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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: The exacerbation of neurological outcomes often occurs in aneurysmal subarachnoid hemorrhage (aSAH). Statins have been commonly used for aSAH; however, there is lack of evidence of the pharmacological efficacy of different dosages and types of statins., Objective: To apply the Bayesian network meta-analysis to analyze the optimal dosage and type of statins for the amelioration of ischemic cerebrovascular events (ICEs) in patients with aSAH., Methods: We developed the Bayesian network meta-analysis and systemic review to analyze the effects of statins on functional prognosis and the impacts of optimal dosage and type of statins on ICEs in patients with aSAH. The outcome variables of the analysis were the incidence of ICEs and functional prognosis., Results: A total of 2569 patients with aSAH across 14 studies were included. Analysis of 6 randomized controlled trials showed that statin use significantly improved functional prognosis in patients with aSAH (risk ratio [RR], 0.73; 95% CI, 0.55-0.97). Statins significantly reduced the incidence of ICEs (RR, 0.78; 95% CI, 0.67-0.90). Pravastatin (40 mg/d) decreased the incidence ICEs compared with placebo (RR, 0.14; 95% CI, 0.03-0.65) and was ranked the most effective, presenting with a significantly lower rate of the incidence ICEs than the worst-ranked simvastatin (40 mg/d) (RR, 0.13; 95% CI, 0.02-0.79)., Conclusion: Statins could significantly diminish the incidence of ICEs and enhance functional prognosis in patients with aSAH. Various types and dosages of statins show distinct efficacies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Background: Delayed cerebral ischemia (DCI) is the most consequential secondary insult after aneurysmal subarachnoid hemorrhage (SAH). It is a multifactorial process caused by a combination of large artery vasospasm and microcirculatory dysregulation. Despite numerous efforts, no effective therapeutic strategies are available to prevent DCI. The trigeminal nerve richly innervates cerebral blood vessels and releases a host of vasoactive agents upon stimulation. As such, electrical trigeminal nerve stimulation (TNS) has the capability of enhancing cerebral circulation., Objective: To determine whether TNS can restore impaired cerebral macrocirculation and microcirculation in an experimental rat model of SAH., Methods: The animals were randomly assigned to sham-operated, SAH-control, and SAH-TNS groups. SAH was induced by endovascular perforation on Day 0, followed by KCl-induced cortical spreading depolarization on day 1, and sample collection on day 2. TNS was delivered on day 1. Multiple end points were assessed including cerebral vasospasm, microvascular spasm, microthrombosis, calcitonin gene-related peptide and intercellular adhesion molecule-1 concentrations, degree of cerebral ischemia and apoptosis, and neurobehavioral outcomes., Results: SAH resulted in significant vasoconstriction in both major cerebral vessels and cortical pial arterioles. Compared with the SAH-control group, TNS increased lumen diameters of the internal carotid artery, middle cerebral artery, and anterior cerebral artery, and decreased pial arteriolar wall thickness. Additionally, TNS increased cerebrospinal fluid calcitonin gene-related peptide levels, and decreased cortical intercellular adhesion molecule-1 expression, parenchymal microthrombi formation, ischemia-induced hypoxic injury, cellular apoptosis, and neurobehavioral deficits., Conclusion: Our results suggest that TNS can enhance cerebral circulation at multiple levels, lessen the impact of cerebral ischemia, and ameliorate the consequences of DCI after SAH., (Copyright © Congress of Neurological Surgeons 2022. 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.)

Background: Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12 U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000 U, 3 × daily)., Objective: To assess the safety and efficacy of LDIVH in aSAH patients., Methods: We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW)., Results: The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9 vs 18%; P = .004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts., Conclusion: This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH)., Objective: To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects., Methods: Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated., Results: The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups., Conclusion: Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Delayed cerebral ischemia (DCI) has a strong impact on outcome of patients with aneurysmal subarachnoid hemorrhage (SAH). Positive effect of antiplatelet therapy on DCI rates has been supposed upon smaller SAH series., Objective: To analyze the benefit/risk profile of antiplatelet use in SAH patients., Methods: This retrospective case-control study was based on institutional observational cohort with 994 SAH patients treated between January 2003 and June 2016. The individuals with postcoiling antiplatelet therapy (aspirin with/without clopidogrel) were compared to a control group without antiplatelet therapy. Occurrence of DCI, major/minor bleeding events in the follow-up computed tomography scans, and favorable outcome at 6 mo after SAH (modified Rankin scale < 3) were compared in both groups., Results: Of 580 patients in the final analysis, 329 patients received post-treatment antiplatelet medication. There were no significant differences between the compared groups with regard to basic outcome confounders. Aspirin use was independently associated with reduced DCI risk (P < .001, adjusted odds ratio = 0.41, 95% confidence interval 0.24-0.65) and favorable outcome (P = .02, adjusted odds ratio = 1.78, 95% confidence interval 1.06-2.98). Regarding bleeding complications, aspirin was associated only with minor bleeding events (P = .02 vs P = .51 for major bleeding events)., Conclusion: Regular administration of aspirin might have a positive impact on DCI risk and outcome of SAH patients, without increasing the risk for clinically relevant bleeding events. In our SAH cohort, dual antiplatelet therapy showed no additional benefit on DCI risk, but increased the likelihood of major bleeding events., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background: Induced hypertension (IH) remains the mainstay of medical management for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). However, raising blood pressure above normal levels may be associated with systemic and neurological complications, of which posterior reversible encephalopathy syndrome (PRES) has been increasingly recognized., Objective: To ascertain the frequency and predisposing factors for PRES during IH therapy., Methods: We identified 68 patients treated with IH from 345 SAH patients over a 3-yr period. PRES was diagnosed based on clinical suspicion, confirmed by imaging. We extracted additional data on IH, including baseline and highest target mean arterial pressure (MAP), comparing PRES to IH-treated controls., Results: Five patients were diagnosed with PRES at median 6.6 d (range 1-8 d) from vasopressor initiation. All presented with lethargy, 3 had new focal deficits, and 1 had a seizure. Although baseline MAP (prior to DCI) did not differ between cases and controls, both MAP immediately prior to IH (112 vs 90) and highest MAP targeted were greater (140 vs 120 mm Hg, both P < .01). Magnitude of MAP elevation was greater (54 vs 34 above baseline, P = .004) while degree of IH was not (37 vs 38 above pre-IH MAP). All 4 surviving PRES patients had complete resolution with IH discontinuation., Conclusion: PRES was diagnosed in 7% of SAH patients undergoing IH therapy, most often when MAP was raised well above baseline to levels that exceed traditional autoregulatory thresholds. High suspicion for this reversible disorder appears warranted in the face of unexplained neurological deterioration during aggressive IH., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background: There remains a proportion of patients with unfavorable outcomes after aneurysmal subarachnoid hemorrhage, of particular relevance in those who present with a good clinical grade. A forewarning of those at risk provides an opportunity towards more intensive monitoring, investigation, and prophylactic treatment prior to the clinical manifestation of advancing cerebral injury., Objective: To assess whether biochemical markers sampled in the first days after the initial hemorrhage can predict poor outcome., Methods: All patients recruited to the multicenter Simvastatin in Aneurysmal Hemorrhage Trial (STASH) were included. Baseline biochemical profiles were taken between time of ictus and day 4 post ictus. The t-test compared outcomes, and a backwards stepwise binary logistic regression was used to determine the factors providing independent prediction of an unfavorable outcome., Results: Baseline biochemical data were obtained in approximately 91% of cases from 803 patients. On admission, 73% of patients were good grade (World Federation of Neurological Surgeons grades 1 or 2); however, 84% had a Fisher grade 3 or 4 on computed tomographic scan. For patients presenting with good grade on admission, higher levels of C-reactive protein, glucose, and white blood cells and lower levels of hematocrit, albumin, and hemoglobin were associated with poor outcome at discharge. C-reactive protein was found to be an independent predictor of outcome for patients presenting in good grade., Conclusion: Early recording of C-reactive protein may prove useful in detecting those good grade patients who are at greater risk of clinical deterioration and poor outcome.

Background: Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid hemorrhage. However, no clinical data are available to answer whether a high-dose regimen is more effective than a normal-dose regimen, even though the biochemical actions and related neuroprotective mechanisms are thought to be dose related., Objective: To determine whether 80 mg simvastatin daily (high dose) over 3 weeks initiated within 96 hours of the ictus will reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with 40 mg simvastatin daily (normal dose), leading to improvements in clinical outcomes and thus cost-effectiveness., Methods: The study design is a randomized, controlled, double-blind clinical trial (www.ClinicalTrials.gov; identifier: NCT01077206). Two hundred forty patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers are being recruited over 3 years. The primary outcome measure is the presence of delayed ischemic deficits. Secondary outcome measures include modified Rankin Disability Score at 3 months and cost-effectiveness analysis., Expected Outcomes: This will be the first study to clarify whether high-dose simvastatin is better than normal-dose simvastatin for patients with acute aneurysmal subarachnoid hemorrhage in terms of neurological outcomes and cost-effectiveness., Discussion: In the present trial, we compare high-dose and normal-dose simvastatin; we know that another ongoing phase III multicenter trial (Simvastatin in Aneurysmal Subarachnoid Haemorrhage; http://www.stashtrial.com/home.html) is comparing normal-dose and no simvastatin. When the results are interpreted together, the research question of a possible beneficial effect of high-dose simvastatin in acute aneurysmal subarachnoid hemorrhage could be answered.

Background: ε-Aminocaproic acid (EACA) has been used to reduce the rate of cerebral aneurysm rerupture before definitive treatment. In centers administering EACA to patients with a subarachnoid hemorrhage (SAH), patients eventually diagnosed with angiographically negative subarachnoid hemorrhage (ANSAH) may also initially receive EACA, perhaps placing them at increased risk for ischemic complications., Objective: To evaluate the effect of short-term EACA on outcomes and secondary measures in patients with ANSAH., Methods: We conducted a retrospective study of 454 consecutive SAH patients over a 2-year period under a current protocol for EACA use. Patients were excluded if a source for the SAH was discovered, yielding a total of 83 ANSAH patients. The patients were assigned to groups that did or did not receive EACA. The primary end points of the study were ischemic complications, pulmonary emboli, vasospasm, ventriculoperitoneal shunting rates, and outcomes., Results: Statistical analysis yielded no significant difference between the 2 arms with respect to any of the end points: vasospasm (P = .65), deep vein thrombosis (P = .51), pulmonary embolism (P = 1.0), stroke (P = 1.0), myocardial infarction (P = 1.0), and ventriculoperitoneal shunt (P = .57). There was no statistically significant outcome difference using the modified Rankin Scale (P = .30)., Conclusion: Short-term (<72 hour) application of EACA does not result in an increase in adverse events in patients with ANSAH.

Background: Nitric oxide (NO) depletion and periadventitial inflammation contribute to the pathogenesis of cerebral vasospasm. L-Citrulline increases L-arginine levels, thereby raising NO synthesis. Transgenic C57Bl6 mice with a haptoglobin (Hp) 2-2 genotype develop more severe vasospasm than wild-type (Hp 1-1) mice after subarachnoid hemorrhage (SAH)., Objective: To evaluate the toxicity of systemic L-citrulline and its effect on basilar artery (BA) vasospasm, neurobehavioral scores, and inducible NO synthase (iNOS)/endothelial NO synthase (eNOS) expression after SAH in Hp 2-2 mice., Methods: The Hp 2-2 genotypes were confirmed by reverse-transcriptase polymerase chain reaction. Toxicity was assessed with escalating L-citrulline doses. To test efficacy, Hp 1-1 and Hp 2-2 mice (n = 64) were divided into 4 groups (n = 32 per genotype): sham surgery (n = 8), SAH with no treatment (n = 8), SAH + vehicle (n = 8), and SAH + L-citrulline (200 mg/kg IP every 8 hours; n = 8). Post-SAH neurobehavioral scores were recorded at 24 hours; animals were perfused; and BAs were processed for analysis. Expression of iNOS and eNOS was determined by reverse-transcriptase polymerase chain reaction., Results: The administration of L-citrulline resulted in higher BA lumen patencies in both genotypes (Hp 1-1: SAH + vehicle, 77.8 ± 3.2% vs SAH + L-citrulline, 91.8 ± 5.9% [mean ± SEM]; P < .05; Hp 2-2: SAH + vehicle, 67.1 ± 2.0% vs SAH + L-citrulline, 86.9 ± 2.2%; P < .001). Neurobehavioral scores were higher in Hp 2-2 mice treated with L-citrulline (SAH + vehicle, 1.2 ± 0.2 vs SAH + L-citrulline, 2.4 ± 0.2; P < .01). Expression of iNOS and eNOS increased in Hp 2-2 mice after L-citrulline treatment, but limited sample sizes prevented further statistical analysis. L-Citrulline was not toxic even at the highest dose., Conclusion: L-Citrulline is safe; increases BA patency, neurobehavioral scores, and NOS expression in Hp 2-2 mice after SAH; and is a potential agent for treatment of vasospasm after SAH.

Background: Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5), an enzyme that degrades cGMP, may play a role because the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered., Objective: To elucidate the mechanism of action of sildenafil against vasospasm and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses., Methods: SAH was induced via endovascular perforation in male C57BL6 mice. Beginning 2 hours later, mice received sildenafil citrate (0.7, 2 or 5 mg/kg orally twice daily) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure, and intracranial pressure were examined., Results: We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to decrease vasospasm and neuronal cell death and markedly improve neurological outcome without causing significant physiological side effects., Conclusion: Sildenafil, a US Food and Drug Administration-approved drug with a proven track record of safety in humans, is a promising new therapy for vasospasm and neurological deficits after SAH.

Background: Heparin-induced thrombocytopenia type II (HIT II) correlates with a higher incidence of thromboembolic complications and unfavorable outcome., Objective: To examine the risk factors and outcomes for patients with HIT II with aneurysmal subarachnoid hemorrhage., Methods: Demographics, risk factors, treatments, and outcomes data of 600 aneurysmal subarachnoid hemorrhage patients admitted to the University of Illinois Medical Center in Chicago between June 2002 and July 2007 were retrospectively reviewed. Patients meeting the clinical criteria for HIT II were compared with those who did not develop thrombocytopenia., Results: Twenty-five patients (6%) met the clinical criteria for HIT II, and 396 (94%) did not develop thrombocytopenia. Both groups were the same with respect to age, Hunt-Hess score and Fisher grade on admission, medical conditions, and social risk factors. The HIT II patients had significantly more unfavorable outcomes (modified Rankin Scale score >3), deep vein thrombosis, stroke, pulmonary embolism, and death. Development of HIT II was strongly associated with symptomatic vasospasm (odds ratio, 5.7; 95% confidence interval, 2.5-13.1; P < .001) and number of angiographic procedures (odds ratio, 1.7; 95% confidence interval, 1.3-2.2; P < .001). Forward buildup selection modeling demonstrated the latter to be the strongest predictor for HIT II development (odds ratio, 2.3; 95% confidence interval, 1.7-3.2; P = .02)., Conclusion: Heparin-induced thrombocytopenia type II correlates with a worse outcome and higher risk of thromboembolic complications in aneurysmal subarachnoid hemorrhage patients. In addition, HIT II was strongly associated with the number of angiographic procedures performed during the same hospitalization.

Background: In patients with aneurysmal subarachnoid hemorrhage (SAH), preliminary results indicate that the amplitude of the single intracranial pressure (ICP) wave is a better predictor of the early clinical state and 6-month outcome than the mean ICP., Objective: To perform a randomized and blinded single-center trial comparing the effect of mean ICP vs mean ICP wave amplitude (MWA)-guided intensive care management on early clinical state and outcome in patients with aneurysmal SAH., Methods: Patients were randomized to 2 different types of ICP management: maintenance of mean ICP less than 20 mm Hg and MWA less than 5 mm Hg. Early clinical state was assessed daily using the Glasgow Coma Scale. The primary efficacy variable was 12-month outcome in terms of the Rankin Stroke Score., Results: Ninety-seven patients were included in the study. There were no significant differences in treatment between the 2 groups apart from a larger volume of cerebrospinal fluid drained during week 1 in the MWA group. There was a tendency toward higher Glasgow Coma Scale scores in the MWA group during weeks 1 (P = .08) and 2 (P = .07). Outcome in terms of Rankin Stroke Score at 12 months was significantly better in the MWA group (P < .05)., Conclusion: This randomized and blinded trial disclosed a significant better primary efficacy variable (Rankin Stroke Score after 12 months) in the MWA patient group. We suggest that proactive intensive care management with MWA-tailored cerebrospinal fluid drainage during the first week improves aneurysmal SAH outcome.

Background: Cerebral vasospasm (VSP) is a major cause of morbidity and mortality associated with subarachnoid hemorrhage. The current endovascular paradigm for VSP refractory to medical therapy is to perform angioplasty for proximal vessel VSP and vasodilator infusion for distal vessel VSP., Objective: To report our experience with a large series of balloon angioplasty for distal VSP refractory to medical therapy in patients with aneurysmal subarachnoid hemorrhage., Methods: This was a retrospective series of 32 patients with subarachnoid hemorrhage and symptomatic VSP refractory to medical therapy who were treated with balloon angioplasty for distal vessel VSP. Immediate angiographic results, procedure-related complications, and clinical outcomes were assessed., Results: From September 2001 to January 2010, 32 patients with symptomatic VSP refractory to medical therapy underwent angioplasty for distal arterial VSP. There were 26 women (81.3%); patients were 29 to 67 years of age. A total of 175 vessels were angioplastied (95 proximal and 80 distal). The only complication was rupture of an incompletely clipped aneurysm that was treated by immediate coiling and did not result in any clinical worsening. Repeated treatment was needed for 6 arteries (6 of 80, 7.5%). There were no procedure-related symptomatic complications. Good outcomes (modified Rankin Scale score ≤ 2) were observed in 23 of 28 patients (82.1%) with follow-up., Conclusion: Balloon angioplasty for distal VSP is safe and effective and decreases the need for repeated intraarterial treatments seen with infusion of vasodilator.

Background: There is substantial evidence to suggest that oxidative stress plays a significant role in the development of acute brain injury after subarachnoid hemorrhage (SAH)., Objective: To investigate the putative neuroprotective effect of nesfatin-1, a novel peptide with anorexigenic properties, in a rat model of SAH., Methods: Male Wistar albino rats were randomly divided into control, saline-treated SAH, and nesfatin-1 (10 μg/kg IP)-treated SAH groups. To induce SAH, rats were injected with 0.3 mL blood into their cisterna magna. Forty-eight hours after SAH induction, neurological examination scores were recorded and the rats were decapitated. Brain tissue samples were taken for the determination of blood-brain barrier (BBB) permeability, brain water content, and oxidative stress markers and for histological analysis., Results: The neurological examination scores were increased on the second day of SAH induction. SAH resulted in impaired blood-brain barrier and edema, along with increased levels of brain tumor necrosis factor-α, interleukin-1β, interleukin-6, lipid peroxidation, protein carbonylation, and myeloperoxidase activity with concomitant decreases in antioxidant enzymes. Conversely, in the nesfatin-1-treated SAH group, SAH-induced neurological impairment and oxidative brain injury were ameliorated by nesfatin treatment. Furthermore, SAH-induced morphological changes in the basilar arteries were improved by nesfatin-1 treatment, whereas caspase-3 activity and SAH-induced elevations in the plasma levels of proinflammatory cytokines were also depressed by nesfatin-1 treatment., Conclusion: These findings suggest that nesfatin-1, which appears to have antiapoptotic and anti-inflammatory properties, exerts neuroprotection in SAH-induced injury in rats by inhibiting neutrophil infiltration and subsequent release of inflammatory mediators., (Copyright © 2011 by the Congress of Neurological Surgeons)

Background: Health-related quality of life has recently been suggested as a supplement to the traditional neurological outcome measures from the patient's perspective according to the World Health Organization model and may capture the effects of other factors such as posttraumatic stress disorder and neuroendocrine dysfunction., Objective: To explore the profile and clinical factors of quality of life after aneurysmal subarachnoid hemorrhage using the data we obtained from the recently completed Intravenous Magnesium Sulphate After Aneurysmal Subarachnoid Hemorrhage (IMASH) trial., Methods: This study was registered at www.strokecenter.org/trials and www.ClinicalTrials.gov (NCT00124150). Data from a patient cohort obtained with the Short Form-36 questionnaire completed at 6 months were used for analysis., Results: Patients with aneurysmal subarachnoid hemorrhage demonstrated a decrease in quality of life according to the Short Form-36 at 6 months. The physical and mental health scores correlated with the Extended Glasgow Outcome Scale and had the potential to avoid the ceiling effect. Multiple regression analyses showed that the physical component scores were related to age, World Federation of Neurological Surgeons grade, and chronic hydrocephalus and that the mental component scores were not related to the traditional prognostic factors., Conclusion: Subarachnoid hemorrhage caused a decrease in quality of life. Chronic hydrocephalus is related to a decrease in physical health quality of life., (Copyright © 2011 by the Congress of Neurological Surgeons)

Background: Long-term administration of the antifibrinolytic agent epsilon aminocaproic acid (EACA) reduces the rate of rehemorrhage in patients with aneurysmal subarachnoid hemorrhage (SAH), but is associated with cerebral ischemia., Objective: To evaluate short-term administration of EACA before early surgery in patients with SAH., Methods: Retrospective review of 356 patients admitted between June 2002 and December 2007 with a diagnosis of aneurysmal SAH. Medical records were reviewed to determine SAH risk factors, clinical grade at the time of admission, and incidence of rehemorrhage, permanent new-onset focal neurological deficits, computed tomography evidence of cerebral infarction, symptomatic vasospasm, and hydrocephalus., Results: Patients underwent treatment of the ruptured aneurysm an average of 47.4 hours after admission and received an average total dose of 40.6 g of EACA. The mean length of time of administration of EACA was 35.6 hours. There was a total of 5 rehemorrhages, for an overall rebleeding rate of 1.4% and a rate of rehemorrhage per 24-hour period of 0.71%. Overall, the rates of symptomatic vasospasm and permanent neurological deficits attributable to ischemic stroke were 11.5% and 7.2%, respectively, and the incidence of shunt-dependent hydrocephalus was 42.3%. Patients who were treated with coiling had higher rates of symptomatic vasospasm and ischemic complications than patients who had surgery., Conclusion: Short-term administration of EACA is associated with rates of rehemorrhage, ischemic stroke, and symptomatic vasospasm that compare favorably with historical controls. The rate of hydrocephalus is relatively high and may be attributable to EACA treatment.

Background: Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is a devastating disease with high mortality and morbidity. The incidence of SAH increases with advancing age., Objective: To determine whether age is an independent predictor of angiographic vasospasm, delayed ischemic neurological deficits (DINDs), or abnormal transcranial Doppler (TCD) measurements in patients with aneurysmal subarachnoid hemorrhage., Methods: Data from CONSCIOUS-1 (Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage study), a dose-finding study of clazosentan, were used. Data on angiographic vasospasm, DINDs, and TCD abnormalities were prospectively recorded as well as baseline characteristics and treatment data. Patient age was considered in 3 ways: as a continuous variable, dichotomized at age 65 years, and categorized by decade. Age was investigated as the main variable, whereas other possible confounding variables were adjusted for in the multiple logistic regression modeling with each of 3 dichotomized vasospasm outcome measures, presence or absence of angiographic vasospasm, DINDs, and TCD abnormalities as the dependent variable., Results: The proportions of patients with angiographic vasospasm, DINDs, and TCD abnormalities were 45%, 19%, and 81%, respectively. Age, whether considered as a continuous, dichotomous, or a categorical variable, was not significantly associated with angiographic vasospasm, DINDs, or abnormal TCD measurements., Conclusion: Age does not seem to be a significant predictor for cerebral vasospasm after subarachnoid hemorrhage.

Objective: It is hypothesized that cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is induced by free radicals released from a subarachnoid clot. This study therefore investigated the effect of a new free radical scavenger, edaravone, in the treatment of patients with aneurysmal SAH., Methods: Ninety-one patients with aneurysmal SAH participated in this study and were randomized into a control group (n = 42) and an edaravone-treated group (n = 49). The difference between the 2 groups in terms of incidence of delayed ischemic neurological deficits (DINDs) and cerebral infarction caused by vasospasm, and Glasgow Outcome Scale score at 3 months after SAH were statistically analyzed., Results: The incidence of DINDs was 21% in the control group and 10% in the edaravone-treated group, yet there was no statistically significant difference between the 2 groups (P = 0.118). In patients with DINDs, the incidence of cerebral infarction caused by vasospasm was 66% in the control group and 0% in the edaravone-treated group (P = 0.028), whereas the incidence of poor outcome caused by vasospasm was 71% in the control group and 0% in the edaravone-treated group (P = 0.046)., Conclusion: We found a trend toward a lesser incidence of DINDs and a lesser incidence of poor outcome caused by cerebral vasospasm in edaravone-treated patients. It might therefore be suggested that edaravone is a useful agent for the treatment of aneurysmal SAH.

Objective: The hypothalamic-pituitary-adrenal axis is an important part of the body's natural response to acute illness. Adrenal insufficiency has the potential to lead to hemodynamic instability and electrolyte imbalances, limit the body's ability to respond to stress, and worsen overall clinical outcome. In this case series, we describe 16 patients evaluated for acute adrenal insufficiency after aneurysmal subarachnoid hemorrhage., Clinical Presentation: Over a 2-year period, the medical records of 16 patients admitted to the adult neurosurgery service for aneurysmal subarachnoid hemorrhage who were nonresponsive to vasopressor therapy and received cosyntropin for the evaluation of adrenal insufficiency within 14 days of their event were reviewed., Intervention: The median baseline cortisol in this population was 22.5 microg/dL, with a poststimulation cortisol level of 31 microg/dL. Of the population surveyed, a total of 11 patients met the preestablished criteria for adrenal insufficiency, 3 with baseline cortisol levels of less than 15 microg/dL and 11 with poststimulation concentration changes of less than 9 microg/dL. Baseline serum cortisol concentrations were significantly correlated with hospital stay (P = 0.045), intensive care unit stay (P = 0.005), and ventilator days (P = 0.006)., Conclusion: To date, this is the only investigation evaluating the incidence of acute relative adrenal insufficiency in this population. In our cohort, 69% of the patients met the preestablished criteria for relative adrenal insufficiency. The impact of low-dose corticosteroid therapy in this population also needs review, as it could have significant implications for the management of cerebral vasospasm.

The management of aneurysmal subarachnoid hemorrhage has evolved over time, including the use of the microscope for aneurysm clip application, improved imaging modalities, endovascular methods for aneurysm treatment, dedicated neurointensive care units, and more aggressive therapy for cerebral vasospasm. Although these advancements have reduced the morbidity and mortality associated with aneurysmal subarachnoid hemorrhage, outcomes for this patient population continue to leave much room for improvement. This work highlights controversial adjuvant techniques, maneuvers, and therapies surrounding the surgical treatment of ruptured cerebral aneurysms that currently lack a consensus opinion. These treatments include centralized care in high-volume centers, as well as the use of antifibrinolytic therapy, routine cerebrospinal fluid diversion, intraoperative hypothermia, temporary clip application, neuroprotective drugs, intraoperative angiography, and decompressive hemicraniectomy. Although definitive answers will only be possible through future multicenter collaboration, we review the controversy surrounding these adjuncts and report the consensus opinion from a highly experienced audience.

Objective: Cerebral infarction would be expected to be associated with poor outcome after aneurysmal subarachnoid hemorrhage (SAH), although there are few data on which to base this assumption. The goals of this study were to determine the impact of cerebral infarction on outcome and to examine predictors of infarction in these patients., Methods: Univariate and multivariable statistical methods were used to examine the impact of cerebral infarction on the Glasgow Outcome Scale score 3 months after SAH among 3567 patients entered into four prospective, randomized, double-blind, placebo-controlled trials of tirilazad conducted in neurosurgical centers around the world between 1991 and 1997. Patient demographics, clinical variables, radiographic characteristics, and treatment variables associated with cerebral infarction were also determined by the same methods., Results: Seven hundred and seven (26%) out of 2741 patients with complete data had cerebral infarction on computed tomographic scans 6 weeks after SAH. Multivariable logistic regression showed that cerebral infarction increased the odds of unfavorable outcome by a factor of 5.4 (adjusted odds ratio, 5.4; 95% confidence interval, 4.2-6.8; P < 0.0001), which was a higher odds ratio than all other factors associated with outcome. The proportion of explained variance in outcome was also highest for cerebral infarction and accounted for 39% of the explained variance. Multivariable analysis found that cerebral infarction was significantly associated with increasing patient age, worse neurological grade on admission, history of hypertension or diabetes mellitus, larger aneurysm, use of prophylactically or therapeutically induced hypertension, temperature more than 38 degrees C 8 days after SAH, and symptomatic vasospasm., Conclusion: Cerebral infarction was strongly associated with poor outcome after aneurysmal SAH. The most important potentially treatable factor associated with infarction was symptomatic vasospasm.

Objective: Efficiency of the treatment of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) by interfering with the nitric oxide-cyclic guanosine monophospate (cGMP) pathway seems to be inconsistent. So far, it remains unclear whether or not insufficient access to the drugs or impaired reactivity of the vessels is responsible for this inconsistency. Therefore, the aim of the present investigation was to characterize this pathway on cerebral arteries during CVS., Methods: CVS was induced using the rat double hemorrhage model and was determined by magnetic resonance perfusion weighted imaging. Rats were sacrificed on Day 3 and Day 5 after SAH. Immunohistochemical staining of the basilar artery for endothelial nitric oxide synthases and the alpha- and beta-subunits of the soluble guanylate cyclase was performed. Basilar artery ring segments on Day 5 were used for measurement of isometric force. Concentration effect curves for acetylcholine, sodium nitroprusside, and 8-bromo-cGMP were constructed and compared by maximum effect and pD2., Results: The immunohistochemical expression of endothelial nitric oxide synthase was comparable in all groups. The soluble guanylate cyclase alpha- and beta-subunits were significantly diminished on Day 3, but recovered by Day 5. The relaxation attributable to acetylcholine and 8-bromo-cGMP was virtually identical in controls and during CVS. Relaxation attributable to sodium nitroprusside, however, was significantly enhanced after SAH (maximum effect, control: 88 +/- 12%; Day 5: 117 +/- 26%)., Conclusion: The present investigations suggest the persistence of endothelium-, nitric oxide-, and cGMP-dependent relaxation during CVS. Therefore, the treatment of CVS interfering with this pathway seems not to be limited by alterations inside the vessel wall.

Objective: Phenytoin (PHT) is widely administered after subarachnoid hemorrhage, often for several weeks or months. In addition to known side effects, PHT use has been correlated with cognitive disability and poor outcome. To reduce the rate of PHT complications, we converted from a multi-week prophylactic regimen to a 3-day course of treatment. This study evaluates the changes in seizure rates and adverse events., Methods: From July 1998 to June 2002, 453 patients with spontaneous subarachnoid hemorrhage were treated. In the first 9 months, 79 patients were administered PHT until discharged from the hospital, unless a drug reaction occurred first. In the last 39 months, PHT was discontinued 3 days after admission (370 patients), unless there was a history of epilepsy (four patients). This study represents a retrospective analysis of prospectively collected data, with follow-up periods of 3 to 12 months after discharge., Results: The 3-day PHT regimen produced a statistically significant reduction (P = 0.002) in the rate of PHT complications. In the first period, seven (8.8%) out of 79 patients experienced a hypersensitivity reaction, compared with two (0.5%) out of 370 patients in the second period. The percentage of patients having seizures, both short- and long-term, did not change significantly. In the first period, the seizure rate during hospitalization was 1.3%; in the second period, it was 1.9% (P = 0.603). At an average follow-up period of 6.7 months, three (5.7%) out of 53 survivors in the first period experienced a seizure (including those who had a seizure during hospitalization). In the second period, 12 (4.6%) out of 261 survivors experienced a seizure at an average follow-up period of 5.4 months (P = 0.573)., Conclusion: A 3-day regimen of PHT prophylaxis is adequate to prevent seizures in subarachnoid hemorrhage patients. Drug reactions are significantly reduced, but seizure rates do not change. Short-term PHT administration may be a superior treatment paradigm.

Objective: One of the phosphodiesterase isoenzymes, Type V (PDE V), specifically hydrolyzes cyclic guanosine monophosphate to cause vasoconstriction. This study analyses the effect of PDE V inhibition with sildenafil citrate (SC) on cerebral vasospasm and its effect on apoptotic changes of the vascular endothelium., Methods: Twenty-four rabbits were divided into four groups. The first group was composed of sham-surgery animals. The second group was the subarachnoid hemorrhage (SAH) group, in which cerebral vasospasm was induced. In the third group, sham-surgery rabbits were treated with SC. In the fourth group, animals were treated with SC after SAH. SC was administered for 48 hours, 0.7 mg/kg, three times per day in Groups 3 and 4. Basilar artery lumen circumferences were measured in all groups by computerized image analysis. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) method was used to evaluate the rate of apoptosis between SAH and SC-treated SAH groups. Results were compared by analysis of variance and paired t tests, and P values less than 0.05 were considered significant., Results: Basilar artery circumferences between groups were significantly different (P < 0.001). SC (0.7 mg/kg, three times per d) significantly dilated the basilar arteries in both the sham-surgery group (2370 +/- 233 microm; P = 0.039) and the SAH group (2142 +/- 195 microm; P = 0.006) after 48 hours of treatment. The TUNEL method for apoptosis revealed that actual numbers of the apoptotic endothelial cells per cross section after SAH in the control (no treatment) (73 +/- 2) and SC-treated (0.7 mg/kg) groups(76 +/- 3) were not significantly different (P > 0.05)., Conclusion: The vasodilatory effect of SC was observed to be significant on normal cerebral vessels and after SAH-induced vasospasm. SC did not prevent apoptosis of the endothelium in our study, which suggests that prevention of apoptosis is not necessary in the treatment of cerebral vasospasm.

Objective: We developed a modification of the Fisher computed tomographic rating scale and compared it with the original Fisher scale to determine which scale best predicts symptomatic vasospasm after subarachnoid hemorrhage., Methods: We analyzed data from 1355 subarachnoid hemorrhage patients in the placebo arm of four randomized, double-blind, placebo-controlled studies of tirilazad. Modified Fisher computed tomographic grades were calculated on the basis of the presence of cisternal blood and intraventricular hemorrhage. Crude odds ratios (OR) reflecting the risk of developing symptomatic vasospasm were calculated for each scale level, and adjusted ORs expressing the incremental risk were calculated after controlling for known predictors of vasospasm., Results: Of 1355 patients, 451 (33%) developed symptomatic vasospasm. For the modified Fisher scale, compared with Grade 0 to 1 patients, the crude OR for vasospasm was 1.6 (95% confidence interval [CI], 1.0-2.5) for Grade 2, 1.6 (95% CI, 1.1-2.2) for Grade 3, and 2.2 (95% CI, 1.6-3.1) for Grade 4. For the original Fisher scale, referenced to Grade 1, the OR for vasospasm was 1.3 (95% CI, 0.7-2.2) for Grade 2, 2.2 (95% CI, 1.4-3.5) for Grade 3, and 1.7 (95% CI, 1.0-3.0) for Grade 4. Early angiographic vasospasm, history of hypertension, neurological grade, and elevated admission mean arterial pressure were identified as risk factors for symptomatic vasospasm. After adjusting for these variables, the modified Fisher scale remained a significant predictor of vasospasm (adjusted OR, 1.28; 95% CI, 1.06-1.54), whereas the original Fisher scale was not., Conclusion: The modified Fisher scale, which accounts for thick cisternal and ventricular blood, predicts symptomatic vasospasm after subarachnoid hemorrhage more accurately than original Fisher scale.

Objective: The prophylactic use of nimodipine in patients with aneurysmal subarachnoid hemorrhage reduces the risk of ischemic brain damage. However, its efficacy seems to be rather moderate. The question arises whether other types of calcium antagonists offer better protection. Magnesium, nature's physiological calcium antagonist, is neuroprotective in animal models, promotes dilatation of cerebral arteries, and has an established safety profile. The aim of the current pilot study is to evaluate the efficacy of magnesium versus nimodipine to prevent delayed ischemic deficits after aneurysmal subarachnoid hemorrhage., Methods: One hundred and thirteen patients with aneurysmal subarachnoid hemorrhage were enrolled in the study and were randomized to receive either magnesium sulfate (loading 10 mg/kg followed by 30 mg/kg daily) or nimodipine (48 mg/d) intravenously until at least postoperative Day 7. Primary outcome parameters were incidence of clinical vasospasm and infarction. Secondary outcome measures were the incidence of transcranial Doppler/angiographic vasospasm, the neuronal markers (neuron-specific enolase, S-100), and the patients' Glasgow Outcome Scale scores at discharge and after 1 year., Results: One hundred and four patients met the study requirements. In the magnesium group (n = 53), eight patients (15%) experienced clinical vasospasm and 20 (38%) experienced transcranial Doppler/angiographic vasospasm compared with 14 (27%) and 17 (33%) patients in the nimodipine group (n = 51). If clinical vasospasm occurred, 75% of the magnesium-treated versus 50% of the nimodipine-treated patients experienced cerebral infarction resulting in fatal outcome in 37 and 14%, respectively. Overall, the rate of infarction attributable to vasospasm was virtually the same (19 versus 22%). There was no difference in outcome between groups., Conclusion: The efficacy of magnesium in preventing delayed ischemic neurological deficits in patients with aneurysmal subarachnoid hemorrhage seems to be comparable with that of nimodipine. The difference in their pharmacological properties makes studies on the combined administration of magnesium and nimodipine seem promising.

Objective: Heparin-induced thrombocytopenia Type II (HIT II) is the autoimmune-mediated severe form of the disease characterized by a significant reduction in platelets, and it carries a high risk of "paradoxical" serious thrombotic complications. Although HIT II has been studied in several different patient populations, the incidence of HIT II and the rate of thrombotic complications have never been reported in a neurosurgical patient population. Subarachnoid hemorrhage (SAH) patients, among neurosurgical patient populations, have a high exposure to heparin because they are in critical care units and have indwelling vascular catheters. In addition, the increase in neuroendovascular procedures with the associated use of heparinization will increase the exposure of SAH patients to heparin., Methods: During a 3.5-year period (January 2000-June 2003), 389 consecutive SAH patients were treated at our center. We retrospectively reviewed their laboratory data and medical records and used accepted clinical criteria for the diagnosis of HIT II to determine the incidence of HIT II, thrombotic complications, management, and outcome., Results: Fifty-nine patients (15%) met the clinical diagnostic criteria for HIT II. The average platelet count nadir in the HIT II patients was 68,600 +/- 25,300/microl (mean +/- standard deviation). Female patients and patients with Fisher Grade 3 were more likely to develop HIT II (P < 0.01). Thirty-six patients (61%) underwent a neuroendovascular procedure. The rate of systemic thrombotic complications in the HIT II patients was 37 versus 7% in SAH patients without HIT II (P < 0.001), and the rate of new hypodensities on head computed tomographic scans was 66% in the HIT II patients versus 40% in the SAH patients without HIT II (P < 0.001). Clinical outcomes were worse in the HIT II patients. The outcome was favorable for 38% in the HIT II patients versus 52% in all SAH patients (P < 0.05), and deaths were more common (29%) in the HIT II patients than in all SAH patients (12%, P < 0.001)., Conclusion: The incidence of HIT II in SAH patients at a single center was 15%. The SAH patients with HIT II had significantly higher rates of thrombotic complications, new hypodensities on head computed tomographic scans, more deaths, and significantly less favorable outcomes. This is the first report of the incidence of HIT II in a neurosurgical patient population.

Objective: Approximately one-third of all patients with acute nontraumatic subarachnoid hemorrhage (SAH) experience complications owing to delayed ischemic deficit. We reported recently that enoxaparin 40 mg once daily for 10 days seems safe and demonstrates thromboprophylactic efficacy, but it failed to improve outcome in a randomized SAH trial. In the present study, we assessed hemostatic variables associated with clinical status and outcome of SAH. We also monitored the effect of enoxaparin on activation of coagulation and fibrinolysis after closure of the ruptured aneurysm., Methods: Blood samples to measure activation of coagulation and fibrinolysis were collected from 42 patients participating in the enoxaparin trial for acute aneurysmal SAH at four time points: 1) at hospital admission; 2) 12 to 24 hours after aneurysm surgery but before initiation of enoxaparin therapy; 3) 3 hours after the first dose; and 4) at the conclusion of treatment., Results: At admission, several variables of coagulation and fibrinolysis were elevated and correlated well with clinical status. Specifically, D-dimer levels at all four time points correlated with patients' long-term outcomes. A single dose of enoxaparin suppressed early coagulation activity, but thrombin generation was not inhibited during thromboprophylaxis. However, PAI-1 activity was suppressed., Conclusion: D-dimer offers a useful laboratory tool for assessing early and late clinical severity of SAH. A thromboprophylactic dose of enoxaparin inhibited PAI-1 activity but failed to down-regulate coagulation activity and D-dimer. These findings are compatible with the lack of efficacy of enoxaparin in reducing ischemic deficit after SAH.

Objective: Adhesion and migration of leukocytes into the periadventitial space play a role in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). Intercellular adhesion molecule-1 is a determinant cell adhesion molecule involved in this process. Ibuprofen has been shown to inhibit intercellular adhesion molecule-1 upregulation and prevent vasospasm in animal models of SAH. In this study, we report the toxicity and efficacy of locally delivered ibuprofen incorporated into controlled-release polymers to prevent vasospasm in a monkey model of SAH., Methods: Ibuprofen was incorporated into ethylene-vinyl acetate (EVAc) polymers at 45% loading (wt:wt). For the toxicity study, cynomolgus monkeys (n = 5) underwent surgical implantation of either blank/EVAc polymers (n = 3) or 45% ibuprofen/EVAc polymers (n = 2) in the subarachnoid space, were followed up for 13 weeks, and were killed for histopathological analysis. For the efficacy study, cynomolgus monkeys (n = 14) underwent cerebral angiography 7 days before and 7 days after surgery and SAH and were randomized to receive either a 45% ibuprofen/EVAc polymer (n = 7; mean dose of ibuprofen, 6 mg/kg) or blank EVAc polymers (n = 7) in the subarachnoid space. Angiographic vasospasm was determined by digital image analysis. Student's t test was used for analysis., Results: Animals implanted with ibuprofen polymers showed no signs of local or systemic toxicity. Animals treated with ibuprofen polymers had 91 +/- 9% lumen patency of the middle cerebral artery, compared with 53 +/- 11% of animals treated with blank/EVAc polymers (P < 0.001)., Conclusion: Ibuprofen polymers are safe and prevent angiographic vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

Objective: Since October 1999, nicardipine prolonged-release implants (NPRIs) have been used to prevent vasospasm in patients with subarachnoid hemorrhage. This study was conducted to examine the incidence of cerebral vasospasm and outcome after the application of NPRIs., Methods: Ninety-seven consecutive patients among 125 patients with subarachnoid hemorrhage who were surgically treated within 72 hours were analyzed. NPRIs were applied principally to patients with thick clots (Fisher Group 3) through a frontotemporal or frontal craniotomy. Sixty-nine patients, including five in Fisher Group 2, were treated with NPRIs, and 28 were not. NPRIs were placed in the cisterns of thick clots where vasospasm was highly probable., Results: Four (6%) of the 69 patients treated with NPRIs and 3 (11%) of the 28 patients not treated with NPRIs developed delayed ischemic neurological deficits (DINDs). Of these patients, clinical deterioration with infarction occurred in two patients (3%). Current smoking (P = 0.0088) and intraventricular hemorrhage on admission computed tomographic (CT) scans (P = 0.0077) were correlated with DIND. CT groupings on admission and postoperatively were not correlated, nor were World Federation of Neurosurgical Societies grades. Hypertension was inversely correlated with DIND (P = 0.0233). Eighty-six patients (89%) had an independent status at 3 months. Logistic regression analysis demonstrated that age (odds ratio [OR], 6.836; P = 0.034), World Federation of Neurosurgical Societies grade (OR, 23.317; P = 0.001), intraventricular hemorrhage on admission CT scans (OR, 6.332; P = 0.024), and surgical complications (OR, 32.861; P = 0.003) were independent risk factors influencing an unfavorable outcome. CT grouping on admission and DIND were not., Conclusion: Our findings suggest that the incidence of DIND may decrease and, therefore, an unfavorable outcome may improve if NPRIs are applied for patients with thick clots (Fisher Group 3) during surgery.

Objective: Thrombolytic agents have been administered through external ventricular drains to treat intraventricular hemorrhage, the goals being to accelerate clot clearance, prevent catheter obstruction, and help control intracranial pressure. We compared these variables in a group of aneurysm patients treated by one surgeon who routinely used intraventricular recombinant tissue plasminogen activator (rt-PA) for obstructive hematocephalus with those in a group of similar patients treated by other surgeons who did not., Methods: Patients included in this analysis were those with repaired cerebral aneurysms causing hemorrhage into at least three ventricles with ventriculomegaly requiring external ventricular drainage. The ventricular system was considered "opened" when all ventricles were patent and reduced in size on computed tomographic scans. Those treated with rt-PA received 4 mg/d through a ventricular drain until ventricular opening., Results: The mean number of days to ventricular opening was 3.9 (standard deviation [SD], 1.0) for the 21 patients treated with rt-PA and 7.1 (SD, 3.7) for the 9 who were not (P = 0.001), and the mean intracranial pressure (mm Hg) 24 hours after treatment with rt-PA was 10.4 (SD, 6.1) compared with 14.1 (SD, 5.9) during the same interval for the group that did not receive rt-PA (P = 0.13). Ventricular catheter replacement was required in 1 rt-PA patient (for a misplaced catheter, before rt-PA treatment) and 3 patients who did not receive rt-PA (all for catheter obstructions with blood clot) (P = 0.07), and ventriculoperitoneal shunts were placed in 4 rt-PA patients and 3 patients who did not receive rt-PA (P = 0.4)., Conclusion: Intraventricular thrombolysis with rt-PA seems to assist in the acute management of patients with large aneurysmal intraventricular hemorrhages, speeding clearance of aneurysmal intraventricular hemorrhage, normalizing intracranial pressure, and reducing ventricular catheter obstruction. A randomized trial is needed to confirm these findings, establish treatment safety, and determine whether treatment affects outcome.

Objective: Despite existing strategies for the treatment of vasospasm after aneurysmal subarachnoid hemorrhage, vasospasm remains a persistent contributor to death and disability. The intracisternal application of thrombolytic agents to dissolve subarachnoid clot has been advocated. The goal of this analysis was to assess the currently available evidence regarding the effectiveness of this treatment., Methods: We conducted a systematic review of the published literature; all controlled trials were included. The outcomes of interest were delayed ischemic neurological deficits, poor Glasgow Outcome Scale scores, and death. A formal meta-analysis was performed with a random-effects model., Results: The search revealed nine trials or trial subgroups (only one of which was randomized), with a total enrollment of 652 patients. Pooled results demonstrated beneficial effects of treatment, with absolute risk reductions of 14.4% (95% confidence interval, 6.5-22.5%; P < 0.001) for delayed ischemic neurological deficits, 9.5% (95% confidence interval, 4.2-14.8%; P < 0.01) for poor Glasgow Outcome Scale scores, and 4.5% (95% confidence interval, 1.5-7.5%; P < 0.05) for death. Regression analysis revealed that treatment effects did not significantly differ among the studies on the basis of the type of thrombolytic agent used (tissue plasminogen activator versus urokinase) or the method of administration (intraoperative versus postoperative) (P > 0.10). Studies that enrolled only patients at high risk for vasospasm seemed to demonstrate greater treatment effects., Conclusion: The meta-analysis suggests a clinically relevant and statistically significant beneficial effect of intracisternal thrombolysis. However, the results of the analysis are limited by the predominance of nonrandomized studies. Further randomized, blinded, placebo-controlled trials of high-risk patients would be justified.

Objective: Inspired by organ culture-induced changes in the vascular endothelin (ET) receptor population, we investigated whether such changes occur in cerebral arteries in a rat subarachnoid hemorrhage (SAH) model., Methods: SAH was induced with injection of 250 microl of blood into the prechiasmatic cistern. After 2 days, the middle cerebral artery, basilar artery, and posterior communicating artery were harvested. Pharmacological studies were performed in vitro, and levels of messenger ribonucleic acid (mRNA) were quantified in real-time reverse transcriptase-polymerase chain reaction assays., Results: In the middle cerebral artery and basilar artery from rats with induced SAH, enhanced biphasic responses to ET-1 were observed. The -log(50% effective concentration) value for the high-affinity phase was approximately 12, compared with approximately 8.5 for sham-operated animals. At a concentration of ET-1 of 10(-9) mmol/L (approximately equal to the physiological concentration of ET-1 in the plasma), submaximal contractions of 50 to 75% of the contraction obtained through stimulation with 60 mmol/L K(+) were now observed. Quantitative mRNA studies with the same arteries demonstrated significant increases in the number of copies of ET(B) receptor mRNA but not ET(A) receptor mRNA. Evidence of functional ET(B) receptors was provided in antagonist studies. The posterior communicating artery did not exhibit significant changes., Conclusion: The altered receptor profile observed may represent the final stage in the series of events leading from SAH to actual spasm of the artery. The pharmacological data for the ET(B) receptor suggest complex interactions between normally present ET(A) receptors and up-regulated ET(B) receptors.

Objective: Despite improvements in the care of patients with aneurysmal subarachnoid hemorrhage, delayed cerebral vasospasm remains a major cause of morbidity and death. There is now evidence that a decrease in the local availability of nitric oxide (NO) plays a role in delayed cerebral vasospasm. We evaluated a controlled-release polymer containing the NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) for the treatment of chronic posthemorrhagic vasospasm in the rat femoral artery model., Methods: The release kinetics of ethylene/vinyl acetate copolymers loaded with 20% (w/w) DETA/NO were determined in vitro. Chronic vasospasm was induced in the left femoral artery of adult male Fischer 344 rats (n = 35) by exposure to autologous blood. At 1, 3, or 7 days after blood exposure, either a 5-mg polymer loaded with 20% (w/w) DETA/NO or an empty 5-mg polymer was placed in the periadventitial space next to the left femoral artery. At the same time, an empty 5-mg polymer was placed next to the right femoral artery. On the 8th day after blood exposure (at the peak of vasospasm in this model), rats were transcardially perfused with 4% paraformaldehyde, and the left and right femoral arteries were removed for histological processing and morphometric analyses. Vasospasm was expressed as the percent lumen patency of the treated left artery, compared with the control right artery., Results: The in vitro release kinetics demonstrated that the 20% DETA/NO-loaded polymers released up to 15% of their total drug load during a 9-day period. DETA/NO treatments initiated at 1, 3, or 7 days after blood deposition all significantly inhibited vasospasm, compared with control values (94.6 +/- 7.2% versus 67.6 +/- 5.8%, 104.6 +/- 5.5% versus 64.9 +/- 1.7%, and 102.4 +/- 5.1% versus 73.6 +/- 1.4%, respectively; mean +/- standard error of the mean percent lumen patency; P < 0.001). No adverse effects of treatment were observed., Conclusion: The diazeniumdiolate NO donor DETA/NO can be effectively released from ethylene/vinyl acetate polymers. Administration of DETA/NO into the periadventitial space can prevent the development of chronic posthemorrhagic vasospasm in the rat femoral artery and can reverse established vasospasm. No adverse effects of DETA/NO were observed in this model.

Objective: The intra-arterial infusion of papaverine has been used for dilation of spastic cerebral vessels after aneurysmal subarachnoid hemorrhage, although its efficacy is controversial. Milrinone is an inotropic drug that dilates vessels by phosphodiesterase inhibition in a mechanism similar to that of papaverine. We examined the effects of intra-arterial and subsequent intravenous administration of milrinone on patients with symptomatic cerebral vasospasm., Methods: Seven patients with cerebral vasospasm were enrolled in this study. Milrinone was delivered intra-arterially via catheter at a rate of 0.25 mg/min. The total delivered dose was between 2.5 and 15 mg. Radiological measurement of the middle cerebral artery diameter and cerebral blood flow was carried out before and after arterial infusion. Intravenous treatment followed at 0.50 or 0.75 microg/kg/min for up to 2 weeks from the onset of subarachnoid hemorrhage., Results: Dilation of the vasospastic vessels occurred in all patients. The rate of cerebral blood flow was calculated in six patients and was increased in all. Subsequent intravenous infusion was effective in preventing a recurrence of symptomatic vasospasm in four of the seven patients., Conclusion: It is suggested that milrinone was effective and safe for the treatment of cerebral vasospasm after subarachnoid hemorrhage in the patients in this series. Intra-arterial infusion with adjunctive intravenous infusion holds promise as a clinically advantageous treatment regimen.

Objective and Importance: Nimodipine is commonly used to improve neurological outcomes after subarachnoid hemorrhage. Although nimodipine reportedly has high specificity for the cerebral vasculature, adverse systemic effects such as hypotension have been described. This case report describes a patient with traumatic subarachnoid hemorrhage who experienced two episodes of previously undescribed, life-threatening hypoxemia that was directly related to nimodipine therapy., Clinical Presentation: The patient experienced acute hypoxemia (partial pressures of oxygen of 32.9 and 58.7 mm Hg), on two separate occasions (3 d apart), that was temporally related to single doses of nimodipine therapy for traumatic subarachnoid hemorrhage. Other disease- and medication-related causes did not explain these episodes., Intervention: After the inspired oxygen concentration was increased to 100% (both episodes) and the positive end expiratory pressure was increased to 7.5 mm Hg (first episode), the arterial oxygen saturation of the patient returned to baseline levels (>99%) within 40 minutes in each instance. Nimodipine therapy was discontinued after each episode., Conclusion: It is hypothesized that, in the presence of concomitant adult respiratory distress syndrome, nimodipine increased ventilation/perfusion ratio mismatch, through its direct vasodilatory effects on the pulmonary artery, and possibly interfered with the reflex hypoxic pulmonary vasoconstriction necessary to maintain adequate oxygenation for this patient. Clinicians should carefully monitor the oxygenation status of patients when nimodipine therapy is initiated.