Search

OBJECTIVECerebral vasospasm (CV) is a delayed, sustained contraction of the cerebral arteries that tends to occur 3–14 days after aneurysmal subarachnoid hemorrhage (aSAH) from a ruptured aneurysm. Vasospasm potentially leads to delayed cerebral ischemia, and despite medical treatment, 1 of 3 patients suffer a persistent neurological deficit. Bedside transcranial Doppler (TCD) ultrasonography is used to indirectly detect CV through recognition of an increase in cerebral blood flow velocity (CBFV). The present study aimed to use TCD ultrasonography to monitor how CBFV changes on both the ipsi- and contralateral sides of the brain in the first 24 hours after patients have received a stellate ganglion block (SGB) to treat CV that persists despite maximum standard therapy.METHODSThe data were culled from records of patients treated between 2013 and 2017. Patients were included if an SGB was administered following aSAH, whose CBFV was ≥ 120 cm/sec and who had either a focal neurological deficit or reduced consciousness despite having received medical treatment and blood pressure management. The SGB was performed on the side where the highest CBFV had been recorded with 8–10 ml ropivacaine 0.2%. The patient’s CBFV was reassessed after 2 and 24 hours.RESULTSThirty-seven patients (male/female ratio 18:19), age 17–70 years (mean age 49.9 ± 11.1), who harbored 13 clipped and 22 coiled aneurysms (1 patient received both a coil and a clip, and 3 patients had 3 untreated aneurysms) had at least one SGB. Patients received up to 4 SGBs, and thus the study comprised a total of 76 SGBs.After the first SGB, CBFV decreased in 80.5% of patients after 2 hours, from a mean of 160.3 ± 28.2 cm/sec to 127.5 ± 34.3 cm/sec (p < 0.001), and it further decreased in 63.4% after 24 hours to 137.2 ± 38.2 cm/sec (p = 0.007). A similar significant effect was found for the subsequent SGB. Adding clonidine showed no significant effect on either the onset or the duration of the SGB. Contralateral middle cerebral artery (MCA) blood flow was not reduced by the SGB.CONCLUSIONSTo the authors’ knowledge, this is the largest study on the effects of administering an SGB to aSAH patients after aneurysm rupture. The data showed a significant reduction in ipsilateral CBFV (MCA 20.5%) after SGB, lasting in about two-thirds of cases for over 24 hours with no major complications resulting from the SGB.

OBJECTIVEDelayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is characterized by large-artery vasospasm, distal autoregulatory dysfunction, cortical spreading depression, and microvessel thrombi. Large-artery vasospasm has been identified as an independent predictor of poor outcome in numerous studies. Recently, several animal studies have identified a strong protective role for inhalational anesthetics against secondary brain injury after SAH including DCI—a phenomenon referred to as anesthetic conditioning. The aim of the present study was to assess the potential role of inhalational anesthetics against cerebral vasospasm and DCI in patients suffering from an SAH.METHODSAfter IRB approval, data were collected retrospectively for all SAH patients admitted to the authors’ hospital between January 1, 2010, and December 31, 2013, who received general anesthesia with either inhalational anesthetics only (sevoflurane or desflurane) or combined inhalational (sevoflurane or desflurane) and intravenous (propofol) anesthetics during aneurysm treatment. The primary outcomes were development of angiographic vasospasm and development of DCI during hospitalization. Univariate and logistic regression analyses were performed to identify independent predictors of these endpoints.RESULTSThe cohort included 157 SAH patients whose mean age was 56 ± 14 (± SD). An inhalational anesthetic–only technique was employed in 119 patients (76%), while a combination of inhalational and intravenous anesthetics was employed in 34 patients (22%). As expected, patients in the inhalational anesthetic–only group were exposed to significantly more inhalational agent than patients in the combination anesthetic group (p < 0.05). Multivariate logistic regression analysis identified inhalational anesthetic–only technique (OR 0.35, 95% CI 0.14–0.89), Hunt and Hess grade (OR 1.51, 95% CI 1.03–2.22), and diabetes (OR 0.19, 95% CI 0.06–0.55) as significant predictors of angiographic vasospasm. In contradistinction, the inhalational anesthetic–only technique had no significant impact on the incidence of DCI or functional outcome at discharge, though greater exposure to desflurane (as measured by end-tidal concentration) was associated with a lower incidence of DCI.CONCLUSIONSThese data represent the first evidence in humans that inhalational anesthetics may exert a conditioning protective effect against angiographic vasospasm in SAH patients. Future studies will be needed to determine whether optimized inhalational anesthetic paradigms produce definitive protection against angiographic vasospasm; whether they protect against other events leading to secondary brain injury after SAH, including microvascular thrombi, autoregulatory dysfunction, blood-brain barrier breakdown, neuroinflammation, and neuronal cell death; and, if so, whether this protection ultimately improves patient outcome.

OBJECTIVEThe authors sought to identify mRNA biomarkers of cerebral vasospasm in whole blood of patients suffering from aneurysmal subarachnoid hemorrhage (aSAH).METHODSA prospective transcriptomic study for vasospasm was conducted in whole blood samples of 44 aSAH patients who developed (VSP+ group, n = 22) or did not develop (VSP− group, n = 22) vasospasm. Samples from all patients were profiled for 21,460 mRNA probes using the Illumina Human HT12v4.0 array. Differential statistical analysis was performed using a linear mixed model.RESULTSLevels of sphingosine-1-phosphate receptor 4 (S1PR4) mRNA were significantly higher (p = 8.03 × 10−6) at presentation in patients who developed vasospasm after aSAH than in patients who did not.CONCLUSIONSThe results, which are consistent with findings of previous experimental investigations conducted in animal models, support the role of S1PR4 and its ligand, sphingosine-1-phosphate (S1P), in arterial-associated vasoconstriction, which suggests that S1PR4 could be used as a biomarker for cerebral vasospasm in aSAH patients.

OBJECTIVEOcclusive treatment of posterior communicating artery (PCoA) aneurysms has been seen as a fairly uncomplicated procedure. The objective here was to determine the radiological and clinical outcome of patients after PCoA aneurysm rupture and treatment and to evaluate the risk factors for impaired outcome.METHODSIn a retrospective clinical follow-up study, data were collected from 620 consecutive patients who had been treated for ruptured PCoA aneurysms at a single center between 1980 and 2014. The follow-up was a minimum of 1 year after treatment or until death.RESULTSOf the 620 patients, 83% were treated with microsurgical clipping, 8% with endovascular coiling, 2% with the two procedures combined, 1% with indirect surgical methods, and 6% with conservative methods. The most common procedural complications were treatment-related brain infarctions (15%). The occurrence of artery occlusions (10% microsurgical, 8% endovascular) was higher than expected. Most patients made a good recovery at 1 year after aneurysmal subarachnoid hemorrhage (modified Rankin Scale [mRS] score 0–2: 386 patients [62%]). A fairly small proportion of patients were left severely disabled (mRS score 4–5: 27 patients [4%]). Among all patients, 20% died during the 1st year. Independent risk factors for an unfavorable outcome, according to the multivariable analysis, were poor preoperative clinical condition, intracerebral or subdural hematoma due to aneurysm rupture, age over 65 years, artery occlusion on postoperative angiography, occlusive treatment–related ischemia, delayed cerebral vasospasm, and hydrocephalus requiring a shunt.CONCLUSIONSEven though most patients made a good recovery after PCoA aneurysm rupture and treatment during the 1st year, the occlusive treatment–related complications were higher than expected and caused morbidity even among initially good-grade patients. Occlusive treatment of ruptured PCoA aneurysms seems to be a high-risk procedure, even in a high-volume neurovascular center.

OBJECTIVEIn patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration.METHODSIn this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled. The concentration of macrophage migration inhibitory factor (MIF) in CSF was assessed for correlation with CV or DCI, the primary outcome measures.RESULTSTwenty-five patients were enrolled in the aSAH group and 9 were enrolled in the NPH group. There was a significant increase in aggregate CSF MIF concentration in patients with aSAH versus those with NPH (24.4 ± 19.2 vs 2.3 ± 1.1 ng/ml, p < 0.0002). Incidence of the day of peak MIF concentration significantly correlated with the onset of clinical vasospasm (rho = 0.778, p < 0.0010). MIF concentrations were significantly elevated in patients with versus those without evidence of DCI (18.7 ± 4.93 vs 8.86 ± 1.28 ng/ml, respectively, p < 0.0025). There was a significant difference in MIF concentrations between patients with infection versus those without infection (16.43 ± 4.21 vs 8.5 ± 1.22 ng/ml, respectively, p < 0.0119).CONCLUSIONSPreliminary evidence from this study suggests that CSF concentrations of MIF are correlated with CV and DCI. These results, however, could be confounded in the presence of clinical infection. A study with a larger patient sample size is necessary to corroborate these findings.

OBJECTIVEDelayed ischemic neurological deficit (DIND) is a leading cause of mortality and morbidity after aneurysmal subarachnoid hemorrhage (aSAH). Arginine vasopressin (AVP) is a hormone released by the posterior pituitary. It is known to cause cerebral vasoconstriction and has been implicated in hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion. Direct measurement of AVP is limited by its short half-life. Copeptin, a cleavage product of the AVP precursor protein, was therefore used as a surrogate marker for AVP. This study aimed to investigate the temporal relationship between changes in copeptin concentrations and episodes of DIND and hyponatremia.METHODSCopeptin concentrations in cerebrospinal fluid were quantified using enzyme-linked immunosorbent assay in 19 patients: 10 patients with DIND, 6 patients without DIND (no-DIND), and 3 controls.RESULTSCopeptin concentrations were higher in DIND and no-DIND patients than in controls. In hyponatremic DIND patients, copeptin concentrations were higher compared with hyponatremic no-DIND patients. DIND was associated with a combination of decreasing sodium levels and increasing copeptin concentrations.CONCLUSIONSIncreased AVP may be the unifying factor explaining the co-occurrence of hyponatremia and DIND. Future studies are indicated to investigate this relationship and the therapeutic utility of AVP antagonists in the clinical setting.

OBJECTIVE Cerebral vasospasm and delayed cerebral ischemia (DCI) contribute to poor outcome following subarachnoid hemorrhage (SAH). With the paucity of effective treatments, the authors describe their experience with intrathecal (IT) nicardipine for this indication. METHODS Patients admitted to the Emory University Hospital neuroscience ICU between 2012 and 2017 with nontraumatic SAH, either aneurysmal or idiopathic, were included in the analysis. Using a propensity-score model, this patient cohort was compared to patients in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository who did not receive IT nicardipine. The primary outcome was DCI. Secondary outcomes were long-term functional outcome and adverse events. RESULTS The analysis included 1351 patients, 422 of whom were diagnosed with cerebral vasospasm and treated with IT nicardipine. When compared with patients with no vasospasm (n = 859), the treated group was significantly younger (mean age 51.1 ± 12.4 years vs 56.7 ± 14.1 years, p < 0.001), had a higher World Federation of Neurosurgical Societies score and modified Fisher grade, and were more likely to undergo clipping of the ruptured aneurysm as compared to endovascular treatment (30.3% vs 11.3%, p < 0.001). Treatment with IT nicardipine decreased the daily mean transcranial Doppler velocities in 77.3% of the treated patients. When compared to patients not receiving IT nicardipine, treatment was not associated with an increased rate of bacterial ventriculitis (3.1% vs 2.7%, p > 0.1), yet higher rates of ventriculoperitoneal shunting were noted (19.9% vs 8.8%, p < 0.01). In a propensity score comparison to the SAHIT database, the odds ratio (OR) to develop DCI with IT nicardipine treatment was 0.61 (95% confidence interval [CI] 0.44–0.84), and the OR to have a favorable functional outcome (modified Rankin Scale score ≤ 2) was 2.17 (95% CI 1.61–2.91). CONCLUSIONS IT nicardipine was associated with improved outcome and reduced DCI compared with propensity-matched controls. There was an increased need for permanent CSF diversion but no other safety issues. These data should be considered when selecting medications and treatments to study in future randomized controlled clinical trials for SAH.

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. The presence of thick, diffuse subarachnoid blood may portend a worse clinical course and outcome, independently of other known prognostic factors such as age, aneurysm size, and initial clinical grade. METHODS In this post hoc analysis, patients with aSAH undergoing surgical clipping (n = 383) or endovascular coiling (n = 189) were pooled from the placebo arms of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS)–2 and CONSCIOUS-3 randomized, double-blind, placebo-controlled phase 3 studies, respectively. Patients without and with thick, diffuse SAH (≥ 4 mm thick and involving ≥ 3 basal cisterns) on admission CT scans were compared. Clot size was centrally adjudicated. All-cause mortality and vasospasm-related morbidity at 6 weeks and Glasgow Outcome Scale–Extended (GOSE) scores at 12 weeks after aSAH were assessed. The effect of the thick and diffuse cisternal aSAH on vasospasm-related morbidity and mortality, and on poor clinical outcome at 12 weeks, was evaluated using logistic regression models. RESULTS Overall, 294 patients (51.4%) had thick and diffuse aSAH. Compared to patients with less hemorrhage burden, these patients were older (median age 55 vs 50 years) and more often had World Federation of Neurosurgical Societies (WFNS) grade III–V SAH at admission (24.1% vs 16.5%). At 6 weeks, all-cause mortality and vasospasm-related morbidity occurred in 36.1% (95% CI 30.6%–41.8%) of patients with thick, diffuse SAH and in 14.7% (95% CI 10.8%–19.5%) of those without thick, diffuse SAH. Individual event rates were 7.5% versus 2.5% for all-cause death, 19.4% versus 6.8% for new cerebral infarct, 28.2% versus 9.4% for delayed ischemic neurological deficit, and 24.8% versus 10.8% for rescue therapy due to cerebral vasospasm, respectively. Poor clinical outcome (GOSE score ≥ 4) was observed in 32.7% (95% CI 27.3%–38.3%) and 16.2% (95% CI 12.1%–21.1%) of patients with and without thick, diffuse SAH, respectively. CONCLUSIONS In a large, centrally adjudicated population of patients with aSAH, WFNS grade at admission and thick, diffuse SAH independently predicted vasospasm-related morbidity and poor 12-week clinical outcome. Patients with thick, diffuse cisternal SAH may be an important cohort to target in future clinical trials of treatment for vasospasm.

OBJECTIVEThe clinical significance of cerebral ultra-early angiographic vasospasm (UEAV), defined as cerebral arterial narrowing within the first 48 hours of aneurysmal subarachnoid hemorrhage (aSAH), remains poorly characterized. The authors sought to determine its frequency, predictors, and impact on functional outcome.METHODSThe authors prospectively studied UEAV in a cohort of 1286 consecutively admitted patients with aSAH between August 1996 and June 2013. Admission clinical, radiographic, and acute clinical course information was documented during patient hospitalization. Functional outcome was assessed at 3 months using the modified Rankin Scale. Logistic regression and Cox proportional hazards models were generated to assess predictors of UEAV and its relationship to delayed cerebral ischemia (DCI) and outcome. Multiple imputation methods were used to address data lost to follow-up.RESULTSThe cohort incidence rate of UEAV was 4.6%. Multivariable logistic regression analysis revealed that younger age, sentinel bleed, and poor admission clinical grade were significantly associated with UEAV. Patients with UEAV had a 2-fold increased risk of DCI (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.4–3.9, p = 0.002) and cerebral infarction (OR 2.0, 95% CI 1.0–3.9, p = 0.04), after adjusting for known predictors. Excluding patients who experienced sentinel bleeding did not change this effect. Patients with UEAV also had a significantly higher hazard for DCI in a multivariable model. UEAV was not found to be significantly associated with poor functional outcome (OR 0.8, 95% CI 0.4–1.6, p = 0.5).CONCLUSIONSUEAV may be less frequent than has been reported previously. Patients who exhibit UEAV are at higher risk for refractory DCI that results in cerebral infarction. These patients may benefit from earlier monitoring for signs of DCI and more aggressive treatment. Further study is needed to determine the long-term functional significance of UEAV.

OBJECTIVEIntravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty.METHODSThe authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm.RESULTSThe cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III–V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01–112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0–2) assessed at a median of 4 months (interquartile range 2–8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512).CONCLUSIONSThe aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.

OBJECTIVEDelayed brain injury (DBI) is considered one of the most important causes of mortality and morbidity after subarachnoid hemorrhage (SAH). However, no suitable experimental rat endovascular perforation (EVP) SAH model was available for investigating DBI. The authors added early cerebral hypoperfusion to a mild EVP SAH model by unilateral common carotid artery occlusion (UCCAO) 24 hours after induction of SAH to mimic the clinical course of early cerebral hypoperfusion after SAH.METHODSA total of 109 adult male Sprague-Dawley rats were randomly divided into 2 groups: no SAH and SAH. Next, no-SAH rats were randomly divided on day 1 into 2 groups: sham and UCCAO. SAH rats with a neurological score of 15 or greater were randomly divided into 2 groups: SAH − UCCAO and SAH + UCCAO group.RESULTSThe mild SAH model had a lower mortality rate of 5.4% within the first 24 hours. No rat died in the SAH + UCCAO group until day 7. DBI as well as early brain injury (EBI), reactive astrogliosis, and cerebral vasospasm significantly worsened in the SAH + UCCAO group.CONCLUSIONSThe present SAH + UCCAO model can simulate EBI with aggravation of reactive astrogliosis, cerebral vasospasm, and DBI but without high mortality.

OBJECTIVE Cerebral vasospasm (cVSP) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on outcome. Beta blockers (BBs) may blunt the sympathetic effect and catecholamine surge associated with ruptured cerebral aneurysms and prevent cardiac dysfunction. The purpose of this study was to investigate the association between preadmission BB therapy and cVSP, cardiac dysfunction, and in-hospital mortality following aSAH. METHODS This was a retrospective cohort study of patients with aSAH who were treated at a tertiary high-volume neurovascular referral center. The exposure was defined as any preadmission BB therapy. The primary outcome was cVSP assessed by serial transcranial Doppler with any mean flow velocity ≥ 120 cm/sec and/or need for endovascular intervention for medically refractory cVSP. Secondary outcomes were cardiac dysfunction (defined as cardiac troponin-I elevation > 0.05 μg/L, low left ventricular ejection fraction [LVEF] < 40%, or LV wall motion abnormalities [LVWMA]) and in-hospital mortality. RESULTS The cohort consisted of 210 patients treated between February 2009 and September 2010 (55% were women), with a mean age of 53.4 ± 13 years and median Hunt and Hess Grade III (interquartile range III–IV). Only 13% (27/210) of patients were exposed to preadmission BB therapy. Compared with these patients, a higher percentage of patients not exposed to preadmission BBs had transcranial Doppler-mean flow velocity ≥ 120 cm/sec (59% vs 22%; p = 0.003). In multivariate analyses, lower Hunt and Hess grade (OR 3.9; p < 0.001) and preadmission BBs (OR 4.5; p = 0.002) were negatively associated with cVSP. In multivariate analysis, LVWMA (OR 2.7; p = 0.002) and low LVEF (OR 1.1; p = 0.05) were independent predictors of in-hospital mortality. Low LVEF (OR 3.9; p = 0.05) independently predicted medically refractory cVSP. The in-hospital mortality rate was higher in patients with LVWMA (47.4% vs 14.8%; p < 0.001). CONCLUSIONS The study data suggest that preadmission therapy with BBs is associated with lower incidence of cVSP after aSAH. LV dysfunction was associated with higher medically refractory cVSP and in-hospital mortality. BB therapy may be considered after aSAH as a cardioprotective and cVSP preventive therapy.

OBJECT The impact of transcranial Doppler (TCD) ultrasonography evidence of vasospasm on patient-centered clinical outcomes following aneurysmal subarachnoid hemorrhage (aSAH) is unknown. Vasospasm is known to lead to delayed cerebral ischemia (DCI) and poor outcomes. This systematic review and meta-analysis evaluates the predictive value of vasospasm on DCI, as diagnosed on TCD. METHODS MEDLINE, Scopus, the Cochrane trial register, and clinicaltrials.gov were searched through September 2014 using key words and the terms “subarachnoid hemorrhage,” “aneurysm,” “aneurysmal,” “cerebral vasospasm,” “vasospasm,” “transcranial Doppler,” and “TCD.” Sensitivities, specificities, and positive and negative predictive values were pooled by a DerSimonian and Laird random-effects model. RESULTS Seventeen studies (n = 2870 patients) met inclusion criteria. The amount of variance attributable to heterogeneity was significant (I2 > 50%) for all syntheses. No studies reported the impact of TCD evidence of vasospasm on functional outcome or mortality. TCD evidence of vasospasm was found to be highly predictive of DCI. Pooled estimates for TCD diagnosis of vasospasm (for DCI) were sensitivity 90% (95% confidence interval [CI] 77%–96%), specificity 71% (95% CI 51%–84%), positive predictive value 57% (95% CI 38%–71%), and negative predictive value 92% (95% CI 83%–96%). CONCLUSIONS TCD evidence of vasospasm is predictive of DCI with high accuracy. Although high sensitivity and negative predictive value make TCD an ideal monitoring device, it is not a mandated standard of care in aSAH due to the paucity of evidence on clinically relevant outcomes, despite recommendation by national guidelines. High-quality randomized trials evaluating the impact of TCD monitoring on patient-centered and physician-relevant outcomes are needed.

OBJECT Delayed ischemic neurological deficits (DINDs) and cerebral vasospasm (CVS) are responsible fora poor outcome in patients with aneurysmal subarachnoid hemorrhage (SAH), most likely because of a decreased availability of nitric oxide (NO) in the cerebral microcirculation. In this study, the authors examined the effects of treatment with the NO donor molsidomine with regard to decreasing the incidence of spasm-related delayed brain infarctions and improving clinical outcome in patients with SAH. METHODS Seventy-four patients with spontaneous aneurysmal SAH were included in this post hoc analysis. Twenty-nine patients with SAH and proven CVS received molsidomine in addition to oral or intravenous nimodipine. Control groups consisted of 25 SAH patients with proven vasospasm and 20 SAH patients without. These patients received nimodipine therapy alone. Cranial computed tomography (CCT) before and after treatment was analyzed for CVS-related infarcts. A modified National Institutes of Health Stroke Scale (mNIHSS) and the modified Rankin Scale (mRS) were used to assess outcomes at a 3-month clinical follow-up. RESULTS Four of the 29 (13.8%) patients receiving molsidomine plus nimodipine and 22 of the 45 (48%) patients receiving nimodipine therapy alone developed vasospasm-associated brain infarcts (p < 0.01). Follow-up revealed a median mNIHSS score of 3.0 and a median mRS score of 2.5 in the molsidomine group compared with scores of 11.5 and 5.0, respectively, in the nimodipine group with CVS (p < 0.001). One patient in the molsidomine treatment group died, and 12 patients in the standard care group died (p < 0.01). CONCLUSIONS In this post hoc analysis, patients with CVS who were treated with intravenous molsidomine had a significant improvement in clinical outcome and less cerebral infarction. Molsidomine offers a promising therapeutic option in patients with severe SAH and CVS and should be assessed in a prospective study.

OBJECTIVECerebral vasospasm causing delayed cerebral ischemia (DCI) is a source of significant morbidity after subarachnoid hemorrhage (SAH). Transcranial Doppler is used at most institutions to detect sonographic vasospasm but has poor positive predictive value for DCI. Automated assessment of the pupillary light reflex has been increasingly used as a reliable way of assessing pupillary reactivity, and the Neurological Pupil Index (NPi) has been shown to decrease hours prior to the clinical manifestation of ischemic injury or herniation syndromes. The aim of this study was to investigate the role of automated pupillometry in the setting of SAH, as a potential adjunct to TCD.METHODSOur analysis included patients that had been diagnosed with aneurysmal SAH and admitted to the neuro–intensive care unit of the University of Texas Southwestern Medical Center between November 2015 and June 2017. A dynamic infrared pupillometer was used for all pupillary measurements. An NPi value ranging from 3 to 5 was considered normal, and from 0 to 2.9 abnormal. Sonographic vasospasm was defined as middle cerebral artery velocities greater than 100 cm/sec with a Lindegaard ratio greater than 3 on either side on transcranial Doppler. Most patients had multiple NPi readings daily and we retained the lowest value for our analysis. We aimed to study the association between DCI and sonographic vasospasm, and DCI and NPi readings.RESULTSA total of 56 patients were included in the final analysis with 635 paired observations of daily TCD and NPi data. There was no statistically significant association between the NPi value and the presence of sonographic vasospasm. There was a significant association between DCI and sonographic vasospasm, χ2(1) = 6.4112, p = 0.0113, OR 1.6419 (95% CI 1.1163–2.4150), and between DCI and an abnormal decrease in NPi, χ2(1) = 38.4456, p < 0.001, OR 3.3930 (95% CI 2.2789–5.0517). Twelve patients experienced DCI, with 7 showing a decrease of their NPi to an abnormal range. This change occurred > 8 hours prior to the clinical decline 71.4% of the time. The NPi normalized in all patients after treatment of their vasospasm.CONCLUSIONSIsolated sonographic vasospasm does not seem to correlate with NPi changes, as the latter likely reflects an ischemic neurological injury. NPi changes are strongly associated with the advent of DCI and could be an early herald of clinical deterioration.

OBJECTIVECerebral vasospasm (VS) is a severe complication of aneurysmal subarachnoid hemorrhage (SAH). Urotensin II (UII) is a potent vasoactive peptide activating the urotensin (UT) receptor, potentially involved in brain vascular pathologies. The authors hypothesized that UII/UT system antagonism with the UT receptor antagonist/biased ligand urantide may be associated with post-SAH VS. The objectives of this study were 2-fold: 1) to leverage an experimental mouse model of SAH with VS in order to study the effect of urotensinergic system antagonism on neurological outcome, and 2) to investigate the association between plasma UII level and symptomatic VS after SAH in human patients.METHODSA mouse model of SAH was used to study the impacts of UII and the UT receptor antagonist/biased ligand urantide on VS and neurological outcome. Then a clinical study was conducted in the setting of a neurosurgical intensive care unit. Plasma UII levels were measured in SAH patients daily for 9 days, starting on the 1st day of hospitalization, and were compared with plasma UII levels in healthy volunteers.RESULTSIn the mouse model, urantide prevented VS as well as SAH-related fine motor coordination impairment. Seventeen patients with SAH and external ventricular drainage were included in the clinical study. The median plasma UII level was 43 pg/ml (IQR 14–80 pg/ml). There was no significant variation in the daily median plasma UII level (median value for the 17 patients) from day 0 to day 8. The median level of plasma UII during the 9 first days post-SAH was higher in patients with symptomatic VS than in patients without VS (77 pg/ml [IQR 33.5–111.5 pg/ml] vs 37 pg/ml [IQR 21–46 pg/ml], p < 0.05). Concerning daily measures of plasma UII levels in VS, non-VS patients, and healthy volunteers, we found a significant difference between SAH patients with VS (median 66 pg/ml [IQR 30–110 pg/ml]) and SAH patients without VS (27 pg/ml [IQR 15–46 pg/ml], p < 0.001) but no significant difference between VS patients and healthy volunteers (44 pg/ml [IQR 27–51 pg/ml]) or between non-VS patients and healthy volunteers.CONCLUSIONSThe results of this study suggest that UT receptor antagonism with urantide prevents VS and improves neurological outcome after SAH in mice and that an increase in plasma UII is associated with cerebral VS subsequent to SAH in humans. The causality link between circulating UII and VS after SAH remains to be established, but according to our data the UT receptor is a potential therapeutic target in SAH.

Object Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication. Free radicals derived from subarachnoid clotting are recognized to play an important role. Oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) have been shown to be related to the pathogenesis of atherosclerosis and may increase in cerebral arteries after SAH, due to the action of free radicals derived from a subarachnoid clot. These molecules may also affect the pathogenesis of vasospasm, generating intracellular reactive oxygen species and downregulating the expression of endothelial NO synthase (eNOS). If so, apple polyphenol might be effective in the prevention of vasospasm due to an abundant content of procyanidins, which exhibit strong radical scavenging effects, and the ability to suppress ox-LDL and LOX-1. The purposes of this study were to investigate changes in levels of ox-LDL and LOX-1 after SAH and whether administering apple polyphenol can modify cerebral vasospasm. Methods Forty Japanese white rabbits were assigned randomly to 4 groups: an SAH group (n = 10); a shamoperation group (n = 10), which underwent intracisternal saline injection; a low-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 10 mg/kg per day from Day 0 to Day 3; and a high-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 50 mg/kg per day. At Day 4, the basilar artery and brain was excised from each rabbit. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar artery, and the expression of ox-LDL, LOX-1, and eNOS was examined for each basilar artery by immunohistochemical staining and reverse transcriptase polymerase chain reaction. In addition, neuronal apoptosis in the cerebral cortex was evaluated by TUNEL. Results Compared with the sham group, the expression of ox-LDL and LOX-1 in the basilar arterial wall was significantly increased in the SAH group, the expression of eNOS was significantly decreased, and the cross-sectional area of basilar artery was significantly decreased. Compared with the SAH group, the cross-sectional area of basilar artery was increased in the polyphenol groups, together with the decreased expression of ox-LDL and LOX-1 and the increased expression of eNOS. In the high-dose polyphenol group, those changes were statistically significant compared with the SAH group. In the low-dose polyphenol group, those changes were smaller than in the high-dose polyphenol group. No apoptosis and no changes were seen in the cerebral cortex in all groups. Conclusions This is the first study suggesting that ox-LDL and LOX-1 increase due to SAH and that they may play a role in the pathogenesis of vasospasm. It is assumed that procyanidins in apple polyphenol may inhibit a vicious cycle of ox-LDL, LOX-1, and ROS in a dose-dependent manner. Apple polyphenol is a candidate for preventive treatment of cerebral vasospasm.

Object Aneurysmal subarachnoid hemorrhage (aSAH) predisposes to delayed neurological deficits, including stroke and cognitive and neuropsychological abnormalities. Heparin is a pleiotropic drug that antagonizes many of the pathophysiological mechanisms implicated in secondary brain injury after aSAH. Methods The authors performed a retrospective analysis in 86 consecutive patients with Fisher Grade 3 aSAH due to rupture of a supratentorial aneurysm who presented within 36 hours and were treated by surgical clipping within 48 hours of their ictus. Forty-three patients were managed postoperatively with a low-dose intravenous heparin infusion (Maryland low-dose intravenous heparin infusion protocol: 8 U/kg/hr progressing over 36 hours to 10 U/kg/hr) beginning 12 hours after surgery and continuing until Day 14 after the ictus. Forty-three control patients received conventional subcutaneous heparin twice daily as deep vein thrombosis prophylaxis. Results Patients in the 2 groups were balanced in terms of baseline characteristics. In the heparin group, activated partial thromboplastin times were normal to mildly elevated; no clinically significant hemorrhages or instances of heparin-induced thrombocytopenia or deep vein thrombosis were encountered. In the control group, the incidence of clinical vasospasm requiring rescue therapy (induced hypertension, selective intraarterial verapamil, and angioplasty) was 20 (47%) of 43 patients, and 9 (21%) of 43 patients experienced a delayed infarct on CT scanning. In the heparin group, the incidence of clinical vasospasm requiring rescue therapy was 9% (4 of 43, p = 0.0002), and no patient suffered a delayed infarct (p = 0.003). Conclusions In patients with Fisher Grade 3 aSAH whose aneurysm is secured, postprocedure use of a low-dose intravenous heparin infusion may be safe and beneficial.

The authors describe a rare case of central auditory dysfunction induced by cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). A 55-year-old woman who was admitted after aneurysmal SAH developed cerebral vasospasm on Day 3 affecting mainly the right middle cerebral artery (MCA) and partly the left MCA. The vasospasm became refractory to conventional therapy and was ultimately improved by intraarterial infusion of nimodipine in the right MCA and angioplasty. Severe auditory dysfunction was apparent from Day 10 as the patient was not reactive to speech or environmental sounds. Brain MRI on Day 17 demonstrated infarcted areas mainly in the right hippocampus, medial occipital lobe, and thalamus. The patient underwent further examination using audiometry, speech testing, auditory evoked potentials, functional MRI, and cerebral PET. The initial diagnosis was extended nonverbal agnosia and total pure word deafness. The central auditory dysfunction improved over 6 months, with persisting hyperacusis, tinnitus, and amusia. Central auditory dysfunction is a rare complication after SAH. While cortical deafness may be associated with bilateral lesions of the temporal cortex, partly reversible central auditory dysfunction was observed in this patient after prominently unilateral right temporal lesions. The role of the interthalamic connections can be discussed, as well as the possibility that a less severe vasospasm on the left MCA could have transiently impaired the left thalamocortical auditory pathways.

Object The object of this study was to determine the relationship between plasma taurine and subarachnoid hemorrhage (SAH) outcome. Methods Forty patients with SAH and mild neurological deficits were included in this prospective, blinded cohort study. Plasma taurine levels were measured using high-performance liquid chromatography on admission and were correlated with patient outcomes at discharge. Results Twenty-five percent of the patients ultimately had a poor outcome. Plasma taurine concentrations at admission were increased (2-fold) in SAH patients with a favorable outcome and were further increased (6-fold) in those who had a poor outcome. Increased taurine levels identified patients who would be discharged with a poor outcome, with sensitivity and specificity values of approximately 80% and 100%, respectively, and positive and negative predictive values of approximately 90%. Delayed cerebral vasospasm showed an OR of 27.9 (95% CI 1.090–714.9) for a poor outcome, whereas an increased taurine concentration had an OR of 105 for a poor outcome (95% CI 8.3–1328.0, p < 0.001). Conclusions Increased plasma taurine concentrations on admission predict a poor outcome in SAH.

ObjectBaicalein has been shown to offer neuroprotection in the ischemic brain, but its effect in subarachnoid hemorrhage (SAH) is unknown. The authors used a double-hemorrhage model to study the role of early baicalein treatment in SAH.MethodsSubarachnoid hemorrhage was induced in male Wistar rats through a repeat injection of autologous blood at a 48-hour interval. Rats subjected or not subjected to SAH received a 30-mg/kg baicalein injection 3 hours after SAH and daily for 6 consecutive days, and results were compared with those obtained in vehicle-treated control rats. Mortality of the rats was recorded. Neurological outcome was assessed daily. Cerebrospinal fluid dialysates were collected and examined for glutamate concentrations. Cerebral vasospasm (CVS), brain water content, neuron variability, expression of glutamate transporter–1 (GLT-1), immunoreactivity of astrocyte, and level of malondialdehyde, activities of superoxide dismutase (SOD), and catalase in brain tissues content were determined on post-SAH Day 7.ResultsMortality rate, neuronal degeneration, brain water content, and CVS were decreased and neurological function improved in the baicalein-treated rats. Baicalein increased astrocyte activity and preserved GLT-1, which attenuated the glutamate surge after SAH. Baicalein also provided antioxidative stress by preserving activities of SOD and catalase and decreased malondialdehydelevel after SAH. The glutamate, body weight, neurological scores, and glial fibrillary acidic protein activity were significantly correlated. The CVS was correlated with neuronal degeneration, and GLT-1 was correlated with oxidative stress.ConclusionsEarly baicalein treatment attenuated CVS and limited neurological injury following SAH. These data may indicate clinical utility for baicalein as an adjunct therapy to reduce brain injury and improve patient outcomes.

Object Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion. Methods In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter. Results In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14. Conclusions Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm. Clinical trial registration no.: NCT00873015 (ClinicalTrials.gov).

OBJECTIVEThe efficacy of statin therapy in treating aneurysmal subarachnoid hemorrhage (SAH) remains controversial. In this meta-analysis, the authors investigated whether statin treatment significantly reduced the incidence of cerebral vasospasm and delayed neurological deficits, promoting a better outcome after aneurysmal SAH.METHODSA literature search of the PubMed, Ovid, and Cochrane Library databases was performed for randomized controlled trials (RCTs) and prospective cohort studies investigating the effect of statin treatment. The end points of cerebral vasospasm, delayed ischemic neurological deficit (DIND), delayed cerebral infarction, mortality, and favorable outcome were statistically analyzed.RESULTSSix RCTs and 2 prospective cohort studies met the eligibility criteria, and a total of 1461 patients were included. The meta-analysis demonstrated a significant decrease in the incidence of cerebral vasospasm (relative risk [RR] 0.76, 95% confidence interval [CI] 0.61–0.96) in patients treated with statins after aneurysmal SAH. However, no significant benefit was observed for DIND (RR 0.88, 95% CI 0.70–1.12), delayed cerebral infarction (RR 0.66, 95% CI 0.33–1.31), mortality (RR 0.69, 95% CI 0.39–1.24) or favorable outcome, according to assessment by the modified Rankin Scale or Glasgow Outcome Scale (RR 0.99, 95% CI 0.92–1.17).CONCLUSIONSTreatment with statins significantly decreased the occurrence of vasospasm after aneurysmal SAH. The incidence of DIND, delayed cerebral infarction, and mortality were not affected by statin treatment. Future research should focus on DIND and how statins influence DIND.

OBJECTIVE MicroRNAs (miRNAs) regulate gene expression and therefore play important roles in many physiological and pathological processes. The aim of this pilot study was to determine the feasibility of extraction and subsequent profiling of miRNA from CSF samples in a pilot population of aneurysmal subarachnoid hemorrhage patients and establish if there is a distinct CSF miRNA signature between patients who develop cerebral vasospasm and those who do not. METHODS CSF samples were taken at various time points during the clinical management of a subset of SAH patients (SAH patient samples without vasospasm, n = 10; SAH patient samples with vasospasm, n = 10). CSF obtained from 4 patients without SAH was also included in the analysis. The miRNA was subsequently isolated and purified and then analyzed on an nCounter instrument using the Human V2 and V3 miRNA assay kits. The data were imported into the nSolver software package for differential miRNA expression analysis. RESULTS From a total of 800 miRNAs that could be detected with each version of the miRNA assay kit, a total of 691 miRNAs were communal to both kits. There were 36 individual miRNAs that were differentially expressed (p < 0.01) based on group analyses, with a number of miRNAs showing significant changes in more than one group analysis. The changes largely reflected differences between non-SAH and SAH groups. These included miR-204-5p, miR-223-3p, miR-337-5p, miR-451a, miR-489, miR-508-3p, miR-514-3p, miR-516-5p, miR-548 m, miR-599, miR-937, miR-1224-3p, and miR-1301. However, a number of miRNAs did exclusively differ between the vasospasm and nonvasospasm SAH groups including miR-27a-3p, miR-516a-5p, miR-566, and miR-1197. CONCLUSIONS The findings indicate that temporal miRNA profiling can detect differences between CSF from aneurysmal SAH and non-SAH patients. Moreover, the miRNA profile of CSF samples from patients who develop cerebral vasopasm may be distinguishable from those who do not. These results provide a foundation for future research at identifying novel CSF biomarkers that might predispose to the development of cerebral vasospasm after SAH and therefore influence subsequent clinical management.

OBJECTIVE Early rehabilitation is effective in an array of acute neurological disorders but it is not established as part of treatment guidelines after aneurysmal subarachnoid hemorrhage (aSAH). This may in part be due to the fear of aggravating the development of cerebral vasospasm, which is the most feared complication of aSAH. The aim of this study was to evaluate the effect of early rehabilitation and mobilization on complications during the acute phase and within 90 days after aSAH. METHODS This was a prospective, interventional study that included patients with aSAH at the neuro-intermediate ward after aneurysm repair. The control group received standard treatment, whereas the early rehab group underwent early rehabilitation and mobilization in addition to standard treatment. Clinical and radiological characteristics of patients with aSAH, progression in mobilization, and treatment variables were registered. The frequency and severity of cerebral vasospasm, cerebral infarction acquired in conjunction with the aSAH, and acute and chronic hydrocephalus, as well as pulmonary and thromboembolic complications, were compared between the 2 groups. RESULTS Clinical and radiological characteristics of patients with aSAH were similar between the groups. The early rehab group was mobilized beginning on the first day after aneurysm repair. The significantly quicker and higher degree of mobilization in the early rehab group did not increase complications. Clinical cerebral vasospasm was not as frequent in the early rehab group and it also tended to be less severe. Each step of mobilization achieved during the first 4 days after aneurysm repair reduced the risk of severe vasospasm by 30%. Acute and chronic hydrocephalus were similar in both groups, but there was a tendency toward earlier shunt implantation among patients in the control group. Pulmonary infections, thromboembolic events, and death before discharge or within 90 days after the ictus were similar between the 2 groups. CONCLUSIONS Early rehabilitation of patients after aSAH is safe and feasible. The earlier and higher degree of mobilization does not increase neurosurgical complications. Rather, the frequency and severity of cerebral vasospasm following aSAH are alleviated and are not aggravated by early rehabilitation. Clinical trial registration no.: NCT01656317 (www.clinicaltrials.gov).

Object Subarachnoid hemorrhage (SAH)-induced vasospasm is a significant underlying cause of aneurysm rupture-related morbidity and death. While long-term intravenous infusion of sodium nitrite (NaNO2) can prevent cerebral vasospasm after SAH, it is not known if the intravenous administration of this compound can reverse established SAH-induced vasospasm. To determine if the intravenous infusion of NaNO2 can reverse established vasospasm, the authors infused primates with the compound after SAH-induced vasospasm was established. Methods Subarachnoid hemorrhage–induced vasospasm was created in 14 cynomolgus macaques via subarachnoid implantation of a 5-ml blood clot. On Day 7 after clot implantation, animals were randomized to either control (saline infusion, 5 monkeys) or treatment groups (intravenous NaNO2 infusion at 300 μg/kg/hr for 3 hours [7 monkeys] or 8 hours [2 monkeys]). Arteriographic vessel diameter was blindly analyzed to determine the degree of vasospasm before, during, and after treatment. Nitric oxide metabolites (nitrite, nitrate, and S-nitrosothiols) were measured in whole blood and CSF. Results Moderate-to-severe vasospasm was present in all animals before treatment (control, 36.2% ± 8.8% [mean ± SD]; treatment, 45.5% ± 12.5%; p = 0.9). While saline infusion did not reduce vasospasm, NaNO2 infusion significantly reduced the degree of vasospasm (26.9% ± 7.6%; p = 0.008). Reversal of the vasospasm lasted more than 2 hours after cessation of the infusion and could be maintained with a prolonged infusion. Nitrite (peak value, 3.7 ± 2.1 μmol/L), nitrate (18.2 ± 5.3 μmol/L), and S-nitrosothiols (33.4 ± 11.4 nmol/L) increased significantly in whole blood, and nitrite increased significantly in CSF. Conclusions These findings indicate that the intravenous infusion of NaNO2 can reverse SAH-induced vasospasm in primates. Further, these findings indicate that a similar treatment paradigm could be useful in reversing cerebral vasospasm after aneurysmal SAH.

Papaverine has been associated with transient cranial nerve dysfunction after topical application during craniotomy. The authors report similar dysfunction after the use of papaverine affected brainstem structures. Two patients undergoing craniotomy for clipping of an aneurysm experienced bilateral depression of cortical somatosensory evoked potentials to both median and tibial nerve stimulation after administration of papaverine. Arterial blood gas analysis, hemodynamic parameters, and anesthetic levels remained constant throughout these somatosensory evoked potential changes. In addition, intraoperative angiography and immediate postoperative CT imaging showed intact blood flow with complete exclusion of the aneurysm. Both patients recovered within 1–2 hours and had normal neurological examination findings after extubation. Topical papaverine use may be associated with direct effects on brainstem structures. The transient nature of those changes suggests that aggressive intervention may not be needed. Maneuvers to limit the spread of papaverine to basal cisterns should be considered.

Object The optimal CSF Mg++ concentration for vasodilation of spastic cerebral arteries after subarachnoid hemorrhage (SAH) and its duration are unknown. The temporal profile of the vasodilatory effect and optimal CSF Mg++ concentration after the intracisternal injection of MgSO4 solution were investigated in an SAH model in canines. Methods Cerebral vasospasm was induced by experimental SAH using a 2-hemorrhage model in 26 female beagles. On Day 7, 0.5 ml/kg of 15, 10, 5, or 0 mmol/L MgSO4 in Ringer solution was injected into the cerebellomedullary cistern. Angiography was performed on Day 1 (before SAH) and before and 1, 3, and 6 hours after the intracisternal injection on Day 7 to measure arterial diameters of the basilar artery (BA), superior cerebellar artery (SCA), and vertebral artery (VA). Cerebrospinal fluid Mg++ was also measured at the same time. Results Arterial diameters of the BA, SCA, and VA were significantly decreased by vasospasm on Day 7. Arterial diameter ratios (ratio of arterial diameter after MgSO4 injection to diameter before injection on Day 7) of the BA and SCA at 1 and 3 hours after and the VA at 1 hour after intracisternal injection of the MgSO4 solution were positively correlated with the CSF Mg++ concentration. All arterial diameter ratios, except 1 point of the SCA, exceeded 1 if the CSF Mg++ concentration was > 3 mEq/L at 1 hour after injection. Animals with CSF Mg++ concentrations > 3 mEq/L at 1 hour after injection (11 dogs) showed significantly increased arterial diameters of the BA at 1 and 3 hours after and of the SCA and VA at 1, 3, and 6 hours after injection, as compared with the diameters before injection. The CSF Mg++ concentration significantly increased at 1 hour (3.73 ± 0.69 mEq/L, p < 0.01) and 3 hours (2.05 ± 0.35 mEq/L, p < 0.01) after the intracisternal injection as compared with the baseline value (1.41 ± 0.20 mEq/L). Conclusions The reversible effect of an intracisternal injection of MgSO4 solution on the spastic artery requires CSF Mg++ concentrations > 3 mEq/L. The vasodilatory effect continues for 3–6 hours after injection. These results suggest that the continuous infusion or intermittent intracisternal injection of MgSO4 is needed to maintain the optimal CSF Mg++ concentration and constantly ameliorate cerebral vasospasm.

Object As many as 33% of patients suffering from subarachnoid hemorrhage (SAH) present with multiple intracranial aneurysms (MIAs). It is believed that aneurysm surgery has the potential to increase the risk of cerebral vasospasm due to surgical manipulations of the parent vessels and brain tissue. Consequently, 1-stage surgery of MIAs, which usually takes longer and requires more manipulation, could even further increase the risk of vasospasm. The aim of this study is to define the correlation between vasospasm and the operative treatment of single intracranial aneurysms versus MIAs in a 1-stage operation. Methods The authors analyzed a database including 1016 patients with SAH, identified retrospectively between 1989 and 1996 and prospectively collected between 1997 and 2004. Exclusion criteria were endovascular treatment, surgery after SAH Day 3, and, in patients with MIAs, undergoing more than 1 operation. Cerebral vasospasm was diagnosed by transcranial Doppler (TCD) ultrasonography and was defined as a maximum mean blood flow velocity > 120 cm/second. The diagnosis of symptomatic vasospasm was made if a new neurological deficit occurred that could not be explained by concomitant complications. Results A total of 643 patients who experienced 810 aneurysms were included. Four hundred twenty-four patients were female (65.9%) and 219 were male (34.1%) with an average age of 53.1 years. One hundred twenty-one patients (18.8%) were diagnosed with MIAs. Maximum mean flow velocities measured by TCD were 131 cm/second in patients with MIAs and 129.5 cm/second in patients with single intracranial aneurysms. The incidence of TCD vasospasm (p = 0.561) as well as of symptomatic vasospasm (p = 0.241) was not significantly different in the 2 groups. Conclusions Clipping of more than 1 aneurysm in a 1-stage operation within 72 hours after SAH can be performed without increasing the risk of cerebral (TCD) vasospasm and symptomatic vasospasm.

Object Vasospasm is one of the leading causes of morbidity and death following aneurysmal subarachnoid hemorrhage (SAH). Many patients suffer devastating strokes despite the best medical therapy. Endovascular treatment is the last line of defense for cases of medically refractory vasospasm. The authors present a series of patients who were treated with a prolonged intraarterial infusion of verapamil through an in-dwelling microcatheter. Methods Over a 1-year period 12 patients with medically refractory vasospasm due to aneurysmal SAH were identified. Data were retrospectively collected, including age, sex, Hunt and Hess grade, Fisher grade, aneurysm location, aneurysm treatment, day of the onset of vasospasm, intracranial pressure, mean arterial pressures, intraarterial treatment of vasospasm, dosages and times of verapamil infusion, presence of a new ischemic area on CT scan, modified Rankin scale score at discharge and at the last clinical follow-up, and discharge status. Results Twenty-seven treatments were administered. Between 25 and 360 mg of verapamil was infused per vessel (average dose per vessel 164.6 mg, range of total dose per treatment 70–720 mg). Infusion times ranged from 1 to 20.5 hours (average 7.8 hours). The number of treated vessels ranged from 1 to 7 per patient. The number of treatments per patients ranged from 1 to 4. There was no treatment-related morbidity or death. Blood pressure and intracranial pressure changes were transient and rapidly reversible. Among the 36 treated vessels, prolonged verapamil infusion was completely effective in 32 cases and partially effective in 4. Only 4 vessels required angioplasty for refractory vasospasm after prolonged verapamil infusion. There was no CT scanning evidence of new ischemic events in 9 of the 12 patients treated. At last clinical follow-up 6–12 months after discharge, 8 of 11 patients had a modified Rankin Scale score ≤2. Conclusions Prolonged intraarterial infusion of verapamil is a safe and effective treatment for medically refractory severe vasospasm and reduces the need for angioplasty in such cases.

Object In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy. Methods The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-β or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or ≥ 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements. Results Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 × 109/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO. Conclusions Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.

Object One mechanism that contributes to cerebral vasospasm is the impairment of potassium channels in vascular smooth muscles. Adenosine triphosphate–sensitive potassium channel openers (PCOs) appear to be particularly effective for dilating cerebral arteries in experimental models of subarachnoid hemorrhage (SAH). A mode of safe administration that provides timed release of PCO drugs is still a subject of investigation. The authors tested the efficacy of locally delivered intrathecal cromakalim, a PCO, incorporated into a controlled-release system to prevent cerebral vasospasm in a rat model of SAH. Methods Cromakalim was coupled to a viscous carrier, hyaluronan, 15% by weight. In vitro release kinetics studies showed a steady release of cromakalim over days. Fifty adult male Sprague-Dawley rats weighing 350–400 g each were divided into 10 groups and treated with various doses of cromakalim or cromakalim/hyaluronan in a rat double SAH model. Treatment was started 30 minutes after the second SAH induction. Animals were killed 3 days after treatment, and the basilar arteries were processed for morphometric measurements and histological analysis. Results Controlled release of cromakalim from the cromakalim/hyaluronan implant at a dose of 0.055 mg/kg significantly increased lumen patency in a dose-dependent manner up to 94 ± 8% (mean ± standard error of the mean) of the basilar arteries of the sham group compared with the empty polymer group (p = 0.006). Results in the empty polymer group were not different from those in the SAH-only group, with a lumen patency of 65 ± 12%. Lumen patencies of the cromakalim-only groups did not differ in statistical significance at low (64 ± 9%) or high (66 ± 7%) doses compared to the SAH-only group. Conclusions Treatment of SAH with a controlled-release cromakalim/hyaluronan implant prevented experimental cerebral vasospasm in this rat double hemorrhage model; this inhibition was dose-dependent. The authors' results confirm that sustained delivery of cromakalim perivascularly to cerebral vessels could be an effective therapeutic strategy in the treatment of cerebral vasospasm after SAH.

Object The use of nicardipine prolonged-release implants (NPRIs) is associated with a significant improvement in the therapy of patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) regarding the occurrence and severity of cerebral vasospasm, new infarcts, and functional outcome (FO). Because quality of life (QOL) measurements more reliably seem to describe the patient's true condition, the present study was conducted to assess FO and QOL 1 year after aneurysm rupture in patients with and without NPRIs. Methods From the initial series of 32 patients, 18 were assessed 1 year after aSAH (7 of the control and 11 of the NPRI group). The patients underwent neurological investigation, a structured interview followed by a measurement of QOL (Mini-Mental State Examination [MMSE]; 36-Item Short Form Health Survey [SF-36]; and the Hamilton Depression Rating Scale). There were no intergroup differences in the patient characteristics (that is, localization of aneurysm, initial Hunt and Hess grade, or age). Results In addition to the previously reported improvement of the National Institutes of Health Stroke Scale and modified Rankin Scale scores, the NPRI group's Karnofsky Performance Scale and the MMSE scores were markedly to significantly improved (p < 0.05 [Karnofsky Performance Scale] and p = 0.053 [MMSE]). In contrast, anxiety, oblivion, and mild symptoms of depression were equally present in both study groups (p = 0.607 [anxiety]; p = 0.732 [oblivion]; and p = 0.509 [Hamilton Depression Rating Scale]). Furthermore, no intergroup differences were observed in any of the SF-36 domains. The scores in the SF-36 domains of Role-Physical, Vitality, and Role-Emotional were significantly reduced in the NRPI group compared with those observed in an age-matched control population (p < 0.001 [Role-Physical]; p = 0.001 [vitality]; and p = 0.01 [Role-Emotional]). Considering consequent costs, no difference was detectable regarding the duration of in- and outpatient rehabilitation (p = 0.135 and 0.171, respectively) or the Prolo score (p = 0.094). Conclusions Despite FO improvement in terms of a lower incidence of cerebral vasospasm, new infarcts, morbidity in the treatment of aSAH in patients with NPRIs, a patient's QOL seems to be related to the severity of the aSAH itself.

Object Aneurysmal subarachnoid hemorrhage (SAH) carries a severe prognosis, which is often related to the development of cerebral vasospasm. Even though several clinical and radiological predictors of vasospasm and functional outcome have been established, the prognostic value of histopathological findings remains unclear. Methods Histopathological findings in resected distal aneurysm walls were examined, as were the clinical and radiological factors in a series of 91 patients who had been neurosurgically treated for aneurysmal SAH. The impact of the histological, clinical, and radiological factors on the occurrence of vasospasm and functional outcome at discharge was analyzed. Results Histopathological findings frequently included lymphocytic infiltrates (60%), fibrosis (60%), and necrosis (50%) of the resected aneurysm wall. On univariate analysis, clinical (Hunt and Hess grade) and radiological (aneurysm size) factors as well as histopathological features—namely, lymphocytic infiltrates and necrosis of the aneurysm wall—were significantly associated with the occurrence of vasospasm. On multivariate analysis, lymphocytic infiltrates (OR 6.35, 95% CI 2.32–17.36, p = 0.0001) and aneurysm size (OR 1.22, 95% CI 1.05–1.42, p = 0.009) remained the only factors predicting the development of vasospasm. A poor functional outcome at discharge was significantly associated with vasospasm, other clinical factors (Hunt and Hess grade, alcohol consumption, hyperglycemia, and elevated white blood cell count [WBC] at admission), and radiological factors (Fisher grade and aneurysm size), as well as with histopathological features (lymphocytic infiltrates [p = 0.0001] and necrosis of the aneurysm wall [p = 0.0015]). On multivariate analysis taking into account all clinical, radiological, and histological factors; vasospasm (OR 9.82, 95% CI 1.83–52.82, p = 0.008), Hunt and Hess grade (OR 5.61, 95% CI 2.29–13.74, p = 0.0001), patient age (OR 1.09, 95% CI 1.02–1.16, p = 0.0013), elevated WBC (OR 1.29, 95% CI 1.01–1.64, p = 0.04), and Fisher grade (OR 4.35, 95% CI 1.25–15.07, p = 0.015) best predicted functional outcome at discharge. Conclusions The demonstration of lymphocytic infiltrates in the resected aneurysm wall is of independent prognostic value for the development of vasospasm in patients with neurosurgically treated aneurysmal SAH. Thus, histopathology might complement other clinical and radiological factors in the identification of patients at risk.

Object Cerebral vasospasm remains a major complication in patients who have suffered a subarachnoid hemorrhage (SAH). Previous studies have shown that 17β-estradiol (E2) attenuates experimental SAH–induced cerebral vasospasm. Moreover, E2 has been shown to reduce neuronal apoptosis and secondary injury following cerebral ischemia. Adenosine A1 receptor (AR-A1) expression is increased following ischemia and may represent an endogenous neuroprotective effect. This study was designed to evaluate the efficacy of E2 in preventing cerebral vasospasm and reducing secondary injury, as evidenced by DNA fragmentation and AR-A1 expression, following SAH. Methods A double-hemorrhage model of SAH in rats was used, and the degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery 7 days after the first SAH. A cell death assay was used to detect apoptosis. Changes in the protein expression of AR-A1 in the cerebral cortex, hippocampus, and dentate gyrus were compared with levels in normal controls and E2-treated groups (subcutaneous E2, 0.3 mg/ml). Results The administration of E2 prevented vasospasm (p < 0.05). Seven days after the first SAH, DNA fragmentation and protein levels of AR-A1 were significantly increased in the dentate gyrus. The E2 treatment decreased DNA fragmentation and prevented the increase in AR-A1 expression in the dentate gyrus. There were no significant changes in DNA fragmentation and the expression of AR-A1 after SAH in the cerebral cortex and hippocampus in the animals in the control and E2-treated groups. Conclusions The E2 was effective in attenuating SAH-induced cerebral vasospasm, decreasing apoptosis in the dentate gyrus, and reducing the expression of AR-A1 in the dentate gyrus after SAH. Interestingly, E2 appears to effectively prevent cerebral vasospasm subsequent to SAH as well as attenuate secondary injury by reducing both apoptosis and a compensatory increase in AR-A1 expression in the dentate gyrus.

Object The goal of this study was to assess the accuracy of the routine clinical use of transcranial Doppler (TCD) ultrasonography and SPECT in predicting angiographically demonstrated vasospasm. Methods Following receipt of institutional review board approval, the authors reviewed the records of patients with subarachnoid hemorrhage who had been admitted between 2004 and 2005 and underwent TCD ultrasonography and SPECT evaluations within 24 hours of cerebral angiography. Patients were categorized based on the presence or absence of vasospasm and/or hypoperfusion in the anterior cerebral arteries (ACAs), middle cerebral arteries (MCAs), and basilar arteries (BAs) or posterior cerebral arteries (PCAs) according to each imaging modality. Logistic regression was used to estimate the odds ratio (OR) of an angiographically demonstrated vasospasm also detected on TCD ultrasonography and SPECT. Results One hundred fifty-two patients (101 women) with a mean age (± standard deviation) of 53 ± 13 years were included in the study. In the ACA, the OR of a vasospasm on TCD ultrasonography was 27 (95% confidence interval [CI] 3–243) and on SPECT 0.97 (95% CI 0.36–2.6); in the MCA, 17 (95% CI 5.4–55) and 2.0 (95% CI 0.71–5.5), respectively; in the BA, 4.4 (95% CI 0.72–27) and 5.6 (95% CI 0.89–36), respectively. There was no substantial change in the relative odds of a vasospasm when the findings on TCD ultrasonography and SPECT were considered jointly. Conclusions Transcranial Doppler ultrasonography appears to be highly predictive of an angiographically demonstrated vasospasm in the MCA and ACA; however, its diagnostic accuracy was lower with regard to vasospasm in the BA. Single-photon emission computed tomography was not predictive of a vasospasm in any of the vascular territories assessed.

Object The extracellular Mg++ has a vasodilatory effect on the cerebral artery. The present study investigated the effect of intracisternal injection of MgSO4 solution on cerebral vasospasm in a canine model of subarachnoid hemorrhage (SAH). Methods Subarachnoid hemorrhage was induced in 10 beagles using the two-hemorrhage model. Angiography of the vertebrobasilar artery was performed on Day 1 (baseline values before SAH) and on Day 7 (during cerebral vasospasm after induced SAH) before and after intracisternal injection of 0.5 ml/kg of 15 mmol/L MgSO4 solution into the cerebellomedullary cistern. Results The cerebrospinal fluid Mg++ concentration was significantly increased to 3.15 ± 1.14 mEq/L after intracisternal injection from the preinjection value (1.45 ± 0.09 mEq/L; p < 0.01). The diameters of the basilar artery, vertebral artery, and superior cerebellar artery on Day 7 were significantly decreased to 58.0 ± 10.9%, 71.0 ± 10.1%, and 60.9 ± 13.8%, respectively, of their baseline diameters on Day 1 (p < 0.01). After intracisternal injection of MgSO4, these diameters significantly increased to 73.8 ± 14.3%, 83.0 ± 14.8%, and 74.1 ± 13.5%, respectively (p < 0.01). Conclusions Intracisternal injection of MgSO4 solution causes significant dilation of spastic cerebral arteries in the canine two-hemorrhage model of SAH.

Object The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH). Although most randomized studies have been focused on the effect of the peroral administration of nimodipine, intravenous infusion is an alternative and the preferred mode of treatment in many centers. It is unknown whether the route of administration is of any importance for the clinical efficacy of the drug. Methods One hundred six patients with acute aneurysmal SAH were randomized to receive either peroral or intravenous nimodipine treatment. The patients were monitored for at least 10 days after bleeding in terms of delayed ischemic neurological deficits (DINDs) and with daily measurements of blood flow velocities in the middle cerebral arteries by using transcranial Doppler ultrasonography. Three months after SAH, clinical outcome and new cerebral infarctions according to MR imaging studies were recorded. Results Baseline characteristics (age, sex distribution, clinical status on admission, radiological findings, and aneurysm treatment) did not differ between the treatment groups. There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively). Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging. Conclusions The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH.

ObjectAcute cerebral hypoperfusion and early disturbances in cerebral autoregulation after subarachnoid hemorrhage (SAH) have been demonstrated repeatedly and have been shown to contribute significantly to acute and secondary brain injury. Acute vasoconstriction has been identified as a major contributing factor. Although increasing evidence implicates endothelin (ET)–1 in the development of cerebral vasospasm, its role in the acute phase after SAH has not yet been investigated. The purpose of this study was to further determine the role of ET in the first minutes to hours after massive experimental SAH induced by prophylactic treatment with the ET receptor antagonist clazosentan.MethodsSubarachnoid hemorrhage was induced in 22 anesthetized rats by injection of 0.5-ml arterial, nonheparinized blood into the cisterna magna over the course of 60 seconds. In addition to monitoring intracranial pressure (ICP) and mean arterial blood pressure, laser Doppler flowmetry (LDF) probes were placed stereotactically over the cranial windows to allow online recording of cerebral blood flow (CBF) starting 30 minutes prior to SAH and continuing for 3 hours after SAH. The control group (Group A, 11 rats) received vehicle saline solution via a femoral catheter before SAH, and a second group (Group B, 11 rats) was treated prophylactically with clazosentan, an ETAreceptor antagonist. Treatment was started 30 minutes prior to bolus injection (1 mg/kg body weight), immediately followed by a continuous infusion of 1 mg/kg body weight/hr until the end of the experiment.ResultsInduction of SAH in the rats caused an immediate increase in ICP, which led to an acute decrease in cerebral perfusion pressure (CPP). Perfusion, as measured with LDF, was found to have decreased relative to baseline by 30 ±20% in the control group and 20 ±9% in the clazosentan-treated group. Intracranial pressure and CPP recovered comparably in both groups thereafter within minutes. Control animals demonstrated prolonged hypoperfusion with a loss of autoregulation independent of CPP changes, finally approaching 80% of baseline values toward the end of the experiment. The authors observed that clazosentan did not influence peracute CPP-dependent hypoperfusion, but prevented continuous CBF reduction. Laser Doppler flowmetry perfusion readings remained depressed in control animals at 73 ±19% of baseline in comparison with 106 ±25% of baseline in clazosentan-treated animals (p = 0.001).ConclusionsThe first hours after a massive experimental SAH can be characterized by a CPP-independent compromise in cerebral perfusion. Prophylactic treatment with the ET receptor antagonist clazosentan prevented hypoperfusion. It is known that in the first days after SAH, a reduction in CBF correlates clinically to high-grade SAH. Although research currently focuses on delayed vasospasm, administration of vasoactive drugs in the acute phase of SAH may reverse perfusion deficits and improve patient recovery.

Object The authors previously demonstrated that 17β-estradiol benzoate (E2) treatment prevents subarachnoid hemorrhage (SAH)–induced cerebral vasospasm and preserves endothelial nitric oxide synthase (eNOS) in male rats. Changes in the expression of estrogen receptor (ER) subtypes ERα and -β and their roles in the E2-mediated preservation of eNOS in SAH remain unknown. In the present study the effects of SAH on the expression of ERα and -β in the cerebral arteries were clarified, and the receptor roles in the E2-mediated preservation of eNOS expression in SAH were differentiated. Methods A 2-hemorrhage SAH model was induced by 2 autologous blood injections into the cisterna magna of adult male rats. The effect of SAH on ERα and -β expression was evaluated. Other rats subcutaneously received implanted Silastic tubes containing corn oil with E2 and daily injections of various doses of an ERα- (methyl-piperidinopyrazole [MPP]) or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. The protein levels of ERα, ERβ, eNOS, and inducible nitric oxide synthase (iNOS) from basilar arteries were examined using Western blot analysis, and their mRNAs were evaluated by reverse transcription–polymerase chain reaction. Results The ERα but not the ERβ was upregulated in the basilar artery after SAH. Treatment with MPP eliminated E2-mediated effects in SAH, relieved cerebral vasospasm, preserved eNOS expression, and suppressed iNOS expression. Conclusions Estrogen receptor α is upregulated in the basilar artery after SAH. Note that E2 exerts its protective effects through ERα-dependent pathways to relieve cerebral vasospasm and preserve eNOS expression. A selective ERα agonist may be the drug of choice for the treatment of patients with SAH.

Object The authors of recent publications have suggested that a combination of cisternal irrigation and head-shaking therapy might reduce cerebral vasospasm after subarachnoid hemorrhage (SAH) and therefore improve outcome. The authors undertook this prospective nonrandomized Phase II study to analyze the effect of enhanced washout by lumboventricular irrigation in combination with head motion (lateral rotational therapy) on the clot clearance (CC) rate, development of cerebral vasospasm, and clinical outcome. Methods Forty patients with aneurysmal SAHs of World Federation of Neurosurgical Societies Grades II–V (Glasgow Coma Scale Scores 13–3) and Fisher Grade 3 or 4 were included in this study. The study and control groups each consisted of 20 patients. The protocol in the study group, after the aneurysm was secured and a ventricular drain inserted, included the insertion of 2 lumbar catheters for intrathecal irrigation with Ringer solution and intrathecal pressure monitoring. Moderate head rotation in a kinetic system was also applied and was continued for 5 days. The CC rate was monitored on daily computed tomography (CT) scans. Vasospasms were identified clinically with a focus on delayed ischemic neurological deficits (DINDs), daily transcranial Doppler (TCD) ultrasonography studies, and analysis of infarction rate on CT and cerebral angiography. The data obtained in both groups were statistically evaluated. Results There were no procedure-related complications. The overall CC rate did not differ significantly between the groups, but there was a trend toward accelerated resolution in the study group. During observation, a new neurological deficit developed in 1 patient (5%) in the study group and 4 patients (20%) in the control group. Ischemic areas on CT scans related to vasospasm were demonstrated in 2 patients (10%) in the study group and 6 patients (30%) in the control group. The incidence of angiographic vasospasm was approximately the same in both groups. The pooled TCD flow velocities measured over a period of 14 days showed lower mean values in the study group than in the control group (p = 0.00002). The clinical outcome in the study group as evaluated with the modified Rankin scale was better in the study group than in the control group after 3 (p = 0.008) and 6 (p = 0.005) months. Conclusions The present study demonstrates that a combination of lumboventricular lavage and mechanical head motion reduces vasospasm on TCD ultrasonography, the incidence of DIND, and secondary infarctions on CT and improves clinical outcome. No obvious effect could be found on the rate of angiographic vasospasm.

Object The gap junction is important in the propagation of dilation/constriction signals along vessels for coordinated behavior in control of vascular tone. The authors hypothesized that gap junctions might play a role in cerebral vasospasm following subarachnoid hemorrhage (SAH). The aims of the present study were to investigate the role of gap junctions and to observe the potential therapeutic efficacy of gap junction blockers in cerebral vasospasm in vitro and in vivo. Methods For the in vitro investigation, the effect of heptanol on the oxyhemoglobin (HbO2)-induced contraction of isolated rabbit basilar arteries (BAs) was observed by using an isometric tension-recording method. For the in vivo experiments, the potential therapeutic efficacy of heptanol and carbenoxolone was surveyed after it was given intravenously in the rabbit double-hemorrhage model. Light microscopy was performed to assess the morphological changes in the arteries examined. Results For the in vitro method, heptanol significantly inhibited the sustained contraction induced both by HbO2 and K+ in the BA rings. The magnitude of the heptanol-induced relaxation was dose dependent. The inhibitory effect of heptanol on the K+-induced vasoconstriction was weaker than that on the HbO2-induced constriction. After arterial rings were pretreated for 10 minutes, heptanol significantly decreased their responses to the HbO2-induced contraction. For the in vivo method, heptanol and carbenoxolone significantly decreased the narrowing of BAs when given intravenously in the rabbit double-hemorrhage model. In both treated groups, the diameters of the arteries had not changed significantly on Day 7 compared with those of the arteries in the SAH + vehicle and the SAH-only group. Conclusions Heptanol and carbenoxolone significantly inhibited the experimental cerebral vasospasm both in vitro and in vivo. Blockage of gap junctions is a probable candidate for a new approach in the treatment of cerebral vasospasm. Gap junctions may play a pathophysiological role in cerebral vasospasm.

Object Because oral calcium channel blockers appear to reduce the severity of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), interest in their application intraarterially has emerged for cases in which noninvasive means of alleviating vasospasm are unsuccessful. Studies to date have been limited to the administration of low intraarterial doses because of concerns about hemodynamic stability and changes in intracranial pressure. These doses, although effective in cases of milder vasospasm, were inadequate in severe cases. The authors present a series of 10 patients with cerebral vasospasm who underwent 12 procedures in which they received ≥ 20 mg of intraarterial verapamil per procedure. Methods A retrospective review was undertaken of all patients who underwent endovascular treatment for cerebral vasospasm due to aneurysmal SAH by the senior author between February 2005 and October 2006. Ten patients were identified who had undergone a total of 12 procedures during which ≥20 mg of intraarterial verapamil had been administered. From angiography reports, anesthesia records, and nursing records, we obtained pre- and postverapamil mean arterial blood pressures (MABPs), heart rates, intracranial pressures (ICPs) (when available), and visible changes in the degree of vasospasm. Results No statistically significant changes in MABP, heart rate, or ICP were observed after administration of ≥ 20 mg of intraarterial verapamil, and the degree of improvement in vasospasm was statistically significant based on our grading system. No correlation was found between the change in hemodynamic parameters and the total dose of verapamil. Conclusions This study indicates that high-dose intraarterial verapamil may be used to treat cerebral vasospasm without compromising hemodynamic stability or increasing ICP.

Object The goal in this study was to create an index (vasospasm probability index [VPI]) to improve diagnostic accuracy for vasospasm after subarachnoid hemorrhage (SAH). Methods Seven hundred ninety-five patients in whom aneurysmal SAH was demonstrated by computed tomography, and in whom one or more intracranial aneurysms had been diagnosed, underwent transcranial Doppler (TCD) studies between April 1998 and January 2000. In 154 patients angiography was performed within 24 hours of the TCD examination, and in 75 133Xe cerebral blood flow (CBF) studies were obtained the same day. Seven cases were excluded because of a limited sonographic window. Forty-one women (60.3%) and 27 men (39.7%) between the ages of 35 and 84 years (58.0 ± 13.2 years [mean ± standard deviation]) were included. Clinical characteristics analyzed included age, sex, Hunt and Hess grade, Fisher grade, days after SAH, day of treatment, type of treatment (coil embolization, surgical clip occlusion, or conservative treatment), smoking history, and hypertension history. Lindegaard ratios and spasm indexes (TCD velocities/hemispheric CBF) were calculated bilaterally. Digital subtraction angiography images were measured at specific points of interest. Sensitivity, specificity, predictive values, and global accuracy of the different tests were calculated. Logistic regression was used to evaluate the possible predictive factors, and the coefficients of the logistic regression were integrated to create the VPI. Results In 18 patients (26.5%) symptomatic vasospasm was diagnosed, and 33 (48.5%) had angiographic evidence of vasospasm. For TCD velocities above 120 cm/second at the middle cerebral artery, the global accuracy was 81.1% for the diagnosis of clinical vasospasm and 77.2% for angiographic vasospasm. For a Lindegaard ratio higher than 3.0, the accuracy was 85% for clinical vasospasm and 83.2% for angiographic vasospasm. A spasm index higher than 3.5 had an accuracy of 82.0% for the diagnosis of clinical vasospasm and 81.6% for angiographic vasospasm. The selected model for estimation of clinical vasospasm included Fisher grade, Hunt and Hess grade, and spasm index. The VPI had a global accuracy of 92.9% for clinical vasospasm detection. For diagnosis of angiographic vasospasm, the model included Fisher grade, Hunt and Hess grade, and Lindegaard ratio. The VPI achieved a global accuracy of 89.9% for angiographic vasospasm detection. Conclusions The use of TCD velocities, Lindegaard ratio, and spasm index independently is of limited value for the diagnosis of clinical and angiographic vasospasm. The combination of predictive factors associated with the development of vasospasm in the new index reported here has a significantly superior accuracy compared with the independent tests and may become a valuable tool for the clinician to evaluate the individual probability of cerebral vasospasm after aneurysmal SAH.

✓ A 52-year-old woman developed subarachnoid hemorrhage (SAH) caused by a ruptured right internal carotid artery (ICA) aneurysm. Because of the aneurysm configuration, the authors decided to delay surgery and instead undertook serial imaging studies of the aneurysm. The patient remained alert but developed acute bilateral deafness on Day 7. Audiological examination and auditory brainstem responses suggested that the hearing disturbance was cortical in origin. Three-dimensional computed tomography (CT) angiography showed severe vasospasm in the right middle cerebral artery (MCA) and moderate vasospasm in the left ICA and MCA. Three-tesla magnetic resonance (MR) imaging was performed 2 days after the onset of symptoms. Diffusion-weighted and T2-weighted MR images showed an acute infarction in the right insular cortex caused by vasospasm. Perfusion-weighted MR imaging, particularly mean transit time mapping, revealed hypoperfusion in both temporal lobes including the auditory cortex and right auditory radiation. The vasospasm was treated with induction of mild hypertension and hypervolemia. Follow-up MR images, 3D CT angiograms, and audiometry performed 2 weeks after the first examination showed recovery of vasospasm and resolution of perfusion abnormality and hearing disturbance. On Day 26, the aneurysm was successfully occluded with clips and the patient was discharged with no deficits. To the authors' knowledge, this is the first reported case of reversible cortical auditory dysfunction purely due to bilateral cerebral vasospasm detected using perfusion MR imaging after SAH.