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.

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.

Vitamin C status and other nutritional indices in patients with stroke and other acute illnesses: a case-control study.

Sixty-three patients with acute thrombotic stroke were compared with 47 age and sex-matched patients admitted concurrently with acute ischaemic cardiac pain and a further 44 with acute noncardiovascular illnesses. Overall the stroke patients scored highest on a questionnaire designed to estimate mean daily intake of vitamin C before hospital admission. There were problems with this retrospective dietary assessment, however, and the diet scores of the 27 stroke patients able to answer the questionnaire themselves fell between those of the other two groups. There were no significant differences between the three patient groups in plasma ascorbic acid or uric acid levels, but plasma magnesium and albumin levels were higher in the stroke patients. These findings were similar for patients aged over and under 70 but intergroup differences in magnesium and albumin levels were more marked in the elderly. These results do not support the postulated inverse relationship between vitamin C status and the risk of stroke.

Measuring disability after a stroke.

A ranked activities of daily living (ADL) scale has been developed for stroke patients, on which an individual's score predicts his/her overall function ability. With an unranked scale the same total score can be obtained from different combinations of items and gives little idea of the patient's general pattern or degree of disability. The items in the scale are easy to assess on both inpatients and outpatients, and accepted criteria for valid ranking are fulfilled. A strong relation was found between scale score one month post-stroke and length of stay in hospital. Low scores at one month were also associated with high mortality during the subsequent five months. "Formal" and "informal" methods of ADL assessment were compared, and only small and unimportant differences were found. Assessments by postal questionnaire were also evaluated and agreed well with formal assessments carried out by visiting the patients' homes. Use of some or all of these methods would help to simplify and standardise follow up records for both routine care and research.

Use of the Nottingham Health Profile with patients after a stroke.

The Nottingham Health Profile (NHP) is easy to use with stroke patients and may be used with those who cannot manage more complicated mood questionnaires, such as the General Health Questionnaire (GHQ). Stroke patients rate their health, and especially emotions and feelings of social isolation, as much worse than that of people of similar age. NHP emotion scores correlate with objective measures of disability, length of hospital stay, and GHQ scores. The NHP is a valid indicator of depressed mood, and combining its components into a total score gives the greatest accuracy in detecting depression. Patients with high scores at one month continued to report large numbers of problems at six months after their stroke. Many patients experienced pain, disturbed sleep, and social isolation, which are important, potentially treatable problems not usually considered in the management of stroke patients. Many patients with problems did not see their general practitioner or any other source of help, and additional follow up was needed.

Emergency care episodes: an economic profile.

A new "episode of care" definition of emergency care was developed, consisting of the emergency department encounter and all subsequent, related care delivered within 48 hrs from the initial contact. Data were analyzed by ICD-9-CM Major Diagnostic Category (MDC) and surgical intervention using 1.6 million episodes generated by 809,145 separate patients from a national claims database. Secondary/adjunct services were a major component of episode charges. For several MDCs, hospitalization and/or surgical procedures were also major determinants of overall episodic charges. Results support the premise that economic analysis and reimbursement of emergency care benefits from the use of episodic data.

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.

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.

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.

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.