Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results.

BACKGROUND AND PURPOSE: A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study. METHODS: A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index > or =60 at last follow-up as the primary outcome measure. RESULTS: The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9+/-5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of > or =60 was 42% in the clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P=0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early (<6 hours) and in those treated later (6 to 12 hours). Somnolence was an expected pharmacological effect of clomethiazole, and this occurred during treatment as an adverse event in half of the patients randomly assigned to study drug. CONCLUSIONS: The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.

Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial.

CONTEXT: Approved treatment options for acute ischemic stroke in the United States and Canada are limited at present to intravenous tissue-type plasminogen activator, but bleeding complications, including intracranial hemorrhage, are a recognized complication. OBJECTIVE: To evaluate the efficacy and safety of the defibrinogenating agent ancrod in patients with acute ischemic stroke. DESIGN: The Stroke Treatment with Ancrod Trial (STAT), a randomized, parallel-group, double-blind, placebo-controlled trial conducted between August 1993 and January 1998. SETTING: Forty-eight centers, primarily community hospitals, in the United States and Canada. PATIENTS: A total of 500 patients with an acute or progressing ischemic neurological deficit were enrolled and included in the intent-to-treat analysis. INTERVENTIONS: Patients were randomly assigned to receive ancrod (n=248) or placebo (n =252) as a continuous 72-hour intravenous infusion beginning within 3 hours of stroke onset, followed by infusions lasting approximately 1 hour at 96 and 120 hours. The ancrod regimen was designed to decrease plasma fibrinogen levels to 1.18 to 2.03 micromol/L. MAIN OUTCOME MEASURES: The primary efficacy end point was functional status, with favorable functional status defined as survival to day 90 with a Barthel Index of 95 or more or at least the prestroke value, compared by treatment group. Primary safety variables included symptomatic intracranial hemorrhage and mortality. RESULTS: Favorable functional status was achieved by more patients in the ancrod group (42.2%) than in the placebo group (34.4%; P=.04) by the prespecified covariate-adjusted analysis. Mortality was not different between treatment groups (at 90 days, 25.4% for the ancrod group and 23% for the placebo group; P=.62), and the proportion of severely disabled patients was less in the ancrod group than in the placebo group (11.8% vs 19.8%; P=.01). The favorable functional status observed with ancrod vs placebo was consistent in all subgroups defined for age, stroke severity, sex, prestroke disability, and time to treatment (< or = 3 or > 3 hours after stroke onset). There was a trend toward more symptomatic intracranial hemorrhages in the ancrod group vs placebo (5.2% vs 2.0%; P=.06), as well as a significant increase in asymptomatic intracranial hemorrhages (19.0% vs 10.7%; P=.01). CONCLUSION: In this study, ancrod had a favorable benefit-risk profile for patients with acute ischemic stroke.

Acute ischemic stroke management.

The use of thrombolytic therapy represents one of many recent developments in the management of acute ischemic stroke. The development of stroke teams and protocols has been driven by these new demands for an urgent response to ischemic stroke. The short time window of 3 hours for therapy with intravenous recombinant tissue plasminogen activator requires efficient evaluation and treatment of stroke patients and also necessitates a rigorous approach to blood pressure management, electrolytes, fluids, and temperature. Anticoagulation has not been proven to safely prevent progression or early recurrence of stroke, but antiplatelet therapy is worthwhile.

Can emergency department physicians safely and effectively initiate thrombolysis for acute ischemic stroke?

OBJECTIVE: To review the clinical outcomes of stroke patients treated with IV tissue plasminogen activator (tPA; alteplase) in a community setting and to compare outcomes when treatment was initiated by a neurologist or an emergency department (ED) physician in telephone consultation with a neurologist and radiologist. METHODS: Clinical information was prospectively collected for 43 stroke patients treated with IV tPA (alteplase) within a five-hospital network of affiliated community hospitals. Blinded 3-month outcomes were obtained with telephone interview or patient visit. RESULTS: Excellent functional recovery measured by a Modified Rankin score of 0 to 1 (42%), symptomatic intracerebral hemorrhages (7%), and mortality (16.3%) were similar to those reported by National Institute of Neurological Disorders and Stroke (39%, 7.7%, 17.3%). After initial screening by an ED physician, 20 patients were directly examined by a stroke neurologist who then prescribed tPA. Twenty-three patients received tPA prescribed by an ED physician after telephone consultation with a neurologist and review of the head CT by a radiologist. Functional outcome, symptomatic intracerebral bleeding rate, and mortality rate were similar between these groups. Door-to-needle time was similar. Protocol deviations were much higher when ED physicians prescribed the tPA compared to when neurologists did (30% versus 5%). These protocol deviations were reduced with staff education. CONCLUSIONS: The clinical results of the National Institute of Neurological Disorders and Stroke tPA Stroke Trial were replicated in this small series of patients treated in a community setting. Outcomes were similar whether the prescribing physician was a neurologist or an ED physician.

Acute stroke medical management.

The average length of hospital stay for acute stroke has been declining gradually in the United States. Medical care traditionally given in the acute setting often is continued in a rehabilitation unit or skilled nursing facility. This article outlines the necessary knowledge base for specialists in rehabilitation regarding acute stroke medical care and management.

Dose escalation study of the NMDA glycine-site antagonist licostinel in acute ischemic stroke.

BACKGROUND AND PURPOSE: Licostinel (ACEA 1021; 5-nitro-6, 7-dichloro-2,3-quinoxalinedione), a competitive antagonist of glycine at the N-methyl-D-aspartate (NMDA) receptor, is an effective neuroprotective agent in animal models of cerebral ischemia. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of licostinel in patients with acute stroke. METHODS: In this 5-center dose escalation trial, patients were enrolled within 48 hours of an ischemic stroke and treated with ascending doses of a short infusion of licostinel or a placebo. Adverse effects were assessed with clinical and laboratory measurements, and patient outcome was determined with the National Institutes of Health Stroke Scale. RESULTS: Sixty-four patients (44 treated with escalating doses of licostinel and 20 who received placebo) were treated. Lower doses of licostinel (0.03 to 0.60 mg/kg) were not associated with any significant adverse effects. Higher doses of licostinel (1.2 to 3.0 mg/kg) were associated with a variety of mild-to-moderate adverse effects including neurological and gastrointestinal complaints. No major psychotomimetic effects or significant safety concerns occurred. At the higher dose levels, peak plasma concentrations of licostinel were substantially higher than those required for neuroprotection in animal stroke models. A similar improvement in National Institutes of Health Stroke Scale scores over time was seen in both the placebo group and the licostinel-treated patients. CONCLUSIONS: A short infusion of licostinel in doses up to 3.0 mg/kg is safe and tolerable in acute stroke patients. Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists.

Rabies in Zimbabwe: reservoir dogs and the implications for disease control.

Using detailed field study observations of the side-striped jackal (Canis adustus) and a simple stochastic model of the transmission dynamics of the virus and host demography, we discuss the epidemiology of rabies virus infection in the jackal population of Zimbabwe. Of the two jackal species in Zimbabwe, the other being the black-backed jackal (Canis mesomelas), the bulk of notified rabies cases are in side-striped jackals. Specifically, we show that the side-striped jackal population itself does not seem able to support rabies infection endemically, i.e. without frequent reintroduction from outside sources of infection. We argue that this is probably because the overall average jackal population density is too low to maintain the chain of infection. This study suggests that the disease is regularly introduced to jackals by rabid dogs from populations associated with human settlements. Given the rapidly rising dog population in Zimbabwe, estimates are derived of the future incidence of jackal rabies based on different dog-vaccination scenarios.

Ancrod in the treatment of acute ischaemic stroke.

Ancrod converts fibrinogen into soluble fibrin products, resulting in a decrease in plasma fibrinogen and blood viscosity, and also induces the release of endogenous tissue-type plasminogen activator from the vessel wall. These activities suggest that treating patients with acute ischaemic stroke with ancrod might result in improved cerebral blood flow and patient outcome. Two large randomised placebo-controlled studies have evaluated treatment with ancrod in patients with acute ischaemic stroke. In the first, patients were treated within 6 hours of symptom onset: this was not successful in quickly lowering fibrinogen levels to the target range (0.7 to 1.0 g/L) and the results were inconclusive. However, a post hoc analysis suggested that treatment with ancrod was effective in patients whose fibrinogen level was reduced to less than 1.3 g/L within 6 hours of starting treatment. A second larger study is still in progress, but preliminary results in patients treated within 3 hours of onset of ischaemic stroke are available and indicate that the target fibrinogen level of less than 1 g/L within 6 hours of instituting treatment is being achieved in most patients.

Implementation of an acute stroke program decreases hospitalization costs and length of stay.

BACKGROUND AND PURPOSE: A large community hospital implemented an acute stroke program to respond to stroke patients in a consistent, systematic, and efficient manner. The primary objectives were to monitor the care delivered, improve the quality of care, and move the patients through their initial hospital stay in a timely manner. METHODS: Acute stroke standing orders were developed, with a critical path developed on the basis of these orders and an expected length of stay. A multidisciplinary team began the rehabilitation process early in the hospital stay, monitored patient progress and length of stay, and provided appropriate discharge placement. Retrospective chart reviews were performed over a 4-year period, and the data were collated on a yearly basis. RESULTS: Over a 4-year period, 414 Medicare patients demonstrated a steady decline of initial hospital length of stay from 7.0 to 4.6 days. During this same period of time, there was a decline in total hospital charges from $14,076 to $10,740 per patient. This represented a total dollar savings in charges of $1,621,296 (approximately $453,000 per year). The mortality rate for 1994 was 4.6%, with 46.5% of survivors discharged to home, 16.9% to acute rehabilitation, and 32.6% to nursing homes. CONCLUSIONS: The implementation of a multidisciplinary acute stroke program decreased length of stay and hospitalization costs of Medicare patients.

Spatial and temporal patterns in the activity of European moles.

Using ratio-tracking data obtained at three sites, we assessed the effects of season and of neighbour avoidance on the activity and patterns of home range use by European moles (Talpa europaea). The home ranges of non-breeding male and female moles did not differ significantly in size, and averaged 2324 m2 (minimum convex polygon). Although overlap between ranges was small (an average of 12.8% of each range being shared with neighbours and an average of only 3.3% of 2×2 m grid cells were shared with an individual neighbour, ranges were not oriented to avoid neighbours. Non-breeding male/female neighbours tended to share more of their grid cells (3.9±5.7%) mean ±SD than did neighbours of the same sex (male:male 1.2±0.95%; female:female 1.1±1.3%), but there was no significant difference in overlap between any combination of sex pairings. On average, each mole spent only 0.9% of its time within 6 m of another mole, and only 3 out of 46 dyads showed evidence of being attracted to each other; there was no evidence from the simultaneous movement patterns of neighbouring moles that they avoided each other. Although moles tended to return to the same part of their range at the same time on successive days, there was also some indication of gradual changes in the spatial pattern of daily home range use. Moles had a triphasic pattern of activity, but this became tetraphasic under drought conditions. There were significant differences between sites, but not between sexes, in sleeping behaviour and activity patterns. These differences could be related to seasonal differences in soil moisture and thus probably to prey renewal rates. We conclude that in our sites, the activity patterns and movements of moles depend on the temporal and spatial dispersion of food, rather than on short-term interactions between the movements of neighbours.

Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group.

BACKGROUND AND PURPOSE: Dextrorphan hydrochloride is a noncompetitive N-methyl-D-aspartate antagonist that is neuroprotective in experimental models of focal brain ischemia. The purpose of this study was to determine the maximum loading dose and maintenance infusion of dextrorphan hydrochloride that are well tolerated in patients with an acute stroke. METHODS: An intravenous infusion of dextrorphan or placebo was begun within 48 hours of onset of a mild-to-moderate hemispheric stroke. Initially, patients were treated with either placebo (n = 15) or dextrorphan (n = 22) using a 1-hour loading dose (60 to 150 mg) followed by a 23-hour ascending-dose maintenance infusion (maximum total dose, 3310 mg). Subsequently, 29 patients were treated with dextrorphan in an open trial using a 1-hour loading dose (145 to 260 mg) followed by an 11-hour constant rate (30 to 70 mg/h) infusion. RESULTS: Transient and reversible adverse effects, including nystagmus, nausea, vomiting, somnolence, hallucinations, and agitation, commonly occurred in dextrorphan-treated patients. Loading-dose escalation was stopped because of rapid-onset, reversible, symptomatic hypotension in 7 of 21 patients treated with doses of 200 to 260 mg/h. At the highest rates of maintenance infusion (> 90 mg/h), 3 patients developed deep stupor or apnea. The maximum tolerated loading dose was 180 mg/h, and the maximum tolerated maintenance infusion was 70 mg/h. Maximum plasma levels of 750 to 1000 ng/mL were obtained in 9 patients. There was no difference in neurological outcome at 48 hours between the dextrorphan-treated and placebo-treated patients. CONCLUSIONS: The highest doses of dextrorphan administered were associated with serious adverse experiences in some patients. Lower doses (loading doses of 145 to 180 mg, maintenance infusions of 50 to 70 mg/h) were better tolerated and rapidly produced potentially neuroprotective plasma concentrations of dextrorphan. These doses were associated with well-defined pharmacological effects compatible with N-methyl-D-aspartate receptor antagonism.

Relationships of hypnotic susceptibility to paranormal beliefs and claimed experiences: implications for hypnotic absorption.

This study examined the relationships of hypnotic susceptibility level to belief in and claimed experience with paranormal phenomena. The Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A) and the Inventory of Paranormal Beliefs and Experiences were administered on consecutive days to 43 undergraduate students (14 men, 29 women) at a midwestern university. A significant multiple correlation was obtained (r = .55, p < .001). A partial correlation between hypnotic susceptibility and belief in paranormal phenomena was also significant (r = .53, p < .001), while hypnotic susceptibility was not found to be significantly related to claimed paranormal experiences. Implications of these relationships for the role of absorption in hypnosis are discussed.

Individual differences in afterimage persistence: relationships to hypnotic susceptibility and visuospatial skills.

To investigate the moderating role of individual differences in hypnotic susceptibility and visuospatial skills on afterimage persistence, we presented a codable (cross) flash of light to 40 men and 46 women who had been dark adapted for 20 min. In an unrelated classroom setting, subjects had previously been given two standardized scales of hypnotic susceptibility (Harvard Group Scale of Hypnotic Susceptibility, Shor & Orne, 1962; Group Stanford Hypnotic Susceptibility Scale, Form C, Crawford & Allen, 1982) and the Mental Rotations Test (Vandenberg & Kuse, 1978). The first afterimage interval and the afterimage duration correlated significantly with hypnotic responsiveness, supporting Wallace (1979), but did not show the anticipated relationships with mental rotation visuospatial skills. Individuals in the high hypnotizable group had (a) significantly longer afterimage intervals between its first appearance and first disappearance than did those in medium or low groups, as well as (b) significantly longer afterimages between the first appearance and the final disappearance than did those in low groups, but those in medium groups did not differ significantly from the other groups. Discriminant analysis using the afterimage persistence measures classified correctly 65.2% of high hypnotizables, 37.5% of medium hypnotizables, and 54.8% of low hypnotizables. Hypothesized cognitive skills that assist in the maintenance of afterimages and underlie hypnotic susceptibility include abilities to maintain focused attention and resist distractions over time and to maintain vivid visual images.

Enhancement of visual perception under conditions of short-term exposure to sensory isolation: a comparison of procedures for altering vigilance.

An experiment was conducted to determine the pre- and posttest performance of subjects on a signal-detection task for the following three experimental conditions: sensory isolation, sensory alertness, and sensory relaxation. All subjects were assessed on 36 pretest and 36 posttest trials. Each block of 36 trials consisted of 12 "strong signals," 12 "weak signals," and 12 "no signals." Exposure durations for each experimental condition lasted for one hour. Analyses showed significant improvements in hits from the pretest trials to the posttest trials on the "strong" and "weak signals" for the sensory isolation condition. Moreover, on the posttest "weak signal" trials, subjects in the sensory isolation condition scored a significantly greater number of hits than did those in the sensory alertness or sensory relaxation conditions. It was concluded that sensory isolation produces perceptual enhancement, as measured by a signal-detection task.