Showing papers by "Werner Hacke published in 2003"

Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): An Adaptive Dose-Response Study of UK-279,276 in Acute Ischemic Stroke

Abstract: Background and Purpose— UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response–finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients. Methods— A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale (ΔSSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo. Results— Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous t...

Imaging-based decision making in thrombolytic therapy for ischemic stroke: present status.

Abstract: Background— Thrombolysis is the treatment of choice for acute stroke within 3 hours after symptom onset. Treatment beyond the 3-hour time window has not been shown to be effective in any single trial; however, meta-analyses suggest a somewhat lesser but still significant effect within 3 to 6 hours after stroke. It seems reasonable to apply improved selection criteria that allow differentiation between patients with and without a relevant indication for thrombolytic therapy. Summary of Review— The present literature on imaging in stroke has been thoroughly reviewed, covering Doppler ultrasound (DU), arteriography, CT, and MRI and including modern techniques such as perfusion CT, diffusion- and perfusion-weighted MRI (DWI, PWI), CT angiography and MR angiography (CTA, MRA), and CTA source image analysis (CTA-SI). The authors present their view of a comprehensive diagnostic approach to acute stroke, which challenges the concept of a rigid therapeutic time window. Conclusions— Information about the presence o...

Stroke MRI in intracerebral hemorrhage: is there a perihemorrhagic penumbra?

Abstract: Background and Purpose— Cerebral ischemia has been proposed as a contributing mechanism to secondary neuronal injury after intracerebral hemorrhage (ICH). The search for surrogate parameters that allow treatment stratification for spontaneous ICH continues. We sought to assess the presence and prognostic effect of perihemorrhagic ischemic changes and hypoperfusion in a prospective stroke MRI study. Methods— We performed stroke MRI in 32 patients with hyperacute ICH (mean, 16.9±17.2 mL) within 6 hours after symptom onset (mean, 3.1±1.3 hours). Clinical data at baseline (National Institutes of Health Stroke Scale) and on day 90 (Barthel Index, modified Rankin Scale) were assessed. Perihemorrhagic perfusion- and diffusion-weighted imaging changes were assessed in a 1-cm-wide area around the clot. Results— Despite a mild perihemorrhagic mean transit time prolongation of 0.7±1.1 second, there were no significant perihemorrhagic apparent diffusion coefficient or mean transit time changes indicating irreversible...

Tolerability of NXY-059 at higher target concentrations in patients with acute stroke.

Abstract: Background and Purpose— NXY-059 is a nitrone-based free radical–trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. Methods— This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. Results— One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39;...

Design of future acute-stroke treatment trials.

Abstract: Summary Very few trials of acute stroke treatments show efficacy of a tested agent on the prespecified primary outcome. We can learn many lessons from the studies that achieve only neutral results. Preclinical studies have been flawed by use of models of transient not permanent brain ischaemia, treatments that aim to protect cerebral grey matter independently of white matter, delivery of the study drug within too short a time window after ischaemic insult, use of surrogate outcome measures in the short term instead of function in the long-term, and small sample sizes. Clinical trials have been hampered by heterogeneity in causes of stroke and inability to classify subtypes of cause; the short time available to rescue ischaemic brain tissue; the haemorrhagic transformation that can cause severe functional consequences seen frequently in infarcted brain tissue; the lack of valid, reliable, sensitive, and simple tools for assessment of functional outcome; and, above all, small treatment effects that are difficult to detect or refute. In this review, we look at the designs and results of all controlled trials of treatments for ischaemic stroke, and try to identify opportunities to improve future treatment assessment.

Surgical decompression of patients with large middle cerebral artery infarcts is effective.

Abstract: Early mortality after acute ischemic stroke is most frequently caused by space-occupying ischemic brain edema. In case of complete middle cerebral artery territory (MCA) infarction, including the basal ganglia, a large space-occupying postischemic edema that finally leads to herniation and brain death may occur. These patients present with almost complete hemiplegia, head- and eye-turning progressive deterioration of consciousness over the first 24 to 48 hours, and a reduced ventilatory drive. Prognosis of large MCA or hemispheric infarctions is poor: in prospective case series, 80% died from herniation despite maximum conservative therapy.1 General measures of treatment of increased intracranial pressure (ICP) after acute ischemic stroke include elevation of the head to a 30-degree angle to improve venous drainage and avoidance of both hyperthermia and hyperglycemia. As part of the specific anti-edematous pharmacological treatment, osmotherapy using glycerol, mannitol, or hyperosmolar saline solutions is used to reduce brain edema. All substances work by means of lowering ICP, but only for a limited time. The same is true for barbiturates, which may reduce critically elevated ICP reading massively, but only …

Evaluation der stentgeschützten Angioplastie zur Therapie von symptomatischen Stenosen der A. carotis

Abstract: During recent years, stent-protected angioplasty of the carotid artery (SPAC) has become an alternative to endartectomy (CEA) in many centers. Despite many case reports, case series, and open records, it has not been proven that these therapeutical regimens are comparable regarding complication rates and long-term outcome. Until now, only three randomized trials were published on this theme, two of them only as abstracts. This is not sufficient for answering the question of whether SPAC is a good alternative to CEA. At present, four major, randomized, multicenter trials are being run (EVA3S in France, CREST in the US, ICSS in Great Britain and several other countries, and SPACE in Germany and Austria). About 7,300 patients will be included in these trials. At present, 24 centers are participating in the SPACE trial, recruiting about 350 patients. It has been prospectively agreed that EVA-3S, ICSS, and SPACE will combine their results after completion of initial randomization and follow-up to conduct a combined European meta-analysis of the data. Three to 5 years are needed until these trials' final results will be published. Until then, stent-protected angioplasty should be done only under the consideration that it has not been scientifically evaluated.

Transcranial oximetry using fast near infrared spectroscopy can detect failure of collateral blood supply in humans

Abstract: We tested the hypothesis that transcranial oximetry by fast scanning near infrared spectroscopy can detect local desaturation of hemoglobin in arterial vessels of cerebral circulation with impaired blood supply. A total of 74 near infrared spectroscopy recordings were taken from the intact skull of humans. Perfusion of the hemisphere under the detector was assessed in one of four groups: (1) healthy volunteer; (2) patient, unaffected side; (3) patient, affected side with intact collateral blood supply; (4) patient, affected side, impaired collateral blood supply. Transcranial saturation was 0.90±0.01 (all values reported as mean±S.E.) in healthy volunteers ( n =24), 0.92±0.008 in the unaffected hemisphere of patients ( n =23), 0.92±0.001 in the affected side if collateral supply with blood was intact ( n =16). There was no statistical significance between these groups. Saturation in affected hemispheres with impaired collateral blood supply ( n =9) was 0.81±0.028, which was significantly different from all other groups ( P

Arterial Pulsations are Present in One Third of the Human Cranial Vascular Volume Penetrated by Near Infrared Light

Abstract: The percentage of cranial vascular volume that undergoes arterial pulsations is estimated by 18 paired measurements in nine healthy volunteers using near infrared spectroscopy (NIRS, 10 Hz sampling frequency, 769 nm). The NIR absorption is decomposed in pulsatile and non-pulsatile components by digital filtering. The time course of absorption changes of these components after sudden intravenous injection of indocyanine-green (ICG) is used to estimate the arterial fraction of vascular volume (f art ). Approximately 28% of the vascular volume within the optical field of the NIR spectroscope was arterial. The range of values was 6 – 43%. Variance of f art was 4.8 times higher between subjects than within subjects, indicating that the variability observed is not due to imprecise estimation but to optode position and subject.