Focused ultrasound in neuro-oncology: the role of the Focused Ultrasound Foundation in driving adoption and innovation.

The Focused Ultrasound Foundation was created to improve the lives of millions of people worldwide by accelerating the development of this noninvasive technology. The Foundation works to clear the path to global adoption by organizing and funding research, fostering collaboration, and building awareness among patients and professionals. Since its establishment in 2006, the Foundation has become the largest nongovernmental source of funding for focused ultrasound research. For more information, visit http://www.fusfoundation.org .

Thalamic connectivity in patients with essential tremor treated with MR imaging-guided focused ultrasound: in vivo fiber tracking by using diffusion-tensor MR imaging.

PURPOSE: To use diffusion-tensor (DT) magnetic resonance (MR) imaging in patients with essential tremor who were treated with transcranial MR imaging-guided focused ultrasound lesion inducement to identify the structural connectivity of the ventralis intermedius nucleus of the thalamus and determine how DT imaging changes correlated with tremor changes after lesion inducement. MATERIALS AND METHODS: With institutional review board approval, and with prospective informed consent, 15 patients with medication-refractory essential tremor were enrolled in a HIPAA-compliant pilot study and were treated with transcranial MR imaging-guided focused ultrasound surgery targeting the ventralis intermedius nucleus of the thalamus contralateral to their dominant hand. Fourteen patients were ultimately included. DT MR imaging studies at 3.0 T were performed preoperatively and 24 hours, 1 week, 1 month, and 3 months after the procedure. Fractional anisotropy (FA) maps were calculated from the DT imaging data sets for all time points in all patients. Voxels where FA consistently decreased over time were identified, and FA change in these voxels was correlated with clinical changes in tremor over the same period by using Pearson correlation. RESULTS: Ipsilateral brain structures that showed prespecified negative correlation values of FA over time of -0.5 or less included the pre- and postcentral subcortical white matter in the hand knob area; the region of the corticospinal tract in the centrum semiovale, in the posterior limb of the internal capsule, and in the cerebral peduncle; the thalamus; the region of the red nucleus; the location of the central tegmental tract; and the region of the inferior olive. The contralateral middle cerebellar peduncle and bilateral portions of the superior vermis also showed persistent decrease in FA over time. There was strong correlation between decrease in FA and clinical improvement in hand tremor 3 months after lesion inducement (P < .001). CONCLUSION: DT MR imaging after MR imaging-guided focused ultrasound thalamotomy depicts changes in specific brain structures. The magnitude of the DT imaging changes after thalamic lesion inducement correlates with the degree of clinical improvement in essential tremor.

Potential of magnetic resonance-guided focused ultrasound for intracranial hemorrhage: an in vivo feasibility study.

BACKGROUND: Because of the paucity of effective treatments for intracranial hemorrhage (ICH), the mortality rate remains at 40%-60%. A novel application of magnetic resonance-guided focused ultrasound (MRgFUS) for ICH may offer an alternative noninvasive treatment through the precise delivery of FUS under real-time MR imaging (MRI) guidance. The purpose of the present study was to optimize the parameters for rapid, effective, and safe trans-skull large clot liquefaction using in vivo porcine and ex vivo human skull models to provide a clinically relevant proof of concept. METHODS: The transcranial effectiveness of MRgFUS was tested ex vivo by introducing a porcine blood clot into a human skull, without introducing tissue plasminogen activator (tPA). We used an experimental human head device to deliver pulsed FUS sonications at an acoustic power of 600-900 W for 5-10 seconds. A 3-mL clot was also introduced in a porcine brain and sonicated in vivo with one 5-second pulse of 700 W through a bone window or with 3000 W when treated through an ex vivo human skull. Treatment targeting was guided by MRI, and the tissue temperature was monitored online. Liquefied volumes were measured as hyperintense regions on T2-weighted MR images. RESULTS: In both in vivo porcine blood clot through a craniectomy model and the porcine clot in an ex vivo human skull model targeted clot liquefaction was achieved, with only marginal increase in temperature in the surrounding tissue. CONCLUSIONS: Our results demonstrate the feasibility of fast, efficient, and safe thrombolysis in an in vivo porcine model of ICH and in 2 ex vivo models using a human skull, without introducing tPA. Future studies will further optimize parameters and assess the nature of sonication-mediated versus natural clot lysis, the risk of rebleeding, the potential effect on the adjacent parenchyma, and the chemical and toxicity profiles of resulting lysate particles.

Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2).

We report here results of a randomized, double-blind, placebo-controlled study ( http://www.ClinicalTrials.gov , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.

Transcranial MR-guided focused ultrasound sonothrombolysis in the treatment of intracerebral hemorrhage.

Intracerebral hemorrhage remains a significant cause of morbidity and mortality. Current surgical therapies aim to use a minimally invasive approach to remove as much of the clot as possible without causing undue disruption to surrounding neural structures. Transcranial MR-guided focused ultrasound (MRgFUS) surgery is an emerging technology that permits a highly concentrated focal point of ultrasound energy to be deposited to a target deep within the brain without an incision or craniotomy. With appropriate ultrasound parameters it has been shown that MRgFUS can effectively liquefy large-volume blood clots through the human calvaria. In this review the authors discuss the rationale for using MRgFUS to noninvasively liquefy intracerebral hemorrhage (ICH), thereby permitting minimally invasive aspiration of the liquefied clot via a small drainage tube. The mechanism of action of MRgFUS sonothrombolysis; current investigational work with in vitro, in vivo, and cadaveric models of ICH; and the potential clinical application of this disruptive technology for the treatment of ICH are discussed.

Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling.

BACKGROUND AND PURPOSE: Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling. METHODS: This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ≤ 14 days intravenous clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12). RESULTS: CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; clazosentan 5 mg/h, n=194; clazosentan 15 mg/h, n=188). The primary end point occurred in 50/189 of placebo-treated patients (27%), compared with 47/194 patients (24%) treated with clazosentan 5 mg/h (odds ratio [OR], 0.786; 95% CI, 0.479-1.289; P=0.340), and 28/188 patients (15%) treated with clazosentan 15 mg/h (OR, 0.474; 95% CI, 0.275-0.818; P=0.007). Poor outcome (extended Glasgow Outcome Scale score ≤ 4) occurred in 24% of patients with placebo, 25% of patients with clazosentan 5 mg/h (OR, 0.918; 95% CI, 0.546-1.544; P=0.748), and 28% of patients with clazosentan 15 mg/h (OR, 1.337; 95% CI, 0.802-2.227; P=0.266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan than in those who received placebo. At week 12, mortality was 6%, 4%, and 6% with placebo, clazosentan 5 mg/h, and clazosentan 15 mg/h, respectively. CONCLUSIONS: Clazosentan 15 mg/h significantly reduced postaSAH vasospasm-related morbidity/all-cause mortality; however, neither dose improved outcome (extended Glasgow Outcome Scale).

Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The long-standing concept that delayed cerebral infarction after aneurysmal subarachnoid hemorrhage results exclusively from large artery vasospasm recently has been challenged. We used data from the CONSCIOUS-1 trial to determine the relationship between angiographic vasospasm and cerebral infarction after subarachnoid hemorrhage. METHODS: We performed a post hoc exploratory analysis of the CONSCIOUS-1 data. All patients underwent catheter angiography before treatment and 9±2 days after subarachnoid hemorrhage. CT was performed before and after aneurysm treatment, and 6 weeks after subarachnoid hemorrhage. Angiograms and CT scans were assessed by centralized blinded review. Angiographic vasospasm was classified as none/mild (0%-33% decrease in arterial diameter), moderate (34%-66%), or severe (≥67%). Infarctions were categorized as secondary to angiographic vasospasm, other, or unknown causes. Logistic regression was conducted to determine factors associated with infarction. RESULTS: Complete data were available for 381 of 413 patients (92%). Angiographic vasospasm was none/mild in 209 (55%) patients, moderate in 118 (31%), and severe in 54 (14%). Infarcts developed in 6 (3%) of 209 with no/mild, 12 (10%) of 118 patients with moderate, and 25 (46%) of 54 patients with severe vasospasm. Multivariate analysis found a strong association between angiographic vasospasm and cerebral infarction (OR, 9.3; 95% CI, 3.7-23.4). The significant association persisted after adjusting for admission neurological grade and aneurysm size. Method of aneurysm treatment was not associated with a significant difference in frequency of infarction. CONCLUSIONS: A strong association exists between angiographic vasospasm and cerebral infarction. Efforts directed at further reducing angiographic vasospasm are warranted.

Endovascular treatment or neurosurgical clipping of ruptured intracranial aneurysms: effect on angiographic vasospasm, delayed ischemic neurological deficit, cerebral infarction, and clinical outcome.

BACKGROUND AND PURPOSE: The effects of aneurysm treatment modality (clipping or coiling) on the incidence of cerebral vasospasm and infarction after subarachnoid hemorrhage have not been clearly defined. We hypothesized that there may be a difference in angiographic and clinical vasospasm, cerebral infarction, and clinical outcome between patients undergoing clipping compared to coiling. METHODS: A retrospective, exploratory analysis of 413 patients randomized into the CONSCIOUS-1 trial was conducted. Patients underwent baseline and follow-up catheter angiography and computed tomography, as well as clinical assessments. Radiology end points were adjudicated by central blinded review, and angiographic vasospasm was quantified by measurements of arterial diameters on catheter angiography. The effect of method of aneurysm treatment (clipping [n=199] or coiling [n=214]) on angiographic vasospasm, delayed ischemic neurological deficit, cerebral infarction, and clinical outcome was analyzed using univariate and multivariate logistic regression. Propensity matching was used to adjust for differences in baseline risk factors between clipped and coiled patients. RESULTS: In all patients and the propensity-matched subset, aneurysm coiling was associated with a significantly reduced risk of angiographic vasospasm and delayed ischemic neurological deficit compared to clipping. Cerebral infarction and clinical outcome were not associated with clipping or coiling. CONCLUSIONS: In this exploratory analysis, aneurysm coiling was associated with less angiographic vasospasm and delayed ischemic neurological deficit than surgical clipping, whereas no effect on cerebral infarction or clinical outcome was observed. Whether this is attributable to differences in baseline risk factors between clipped and coiled patients or a true difference cannot be proven here.

Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials.

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18-75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.

Impact of systemic inflammatory response syndrome on vasospasm, cerebral infarction, and outcome after subarachnoid hemorrhage: exploratory analysis of CONSCIOUS-1 database.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) may develop after aneurysmal subarachnoid hemorrhage (SAH). We investigated factors associated with SIRS after SAH, whether SIRS was associated with complications of SAH such as vasospasm, cerebral infarction, and clinical outcome, and whether SIRS could contribute to a difference in outcome between patients treated by endovascular coiling or neurosurgical clipping of the ruptured aneurysm. METHODS: This was exploratory analysis of 413 patients in the CONSCIOUS-1 study. SIRS was diagnosed if the patient had at least 2 of 4 variables (hypothermia/fever, tachycardia, tachypnea, and leukocytosis/leukopenia) within 4 days of admission. Clinical outcome was measured on the Glasgow outcome scale 3 months after SAH. The relationship between clinical and radiologic variables and SIRS, angiographic vasospasm, delayed ischemic neurologic deficit (DIND), cerebral infarction, vasospasm-related infarction, and clinical outcome were modeled with uni- and multivariable analyses. RESULTS: 63% of patients developed SIRS. Many factors were associated with SIRS in univariate analysis, but only poor WFNS grade and pneumonia were independently associated with SIRS in multivariable analysis. SIRS burden (number of SIRS variables per day over the first 4 days) was associated with poor outcome, but not with angiographic vasospasm, DIND, or cerebral infarction. The method of aneurysm treatment was not associated with SIRS. CONCLUSION: SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Influence of weekend hospital admission on short-term mortality after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: There is expanding literature to show that certain patients admitted during the weekend have worse outcomes than similar patients admitted during the week. Although many clinicians have hypothesized the presence of this "weekend effect" with patients with intracerebral hemorrhage, there is a paucity of studies validating this conjecture. METHODS: We performed a retrospective cohort study of patients with intracerebral hemorrhage (International Classification of Diseases, 9th Revision, Clinical Modification=431) extracted from the 2004 Nationwide Inpatient Sample. Multivariable logistic regression analyses and Cox proportional hazards regression were conducted to calculate the odds of death (within 7, 14, and 30 days) and the hazard ratio of death for patients with weekend intracerebral hemorrhage admissions compared with weekday intracerebral hemorrhage admissions. All analyses were adjusted for concurrent differences in length of stay, patient demographics, and comorbid disease. RESULTS: Weekend hospital admissions accounted for 26.8% of the 13 821 patients with a diagnosis of intracerebral hemorrhage in the National Inpatient Sample. Admission during the weekend was a statistically significant independent predictor of death within 7 days (OR, 1.14; 95% CI, 1.05 to 1.25), within 14 days (OR, 1.15; 95% CI, 1.05 to 1.25), and within 30 days (OR, 1.15; 95% CI, 1.05 to 1.25). The adjusted hazard of in-hospital death (hazard ratio, 1.12; CI, 1.05 to 1.20) indicates that the overall risk of in-hospital death with intracerebral hemorrhage is 12% higher with weekend admission. CONCLUSIONS: Weekend admission for intracerebral hemorrhage was associated with increased risk-adjusted mortality when compared with admission during the remainder of the week.

Strict glucose control does not affect mortality after aneurysmal subarachnoid hemorrhage.

BACKGROUND: The effects of both hyperglycemia and hypoglycemia are deleterious to patients with neurologic injury. METHODS: On January 1, 2002, the neurointensive care unit at the University of Virginia Health System initiated a strict glucose control protocol (goal glucose < 120 mg/dl). The authors conducted an impact study to determine the effects of this protocol on patients presenting with aneurysmal subarachnoid hemorrhage. RESULTS: Among the 834 patients admitted between 1995 and 2007, the in-hospital mortality was 11.6%. The median admission glucose for survivors was lower (135 vs. 176 mg/dl); however, on multivariate analysis, increasing admission glucose was not associated with a statistically significant increase in the risk of death (P = 0.064). The median average glucose for survivors was also lower (116 vs. 135 mg/dl). This was significant on multivariate analysis (P < 0.001); however, the effect was small (odds ratio, 1.045). Implementation of the strict glucose protocol decreased median average glucose (121 vs. 116 mg/dl, P < 0.001) and decreased the incidence of hyperglycemia. Implementation of the protocol had no effect on in-hospital mortality (11.7% vs. 12.0%, P = 0.876 [univariate], P = 0.132 [multivariate]). Protocol implementation was associated with an increased incidence of hypoglycemia (P < 0.001). Hypoglycemia was associated with a substantially increased risk of death on multivariate analysis (P = 0.009; odds ratio = 3.818). CONCLUSIONS: The initiation of a tight glucose control regimen lowered average glucose levels but had no effect on overall in-hospital mortality.

Influence of weekend versus weekday hospital admission on mortality following subarachnoid hemorrhage. Clinical article.

OBJECT: Several studies have indicated that short-term mortality risk is higher among patients who are admitted on the weekends. This "weekend effect" has been observed among patients admitted with a variety of diagnoses, including myocardial infarction, pulmonary embolism, ruptured abdominal aortic aneurysm, and stroke. This study examines the relationship between short-term mortality risk and weekend admission among patients hospitalized following subarachnoid hemorrhage (SAH). METHODS: This retrospective cohort study examines mortality outcomes among patients included in the Nationwide Inpatient Sample (NIS) for 2004. Patients included in the cohort were identified using the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code for SAH. Multivariable logistic regression analyses and Cox proportional hazard regression analyses are used to measure the association of weekend admission on mortality for patients with SAH, adjusted for differences in patient characteristics that also contribute to mortality risk. RESULTS: Weekend admissions occurred among 27.5% of the 5667 patients with SAH in the NIS database. Weekend admission was not a statistically significant independent predictor of death in the SAH study population at 7 days (OR 1.07, 95% CI 0.91-1.25), 14 days (OR 1.01, 95% CI 0.87-1.17), or 30 days (OR 1.03, 95% CI 0.89-1.19). CONCLUSIONS: Weekend admission is not associated with significantly increased short-term mortality risk among patients hospitalized with SAH.

Attenuation of cerebral vasospasm and secondary injury by 17beta-estradiol following experimental subarachnoid hemorrhage.

OBJECT: Cerebral vasospasm remains a major complication in patients who have suffered a subarachnoid hemorrhage (SAH). Previous studies have shown that 17beta-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.

Applications of Focused Ultrasound in Cerebrovascular Diseases and Brain Tumors.

Oncology and cerebrovascular disease constitute two of the most common diseases afflicting the central nervous system. Standard of treatment of these pathologies is based on multidisciplinary approaches encompassing combination of interventional procedures such as open and endovascular surgeries, drugs (chemotherapies, anti-coagulants, anti-platelet therapies, thrombolytics), and radiation therapies. In this context, therapeutic ultrasound could represent a novel diagnostic/therapeutic in the armamentarium of the surgeon to treat these diseases. Ultrasound relies on mechanical energy to induce numerous physical and biological effects. The application of this technology in neurology has been limited due to the challenges with penetrating the skull, thus limiting a prompt translation as has been seen in treating pathologies in other organs, such as breast and abdomen. Thanks to pivotal adjuncts such as multiconvergent transducers, magnetic resonance imaging (MRI) guidance, MRI thermometry, implantable transducers, and acoustic windows, focused ultrasound (FUS) is ready for prime-time applications in oncology and cerebrovascular neurology. In this review, we analyze the evolution of FUS from the beginning in 1950s to current state-of-the-art. We provide an overall picture of actual and future applications of FUS in oncology and cerebrovascular neurology reporting for each application the principal existing evidences.

New insights into the causes and therapy of cerebral vasospasm following subarachnoid hemorrhage.

Cerebral vasospasm lingers as the leading preventable cause of death and disability in patients who experience aneurysmal subarachnoid hemorrhage. Despite the potentially devastating consequences of cerebral vasospasm, the mechanisms behind it are incompletely understood. Nitric oxide, endothelin-1, bilirubin oxidation products and inflammation appear to figure prominently in its pathogenesis. Therapies directed at many of these mechanisms are currently under investigation and hold significant promise for an ultimate solution to this substantial problem.

Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial.

BACKGROUND AND PURPOSE: This randomized, double-blind, placebo-controlled, dose-finding study assessed efficacy and safety of 1, 5, and 15 mg/h intravenous clazosentan, an endothelin receptor antagonist, in preventing vasospasm after aneurysmal subarachnoid hemorrhage. METHODS: Patients (n=413) were randomized to placebo or clazosentan beginning within 56 hours and continued up to 14 days after initiation of treatment. The primary end point was moderate or severe angiographic vasospasm based on centrally read, blinded evaluation of digital subtraction angiography at baseline and 7 to 11 days postsubarachnoid hemorrhage. A morbidity/mortality end point, including all-cause mortality, new cerebral infarct from any cause, delayed ischemic neurological deficit due to vasospasm, or use of rescue therapy, was evaluated by local assessment. Clinical outcome was assessed by the extended Glasgow Outcome Scale at 12 weeks. RESULTS: Moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15 mg/h clazosentan group (risk reduction, 65%; 95% CI, 47% to 78%; P<0.0001). No significant effects were seen on secondary end points. Post hoc analysis using a centrally assessed morbidity/mortality end point that included death and rescue therapy but only cerebral infarcts and delayed ischemic neurological deficit due to vasospasm on central review showed a trend toward improvement with clazosentan (37%, 28%, and 29% in the 1, 5, and 15 mg/h groups versus 39% in the placebo group, nonsignificant). Clazosentan was associated with increased rates of pulmonary complications, hypotension, and anemia. CONCLUSIONS: Clazosentan significantly decreased moderate and severe vasospasm in a dose-dependent manner and showed a trend for reduction in vasospasm-related morbidity/mortality in patients with aneurysmal subarachnoid hemorrhage when centrally assessed. Overall, the adverse effects were manageable and not considered serious.

Complications associated with anemia and blood transfusion in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Patients with subarachnoid hemorrhage (SAH) frequently develop delayed cerebral ischemia and may be especially vulnerable to the effects of anemia. However, the potentially harmful effects of allogeneic red blood cells are increasingly being recognized. The optimal transfusion threshold is unknown, but current practice most often uses a liberal approach. We assessed the association between anemia or transfusion and subsequent adverse outcomes. DESIGN: Retrospective cohort study. SETTING: Neuroscience intensive care unit of a university hospital. PATIENTS: A total of 245 consecutive patients with aneurysmal SAH. INTERVENTIONS: None. MEASUREMENTS: Logistic regression models were used to adjust for baseline differences in age, severity of neurologic impairment, and amount of blood on computed tomography. Patients were dichotomized based on whether symptomatic vasospasm was diagnosed. MAIN RESULTS: Individually, anemia (nadir hemoglobin <10 g/dL) and the use of transfusions were both associated with the combined outcome of death, severe disability, or delayed infarction (odds ratio [OR] for anemia, 2.7; 95% confidence interval [CI] 1.5-5; p < .01; OR for transfusion, 4.8; 95% CI, 2.5-9.1; p < .01). When both variables were together introduced into a logistic regression model, only transfusion remained significantly predictive (OR, 4.3; 95% CI, 1.5-9.3; p < .01). The relationship between anemia and adverse outcomes was stronger among patients diagnosed with vasospasm, whereas for transfusion, it was stronger among patients without vasospasm. Transfusion also was associated with the development of nosocomial infections (OR, 3.2; 95% CI, 1.7-5.5; p < .01). There was no statistically significant difference in complications based on the duration of blood storage before transfusion. CONCLUSIONS: Although anemia is predictive of adverse outcomes in patients with SAH, this observation cannot be considered justification for a liberal transfusion strategy. Appropriate transfusion thresholds may vary depending on the presence or absence of clinical vasospasm. Randomized trials that compare liberal and restrictive transfusion strategies in patients with SAH are needed.