Viva la VOSCE?

BACKGROUND: The COVID-19 pandemic lockdown precluded face-to-face final Objective Structured Clinical Examinations (OSCE) in the UK. RESULTS: In response, we rapidly developed and then successfully implemented a novel Virtual Objective Structured Clinical Examination (VOSCE). CONCLUSIONS: In this article we both describe and reflect on our experience as well as discuss the implications for future undergraduate assessment as the situation evolves.

Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.

OBJECTIVE: Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA). METHODS: We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1-year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible. RESULTS: Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [-6.6 mm Hg (95% CI -13.0 to -0.3), p=0.042] and augmentation index [-4.4% (95% CI -7.9 to -1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [-0.097 mm (95% CI -0.175 to -0.019), p=0.015]. No difference was observed for measures of endothelial function. CONCLUSIONS: Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy. TRIAL REGISTRATION NUMBER: ISRCTN11970568.

Preoperative risk factors in 10 418 patients with prior myocardial infarction and 5241 patients with prior unstable angina undergoing elective coronary artery bypass graft surgery.

BACKGROUND: The EuroSCORE associates coronary artery bypass graft (CABG) surgery with higher perioperative risk in the first 3 months after a myocardial infarction (MI). The optimal scheduling of CABG surgery after unstable angina (UA) is unknown. We investigated the preoperative predictors of adverse outcomes in patients undergoing CABG with prior MI or UA and investigated the importance of time interval between the cardiac event and CABG. METHODS: The Hospital Episode Statistics database (April 2006-March 2010) was analysed for elective admissions for CABG. Independent preoperative patient factors influencing length of stay, readmission rates, and mortality, were identified by logistic regression and presented as adjusted odds ratios (ORs). RESULTS: A total of 10 418 patients with prior MI (mortality 1.8%) and 5241 patients with prior UA (mortality 2.2%) were included in the respective cohorts. Multiple risk factors were identified in each population including liver disease and renal failure. The time interval from cardiac event (MI or UA) to elective CABG surgery did not influence perioperative outcomes when analysed as a continuous measure or using the arbitrary 3-month threshold [MI, OR 1.1 (0.78-1.57) and UA, OR 0.65 (0.39-1.09)]. CONCLUSIONS: Our hypothesis generating data suggest that the increased risk currently allocated in the EuroSCORE for an interval of 3 months between MI and CABG should be critically re-evaluated. Furthermore, prior MI should not be discounted as a risk factor if it is more than 3 months old.

All I want for coagulation.

Evidence-based medicine underpins modern practice of medicine. This paper describes a fictional consultation between Santa Claus and a doctor regarding deep vein thrombosis (DVT) prophylaxis, giving a review of the evidence for DVT prophylaxis in travellers while exposing the difficulty in applying evidence to atypical clinical encounters. Medline and the Cochrane Library were searched, and guidelines reviewed. Keywords used were DVT, thromboembolism, deep vein thrombosis and air travel-related venous thromboembolism. All relevant studies found, have been included in this review, with additional studies identified from the references in these articles. In conclusion, compression stockings, with or without a one-off dose of either aspirin or heparin, are the most evidence-based approaches for prophylaxis in someone with established risk factors for DVT prior to a long-haul flight. Simple exercises should also be encouraged.

Long-term outcome following attendance at a transient ischemic attack clinic.

BACKGROUND AND PURPOSE: Many patients who attend transient ischemic attack clinics have a noncerebrovascular diagnosis. The long-term outcomes in this group are not well described. We evaluated these in a cohort referred to a transient ischemic attack clinic with a suspected transient ischemic attack. METHODS: Patients were clinically classified as having stroke or a transient ischemic attack or a noncerebrovascular diagnosis (nontransient ischemic attack). Follow-up was via electronic record linkage. The primary endpoint was cardiovascular death or a major cardiovascular event. Secondary outcomes included incident neurological disease (excluding stroke or transient ischemic attack) and the need for permanent pacemaker insertion. Outcomes in the transient ischemic attack and nontransient ischemic attack cohorts were compared using Cox's proportional hazards models. Mortality outcomes were further compared with those in a contemporary control group of individuals with hypertension. RESULTS: Of the 3533 patients who attended the transient ischemic attack clinic, 53.5% had a transient ischemic attack. Of these, 769 (40.7%) suffered a cardiovascular endpoint, compared with 458 (27.9%) with a nontransient ischemic attack (hazard ratio 1.53, 95% confidence interval 1.36-1.72). The risk remained higher but was attenuated following adjustment (hazard ratio 1.21, 95% confidence interval 1.05-1.41). Cardiovascular mortality in both groups was higher than that in hypertensive controls. The risk of a subsequent nonstroke neurological event was higher in those without a transient ischemic attack. CONCLUSIONS: Patients without a transient ischemic attack referred to a transient ischemic attack clinic have a high risk of future vascular events that exceeds risk in a cohort with hypertension. All patients attending transient ischemic attack clinics should undergo assessment of their cardiovascular risk and the use of methods to reduce this risk should be explored.

Sugar and stroke: cerebrovascular disease and blood glucose control.

In this review we will discuss the cerebrovascular consequences of dysglycemia and current evidence for therapy, making reference to recent work in the fields of neuropathology, epidemiology, and relevant clinical trial data. Prospective observational and clinical trial data show a clear association between diabetes mellitus and vascular disease, which extends to cerebrovascular disease. The benefits of intervention to lower blood glucose in terms of microvascular health are well established but benefit on macrovascular, especially cerebrovascular, health has been less apparent. Recent large-scale trials and metaanalyses have helped us to better define the role of glycemic control in macrovascular disease. Although few studies of glycemic therapy have used cerebrovascular disease as a primary endpoint, stroke-specific data can be derived. Associations between blood glucose and outcome are also apparent for acute stroke. A period of hyperglycemia is common, with elevated blood glucose in the periinfarct period consistently linked with poor outcome in patients with and without diabetes. The mechanisms that underlie this deleterious effect of dysglycemia on ischemic neuronal tissue remain to be established, although in vitro research, functional imaging, and animal work have provided clues. While prompt correction of hyperglycemia can be achieved, trials of acute insulin administration in stroke and other critical care populations have been equivocal. Diabetes mellitus and hyperglycemia per se are associated with poor cerebrovascular health, both in terms of stroke risk and outcome thereafter. Interventions to control blood sugar are available but evidence of cerebrovascular efficacy are lacking. In diabetes, glycemic control should be part of a global approach to vascular risk while in acute stroke, theoretical data suggest intervention to lower markedly elevated blood glucose may be of benefit, especially if thrombolysis is administered. Trials have been underpowered to demonstrate treatment effect and any intervention must be balanced against risk of hypoglycemia.

Anti-platelet therapy and aspirin resistance - clinically and chemically relevant?

Platelets play a central role in the pathogenesis of the atherothrombosis which ultimately causes myocardial infarction, stroke and peripheral vascular disease. Commonly used oral anti-platelet drugs include aspirin (an irreversible inhibitor of cyclo-oxygenase), clopidogrel (an ADP receptor antagonist), other thienopyridines such as ticlopidine and prasgruel, and dipyridamole (an inhibitor of adenosine reuptake and platelet phosphodiesterase). Newer agents are in development and one, ticagrelor, a reversible ADP receptor antagonist has shown promise. Despite their proven benefit, recurrent vascular events still occur in those taking anti-platelet drugs. This has led to the concept of anti-platelet resistance, most commonly aspirin resistance as this drug is the cornerstone of most regimens. The causes of aspirin resistance are numerous but potential mechanisms include lack of patient adherence, non COX-1 mediated thromboxane A2 synthesis, increased activity of alternate platelet activation pathways, interference of aspirin action by other drugs and probably pharmacogenetic factors. Measurement of platelet response to aspirin is made possible using a number of in-vitro laboratory assays of platelet function which include measurement of thromboxane A2 metabolites as well as newer point-of-care assays of platelet aggregation. The phenomenon of aspirin resistance is important as it raises the possibility of developing strategies to identify those who respond best to a particular anti-platelet regimen, or to development of newer anti-platelet therapies to which more patients respond. This review discusses important aspects of aspirin resistance both in terms of clinical medicine, alternative anti-platelet strategies, and the potential to overcome its various causes.

Equality of access to "fast-track" stroke services in an older, socio-economically deprived Scottish population.

BACKGROUND AND AIMS: Unequal access to specialist stroke services may contribute to the disproportionate stroke burden in certain populations. We evaluated the relationship between access to TIA services, deprivation and age. METHODS: We prospectively recorded referral pattern data on consecutive TIA service patients. Socio-economic deprivation was derived from postcode and census data. Associations were described using Kruskal-Wallis statistics. RESULTS: Of 3,462 patients assessed, there was no association between time to clinic referral or attendance and increasing deprivation or age. CONCLUSION: Inequality of access to TIA services for older, deprived patients was not evident. However, delay to assessment and prevalence of risk factors was substantial for all patients.

Functional outcome measures in contemporary stroke trials.

Various instruments are used to describe poststroke functional outcome, with limited consensus as to optimal end-point for clinical trial use. Many of the popular assessment tools are administered with little formal guidance on best practice. Thus there is potential for substantial heterogeneity in functional outcome assessment poststroke, with consequent effects on trial quality. We examined functional assessment methodology in recent stroke trials. We reviewed six journals representing high-impact international publications in the fields of: stroke (Stroke); neurology (Neurology, Lancet Neurology) and internal medicine (Lancet, New England Journal Medicine; Journal of the American Medical Association). Journals were hand searched for all interventional studies in stroke patients between 2001 and 2006 inclusive. Chosen manuscripts were then analyzed for outcome assessment methodology. We identified 126 trials, comprising a mix of early hypothesis generating studies through to multi-centre trials (phase I: four trials; phase II: 46 trials; phase III: 20 trials; noninvestigational medicinal product studies: 56 trials). The median number of patients assessed per trial was 100. Across the trials, 47 different outcome measures were used. One hundred trials had functional outcome assessment as the primary study end-point. The median number of outcome measures was two per trial (range 1-9). The modified Rankin scale was the most prevalent outcome assessment (64.3%); followed by Barthel index (40.5%). A minority of trials (33.3%) provided full details on outcome assessment methodology. Among these trials there was substantial heterogeneity in data collection procedures. There is heterogeneity in the use of functional outcome measures in stroke trials. This compromises comparison and meta-analysis. Trialists continue to use poorly validated approaches to outcome assessment. Given the potential effects on data quality, explicit description of methodology should be mandatory for all trials and rigour is desirable.

A recognition tool for transient ischaemic attack.

BACKGROUND: Scoring systems exist to assist rapid identification of acute stroke but not for the more challenging diagnosis of transient ischaemic attack (TIA). AIM: To develop a clinical scoring system to assist with diagnosis of TIA. METHODS: We developed and validated a clinical scoring system for identification of TIA patients. Logistic regression analysis was employed. RESULTS: Our development cohort comprised 3216 patients. The scoring system included nine clinically useful predictive variables. After adjustment to reflect the greater seriousness of missing true TIA patients (a 2:1 cost ratio), 97% of TIA and 24% of non-TIA patients were accurately identified. Our results were confirmed during prospective validation. CONCLUSION: This simple scoring system performs well and could be used to facilitate accurate detection of TIA.

Thrombolytic therapy for acute stroke in the United Kingdom: experience from the safe implementation of thrombolysis in stroke (SITS) register.

AIM: To describe the United Kingdom (UK) experience with thrombolytic therapy with intravenous alteplase (rt-PA) for stroke, as captured by the Implementation of Thrombolysis in Stroke (SITS) project. METHODS: The multinational Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was an observational study to assess the safety and efficacy of thrombolytic therapy, when administered within the first 3 h after onset of ischaemic stroke. SITS-MOST was embedded within the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), an internet-based, international monitoring registry for auditing the safety and efficacy of routine therapeutic use of thrombolysis in acute ischaemic stroke. We performed an analysis of data contributed to SITS-MOST and SITS-ISTR from UK centres. RESULTS: A total of 614 patients received thrombolysis for stroke between December 2002 and April 2006, 327 were registered to SITS-MOST and 287 to SITS-ISTR. Thirty-one centres treated patients in the UK, of which 23 registered patients in both SITS-MOST and SITS-ISTR and eight solely to SITS-ISTR. The median age from the UK SITS-MOST was identical to the non-UK SITS-MOST register: 68 years (IQR 59-75). The majority (96.1%) of patients from the UK were treated between 8.00 a.m. and 9.00 p.m., and only 18.4% were treated on weekend days, reflecting the difficulties of maintaining provision of a thrombolytic service out of hours. Median onset-to-treatment-time was 155 min (IQR 130-170 min) for the UK, compared to 140 min (IQR 114-165 min) for the non-UK SITS-MOST group (P < 0.001). UK SITS-MOST patients at baseline had more severe stroke in comparison with non-UK patients [median NIHSS 14.5 (IQR 9-19) vs. 12 (IQR 8-17) (P < 0.001)]. Forty-eight percent of UK patients achieved mRS of 0-2 (independence), compared to 55% of the non-UK SITS-MOST register. There was no significant difference in symptomatic intracerebral haemorrhage rate in the UK compared with the non-UK SITS-MOST patients [2.5% (95% CI 1.3-4.8) vs. 1.7% (95% CI 1.4-2.0) P = 0.28]. In the multivariate analysis, there was no statistically significant difference in any outcome between UK and non-UK SITS-MOST patients. CONCLUSION: Thrombolytic therapy for stroke has been implemented successfully at a small number of UK stroke centres, with patchy provision throughout the country. The low frequency of treatment out with office hours suggests deficient infrastructure to support delivery. UK patients tended to be more severely affected at baseline and to be treated later. Outcomes are comparable to those seen at the non-UK SITS centres.

Acute medicine teaching in an undergraduate medical curriculum: a blended learning approach.

BACKGROUND: Acute medical management is an important component of the Modernising Medical Careers (MMC) project which has recently been implemented in the UK. A web-based interactive course in acute medicine has been developed which complements the clinical teaching provided to senior medical students at the University of Glasgow. A study was undertaken to evaluate the teaching and assess the knowledge of acute medicine among final year medical students using an online questionnaire. METHODS: The undergraduate medical school Virtual Learning Environment (VLE) was constructed using the Moodle learning management system. The online questionnaire was constructed as part of the interactive acute medicine course hosted on the VLE. Final year students using this course were asked to complete the questionnaire anonymously. A 5-point Likert scale was used to assess different aspects of acute medical management and evaluate the teaching. RESULTS: From 210 students using the website, 99 (47.1%) completed the online questionnaire. Nephrology and neurology were identified as the most challenging specialties in acute medicine. The areas of acute management in which students felt they lacked most knowledge were drug overdose and acute renal failure. Drug prescribing was also identified as an area of the curriculum requiring further development. CONCLUSIONS: This approach to blended learning is popular with our medical students. Online evaluation has helped with curriculum development and, by identifying important areas of acute medicine teaching that can be improved, is feeding into our curriculum revision.

A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients.

BACKGROUND: Hyperglycaemia on presentation with acute ischaemic stroke (AIS) is associated with poor outcome, but intervention is unproven. We investigated the safety and tolerability of one method of glycaemic control. METHODS: Patients within 24 h of AIS and plasma glucose 8-20 mmol/l were randomised to receive either rigorous glycaemic control (RC) or standard management (SM) for 48 h. RC comprised i.v. insulin at a variable rate adjusted for target glucose concentration of 5-8 mmol/l, and intravenous crystalloid. The SM group received intravenous crystalloid alone in an open-label design. RESULTS: Thirteen patients were randomised to RC and 12 to SM (age 75 +/- 6.2 years; 40% male; 20% lacunar stroke; time to treatment 8 +/- 6.1 h; plasma glucose 10.6 +/- 0.9 mmol/l; known diabetes 52%; NIHSS 8, range 2-28). The glucose concentration-time curve was reduced in the RC group (AUC 324 +/- 15 versus 385 +/- 28 h.mmol/l, p = 0.04). By 48 h, plasma glucose in both groups was 6.8 +/- 1.1 and 7.5 +/- 1.3 mmol/l respectively, but mean hourly insulin requirements in the RC group had dropped from 3.25 +/- 0.32 units to 1.25 +/- 0.5 units (p < 0.01). One transient episode of hypoglycaemic symptoms occurred in the RC group. CONCLUSION: Glycaemic control with sliding scale insulin for 48 h is feasible and well-tolerated after AIS. Treatment after 48 h may be unnecessary.

Blunted response to systemic nitric oxide synthase inhibition in the cerebral circulation of patients with Type 2 diabetes.

AIMS: Diabetes is a major risk factor for stroke, but the mechanisms that impart the excess risk are unclear. Endothelial dysfunction, which has been demonstrated in the coronary and peripheral vasculature of diabetic patients, is an important early marker of vascular disease. However, the effect of diabetes on cerebrovascular endothelium has not been examined. We sought to investigate the effect of diabetes on basal cerebrovascular endothelial function as assessed by response to the nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA). METHODS: Fourteen men with Type 2 diabetes and 15 age-matched male control subjects were recruited. The participants had no clinically evident vascular disease and were taking no vasoactive or lipid-lowering medication. Each received a single 15-min intravenous infusion of L-NMMA (0.8 mol/kg/min). Cerebral blood flow was assessed by colour Doppler imaging of the internal carotid artery (ICA) at 10-min intervals for 20 min prior to and following the infusion. Middle cerebral artery velocity (MCAv) was assessed by transtemporal Doppler ultrasound at the same time points. RESULTS: L-NMMA produced a mean reduction in ICA flow area under curve (AUC) in the control group of 12.8 +/- 17.8% compared with a 2.1 +/- 21.7% reduction in the group with diabetes (P < 0.05), indicating blunted basal cerebrovascular response to NOS inhibition in the diabetic group. There was no significant change in MCAv following L-NMMA in either group. Mean +/- sd MAP rose 6.4 +/- 4.2 mmHg in the control group vs. 8.8 +/- 3.5 mmHg in the diabetic group [P = not significant (NS)]. No adverse event or symptom was reported. CONCLUSIONS: Response to NOS inhibition is impaired in the cerebral circulation of patients with diabetes. This observation is consistent with the elevated cerebrovascular risk reported in this population, and may represent a future therapeutic target in stroke prevention.

The prognostic significance of visible infarction on computed tomography following lacunar stroke: results of a long-term follow-up study.

BACKGROUND AND PURPOSE: Substantial variability in functional outcome and relatively few factors predictive of death or degree of recovery have been observed in patients with lacunar stroke. Such indicators are of great use in the selection of optimal rehabilitation strategies after stroke. Although computed tomography (CT) of patients with a clinical diagnosis of lacunar stroke performed within the first 10 days shows evidence of cerebral infarction in 50% to 60%, the prognostic significance of a visible ischemic lesion on CT is unclear. METHODS: 633 patients who presented with symptoms consistent with lacunar stroke between June 1990 and February 1998 were studied. One hundred fourteen patients imaged with magnetic resonance, 41 patients with nonischemic diagnoses (hemorrhage or tumor), 57 patients imaged within 12 hours of ictus, and 17 patients with incomplete follow-up were excluded from the analysis. The remaining 404 patients were divided into 2 groups, depending on the appearance of the CT scan. Patients with a low-attenuation area on the CT scan consistent with an ischemic lesion in an appropriate region of the brain to explain the presenting symptoms were classified as "CT positive." Patients with either a normal CT scan of the brain or a scan that showed a lesion in an area inconsistent with the presenting symptoms were classified as "CT negative." A series of known or suspected prognostic factors were recorded for each patient: blood pressure, age, smoking, plasma glucose level, serum cholesterol level, and serum triglyceride level. Delay from stroke onset to scanning was also noted. The authors considered 3 outcome measures: survival time, outcome at 6 months after the stroke, and total length of hospital stay for the stroke admission. Six-month outcome was categorized as good (alive at home) or poor (alive in care or dead). RESULTS: There was no difference in survival between the 2 groups (P= .29, log-rank test). After adjusting for other significant prognostic factors (age; relative hazard per additional decade 1.67, P< .0001: plasma glucose level; relative hazard per additional mmol/l 1.08, P= .03) in a proportional hazards model, presence of visible infarction remained nonsignificant (relative hazard 0.84, P= .40). After adjustment for the other significant factor (age, P= .0001), there was no significant difference in 6-month outcome between CT positive and CT negative patients (P= .61). Median total length of hospital stay was not significantly different between the 2 groups (CT positive, 9 days; CT negative, 8 days; Mann-Whitney test, P= .29). CONCLUSION: The authors conclude that in their cohort of patients, having corrected for other prognostic variables, the presence of visible infarction on CT brain scan performed between 12 hours and 30 days of onset of lacunar symptoms is not predictive of duration of hospital stay or of longer term outcome.

Intravenous thrombolysis for acute ischaemic stroke: preliminary experience with recombinant tissue plasminogen activator in the UK.

OBJECTIVE: To present the preliminary experience of implementing intravenous thrombolytic therapy for acute ischaemic stroke in three UK stroke centres. BACKGROUND: Recombinant tissue plasminogen activator for ischaemic stroke received approval from UK regulatory authorities in April 2003. Since 1997, a small number of UK centres had used thrombolytic therapy in highly selected stroke patients. We present the early experience of that treatment in Glasgow and Newcastle. DESIGN: Patients were selected and treated in accordance with the American Heart Association guidelines. Additionally, radiologic criteria employed in the European-Australasian Acute Stroke Studies were applied. National Institutes of Health Stroke Scale (NIHSS) scores were measured on admission, and Modified Rankin Scale (MRS) scores were assessed at 3 months for all patients with stroke treated prior to initiation of the Safe Implementation of Thrombolysis in Stroke monitoring program for implementation of thrombolysis in stroke in April 2001. Intracranial and systemic haemorrhagic complications were recorded. RESULTS: 120 patients received thrombolytic treatment (approximately 1% of all admissions with presumed stroke). Mean age was 69 years (range 22-93) and initial median NIHSS score was 17 (range 3-31). In the two centres for which temporal data were available, the mean delay between symptom onset and treatment was 139 min (range 20-185). Sixteen episodes of cerebral haemorrhage or haemorrhagic transformation of any degree occurred, of which 5 (4%) were symptomatic. One patient deteriorated and died before repeat CT imaging could be performed. One non-fatal episode of systemic bleeding occurred. One patient was lost to follow-up. At 3 months, 31% of recipients had achieved good (MRS 0-1) outcome, 22% moderate (MRS 2-3) outcome and 21% (MRS 4-5) poor outcome. Twenty-one per cent died within 3 months of stroke. Observed frequency of bleeding complications and protocol violations (6%) was similar to those reported elsewhere. CONCLUSION: A small proportion of stroke patients received thrombolytic treatment. Patients treated were more severely affected than in other published European and North American series. Outcomes and complications were consistent with experience elsewhere.

The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study.

BACKGROUND AND PURPOSE: ZK 200775 is a selective competitive AMPA receptor antagonist. It has demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers. We tested the safety and tolerability of ZK 200775 in patients with acute ischaemic stroke. METHODS: In a multicentre double-blind, randomised, placebo-controlled phase II trial, 61 ischaemic stroke patients were treated with either placebo or active drug in a dose finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 h (group 1) and 13 patients received a total dose of 525 mg in 48 h (group 2), and 11 patients received a total dose of 105 mg over a period of 6 h (group 3). We studied the pharmacokinetics of the compound and the effect of the infusion on the neurologic and haemodynamic parameters of the patients. The study was not powered to detect neuroprotective efficacy. RESULTS: In group 2 there was a significant transient worsening in the mean NIH stroke scale score 14- 18 h after the start of treatment. This was due to reduction of consciousness (stupor and coma) in 8 out of 13 patients. Level of consciousness improved approximately 6 h after cessation of infusion. No significant haemodynamic responses were observed. Even after reduction of the administered dose and duration of infusion to 6 h (group 3), 2 patients experienced a reduction in level of consciousness. The effect of ZK 200775 on level of consciousness gave cause for concern and the trial was stopped prematurely for safety reasons. CONCLUSIONS: The AMPA antagonist ZK 200775 reversibly worsened the neurological condition in patients with acute ischaemic stroke. Our results suggest that ZK 200775 exerts significant sedative effects in patients with acute stroke which preclude its further development as a neuroprotective agent in this indication.

Effect of a gonadotropin releasing hormone analog on cerebral hemodynamics in premenopausal women.

BACKGROUND: Impaired reactivity of cerebral blood vessels is associated with increased risk of stroke. Female sex hormones have vasoactive effects in a number of vascular beds but their effects upon the cerebral circulation are not well understood. Ultrasound techniques allow us to examine the ability of intracranial vessels to dilate in response to a pharmacological stimulus (the carbonic anhydrase inhibitor acetazolamide). We studied intracranial hemodynamics in a group of premenopausal women before and after induction of a temporary hypoestrogenic state. METHODS: We examined middle cerebral artery mean flow velocity, common and internal carotid artery pulsatility index and cerebrovascular reactivity to acetazolamide (CVR) in a group of women undergoing treatment for menstrual disorders. Volunteers underwent ultrasound examination during the follicular phase of the menstrual cycle and after completing treatment with gonadotropin releasing hormone (GnRH, goserelin 3.6 mg) administered subcutaneously every 28 days for 12 weeks. The study was conducted in a prospective, single-blind fashion and analyzed using parametric comparisons of means to examine change in intracranial hemodynamic parameters between pre- and postmenopausal states. RESULTS: Twelve premenopausal women aged 37.2+/-7 years and without overt vascular disease completed the protocol. GnRH reduced serum estrogen concentration (215.6+/-122 pg/ml vs. 82.4+/-12 pg/ml, p=0.0047) but this was not associated with a change in CVR (145+/-19% and 146+/-14% for follicular and post-GnRH studies, respectively (p=0.6). No significant changes in blood pressure, internal carotid or middle cerebral artery pulsatility or mean flow velocity were observed between time points. CONCLUSION: Neither resting cerebral hemodynamics nor reactivity of cerebral resistance vessels to a potent vasodilatory stimulus changed when the circulating concentration of estradiol was artificially decreased using a GnRH agonist. Induction of a hypoestrogenic state does not appear to influence cerebral vasodilatory capacity in the short term.

Statin administration prior to ischaemic stroke onset and survival: exploratory evidence from matched treatment-control study.

In addition to their lipid-lowering effects, it has been speculated that statins may also have beneficial effects on cerebral circulation and brain parenchyma during ischaemic stroke and reperfusion. We hypothesized that patients who had taken statins prior to stroke onset may have a better survival rate at 1 month and during the follow-up period. We retrospectively studied consecutive ischaemic stroke patients admitted to an acute stroke unit and at least a month's follow-up. From these, we included those patients who, at admission, had reported the use of a statin prior to the stroke onset in the statin group (n = 205). Each patient in the statin group was matched with two patients who reported no statin use (n = 410). Using logistic regression and Cox proportional hazards models, we adjusted for variables that significantly differed between treatment groups or that independently predicted mortality. After adjusting for those variables, statin use was associated with reduced mortality at 1 month [odds ratio 0.24; 95% confidence interval (CI) 0.09-0.67] and during the follow-up period (hazard ratio 0.57; 95% CI 0.35-0.93). The use of statins prior to stroke onset is associated with improved stroke survival within this cohort study with matched controls.