Does neuroprotection improve stroke outcome?
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Cerebrovascular Disorders↗
Biomedical subjects
K R Lees
Publications and source records attributed to K R Lees.
Determinants of the blood pressure response to the first dose of ACE inhibitor in mild to moderate congestive heart failure.
AIMS: To investigate the relationship in patients with heart failure between BP response to the first dose of ACE inhibitor and (1) plasma drug concentration and (2) baseline clinical and laboratory variables. METHODS: We studied individual placebo-corrected BP responses to initiation of treatment with one of a number ACE inhibitor preparations in 132 patients with mild to moderate CHF. Various pharmacokinetic/pharmacodynamic models were compared. We assessed the strength of association between baseline physiological and laboratory variables and the BP response as assessed directly from the AUC(0,10 h) and indirectly from the slope of the PK/PD relationship. Predictive models for response variables were developing using regression analysis. RESULTS: BP response was primarily related to plasma drug concentration. The association between the fall in BP and baseline variables was weak. The strongest single predictor of BP response was baseline mean arterial pressure (r2 = 5.8%, P = 0.02). The best combinations of predictor variables contained mean arterial pressure, plasma renin activity, creatinine concentration and age (r2 = 14.4%, P = 0.37). When the choice of ACE inhibitor was added, the predictive power of the model increased (r = 23.6%, P < 0.01) but left the majority of the variability in response unexplained. CONCLUSIONS: The first-dose blood pressure response to ACE inhibition cannot be accurately predicted from baseline pathophysiological variables in patients with mild to moderate CHF. The choice of ACE inhibitor accounts for a small proportion of the variability in response but wide inter-individual variability exists in the response to each treatment.
Aged↗
Duration of neuroprotective treatment for ischemic stroke.
BACKGROUND: The therapeutic time window for thrombolysis appears to be extremely short, probably because of the hemorrhagic complications associated with late reperfusion of ischemic brain tissue. Other neuroprotective forms of treatment continue to be developed, although their efficacy has yet to be conclusively proved in patients. The duration of treatment in recent phase 3 trials ranges from a single bolus injection to 12 weeks of oral therapy. SUMMARY OF REVIEW: In this article we discuss the factors that should influence the choice of route and duration of treatment. Excitotoxic injury following stroke evolves over at least 4 hours in rodents and possibly beyond 48 hours in humans. In addition, autoregulation and local cerebral perfusion are deranged for approximately 72 hours in patients with stroke. Neuroprotection should provide cover during this critical time. CONCLUSIONS: Important considerations influencing drug administration should include the pharmacology of the compound (pharmacokinetics, mechanism of action, preclinical toxicity, and pharmaceutical properties), its safety and tolerability in patients, and the likelihood of continuing or recurrent cerebral ischemia, along with practical issues such as ease of administration and interactions with early rehabilitation and other therapies. Optimization of treatment will be possible only when neuroprotection is confirmed to be effective.
Animals↗
Susceptibility to cerebral infarction in the stroke-prone spontaneously hypertensive rat is inherited as a dominant trait.
BACKGROUND AND PURPOSE: Susceptibility to cerebral infarction was compared in stroke-prone spontaneously hypertensive (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and F1 hybrids derived from a SHRSP/WKY cross. METHODS: The proximal left middle cerebral artery (MCA) was occluded under anesthesia and infarct volume assessed 24 hours later by magnetic resonance imaging and confirmed 5 days later by quantitative histopathology. Total hemispheric infarct volume was expressed as a percentage of the total brain volume. RESULTS: Infarct volumes measured by MRI in adult SHRSP (19.5 +/- 2.0%) and F1 hybrid rats (19.4 +/- 1.9%) were significantly greater than in WKY (11.1 +/- 2.4; CI [6.07, 10.76]) and (5.93, 10.52), respectively, P<.001). Sensitivity to an ischemic insult was unrelated to blood pressure: although systolic blood pressures differed between young versus adult male SHRSP and between female versus male SHRSP and F1 hybrids, infarct volumes were equal. A close correlation was found between infarct volumes measured by MRI and histology (r=.92, P<.0001). CONCLUSIONS: Outcome to MCA occlusion (MCAO) measured with MRI provides a reproducible and nonterminal quantitative phenotypic marker of stroke susceptibility in the SHRSP. This is the first study to employ MCAO with MRI to quantify stroke susceptibility in F1 hybrid rats and indicates a dominant mode of inheritance for this phenotype.
Animals↗
Dose optimization of intravenous magnesium sulfate after acute stroke.
BACKGROUND AND PURPOSE: Parenterally administered MgSO4 is neuroprotective in standard animal models of focal cerebral ischemia and in many other paradigms of brain injury. Previous small clinical trials in stroke patients have explored the safety and tolerability of different infusion regimens. This study was undertaken to optimize the regimen for a multicenter trial. METHODS: Within 24 hours of the onset of clinically diagnosed stroke, patients were randomized to receive placebo or one of three intravenous MgSO4 infusions: a loading infusion of 8, 12, or 16 mmol, followed by 65 mmol over 24 hours. Cardiovascular parameters, serum magnesium concentrations, and blood glucose concentrations were determined. Outcome at 30 and 90 days was recorded. RESULTS: Twenty-five patients were recruited and treated at a mean time of 20 hours after stroke. No tolerability problems were identified. No effects of magnesium on heart rate, blood pressure, or blood glucose were evident. Serum magnesium concentrations rose to target levels most rapidly in the highest loading infusion group and were maintained in all groups for at least 24 hours. CONCLUSIONS: MgSO4 infusions that rapidly elevate the serum magnesium concentration to potentially therapeutic levels are well tolerated and have no major hemodynamic effects in patients with acute stroke. The 16-mmol loading infusion achieved target serum concentrations most rapidly and has been chosen for further trials.
Acute Disease↗
The apolipoprotein E epsilon4 allele and outcome in cerebrovascular disease.
BACKGROUND AND PURPOSE: Polymorphism of the apolipoprotein E gene (APOE) may influence outcome after traumatic brain injury and intracerebral hemorrhage, with the epsilon4 allele being associated with poorer prognosis. We investigated APOE allele distribution in acute stroke and the effect of the epsilon4 allele on outcome. METHODS: APOE genotypes were determined in 714 stroke patients: 640 ischemic stroke and 74 intracerebral hemorrhage patients. The survival effect of the epsilon4 allele was assessed with the use of a stratified log-rank test. A Cox proportional hazards regression model was used to estimate the independent effect of epsilon4 dose (0, 1, or 2) on survival, and logistic regression was used to determine the effect on 3-month outcome (good if alive at home, poor if in care or dead). RESULTS: Allele distribution matched the general population with no difference between the ischemic and hemorrhagic groups. Survival in the entire cohort was unaffected by epsilon4 dose. Improved survival with increasing epsilon4 dose was found in the ischemic group (relative hazard=0.76 per allele; P=0.04). If transient ischemic attacks were excluded, a trend for improved survival persisted (P=0.06). With intracerebral hemorrhage, a trend was seen toward reduced survival with epsilon4 (P=0.07, log-rank test). Three-month outcome in the ischemic group was unaffected by epsilon4 dose, and a trend toward poorer outcome with epsilon4 was seen for intracerebral hemorrhage (P=0.10). CONCLUSIONS: The APOE epsilon4 allele had divergent effects on survival and outcome in ischemic and hemorrhagic strokes in this population. The reported adverse effect on patients with intracerebral hemorrhage was supported. The favorable survival effect on ischemic stroke patients requires further study.
Adult↗
Thrombolytic therapy for acute ischaemic stroke.
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Aspirin↗
Adverse event with first-dose perindopril in congestive heart failure.
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Angiotensin-Converting Enzyme Inhibitors↗
Interpretation of IST and CAST stroke trials. International Stroke Trial. Chinese Acute Stroke Trial.
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Aspirin↗
Influence of cholesterol on survival after stroke: retrospective study.
OBJECTIVE: To investigate the association between serum cholesterol concentration and cerebrovascular disease. DESIGN: Retrospective study. SETTING: Acute stroke unit of inner city general hospital. SUBJECTS: 977 patients with acute stroke. MAIN OUTCOME MEASURES: Serum total cholesterol concentration, type of stroke investigated by computed tomography or magnetic resonance imaging, three month outcome (good (alive at home) or bad (dead or in care)), long term mortality. RESULTS: After adjustment for known prognostic factors, higher serum cholesterol concentrations were associated with reduced long term mortality after stroke (relative hazard 0.91 (95% confidence interval 0.84 to 0.98) per mmol/l increase in cholesterol) independently of stroke type, vascular territory and extent, age, and hyperglycaemia. Three month outcome was also influenced independently by serum cholesterol (P = 0.024). CONCLUSIONS: Our data suggest an association between poor stroke outcome and lower serum cholesterol concentration. Until a prospective controlled study has confirmed the benefits of lowering cholesterol concentration in elderly subjects, the application of cholesterol lowering guidelines cannot be justified as secondary prevention of acute stroke.
Adult↗
Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study.
OBJECTIVE: To determine whether raised plasma glucose concentration independently influences outcome after acute stroke or is a stress response reflecting increased stroke severity. DESIGN: Long-term follow up study of patients admitted to an acute stroke unit. SETTING: Western Infirmary, Glasgow. SUBJECTS: 811 patients with acute stroke confirmed by computed tomography. Analysis was restricted to the 750 non-diabetic patients. MAIN OUTCOME MEASURES: Survival time and placement three months after stroke. RESULTS: 645 patients (86%) had ischaemic stroke and 105 patients (14%) haemorrhagic stroke. Cox's proportional hazards modelling with stratification according to Oxfordshire Community Stroke Project categories identified increased age (relative hazard 1.36 per decade; 95% confidence interval 1.21 to 1.53), haemorrhagic stroke (relative hazard 1.67; 1.22 to 2.28), time to resolution of symptoms > 72 hours (relative hazard 2.15; 1.15 to 4.05), and hyperglycaemia (relative hazard 1.87; 1.43 to 2.45) as predictors of mortality. The effect of glucose concentration on survival was greatest in the first month. CONCLUSIONS: Plasma glucose concentration above 8 mmol/l after acute stroke predicts a poor prognosis after correcting for age, stroke severity, and stroke subtype. Raised plasma glucose concentration is therefore unlikely to be solely a stress response and should arguably be treated actively. A randomised trial is warranted.
Aged↗
Termination of Acute Stroke Studies Involving Selfotel Treatment. ASSIST Steering Committed.
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Aged↗
Prognostic value of single-photon emission tomography in acute ischaemic stroke.
Single-photon emission tomography (SPET) is widely used in the investigation of acute stroke. We investigated the relationship between SPET data and functional outcome in a large group of acute stroke patients. One hundred and eight patients underwent cerebral computed tomography (CT) and technetium-99m hexamethylpropylene amine oxime SPET after acute ischaemic stroke. We categorised the clinical presentation according to the Oxford classification of acute stroke. Outcome was measured 1 year after stroke using mortality and the Barthel Index for survivors. SPET scans were interpreted without reference to the clinical data using a semi-automatic technique. Three experienced observers determined the presence of luxury perfusion using suitably scaled SPET images in conjunction with the CT scan. Both SPET volume and severity of deficit were significantly negatively correlated with Barthel Index at 1 year (rs=-0.310, P<0.0001, and rs=-0.316, P<0.0001 respectively). In patients scanned with SPET within 16 h of stroke onset, the correlations were more strongly negative (rs=-0.606, P<0. 001, and rs=-0.492, P<0.005 respectively). Luxury perfusion was not associated (chi2=0.073, df=1, P=0.79) with good functional outcome (Barthel score >/=60). Stepwise logistic regression identified Oxford classification, total deficit volume and patient's age as significant predictors of functional outcome. Overall predictive accuracy was 72%. Predictive accuracy was better in patients who received SPET within 16 h of stroke onset. SPET provides useful information about the functional outcome of acute stroke at 1 year. However, the accuracy of prediction decreases the longer SPET is delayed. Prognostication using SPET in combination with clinical assessment and other investigations may also be considered.
Aged↗
Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers.
Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.
Adolescent↗
Cerestat and other NMDA antagonists in ischemic stroke.
A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes to ischemic injury. Glutamate antagonism by any of several mechanisms can ameliorate the extent of infarction. These antagonists comprise noncompetitive blockers of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor [e.g., aptiganel (Cerestat)], competitive antagonists of the glutamate recognition site of the NMDA receptor (e.g., selfotel) or of the glycine recognition site (e.g., ACEA 1021, GV150526), antagonists at the polyamine site (e.g., eliprodil), and drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions (e.g., lubeluzole, 619C89). Clinical experience suggests that although some NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g., aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include hypertension (which is probably preferable to the hypotension seen with nimodipine and lifarizine), sedation, confusion or hallucinations and, at high doses, catatonia. Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with aptiganel, magnesium, and glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with aptiganel (Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.
Brain Ischemia↗
White-coat hypertension as a cause of cardiovascular dysfunction.
BACKGROUND: The increasing use of 24 h ambulatory blood pressure monitoring has allowed diagnosis of white-coat hypertension, in which blood pressures are higher on clinic measurements than on ambulatory monitoring. Treatment is not generally thought to be necessary for this disorder. However, there is evidence that patients with white-coat hypertension develop renal impairment and left ventricular hypertrophy. We undertook this study to assess whether white-coat hypertension, in the absence of cardiovascular structural abnormalities, is associated with cardiovascular functional abnormalities. METHODS: Cardiovascular function was assessed by ultrasonography in three groups of patients classified as normotensive, persistently hypertensive, or white-coat hypertensive (23, 20, and 22 patients, respectively) on the basis of ambulatory blood pressure monitoring, carried out for 28 h with recordings taken every 15 min during the day and every 20 min during the night, and clinic measurements, made with a semi-automatic oscillometric device. RESULTS: Similar abnormalities of diastolic left ventricular function were identified in the patients with persistent hypertension and those with white-coat hypertension; both groups differed in these indices from the normotensive group (E/A ratios 0.94 [SD 0.23], 1.06 [0.21], and 1.24 [0.31] respectively; ANOVA p < 0.005). In addition, the white-coat and persistently hypertensive groups, when compared with the normotensive group, showed similar abnormalities of elasticity, compliance, and stiffness (stiffness index 4.32 [1.90], 4.53 [1.38], and 3.27 [0.95] respectively; ANOVA p < 0.05) of the large arteries. INTERPRETATION: Functional cardiovascular abnormalities were identified in white-coat hypertensive patients who had no identifiable structural abnormalities. Such functional abnormalities can be reversed by antihypertensive treatment. We propose that patients with white-coat hypertension might benefit from antihypertensive treatment as well as those with persistent hypertension. This hypothesis should be addressed in prospective clinical trials.
Aged↗
Peroneal stimulator; evaluation for the correction of spastic drop foot in hemiplegia.
OBJECTIVE: The objective of the study was to assess the orthotic and therapeutic value of the peroneal stimulator (PS) for adult hemiplegic patients. DESIGN: This was a two-period crossover study lasting 11 weeks. After recruitment each patient had a 4-week control period followed by a 4-week treatment period. The patients were assessed before the control period, after the control period, and after the treatment period. SETTING: Nineteen patients were recruited from physiotherapy departments in the Glasgow area; 2 subsequently dropped out before the treatment period. PATIENTS: All patients had hemiplegia as a result of cerebrovascular accident (CVA) and were greater than 3 months but less than 36 months post-CVA. Average time since stroke was 7 months. MAIN OUTCOME MEASURES: The patients' gait was assessed over smooth linoleum, carpet, and uneven ground. Gait was evaluated using a switch-based portable system. Outcome measures were the temporal gait parameters of speed, symmetry, heel strike, and foot inversion during stance. The gait evaluation was repeated on 5 separate days at each assessment. The Barthel Index was applied to each session. RESULTS: There was a significant orthotic improvement in inversion on all surfaces and for symmetry on linoleum (AN-OVA, p = .05). There was no significant improvement in patients' gait when not using the PS. There was a significant improvement in the Barthel Index over the treatment period (Wilcoxon, p = .05). CONCLUSION: Use of the PS an an orthotic device late in the rehabilitation program would be appropriate for a selected subpopulation of patients.
Adaptation, Physiological↗
Transcranial Doppler detection of microemboli in prosthetic heart valve patients: dependency upon valve type.
Transcranial Doppler ultrasound has revealed the existence of cerebrovascular microemboli in asymptomatic patients with prosthetic heart valves. We investigated the relation between the presence and number of emboli signals and valve type. Patients with six types of prosthetic valves (Björk-Shiley monostrut, Medtronic-Hall, Carbomedics, ATS, Carpentier-Edwards standard, Carpentier-Edwards supraannular) were examined using transcranial Doppler ultrasound in two centers. The monitoring time was 30 min over the right middle cerebral artery. All patients were stabilized on warfarin at the time of study. Microemboli signals were identified by their characteristic audiovisual signal and on subsequent spectral analysis, based on accepted criteria. A standard neurologic questionnaire was completed by all patients. The prevalence of microemboli signals varied between 49% (Medtronic Hall) and 97% (Björk-Shiley monostrut), while their number varied between 1 [0-3] (Carpentier-Edwards standard) and 187 [136-240] (Björk-Shiley monostrut) per hour (median and 95% CI). Both parameters were significantly higher in patients with Björk-Shiley monostrut valves compared to the other patient groups. There were no significant differences in the prevalence of neurologic complications among the groups examined (overall 16%), or in emboli numbers between symptomatic and asymptomatic patients. The prevalence and quantity of microemboli signals in patients with prosthetic heart valves, as detected by transcranial Doppler, is dependent upon valve type. The clinical significance of these microemboli signals remains to be further evaluated.
Aged↗