (NO) depletion, and was associated with multiple secondary complications such as microthrombosis, neuronal apoptosis, and release of reactive oxygen species. Thus, we hypothesized that genetic abbrogation of eNOS would confer a beneficial effect on the brain after SAH. Using a prechiasmatic injection model of SAH, we show here that eNOS knockout (KO) significantly alleviates vasospasm of the middle cerebral artery and reduces superoxide production. Endothelial nitric oxide synthase KO also affected other nitric oxide synthase isoforms. It significantly increases neuron nitric oxide synthase expression but has no effect on inducible nitric oxide synthase. Endothelial nitric oxide synthase KO decreases Zn(2+) release after SAH, reduces microthrombi formation, and prevent neuronal degeneration. This work is consistent with our findings where, after SAH, increased oxidative stress can uncouple eNOS via Zn(2+) thiolate oxidation, or theoretically by depletion or oxidation of tetrahydrobiopterin, resulting in a paradoxical release of superoxide anion radical, further exacerbating oxidative stress and microvascular damage.

The effect of irrigation with artificial cerebrospinal fluid (CSF) containing various magnesium ion (Mg(2+)) concentrations on vasospastic arteries was investigated in the dog. Cerebral vasospasm was induced by the experimental subarachnoid hemorrhage model in 15 beagle dogs. Cisternal irrigation was performed for 1 hour via a microcatheter placed in the cisterna magna with commercially available artificial CSF (ARTCEREB®) with physiological concentration of Mg(2+) (2.2 mEq/l) (ACM group, n = 5), ARTCEREB solution without Mg(2+) (ACR group, n = 5), and ARTCEREB solution with higher Mg(2+) concentration (5 mEq/l) (ACMM group, n = 5). CSF electrolyte concentrations and the diameters of the basilar and vertebral arteries were measured. In the ACM group, no changes were detected in either CSF Mg(2+) concentration or arterial diameters. In the ACR group, the CSF Mg(2+) decreased significantly to 0.8 ± 0.07 mEq/l from the baseline value of 1.4 ± 0.03 mEq/l, and both basilar and vertebral artery diameters were significantly decreased to 0.61 ± 0.18 mm and 0.57 ± 0.23 mm from their baseline values of 0.74 ± 0.22 mm and 0.68 ± 0.17 mm, respectively. In the ACMM group, the CSF Mg(2+) significantly increased to 2.4 ± 0.15 mEq/l from the baseline value of 1.4 ± 0.05 mEq/l, and both basilar and vertebral artery diameters were significantly increased to 0.84 ± 0.19 mm and 0.90 ± 0.22 mm from their baseline values of 0.71 ± 0.21 mm and 0.69 ± 0.24 mm, respectively. Irrigation with artificial CSF solution without Mg(2+) causes vasoconstriction of the cerebral artery. Irrigation with artificial CSF with appropriate Mg(2+) concentration is essential, especially in patients with subarachnoid hemorrhage.

Background: A subarachnoid hemorrhage (SAH) is a serious and potentially life-threatening condition where blood leaks out of blood vessels over the surface of the brain. Delayed ischemic neurological deficit (DIND) and the related feature of vasospasm, where patients experience a delayed deterioration, have long been recognized as the leading potentially treatable cause of death and disability in patients with SAH. Endothelin is a potent, long-lasting endogenous vasoconstrictor that has been implicated in the pathogenesis of DIND. Therefore, endothelin receptor antagonists (ETAs) have emerged as a promising therapeutic option for SAH-induced cerebral vasospasm., Objectives: To assess the efficacy and tolerability of ETAs for SAH., Search Methods: We searched the Cochrane Stroke Group Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11), MEDLINE (1950 to December 2011), EMBASE (1946 to December 2011) and the Chinese Biomedical Database (1978 to December 2011). In an effort to identify further published, unpublished and ongoing trials we searched additional Chinese databases, ongoing trials registers, Google Scholar and Medical Matrix, handsearched journals, scanned reference lists, and contacted researchers and pharmaceutical companies., Selection Criteria: We only included randomized controlled trials (RCTs) that compared an ETA with placebo for SAH in adult (18 years of age or older) patients who met the diagnostic criteria for SAH based on clinical symptoms, with confirmation on computerized tomography scan results or angiography. Two review authors independently selected RCTs according to the inclusion criteria. We resolved disagreements by discussion with a third review author., Data Collection and Analysis: Two review authors independently selected relevant articles and assessed their eligibility according to the inclusion and exclusion criteria. We resolved disagreements by discussion with a third review author. We used the random-effects model and expressed the results as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI)., Main Results: We included four RCTs with 2024 participants that compared ETAs with placebo for SAH. All RCTs were multicenter, double-blind studies with a low risk of bias. ETAs reduced the incidence of DIND (RR 0.80; 95% CI 0.67 to 0.95) and angiographic vasospasm (RR 0.62; 95% CI 0.52 to 0.72) but did not reduce the incidence of unfavorable outcomes (RR 0.87; 95% CI 0.74 to 1.02) or mortality (RR 1.05; 95% CI 0.77 to 1.45). ETAs increased the incidence of hypotension (RR 2.53; 95% CI 1.77 to 3.62) and pneumonia (RR 1.56; 95% CI 1.23 to 1.97)., Authors' Conclusions: ETAs appear to reduce DIND and angiographic vasospasm but there were adverse events and the impact on clinical outcome is unclear. Additional well-designed RCTs are needed.

Background and Purpose: Early identification of patients at risk of angiographic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may mitigate its sequelae. One mechanism that may contribute to angiographic vasospasm is increased central sympathetic activity, which is also thought to cause electrocardiographic (ECG) changes after SAH. Here, we perform the first study to determine the association between ECG changes and angiographic vasospasm after SAH., Methods: Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. ECGs were obtained within 24 hours of aneurysm rupture and during the vasospasm risk period. Angiographic vasospasm was assessed using catheter angiography at baseline and 7 to 11 days after SAH. Multivariate logistic regression was used to identify significant associations., Results: The most prevalent finding on ECG both immediately following SAH and during the vasospasm risk period was QT prolongation (42% and 25%, respectively). A prolonged QT interval and tachycardia on the baseline ECG were associated with angiographic vasospasm (OR, 1.86; 95% CI, 1.00-3.45; and OR, 10.83; 95% CI, 1.17-100.50, respectively). QT prolongation on ECG during the vasospasm risk period was also associated with angiographic vasospasm (OR, 3.53; 95% CI, 1.67-7.39). No ECG findings were associated with delayed ischemic neurological deficit, but tachycardia and ST changes were associated with worse clinical outcome., Conclusions: QT prolongation and tachycardia on ECG were independently associated with angiographic vasospasm after aneurysmal SAH on multivariate analysis., Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique Identifier: NCT00111085.

Alterations in the activity of vascular K channels are commonly associated with abnormalities in cerebral vascular function after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage-induced vasospasm remains incompletely understood; nevertheless, activation of K channels may be of benefit in relieving spastic constriction. This study was to examine whether the vasodilators KMUP-1 and pinacidil, a KATP-channel opener, have the ability to prevent SAH-induced vasospasm via the large-conductance Ca-activated K (BKCa) channels in cerebral arteries. Rats were divided into four groups including sham-operated, SAH, KMUP-1 treated, and pinacidil treated. Subarachnoid hemorrhage rats were induced by injecting autologous blood into cisterna magna, and then KMUP-1 or pinacidil (1 mg/kg) was injected intraperitoneally 1 and 24 h after SAH. Behavioral tests were assessed on day 2 after SAH before the rats were killed. Cerebral myocytes were enzymatically isolated from rat basilar arteries and used to monitor BKCa-channel activities. In isolated basilar arteries, KMUP-1-treated and pinacidil-treated rats showed normalized vascular reactivity. In whole-cell recordings, BKCa currents were attenuated in SAH rats compared with sham-operated rats. In inside-out patches, the conductance and voltage sensitivity of single BKCa-channels were unchanged among the four groups. In contrast, SAH rats showed markedly decreased BKCa-channel activity and β1-subunit expression associated Ca sensitivity that was further confirmed by immunofluorescence staining and Western blotting. Subarachnoid hemorrhage-induced deficits in motor function and BKCa-channel inhibition were improved by KMUP-1-treated and pinacidil-treated rats. In addition, SAH appears to modify BKCa-channel calcium sensitivity. KMUP-1 and pinacidil prevent SAH-induced vasospasm at least in part by the restoration of BKCa-channel activities.

Background: Vasospasm-related delayed cerebral ischemia (DCI) significantly impacts on outcome after aneurysmal subarachnoid hemorrhage (SAH). Erythropoietin (EPO) may reduce the severity of cerebral vasospasm and improve outcome, however, underlying mechanisms are incompletely understood. In this study, the authors aimed to investigate the effect of EPO on cerebral metabolism and brain tissue oxygen tension (PbtO2)., Methods: Seven consecutive poor grade SAH patients with multimodal neuromonitoring (MM) received systemic EPO therapy (30.000 IU per day for 3 consecutive days) for severe cerebral vasospasm. Cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP), intracranial pressure (ICP), PbtO2 and brain metabolic changes were analyzed during the next 24 hours after each dose given. Statistical analysis was performed with a mixed effects model., Results: A total of 22 interventions were analyzed. Median age was 47 years (32-68) and 86 % were female. Three patients (38 %) developed DCI. MAP decreased 2 hours after intervention (P < 0.04) without significantly affecting CPP and ICP. PbtO2 significantly increased over time (P < 0.05) to a maximum of 7 ± 4 mmHg increase 16 hours after infusion. Brain metabolic parameters did not change over time., Conclusions: EPO increases PbtO2 in poor grade SAH patients with severe cerebral vasospasm. The effect on outcome needs further investigation.

Background and Purpose: The presence of low-density areas on CT is used in clinical decision-making regarding treatment of angiographic vasospasm as well as in research as a surrogate marker for severity of angiographic vasospasm. We assess the interobserver variability in attributing hypodensities on CT to angiographic vasospasm-related delayed ischemic neurological deficit., Methods: Three experienced reviewers, 2 neurosurgeons, and a neuroradiologist independently reviewed CT scans of 413 patients enrolled in the Clazosentan to Overcome Neurological iSChemia and Infarction OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1) trial, who universally underwent catheter angiography to determine severity of angiographic vasospasm. Interobserver variability was calculated using the κ statistic and the χ(2) test was used to determine associations between dichotomized outcomes., Results: There was considerable interobserver variability in attributing CT hypodensities to vasospasm-related delayed ischemic neurological deficit (κ=0.51-0.78; 95% CI, 0.35-0.90). Patients with hypodensities attributed to delayed ischemic neurological deficit were significantly more likely to have severe angiographic vasospasm (P=0.001), but a substantial proportion of these patients (19%) also had mild or no spasm. CT hypodensities had a sensitivity and specificity of 41% and 93%, respectively, in identifying patients with severe angiographic vasospasm, even with expert consensus that these represent angiographic vasospasm-related delayed ischemic neurological deficit., Conclusions: We find considerable interobserver variability in attributing CT hypodensities to angiographic vasospasm and propose that they may not be a robust marker of severity of angiographic vasospasm, even with unanimous expert agreement that they are a result of vasospasm-related delayed ischemic neurological deficit., Clinical Trial Registration: URL: www.clinicaltrials.gov. Unique identifier: NCT00111085.

Background: Cerebral vasospasm is the most important potentially treatable cause of mortality and morbidity following aneurysmal subarachnoid hemorrhage (aSAH). Clazosentan, a selective endothelinreceptor antagonist, has been suggested to help reduce the incidence of vasospasm in patients with aSAH. However, the results were controversial in previous trials. This meta-analysis attempts to assess the effect of clazosentan in patients with aSAH., Methodology/principal Findings: We systematically searched Pubmed, Embase, and the Cochrane Library from their inception until June, 2012. All randomized controlled trials (RCTs) related to the effect of clazosentan in aSAH were included. The primary outcomes included the incidence of angiographic vasospasm, new cerebral infarction (NCI), delayed ischemic neurological deficits (DIND), and vasospasm-related morbidity/mortality (M/M); the second outcomes included the occurrence of rescue therapy, all-cause-mortality, and poor outcome. 4 RCTs were included with a total of 2156 patients. The risk of angiographic vasospasm (relative risk [RR] =0.58; 95% CI, 0.48 to 0.71), DIND (RR=0.76; 95% CI, 0.62 to 0.92), and vasospasm-related M/M (RR=0.80; 95% CI, 0.67 to 0.96) were statistically significantly reduced in the clazosentan group. Patients treated with clazosentan had a reduced occurrence of rescue therapy (RR=0.62; 95% CI, 0.49 to 0.79). However, no statistically significant effects were observed in NCI (RR=0.74; 95% CI, 0.52 to 1.04), mortality (RR=1.03; 95% CI, 0.71 to 1.49), and poor outcome (RR=1.12; 95% CI, 0.96 to 1.30)., Conclusions/significance: Our pooling data supports that clazosentan is probably effective in preventing the occurrence of angiographic vasospasm, vasospasm-related DIND, vasospasm related M/M, and rescue therapy. However, no evidence lends significant supports to the benefits of clazosentan in decreasing the occurrence of NCI, mortality or improving the functional outcome.

Primary thunderclap headache (TCH) is a rare condition, of which the onset can be triggered by coughing, exercise, and sexual activity. Micturition is a recognized trigger of secondary TCH with pheochromocytoma in bladder, but not of primary TCH. We describe a patient with an apparent primary TCH, which repeatedly occurred immediately after micturition until she achieved a therapeutic dosage of nimodipine.