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K R Lees

Publications and source records attributed to K R Lees.

At least 73 records · Page 4Linked to original sources
PubMed1998

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↗
PubMed1998

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions.

1. This was a multi-centre, placebo controlled, randomized, dose-escalating design study in which five dosing regimens of 619C89/placebo were evaluated in 48 stroke patients. Loading infusions of 0.5, 1, 1.5, 2 and 2.5 mg kg-1 over 1 h were followed by respective maintenance infusions of 0.25, 0.5, 0.75, 1 and 1.25 mg kg-1 over 30 min at 8 hourly intervals for 3 days. 2. Plasma concentrations of 619C89 and its N-oxide, 341C90, and N-demethylated, 78C90, metabolites were assayed using an LC-MS-MS method. Plasma concentration-time profiles after the final maintenance infusion were subjected to conventional noncompartmental pharmacokinetic analysis. 3. For 619C89, geometric CL means ranged between 0.71 and 0.99 1 h-1 kg-1 for maintenance infusions up to 1.25 mg kg-1 over 30 min, with an overall mean of 0.85 l h-1 kg-1 (95% CI: 0.70-1.04 l h-1 kg-1). Geometric Vss means ranged between 13.2 and 27.9 l kg-1 for the same doses, with an overall mean of 22.5 l kg-1 (95% CI: 16.4-30.9 l kg-1). The ANOVA results revealed that neither CL, Vss nor t1/2 were significantly different across the five dosing regimens (P values: 0.82, 0.54 and 0.61, respectively). 4. Average AUC for 341C90 was 270% and that for 78C90 was 62% of the AUC for 619C89. The AUCm/AUCp-ratios were similar at all dose levels for each metabolite. Values of t 1/2 for 341C90 were similar to those of 619C89 whereas t1/2 for 78C90 was about three-fold longer than that of parent drug. 5. In conclusion, the pharmacokinetics of 619C89 are independent of dose in acute stroke patients. The pharmacokinetics of 341C90 are probably formation rate-limited and those of 78C90 are elimination rate-limited and are also dose-independent.

Aged↗
PubMed1996

Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure.

We previously demonstrated differing blood pressure (BP) responses to the first dose of angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF). We wished to confirm the disparate responses to the first dose of these agents, study the response to repeated dosing, and explore possible explanations (slow, tight binding, and steric hindrance) for the phenomenon. Forty-eight elderly patients (aged 51-85 years) with stable CHF were studied for 48 hours. Groups (n = 12) received one of the following: (a) perindopril 2 mg orally (p.o.) + placebo intravenously (i.v.) (day 1) and perindopril 2 mg p.o. (day 2); (b) enalapril 2.5 mg p.o. + placebo i.v. (day 1) and enalapril 2.5 mg p.o. (day 2); (c) placebo p.o. + perindopril at 0.167 mg i.v. (day 1) and perindopril 2 mg p.o. (day 2); or (d) placebo p.o. + placebo i.v. (day 1) and placebo p.o. (day 2). Supine BP was measured on day 1. On day 2, BP was recorded by ambulatory BP monitor. Blood samples were taken at baseline and at intervals during the 48-h study period for estimation of neurohumoral parameters. Inhibition of the renin-angiotensin system (RAS) was estimated by plasma ACE inhibition and also by the ratio of angiotensin II (Ang II)/Ang I + Ang II. On day I, enalapril 2.5 mg caused a greater decrease in BP than did placebo response between 6 and 9 h postdose. Perindopril 2 mg produced a profile of BP response similar to that of placebo. Ambulatory BP on day 2 was consistently lower with enalapril as compared with perindopril. Profiles of plasma ACE inhibition were similar with each active therapy. Enalapril therapy produced a greater increase in plasma renin activity (PRA) than did other treatments. There was no temporal dissociation between plasma ACE inhibition and profile of Ang peptides for any treatment. We have confirmed the disparate BP responses to perindopril and enalapril in CHF. We noted no evidence of slow, tight binding or steric hindrance to explain these differences.

Aged↗
PubMed1996

The rationale for new therapies in acute ischaemic stroke.

Although stroke is a major cause of morbidity and mortality, it is only relatively recently that a concerted effort has been made to develop acute treatments. Thrombolytics, such as recombinant tissue plasminogen activator (rt-PA), may benefit selected patients within 3 h of cerebral infarction. CUrrently, rt-PA is only licensed for use in the United States. Many potential strategies for neuroprotection exist and are currently under investigation. Because the mechanisms of neurotoxicity involve numerous interdependent processes, it may be that the interpretation of a single site in the cascade of events is insufficient to provide effective neuroprotection. Drugs acting at several sites in the neurotoxic cascade may be more effective, and the results of Phase III studies with the novel neoroprotectant lubeluzole are anticipated.

Cerebrovascular Disorders↗
PubMed1996

Comparison of neurological scales and scoring systems for acute stroke prognosis.

BACKGROUND AND PURPOSE: Clinical trials routinely use stroke scales to compare baseline characteristics of treatment groups. It is unclear which stroke scale provides the most prognostic information. This often leads to collection of multiple scales in clinical trials. We aimed to determine which of several commonly used scales best predicted outcome. METHODS: A single observer scored consecutive admissions to an acute stroke unit on the National Institutes of Health Stroke Scale (NIHSS), the Canadian Neurological Scale, and the Middle Cerebral Artery Neurological Score. Guy's prognostic score was determined from clinical data. Outcome at 2, 3, 6, and 12 months was categorized as good (alive at home) or poor (alive in care or dead). Predictive accuracy of the variables was compared by receiver operating characteristic curves and stepwise logistic regression. RESULTS: Of the 408 patients studied, 373 had confirmed acute stroke and completed follow-up. The three stroke rating scales each predicted 3-month outcome with an accuracy of .79 or greater. The NIHSS provided the most prognostic information: sensitivity to poor outcome, .71 (95% confidence interval [CI], .64 to .79); specificity, .90 (95% CI, .86 to .94); and overall accuracy, .83 (95% CI, .79 to .87). Logistic regression showed that the NIHSS added significantly to the predictive value of all other scores. No score added useful information to the NIHSS. A cut point of 13 on the NIHSS best predicted 3-month outcome. CONCLUSIONS: Baseline NIHSS best predicts 3-month outcome. The Canadian Neurological Scale and Middle Cerebral Artery Neurological Score also perform well. Baseline assessments in clinical trials only need to include a single stroke rating scale.

Acute Disease↗