Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Clinical trials for prevention of vasospasm after aneurysmal subarachnoid hemorrhage (SAH) seldom have improved overall outcome; one reason may be inadequate sample size. We used data from the tirilizad trials and the Columbia University subarachnoid hemorrhage outcomes project to estimate sample sizes for clinical trials for reduction of vasospasm after SAH, assuming trials must show effect on 90-day patient-centered outcome. METHODS: Sample size calculations were based on different definitions of vasospasm, enrichment strategies, sensitivity of short- and long-term outcome instruments for reflecting vasospasm-related morbidity, different event rates of vasospasm, calculation of effect size of vasospasm on outcome instruments, and different treatment effect sizes. Sensitivity analysis was performed for variable event rates of vasospasm for a given treatment effect size. Sample size tables were constructed for different rates of vasospasm and outcome instruments for a given treatment effect size. RESULTS: Vasospasm occurred in 12% to 30% of patients. Symptomatic deterioration and infarction from vasospasm exhibited the strongest relationship to mortality and morbidity after SAH. Enriching for vasospasm by selection of patients with thick SAH slightly decreased sample sizes. Assuming beta=0.80, alpha=0.05 (2-tailed) and treatment effect size of 50%, total sample size exceeds 5000 patients to demonstrate efficacy on 3-month patient-centered outcome (modified Rankin Scale). CONCLUSIONS: Clinical trials targeting vasospasm and using traditional patient-centered outcome require very high sample sizes and will therefore be costly, time-consuming, and impractical. This will hinder development of new treatment strategies.

Recent racial/ethnic disparities in stroke hospitalizations and outcomes for young adults in Florida, 2001-2006.

BACKGROUND: Black-white disparities in stroke mortality are well documented, but few recent studies have examined racial/ethnic disparities in stroke hospitalizations among young adults. We analyzed recent (2001-2006) trends in stroke hospitalizations and hospital case-fatality for black, Hispanic, and white adults aged 25-49 years in Florida. METHODS: Hospitalization rates were calculated using population estimates from the census, and hospital discharges with a primary diagnosis of stroke (ICD-9-CM 430, 431, 434, 436) (n = 16,317). Multivariate logistic regression modeling was used to examine racial/ethnic disparities in stroke mortality prior to discharge, after adjustment for patient sociodemographics, stroke subtype, risk factors, and comorbidities. RESULTS: Age-adjusted stroke hospitalization rates for blacks were over 3 times higher than rates for whites, while rates for Hispanics were slightly higher than rates for whites. Hemorrhagic strokes were proportionally greater among Hispanics compared with blacks and whites (p < 0.0001). Blacks were most likely to have diagnosed hypertension (62.3%), morbid obesity (10.9%) or drug abuse (13.6%). Whites were most likely to have diagnosed hyperlipidemia (21.0%), alcohol abuse (9.5%), and to be smokers (30.6%). The in-hospital fatality rate for all strokes was highest among blacks (10.0%) compared with whites (9.0%) and Hispanics (8.2%). After adjustment for age, gender, insurance status, and all diagnosed risk factors and comorbidities, the black excess was no longer observed [odds ratio (OR) 1.01, 95% confidence interval (CI) 0.88-1.15, p = 0.93]. However, the Hispanic advantage in case-fatality was strengthened (OR 0.66, 95% CI 0.55-0.79, p < 0.0001). Separate case-fatality analyses for ischemic versus hemorrhagic strokes yielded similar results. CONCLUSIONS: Our study found a strong and persistent black-white disparity in stroke hospitalization rates for young adults. In contrast, rates were similar for Hispanics and whites. Multivariate adjustment explained the 15% excess case-fatality for blacks; the short-term mortality advantage among Hispanics was strengthened after adjustment.

Advances in transcranial Doppler ultrasonography.

Transcranial Doppler ultrasonography (TCD) is the only noninvasive real-time neuroimaging modality for the evaluation of characteristics of blood flow in basal intracerebral vessels that adds physiologic information to structural imaging. TCD has been rapidly evolving from a simple noninvasive diagnostic tool to an imaging modality with a broad spectrum of clinical applications. In acute stroke, TCD can provide rapid information about vascular stenosis and occlusion, the hemodynamic status of the cerebral circulation, and real-time monitoring of recanalization. Extended applications such as vasomotor reactivity testing, emboli monitoring, and right-to-left shunt detection help clinicians ascertain stroke mechanisms at the bedside, plan and monitor treatment, and determine prognosis. In the neurointensive care unit, TCD is useful for detecting increased intracranial pressure and confirming cerebral circulatory arrest. TCD is of established value for screening children with sickle cell disease and detecting and monitoring vasospasm after spontaneous subarachnoid hemorrhage.

Practice standards for transcranial Doppler ultrasound: part I--test performance.

Indications for the clinical use of transcranial Doppler (TCD) continue to expand while scanning protocols and quality of reporting vary between institutions. Based on literature analysis and extensive personal experience, an international expert panel started the development of guidelines for TCD performance, interpretation, and competence. The first part describes complete diagnostic spectral TCD examination for patients with cerebrovascular diseases. Cranial temporal bone windows are used for the detection of the middle cerebral arteries (MCA), anterior cerebral arteries (ACA), posterior cerebral arteries (PCA), C1 segment of the internal carotid arteries (ICA), and collateralization of flow via the anterior (AComA) and posterior (PComA) communicating arteries; orbital windows-for the ophthalmic artery (OA) and ICA siphon; the foraminal window-for the terminal vertebral (VA) and basilar (BA) arteries. Although there is a significant individual variability of the circle of Willis with and without disease, the complete diagnostic TCD examination should include bilateral assessment of the M2 (arbitrarily located at 30-40 mm depth), M1 (40-65 mm) MCA [with M1 MCA mid-point at 50 mm (range 45-55 mm), average length 16 mm (range 5-24 mm), A1 ACA (60-75 mm), C1 ICA (60-70 mm), P1-P2 PCA (average depth 63 mm (range 55-75 mm), AComA (70-80 mm), PComA (58-65 mm), OA (40-50 mm), ICA siphons (55-65 mm), terminal VA (40-75 mm), proximal (75-80), mid (80-90 mm), and distal (90-110 mm) BA]. The distal ICA on the neck (40-60 mm) can be located via submandibular windows to calculate the VMCA/VICA index, or the Lindegaard ratio for vasospasm grading after subarachnoid hemorrhage. Performance goals of diagnostic TCD are to detect and optimize arterial segment-specific spectral waveforms, determine flow direction, measure cerebral blood flow velocities and flow pulsatility in the above-mentioned arteries. These practice standards will assist laboratory accreditation processes by providing a standard scanning protocol with transducer positioning and orientation, depth selection and vessel identification for ultrasound devices equipped with spectral Doppler and power motion Doppler.

Recommendations of the National Heart, Lung, and Blood Institute working group on cerebrovascular biology and disease.

The National Heart, Lung, and Blood Institute (NHLBI) convened a conference call working group, consisting of experts in stroke and cerebrovascular biology on January 28, 2005. The purpose of this working group was to develop a prioritized set of recommendations for NHLBI to establish a focused and comprehensive set of research activities in cerebrovascular biology and disease. Three thematic areas of research emerged: (1) molecular and cellular neurobiology of cerebral blood vessels, focusing on genomics and proteomics, neurovascular signaling and cerebrovascular embryogenesis, development and plasticity; (2) resource development, involving the development of new methodological approaches for normal and altered function of the neurovascular unit, collaborative research, and training in cerebrovascular pathobiology; and (3) cerebrovascular diseases and translational approaches, addressing vascular mechanisms of disease, the role of risk factors, importance of biomarkers with the ultimate goal of developing new treatments.

Prevention of ischemic neurologic injury with intraoperative monitoring of selected cardiovascular and cerebrovascular procedures: roles of electroencephalography, somatosensory evoked potentials, transcranial Doppler, and near-infrared spectroscopy.

All neuromonitoring techniques, although imperfect, provide useful information for monitoring cardiothoracic and carotid vascular operations. They may be viewed as providing complementary information, which may help surgical technique and, as a result, possibly improve clinical outcomes. As of this writing, the efficacy of TCD and NIRS monitoring during cardiothoracic and vascular surgery cannot be considered established. Well designed, prospective, adequately powered, double-blind, and randomized outcome studies are needed to determine the optimal neurologic monitoring modality (or modalities), in specific surgical settings.

Acquired immunodeficiency syndrome and the risk of stroke.

BACKGROUND AND PURPOSE: Although acquired immunodeficiency syndrome (AIDS) is thought to increase the risk of stroke, few data exist to quantify this risk. This is the first population-based study to quantify the AIDS-associated risk of stroke. METHODS: We identified all incident ischemic stroke (IS) and intracerebral hemorrhage (ICH) cases among young adults 15 to 44 years of age in central Maryland and Washington, DC, who were discharged from any of the 46 hospitals in the study area in 1988 and 1991. Using data from the medical records, 2 neurologists reviewed each case to confirm the diagnosis. Cases of AIDS among these patients with stroke were defined using Centers for Disease Control and Prevention criteria (1987). The number of cases of AIDS in the central Maryland and Washington population during 1988 and 1991 was determined from regional health departments working with the Centers for Disease Control and Prevention. Poisson regression was used to estimate the age-, race-, and sex-adjusted relative risk of stroke associated with AIDS. RESULTS: There were 385 IS cases (6 with AIDS) and 171 ICH cases (6 with AIDS). The incidences of IS and ICH among persons with AIDS were both 0.2% per year. AIDS conferred an adjusted relative risk of 13.7 (95% confidence interval [CI], 6.1 to 30.8) for IS and 25.5 (95% CI, 11.2 to 58.0) for ICH. After exclusion of 5 cases of stroke in AIDS patients in whom other potential causes were identified, AIDS patients continued to have an increased risk of stroke with an adjusted relative risk of 9.1 (95% CI, 3.4 to 24.6) for IS and 12.7 (95% CI, 4.0 to 40.0) for ICH. CONCLUSIONS: This population-based study found that AIDS is strongly associated with both IS and ICH.

Antiphospholipid antibodies and stroke in young women.

BACKGROUND AND PURPOSE: Antiphospholipid antibodies have been associated with ischemic stroke in some but not all studies. METHODS: We performed a population-based case-control study examining antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulants) using stored frozen sera and plasma in 160 cases and 340 controls enrolled in the Stroke Prevention in Young Women study. We evaluated for the presence of anticardiolipin antibody (IgG, IgM, and IgA isotypes) by an enzyme-linked immunosorbent assay and for the lupus anticoagulant using several phospholipid-dependent coagulation tests (activated partial thromboplastin time, dilute Russell's viper venom time) with mixing studies. If mixing studies were prolonged, confirmatory tests were performed. RESULTS: A positive anticardiolipin antibody level of any isotype was seen in 43 cases (26.9%) and 62 controls (18.2%) (P=0.03), lupus anticoagulant in 29 cases (20.9%) and 38 controls (12.8%) (P=0.03), and either anticardiolipin antibody or lupus anticoagulant in 61 cases (42.1%) and 86 controls (27.9%) (P=0.003). After adjustment for age, current cigarette smoking, hypertension, diabetes, angina, ethnicity, body mass index, and high-density lipoprotein levels, the relative odds of stroke for women with anticardiolipin antibody immunoreactivity of any isotype or a lupus anticoagulant was 1.87 (95% confidence interval, 1.24 to 2.83; P=0.0027). CONCLUSIONS: The results from this study support the importance of antiphospholipid antibodies as an independent risk factor for stroke in young women.

Practice standards for transcranial Doppler (TCD) ultrasound. Part II. Clinical indications and expected outcomes.

INTRODUCTION: Transcranial Doppler (TCD) is a physiological ultrasound test with established safety and efficacy. Although imaging devices may be used to depict intracranial flow superimposed on structural visualization, the end-result provided by imaging duplex or nonimaging TCD is sampling physiological flow variables through the spectral waveform assessment. SUMMARY OF RESULTS: Clinical indications considered by this multidisciplinary panel of experts as established are: sickle cell disease, cerebral ischemia, detection of right-to-left shunts (RLS), subarachnoid hemorrhage, brain death, and periprocedural or surgical monitoring. The following TCD-procedures are performed in routine in- and outpatient clinical practice: complete or partial TCD-examination to detect normal, stenosed, or occluded intracranial vessels, collaterals to locate an arterial obstruction and refine carotid-duplex or noninvasive angiographic findings; vasomotor reactivity testing to identify high-risk patients for first-ever or recurrent stroke; emboli detection to detect, localize, and quantify cerebral embolization in real time; RLS-detection in patients with suspected paradoxical embolism or those considered for shunt closure; monitoring of thrombolysis to facilitate recanalization and detect reocclusion; monitoring of endovascular stenting, carotid endarterectomy, and cardiac surgery to detect perioperative embolism, thrombosis, hypo- and hyperperfusion. CONCLUSION: By defining the scope of practice, these standards will assist referring and reporting physicians and third parties involved in the process of requesting, evaluating, and acting upon TCD results.