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.

The influence of visual and tactile inattention on predictions for recovery from acute stroke.

Simple screening tests for visual and tactile inattention were used to investigate the influence of perceptual deficits on predictions for the outcome of acute stroke. This influence appeared to be minimal in patients aged over 70 and greatest in younger patients who were incontinent or more severely functionally impaired at the time of the perceptual assessment. When multivariate analysis was used to control for the effects of other prognostic factors, the relationship between visual inattention/hemianopia and functional outcome became very weak, but there was still a significant association with length of stay in hospital. By contrast, even after adjusting for covariates, tactile inattention at one month was still associated with a greater degree of functional impairment at six months. These results could have important practical implications. Poor performance on visuospatial tests may indicate the need for more prolonged rehabilitation rather than predicting failure of recovery. The inclusion of a test for tactile inattention may improve the predictive power of perceptual testing. Further prospective studies are needed to test these hypotheses.

The natural history and functional consequences of dysphagia after hemispheric stroke.

Data from 357 conscious stroke patients taking part in an acute intervention trial and assessed within 48 hours of the onset of symptoms, were used to investigate the prevalence and natural history of swallowing problems. Nearly 30% of patients with single-hemisphere strokes were initially found to have difficulty swallowing a mouthful of water, but in most of those who survived, the deficit had resolved by the end of the first week. Strong correlations were found between dysphagia and speech impairment (comprehension and expression) and with facial weakness, but there was no association with the side of the stroke. After controlling for other markers of overall stroke severity such as conscious level, urinary continence, white blood cell count and strength in the affected limbs, swallowing impairment still showed a significant inverse correlation with functional ability at 1 and 6 months. These results indicate that, even if dysphagia itself is not responsible for much excess mortality in acute stroke, it might still lead to complications which hamper functional recovery.

Continence after stroke: useful predictor or goal of therapy?

Natural-history data from 362 conscious stroke victims, taking part in an acute intervention trial, were used to explore the prevalence and time course of recovery of urinary incontinence, associations with other variables and the relationship between bladder control and neurological, functional and overall outcome. More than half the patients were incontinent when first seen, at a mean of 24 h after onset, but this proportion fell to 29% by 1 month and was halved again by 6 months. Outcome was so much better in those who remained or became dry that it seems possible that recovery of continence may promote morale and self-esteem which could actually hasten overall recovery. A controlled trial of a rehabilitation programme, concentrating on restoration of bladder control in the early stages of stroke, is now needed to test this possibility.

Predicting the outcome of acute stroke: do multivariate models help?

Data collected by a single observer on 362 patients taking part in an acute intervention trial were used to derive simple methods of predicting outcome in conscious stroke victims. The effectiveness of these univariate methods was then compared with that of multivariate models based on discriminant function analysis. The multivariate models were somewhat better at predicting death within the first month in newly-admitted patients, and in predicting lack of functional improvement between one and six months in those still in hospital at one month. Even so, these predictions could not be made with certainty and the improvements in probability offered by multivariate over univariate analysis are unlikely to be of practical benefit to the clinician. Single variables such as power in the affected arm and continence were as good as the discriminant functions at predicting discharge within the first month and first six months, respectively. The predictive power of these single simple clinical variables was validated in a separate group of 277 stroke patients. The various proposed methods of prognostication in stroke need to be compared in prospective studies, but until this is done, we recommend a simple approach using the best available clinical information.

The pragmatic approach to stroke trial design: stroke register, pilot trial, assessment of neurological then functional outcome.

Assessment of the results of medical intervention in acute stroke presents particular difficulties. Firstly the condition is extremely variable both in its clinical presentation and in its underlying pathology. Secondly, extreme care must be taken over the methods used to assess outcome. A reduction in mortality is no indication of success if there is a consequent increase in the number of survivors with extreme disability. Nor is it valid to compare functional or neurological outcome in survivors, since differences in mortality between treatment groups may upset the balancing effect of initial randomisation. Furthermore, overall 'neurological scores' are of dubious validity when the progress of patients with different patterns of disability has to be compared. Despite these difficulties a pragmatic approach can be used in which the design and conduct of a stroke trial closely resemble the normal clinical situation. This requires a knowledge of the range and natural history of stroke cases seen, best obtained from a stroke register. A pilot trial is then needed to assess the extent of variation in outcome and thus to estimate the numbers needed for the main study. The latter should then be conducted in two stages. Initially 'neurological benefit' should be assessed by counting the number of individual neurological signs which show improvement or deterioration in patients in each treatment group. Finally, a simple functional end-point should be compared in large numbers of patients with death being treated as equivalent to the worst possible non-fatal outcome. These principles are now being applied in a large, double-blind, placebo-controlled trial of low-dose beta-blockers in conscious stroke victims.

Predicting the outcome of acute stroke: prospective evaluation of five multivariate models and comparison with simple methods.

Five multivariate models designed to predict the outcome of stroke were tested prospectively on 102 consecutive stroke patients admitted to a district general hospital. The results were compared with predictions made using two simple clinical variables (the conscious level on admission and the state of urinary continence at four weeks). Of the three models (developed in Belfast, Guy's Hospital and Uppsala) intended for use in the acute stages of stroke the last two were slightly more accurate in their prediction of death (75%) than was the admission conscious level alone (65%), whereas the Belfast model had an accuracy of only 50% in this situation. At a later stage, the state of urinary continence predicted good and poor outcomes with similar accuracy to that of a multivariate model from Edinburgh. A model developed in Bristol performed poorly. When tested prospectively, these multivariate models proved considerably less accurate than when they were first described. Only the Uppsala model showed any advantage over simple clinical methods. This might be of value in defining prognostic strata for clinical studies, but not in the management of individual patients. Simple clinical variables thus offer as much to clinicians as complex multivariate models.

A randomised controlled trial of domiciliary and hospital-based rehabilitation for stroke patients after discharge from hospital.

This study compared the functional ability and perceived health status of stroke patients treated by a domiciliary rehabilitation team or by routine hospital-based services after discharge from hospital. Patients discharged from two acute and three rehabilitation hospitals in Nottingham were randomly allocated in three strata (Health Care of the Elderly, General Medical and Stroke Unit) to receive domiciliary or hospital-based care after discharge. Functional recovery was assessed by the Extended Activities of Daily Living (ADL) scale three and six months after discharge and perceived health at six months was measured by the Nottingham Health Profile. A total of 327 eligible patients of 1119 on a register of acute stroke admissions were recruited over 16 months. Overall there were no differences between the groups in their Extended ADL scores at three or six months, or their Nottingham Health Profile scores at six months. In the Stroke Unit stratum, patients treated by the domiciliary team had higher household (p = 0.02) and leisure activity (p = 0.04) scores at six months than those receiving routine care. In the Health Care of the Elderly stratum, death or a move into long-term institutional care at six months occurred less frequently in patients allocated to the routine service, about half of whom attended a geriatric day hospital. Overall there was no difference in the effectiveness of the domiciliary and hospital-based services, although younger stroke unit patients appeared to do better with home therapy while some frail elderly patients might have benefited from day hospital attendance.

Low dose beta blockade in acute stroke ("BEST" trial): an evaluation.

The beta blocker stroke ("BEST") trial was designed to see if the apparent protective effect of propranolol on cerebral function in patients with subarachnoid haemorrhage applied also to patients suffering from acute stroke. Three hundred and two conscious patients with clinically diagnosed hemispheric strokes sustained within the past 48 hours were randomly assigned to receive atenolol, propranolol, or matching placebo capsules for three weeks. More early deaths occurred among the patients allocated to receive beta blockers, but this was largely explained by differences in the initial characteristics of the patients among the different treatment groups. By contrast, the outcome in a further 60 patients, who had been taking beta blockers at the time of their stroke but were otherwise similar to the patients in the trial, was considerably better, suggesting that prior treatment with beta blockers might be protective. The search for an effective medical treatment for acute stroke must continue. The approach used here, in which neurological outcome was assessed in a modest number of patients with a view to proceeding subsequently to a full scale trial of functional outcome, allows practical benefits of a treatment to be evaluated under realistic conditions and an ineffective treatment to be eliminated without undue cost.

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.

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.