Effects of NOS inhibition on the cardiopulmonary system and brain microvascular markers after intermittent hypoxia in rats.

We previously demonstrated that rats subjected to intermittent hypoxia (IH) by exposure to 10% O(2) for 4 h daily for 56 days in a normobaric chamber, developed pulmonary hypertension, right ventricular hypertrophy and wall-thickening in pulmonary arterioles, compared with normoxic (N) controls. These changes were greater in rats subjected to continuous hypoxia (CH breathing 10% O(2) for 56 days). Cerebral angiogenesis was demonstrated by immunostaining with glucose transporter 1 (GLUT1) antibody, in viable vessels, in CH and to a lesser degree in IH. In this study, adult Wistar rats were subjected to the same hypoxic regimes and given the nitric oxide synthase (NOS) inhibitor N(6)-nitro-L-arginine methyl ester (L-NAME) in drinking water (NLN, IHLN and CHLN regimes) to induce hypertension. There was significant systemic hypertension in NLN and IHLN rats, compared with N and IH, but surprisingly not in CHLN compared with CH. Hematocrit rose in all hypoxic groups (up to 79% in CHLN). There was no significant pulmonary hypertension in IHLN versus NLN rats, although there was asymmetric wall thickening in pulmonary arterioles. Cerebral GLUT1 immunoreactivity increased with L-NAME, with or without hypoxia, especially in CHLN rats, but conspicuously there was no evidence of angiogenesis in brains of IHLN compared with NLN rats. NOS blockade may attenuate the cerebral and pulmonary vascular changes of IH while augmenting cerebral angiogenesis in continuous hypoxia. However, whether cerebral effects are due to systemic hypertension or changes in cerebral nitric oxide production needs to be evaluated.

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

BACKGROUND AND PURPOSE: NXY-059 is a nitrone-based free radical-trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. RESULTS: One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260+/-79 micromol/L, exceeding the target of 200 micromol/L in the high-dose group. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia.

An inter-disciplinary approach to swallowing problems in acute stroke.

Many speech and language therapy (SLT) departments are in danger of being swamped with dysphagia referrals, often to the detriment of other work. At the same time surveys have shown that large numbers of patients with acute stroke have swallowing problems which are poorly managed during the critical early phase, not referred or missed altogether. The Collaborative Dysphagia Audit (CODA) study, carried out in six British hospitals, showed that nurses could quickly be trained to carry out basic screening assessments for dysphagia and that implementation of a co-ordinated inter-disciplinary dysphagia management policy (DMP) could substantially improve the proportion of dysphagic patients in whom appropriate feeding precautions were taken. These early DMPs were limited by the need for ward staff to keep all patients with suspected swallowing impairment nil by mouth until assessed by SLT, so in some acute stroke units nurses have been trained to a higher level which allows them to manage most routine transient swallowing problems, leaving only complex or persistent cases for referral to SLT. This approach has been used successfully in our unit in Gateshead, where a dysphagia nurse specialist post has been set up to act as a link between ward staff and SLTs, to ensure that the necessary training levels are maintained and to co-ordinate the DMP.

Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke.

BACKGROUND AND PURPOSE: Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat. METHODS: This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days. RESULTS: One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 micromol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.

The COSTAR wheelchair study: a two-centre pilot study of self-propulsion in a wheelchair in early stroke rehabilitation. Collaborative Stroke Audit and Research.

OBJECTIVE: It is uncertain whether self-propulsion in a wheelchair should be encouraged or discouraged in the early stages of stroke rehabilitation. DESIGN: A two-centre pilot study to assess the feasibility of performing a multicentre randomized controlled trial on this subject. SETTING: Clatterbridge and Aintree Stroke Rehabilitation Units, Merseyside, UK. SUBJECTS: Forty early stroke patients (mean age 67 years) in whom it was uncertain whether self-propulsion in a wheelchair should be encouraged were studied. INTERVENTION: A central randomization service at Newcastle University was used to determine the policy about wheelchair provision and use for each patient. They were allocated to either an 'encouraged to self-propel' or a 'discouraged from self-propulsion group'. OUTCOME MEASURES USED: Independent outcome assessment was performed by postal questionnaire and telephone interview using the Barthel ADL Scale, Nottingham Extended ADL Scales and the shortened General Health Questionnaire (GHQ-12) at 3 and 12 months. Patient's length of stay and their Ashworth tone score were also measured either at three months or when they were discharged from hospital. RESULTS: After considerable preparation time it was possible to conduct a trial on self-propulsion in early stroke rehabilitation in the two-pilot centres. No major differences were found between the pilot groups for any of the outcome measures. CONCLUSIONS: A multicentre randomized controlled trial to assess this question is feasible but further work is being conducted before proceeding, to satisfy the concerns expressed to our group regarding the appropriateness of the intervention and the outcome measures.

A multicentre randomized controlled trial of leisure therapy and conventional occupational therapy after stroke. TOTAL Study Group. Trial of Occupational Therapy and Leisure.

OBJECTIVE: To evaluate the effects of leisure therapy and conventional occupational therapy (OT) on the mood, leisure participation and independence in activities of daily living (ADL) of stroke patients 6 and 12 months after hospital discharge. DESIGN: Multicentre randomized controlled trial. SETTING AND PARTICIPANTS: Four hundred and sixty-six stroke patients from five UK centres. MAIN OUTCOME MEASURES: The General Health Questionnaire (12 item), the Nottingham Extended ADL Scale and the Nottingham Leisure Questionnaire, assessed by post, with telephone clarification. RESULTS: Four hundred and forty (94%) and 426 (91%) subjects were alive at 6 and 12 months, respectively. Three hundred and seventy-four (85% of survivors) and 311 (78% of survivors) responded at 6 and 12 month follow-up respectively. At six months and compared to the control group, those allocated to leisure therapy had nonsignificantly better GHQ scores (-1.2: 95% CI -2.9, +0.5), leisure scores (+0.7, 95% CI -1.1, +2.5) and Extended ADL scores (+0.4: 95% CI -3.8, +4.5): the ADL group had nonsignificantly better GHQ scores (-0.1: 95% CI -1.8, +1.7) and Extended ADL scores (+1.4: 95% CI -2.9, +5.6) and nonsignificantly worse leisure scores (-0.3: 95% CI -2.1, +1.6). The results at 12 months were similar. CONCLUSION: In contrast to the findings of previous smaller trials, neither of the additional OT treatments showed a clear beneficial effect on mood, leisure activity or independence in ADL measured at 6 or 12 months.

Development and validation of a brief observer-rated screening scale for depression in elderly medical patients.

OBJECTIVE: to develop a depression screening scale that does not rely on verbal communication. SETTING: an acute geriatric unit in a teaching hospital. SUBJECTS: 96 patients (mean age 81 years, range 68-92, 59 women); 40% of the initial study group of 50 and 22% of the validation group of 46 were diagnosed as depressed. METHODS: we devised a scale using nine items which could be rated by an observer; we determined inter-rater reliability, sensitivity, specificity and predictive values for each item compared with a Geriatric Mental State-AGECAT diagnosis of depression; we validated a final scale of six items. RESULTS: inter-rater reliability was poor for two items (irritability and sleep disturbance) while two items (sleep disturbance and night sedation) had poor sensitivity; we omitted these items in a revised scale. Re-analysis of data from the initial study showed that a cut-off of > or = 3 on the revised scale gave a sensitivity of 83%, a specificity of 95%, a positive predictive value of 0.89 and a negative predictive value of 0.90. Spearman's correlation coefficient between the six-item questionnaire and the Hamilton rating scale was 0.79. In the validation study, the cut-off score of > or = 3 on the revised six-item scale had a sensitivity of 90%, specificity of 72%, a positive predictive value of 0.69 and a negative predictive value of 0.96. CONCLUSIONS: this simple, short, observation-based screening scale completed by nurses is sensitive and specific in identifying depression in elderly medically ill patients, and may be a useful addition to clinical practice.

Neuroprotection in acute ischaemic stroke. II: Clinical potential.

In the 4 years since our first article, there has been considerable progress in our understanding of the pathophysiology of acute ischaemic stroke, and the results of well-conducted trials have at last begun to change everyday clinical practice. The timing of the various processes of the ischaemic cascade and the potential time windows for different interventions are better understood. Furthermore, the importance of maintaining cerebral perfusion and optimizing systemic physiological and biochemical factors in order to prevent neurological deterioration ('progressing stroke') is increasingly being realized. Numerous antithrombotic and neuroprotective drugs have been evaluated in clinical trials, and while none has shown unequivocal benefits on its own, prospects for successful intervention are still good. This will probably involve different combinations of treatments targeted on different pathophysiological stroke types, so that the management of acute stroke will offer a considerable challenge to the stroke physicians of the future.

Estimating total Barthel scores from just three items: the European Stroke Database 'minimum dataset' for assessing functional status at discharge from hospital.

BACKGROUND: The European Stroke Database (ESDB) Project aims to develop a 'common clinical language' for stroke care by agreeing on terminology, definitions and clinical assessments. Each area of stroke assessment has a 'minimum dataset', which can be collected routinely and more detailed information can be added for particular studies. Measurement of patients' functional status at discharge is essential for assessing the impact of hospital care, but even simple activities of daily living scales like the Barthel index may not be easy to use routinely on busy acute units. We thus aimed to further simplify the 20-point Barthel index by reducing it to a few key items. METHODS: We initially analysed data on 169 consecutive stroke patients discharged from one British hospital and found that a simple formula involving the combined subscores for urinary continence (Blad), bed-chair transfers C (Trans) and indoor mobility (Mob)-(Blad + Trans + Mob) x 2.39 + 0.14-predicted the total BI score to within 1 point in 79% and to within 2 points in 95% of cases. We then tested this three-item Barthel index (BI3) in four different stroke datasets (total n = 824). RESULTS: The predictions were accurate to +/-1 point in 72-81% and to +/-2 points in 88-97% of cases, and BI3 accounted for 95% of the variance in total Barthel score. It was more accurate in patients without obvious mental impairment. CONCLUSIONS: For studies involving large groups of stroke patients, it is sufficient to know about each patient's continence, transfers and indoor mobility at discharge, in order to estimate the total Barthel score. These measures have therefore been incorporated, together with a simple observational measure of cognitive status, into the database minimum dataset for short-term functional outcome and are now being validated in international studies.