The role of cortisol in immunosuppression in subarachnoid haemorrhage.

BACKGROUND: We sought to determine the extent to which cortisol suppressed innate and T cell-mediated cytokine production and whether it could be involved in reducing peripheral cytokine production following subarachnoid haemorrhage (SAH). METHODS: Whole blood from healthy controls, patients with SAH and healthy volunteers was stimulated with lipopolysaccharide (LPS), to stimulate innate immunity, or phytohaemagglutinin (PHA), to stimulate T cell-mediated immunity. Varying concentrations of cortisol were included, with or without the cortisol antagonist RU486. Concentration of interleukin-6 (IL-6), IL-1ß and tumour necrosis factor-alpha) TNFα were determined as a measure of innate immunity. IL-6, IL-17 (interferon gamma) IFNƔ and IL-17 were determined as an indicator of T cell-mediated immunity. RESULTS: Suppression of innate responses to LPS was apparent in whole blood from SAH patients, relative to healthy controls, and TNFα production was inversely correlated with plasma cortisol concentration. Cytokine production in whole blood from healthy volunteers was inhibited by cortisol concentrations from 0.33 µM, or 1 µM and above, and these responses were effectively reversed by the cortisol antagonist RU-486. In SAH patients, RU-486 reversed suppression of innate TNF-α and IL-6 responses, but not IL-1ß or T cell-mediated responses. CONCLUSION: These data suggest that cortisol may play a role in reducing innate, but not T cell-mediated immune responses in patients with injuries such as SAH and that cortisol antagonists could be effective in boosting early innate responses.

Six-month reviews for stroke survivors: a study of the modified Greater Manchester Stroke Assessment Tool with care home residents.

OBJECTIVES: To explore the feasibility of using a stroke-specific toolkit for six-month post-stroke reviews in care homes to identify unmet needs and actions. DESIGN: An observational study including qualitative interviews to explore the process and outcome of reviews. SETTING: UK care homes. PARTICIPANTS: Stroke survivors, family members, care home staff (review participants) and external staff involved in conducting reviews (assessors). INTERVENTIONS: Modified Greater Manchester Stroke Assessment Tool (GM-SAT). RESULTS: The observational study provided data on 74 stroke survivors across 51 care homes. In total, out of 74, 45 (61%) had unmet needs identified. Common unmet needs related to blood pressure, mobility, medicine management and mood. We conducted 25 qualitative interviews, including 13 review participants and 12 assessors. Three overarching qualitative themes covered acceptability of conducting reviews in care homes, process and outcomes of reviews, and acceptability of modified GM-SAT review toolkit. The modified GM-SAT review was positively valued, but stroke survivors had poor recall of the review event including the actions agreed. Care home staff sometimes assisted with reviews and highlighted their need for training to support day-to-day needs of stroke survivors. Assessors highlighted a need for clearer guidance on the use of the toolkit and suggested further modifications to enhance it. They also identified organizational barriers and facilitators to implementing reviews and communicating planned actions to GPs and other agencies. CONCLUSION: The modified GM-SAT provides a feasible means of conducting six-month reviews for stroke survivors in care homes and helps identify important needs. Further modifications have enhanced acceptability. Full implementation into practice requires staff training and organizational changes.

Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2).

BACKGROUND: Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute-chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study. METHODS: We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2-13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation. FINDINGS: Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures. INTERPRETATION: Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials. FUNDING: ReNeuron, Innovate UK (application no 32074-222145). TRIAL REGISTRATION NUMBER: EudraCT Number: 2012-003482-18.

Impact and sustainability of centralising acute stroke services in English metropolitan areas: retrospective analysis of hospital episode statistics and stroke national audit data.

OBJECTIVES: To investigate whether further centralisation of acute stroke services in Greater Manchester in 2015 was associated with changes in outcomes and whether the effects of centralisation of acute stroke services in London in 2010 were sustained. DESIGN: Retrospective analyses of patient level data from the Hospital Episode Statistics (HES) database linked to mortality data from the Office for National Statistics, and the Sentinel Stroke National Audit Programme (SSNAP). SETTING: Acute stroke services in Greater Manchester and London, England. PARTICIPANTS: 509 182 stroke patients in HES living in urban areas admitted between January 2008 and March 2016; 218 120 stroke patients in SSNAP between April 2013 and March 2016. INTERVENTIONS: Hub and spoke models for acute stroke care. MAIN OUTCOME MEASURES: Mortality at 90 days after hospital admission; length of acute hospital stay; treatment in a hyperacute stroke unit; 19 evidence based clinical interventions. RESULTS: In Greater Manchester, borderline evidence suggested that risk adjusted mortality at 90 days declined overall; a significant decline in mortality was seen among patients treated at a hyperacute stroke unit (difference-in-differences -1.8% (95% confidence interval -3.4 to -0.2)), indicating 69 fewer deaths per year. A significant decline was seen in risk adjusted length of acute hospital stay overall (-1.5 (-2.5 to -0.4) days; P<0.01), indicating 6750 fewer bed days a year. The number of patients treated in a hyperacute stroke unit increased from 39% in 2010-12 to 86% in 2015/16. In London, the 90 day mortality rate was sustained (P>0.05), length of hospital stay declined (P<0.01), and more than 90% of patients were treated in a hyperacute stroke unit. Achievement of evidence based clinical interventions generally remained constant or improved in both areas. CONCLUSIONS: Centralised models of acute stroke care, in which all stroke patients receive hyperacute care, can reduce mortality and length of acute hospital stay and improve provision of evidence based clinical interventions. Effects can be sustained over time.

The potential role of cost-utility analysis in the decision to implement major system change in acute stroke services in metropolitan areas in England.

BACKGROUND: The economic implications of major system change are an important component of the decision to implement health service reconfigurations. Little is known about how best to report the results of economic evaluations of major system change to inform decision-makers. Reconfiguration of acute stroke care in two metropolitan areas in England, namely London and Greater Manchester (GM), was used to analyse the economic implications of two different implementation strategies for major system change. METHODS: A decision analytic model was used to calculate difference-in-differences in costs and outcomes before and after the implementation of two major system change strategies in stroke care in London and GM. Values in the model were based on patient level data from Hospital Episode Statistics, linked mortality data from the Office of National Statistics and data from two national stroke audits. Results were presented as net monetary benefit (NMB) and using Programme Budgeting and Marginal Analysis (PBMA) to assess the costs and benefits of a hypothetical typical region in England with approximately 4000 strokes a year. RESULTS: In London, after 90 days, there were nine fewer deaths per 1000 patients compared to the rest of England (95% CI -24 to 6) at an additional cost of £770,027 per 1000 stroke patients admitted. There were two additional deaths (95% CI -19 to 23) in GM, with a total costs saving of £156,118 per 1000 patients compared to the rest of England. At a £30,000 willingness to pay the NMB was higher in London and GM than the rest of England over the same time period. The results of the PBMA suggest that a GM style reconfiguration could result in a total greater health benefit to a region. Implementation costs were £136 per patient in London and £75 in GM. CONCLUSIONS: The implementation of major system change in acute stroke care may result in a net health benefit to a region, even one functioning within a fixed budget. The choice of what model of stroke reconfiguration to implement may depend on the relative importance of clinical versus cost outcomes.

Why do stroke survivors not receive recommended amounts of active therapy? Findings from the ReAcT study, a mixed-methods case-study evaluation in eight stroke units.

OBJECTIVE: To identify why the National Clinical Guideline recommendation of 45 minutes of each appropriate therapy daily is not met in many English stroke units. DESIGN: Mixed-methods case-study evaluation, including modified process mapping, non-participant observations of service organisation and therapy delivery, documentary analysis and semi-structured interviews. SETTING: Eight stroke units in four English regions. SUBJECTS: Seventy-seven patients with stroke, 53 carers and 197 stroke unit staff were observed; 49 patients, 50 carers and 131 staff participants were interviewed. RESULTS: Over 1000 hours of non-participant observations and 433 patient-specific therapy observations were undertaken. The most significant factor influencing amount and frequency of therapy provided was the time therapists routinely spent, individually and collectively, in information exchange. Patient factors, including fatigue and tolerance influenced therapists' decisions about frequency and intensity, typically resulting in adaptation of therapy rather than no provision. Limited use of individual patient therapy timetables was evident. Therapist staffing levels were associated with differences in therapy provision but were not the main determinant of intensity and frequency. Few therapists demonstrated understanding of the evidence underpinning recommendations for increased therapy frequency and intensity. Units delivering more therapy had undertaken patient-focused reorganisation of therapists' working practices, enabling them to provide therapy consistent with guideline recommendations. CONCLUSION: Time spent in information exchange impacted on therapy provision in stroke units. Reorganisation of therapists' work improved alignment with guidelines.

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial.

BACKGROUND AND PURPOSE: The proinflammatory cytokine IL-1 (interleukin-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. METHODS: SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale. RESULTS: We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 (P<0.001) and plasma C-reactive protein (P<0.001). IL-1Ra was well tolerated with no safety concerns. Allocation to IL-1Ra was not associated with a favorable outcome on modified Rankin Scale: odds ratio (95% confidence interval)=0.67 (0.29-1.52), P=0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. CONCLUSIONS: IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229.

Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study.

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event with long-term morbidity and mortality. Patients who survive the initial bleeding are likely to suffer further early brain injury arising from a plethora of pathological processes. These may result in a worsening of outcome or death in approximately 25% of patients and may contribute to longer-term cognitive dysfunction in survivors. Inflammation, mediated by the cytokine interleukin-1 (IL-1), is an important contributor to cerebral ischemia after diverse forms of brain injury, including aSAH. Its effects are attenuated by its naturally occurring antagonist, IL-1 receptor antagonist (IL-1Ra [anakinra]). The authors hypothesized that administration of additional subcutaneous IL-1Ra would reduce inflammation and associated plasma markers associated with poor outcome following aSAH. METHODS This was a randomized, open-label, single-blinded study of 100 mg subcutaneous IL-1Ra, administered twice daily in patients with aSAH, starting within 3 days of ictus and continuing until 21 days postictus or discharge from the neurosurgical center, whichever was earlier. Blood samples were taken at admission (baseline) and at Days 3-8, 14, and 21 postictus for measurement of inflammatory markers. The primary outcome was difference in plasma IL-6 measured as area under the curve between Days 3 and 8, corrected for baseline value. Secondary outcome measures included similar area under the curve analyses for other inflammatory markers, plasma pharmacokinetics for IL-1Ra, and clinical outcome at 6 months. RESULTS Interleukin-1Ra significantly reduced levels of IL-6 and C-reactive protein (p < 0.001). Fibrinogen levels were also reduced in the active arm of the study (p < 0.002). Subcutaneous IL-1Ra was safe, well tolerated, and had a predictable plasma pharmacokinetic profile. Although the study was not powered to investigate clinical effect, scores of the Glasgow Outcome Scale-extended at 6 months were better in the active group; however, this outcome did not reach statistical significance. CONCLUSIONS Subcutaneous IL-1Ra is safe and well tolerated in aSAH. It is effective in reducing peripheral inflammation. These data support a Phase III study investigating the effect of IL-1Ra on outcome following aSAH. Clinical trial registration no.: EudraCT: 2011-001855-35 ( www.clinicaltrialsregister.eu ).

Bespoke versus off-the-shelf ankle-foot orthosis for people with stroke: randomized controlled trial.

OBJECTIVE: The aim of the study was to compare the effect of two designs of ankle-foot orthosis on people with stroke. DESIGN: The study design was an assessor-blind, multicentre randomized controlled trial. SETTING: The setting was community stroke services. PARTICIPANTS: A total of 139 community-dwelling stroke survivors with limited mobility were recruited. INTERVENTIONS: The two most commonly used types of ankle-foot orthosis (bespoke and off-the-shelf) were chosen. MAIN MEASURES: The main measures of the study were as follows: short- (6 weeks) and long-term (12 weeks) effects on stroke survivors' satisfaction; adverse events; mobility (Walking Handicap Scale); fear of falling (Falls Efficacy Scale-International (FES-I)) and walking impairments (gait speed and step length using the 5-m walk test). RESULTS: Long-term satisfaction was non-significantly higher in the off-the-shelf group: 72% versus 64%; OR (95% CI) = 0.64 (0.31 to 1.3); P = 0.21. No statistically significant differences were found between the orthoses except that the off-the-shelf group had less fear of falling at short-term follow-up than the bespoke group: mean difference (95% CI) = -4.6 (-7.6 to -1.6) points on the FES-I; P = 0.003. CONCLUSION: No differences between off-the-shelf and bespoke ankle-foot orthoses were found except that participants in the off-the-shelf orthosis group had less fear of falling at short-term follow-up.

The Nottingham Fatigue after Stroke (NotFAST) study: factors associated with severity of fatigue in stroke patients without depression.

OBJECTIVE: To identify factors associated with post-stroke fatigue in a sample of stroke survivors without depression. DESIGN: Cross-sectional cohort study. SETTING: Recruitment was from four stroke units in the UK. SUBJECTS: Participants were assessed within four to six weeks of first stroke; those with high levels of depressive symptoms (score ⩾7 Brief Assessment Schedule Depression Cards) were excluded. MAIN MEASURES: Participants were assessed after stroke on the Fatigue Severity Scale of the Fatigue Assessment Inventory, the Rivermead Mobility Index, Nottingham Extended Activities of Daily Living scale, Beck Anxiety Index, Sleep Hygiene Index, 6m walk test, and measures of cognitive ability. RESULTS: Of the 371 participants recruited, 103 were excluded and 268 were assessed. Of the latter, the mean age was 67.7 years (SD 13.5) and 168 (63%) were men. The National Institutes of Health Stroke Scale mean score was 4.96 (SD 4.12). Post-stroke fatigue was reported by 115 (43%) of participants, with 71 (62%) reporting this to be a new symptom since their stroke. Multivariate analysis using the Fatigue Severity Scale as the outcome variable found pre-stroke fatigue, having a spouse/partner, lower Rivermead Mobility Index score, and higher scores on both the Brief Assessment Schedule Depression Cards and Beck Anxiety Index were independently associated with post-stroke fatigue, accounting for approximately 47% of the variance in Fatigue Severity Scale scores. CONCLUSIONS: Pre-stroke fatigue, lower mood, and poorer mobility were associated with post-stroke fatigue.

The Nottingham Fatigue After Stroke (NotFAST) study: results from follow-up six months after stroke.

Background Post-stroke fatigue is common and disabling. Objectives The aim of NotFAST was to examine factors associated with fatigue in stroke survivors without depression, six months after stroke. Methods Participants were recruited from four UK stroke units. Those with high levels of depressive symptoms (score ≥7 on Brief Assessment Schedule Depression Cards) or aphasia were excluded. Follow-up assessment was conducted at six months after stroke. They were assessed on the Fatigue Severity Scale, Rivermead Mobility Index, Nottingham Extended Activities of Daily Living scale, Barthel Index, Beck Anxiety Index, Brief Assessment Schedule Depression Cards, Impact of Event Scale-Revised, and Sleep Hygiene Index. Results Of the 371 participants recruited, 263 (71%) were contacted at six months after stroke and 213 (57%) returned questionnaires. Approximately half (n = 109, 51%) reported fatigue at six months. Of those reporting fatigue initially (n = 88), 61 (69%) continued to report fatigue. 'De novo' (new) fatigue was reported by 48 (38%) of those not fatigued initially. Lower Nottingham Extended Activities of Daily Living scores and higher Beck Anxiety Index scores were independently associated with fatigue at six months. Conclusions Half the stroke survivors reported fatigue at six months post-stroke. Reduced independence in activities of daily living and higher anxiety levels were associated with the level of fatigue. Persistent and delayed onset fatigue may affect independence and participation in rehabilitation, and these findings should be used to inform the development of appropriate interventions.

The association between delays in screening for and assessing dysphagia after acute stroke, and the risk of stroke-associated pneumonia.

BACKGROUND: There is no robust evidence that screening patients with acute stroke for dysphagia reduces the risk of stroke-associated pneumonia (SAP), or of how quickly it should be done after admission. We aimed to identify if delays in bedside dysphagia screening and comprehensive dysphagia assessments by a speech and language therapist (SALT) were associated with patients' risk of SAP. METHODS: Nationwide, registry-based, prospective cohort study of patients admitted with acute stroke in England and Wales. Multilevel multivariable logistic regression models were fitted, adjusting for patient variables and stroke severity. The exposures were time from (1) admission to bedside dysphagia screen, and (2) admission to comprehensive dysphagia assessment. RESULTS: Of 63 650 patients admitted with acute stroke, 55 838 (88%) had a dysphagia screen, and 24 542 (39%) a comprehensive dysphagia assessment. Patients with the longest delays in dysphagia screening (4th quartile adjusted OR 1.14, 1.03 to 1.24) and SALT dysphagia assessment (4th quartile adjusted OR 2.01, 1.76 to 2.30) had a higher risk of SAP. The risk of SAP increased in a dose-response manner with delays in SALT dysphagia assessment, with an absolute increase of pneumonia incidence of 1% per day of delay. CONCLUSIONS: Delays in screening for and assessing dysphagia after stroke, are associated with higher risk of SAP. Since SAP is one of the main causes of mortality after acute stroke, early dysphagia assessment may contribute to preventing deaths from acute stroke and could be implemented even in settings without access to high-technology specialist stroke care.

Development and feasibility testing of an oral hygiene intervention for stroke unit care.

OBJECTIVE: To develop an oral hygiene complex intervention and evaluate its feasibility in a single UK stroke centre. BACKGROUND: Oral hygiene interventions might improve clinical outcomes after stroke but evidence-based practice is lacking. MATERIALS AND METHODS: We used a sequential mixed methods approach and developed an oral hygiene complex intervention comprising: (i) web-based education and 'hands-on' practical training for stroke unit nursing staff, (ii) a pragmatic oral hygiene protocol consisting of twice-daily powered (or manual if preferred) brushing with chlorhexidine gel (or non-foaming toothpaste) ± denture care. We evaluated feasibility of (i) the staff education and training and (ii) the oral hygiene protocol in consenting inpatients with confirmed stroke, requiring assistance with at least one aspect of personal care. RESULTS: The staff education and training were feasible, acceptable and raised knowledge and awareness. Several barriers to completing the education and training were identified. The oral hygiene protocol was feasible and well-tolerated. 22% of eligible patients screened declined participation in the study. Twenty-nine patients (median age = 78 year; National Institutes of Health Stroke Scale score = 8.5; 73% dentate) were recruited at a median of 7 days from stroke onset. 97% of participants chose the default chlorhexidine-based protocol; the remainder chose the non-foaming toothpaste-based protocol. The mouth hygiene protocol was administered as prescribed on 95% of occasions, over a median duration of 28 days. There were no adverse events attributed to the oral hygiene protocol. CONCLUSION: Our oral hygiene complex intervention was feasible in a single UK stroke centre. Further studies to optimise patient selection, model health economics and explore efficacy are now required.

Explaining outcomes in major system change: a qualitative study of implementing centralised acute stroke services in two large metropolitan regions in England.

BACKGROUND: Implementing major system change in healthcare is not well understood. This gap may be addressed by analysing change in terms of interrelated components identified in the implementation literature, including decision to change, intervention selection, implementation approaches, implementation outcomes, and intervention outcomes. METHODS: We conducted a qualitative study of two cases of major system change: the centralisation of acute stroke services in Manchester and London, which were associated with significantly different implementation outcomes (fidelity to referral pathway) and intervention outcomes (provision of evidence-based care, patient mortality). We interviewed stakeholders at national, pan-regional, and service-levels (n = 125) and analysed 653 documents. Using a framework developed for this study from the implementation science literature, we examined factors influencing implementation approaches; how these approaches interacted with the models selected to influence implementation outcomes; and their relationship to intervention outcomes. RESULTS: London and Manchester's differing implementation outcomes were influenced by the different service models selected and implementation approaches used. Fidelity to the referral pathway was higher in London, where a 'simpler', more inclusive model was used, implemented with a 'big bang' launch and 'hands-on' facilitation by stroke clinical networks. In contrast, a phased approach of a more complex pathway was used in Manchester, and the network acted more as a platform to share learning. Service development occurred more uniformly in London, where service specifications were linked to financial incentives, and achieving standards was a condition of service launch, in contrast to Manchester. 'Hands-on' network facilitation, in the form of dedicated project management support, contributed to achievement of these standards in London; such facilitation processes were less evident in Manchester. CONCLUSIONS: Using acute stroke service centralisation in London and Manchester as an example, interaction between model selected and implementation approaches significantly influenced fidelity to the model. The contrasting implementation outcomes may have affected differences in provision of evidence-based care and patient mortality. The framework used in this analysis may support planning and evaluating major system changes, but would benefit from application in different healthcare contexts.

Weekly variation in health-care quality by day and time of admission: a nationwide, registry-based, prospective cohort study of acute stroke care.

BACKGROUND: Studies in many health systems have shown evidence of poorer quality health care for patients admitted on weekends or overnight than for those admitted during the week (the so-called weekend effect). We postulated that variation in quality was dependent on not only day, but also time, of admission, and aimed to describe the pattern and magnitude of variation in the quality of acute stroke care across the entire week. METHODS: We did this nationwide, registry-based, prospective cohort study using data from the Sentinel Stroke National Audit Programme. We included all adult patients (aged >16 years) admitted to hospital with acute stroke (ischaemic or primary intracerebral haemorrhage) in England and Wales between April 1, 2013, and March 31, 2014. Our outcome measure was 30 day post-admission survival. We estimated adjusted odds ratios for 13 indicators of acute stroke-care quality by fitting multilevel multivariable regression models across 42 4-h time periods per week. FINDINGS: The study cohort comprised 74,307 patients with acute stroke admitted to 199 hospitals. Care quality varied across the entire week, not only between weekends and weekdays, with different quality measures showing different patterns and magnitudes of temporal variation. We identified four patterns of variation: a diurnal pattern (thrombolysis, brain scan within 12 h, brain scan within 1 h, dysphagia screening), a day of the week pattern (stroke physician assessment, nurse assessment, physiotherapy, occupational therapy, and assessment of communication and swallowing by a speech and language therapist), an off-hours pattern (door-to-needle time for thrombolysis), and a flow pattern whereby quality changed sequentially across days (stroke-unit admission within 4 h). The largest magnitude of variation was for door-to-needle time within 60 min (range in quality 35-66% [16/46-232/350]; coefficient of variation 18·2). There was no difference in 30 day survival between weekends and weekdays (adjusted odds ratio 1·03, 95% CI 0·95-1·13), but patients admitted overnight on weekdays had lower odds of survival (0·90, 0·82-0·99). INTERPRETATION: The weekend effect is a simplification, and just one of several patterns of weekly variation occurring in the quality of stroke care. Weekly variation should be further investigated in other health-care settings, and quality improvement should focus on reducing temporal variation in quality and not only the weekend effect. FUNDING: None.

Lessons for major system change: centralization of stroke services in two metropolitan areas of England.

OBJECTIVES: Our aim was to identify the factors influencing the selection of a model of acute stroke service centralization to create fewer high-volume specialist units in two metropolitan areas of England (London and Greater Manchester). It considers the reasons why services were more fully centralized in London than in Greater Manchester. METHODS: In both areas, we analysed 316 documents and conducted 45 interviews with people leading transformation, service user organizations, providers and commissioners. Inductive and deductive analyses were used to compare the processes underpinning change in each area, with reference to propositions for achieving major system change taken from a realist review of the existing literature (the Best framework), which we critique and develop further. RESULTS: In London, system leadership was used to overcome resistance to centralization and align stakeholders to implement a centralized service model. In Greater Manchester, programme leaders relied on achieving change by consensus and, lacking decision-making authority over providers, accommodated rather than challenged resistance by implementing a less radical transformation of services. CONCLUSIONS: A combination of system (top-down) and distributed (bottom-up) leadership is important in enabling change. System leadership provides the political authority required to coordinate stakeholders and to capitalize on clinical leadership by aligning it with transformation goals. Policy makers should examine how the structures of system authority, with performance management and financial levers, can be employed to coordinate transformation by aligning the disparate interests of providers and commissioners.

Care-limiting decisions in acute stroke and association with survival: analyses of UK national quality register data.

BACKGROUND: Prognosis after intracerebral hemorrhage (ICH) is poor and care-limiting decisions may worsen outcomes. AIMS: To determine whether in current UK stroke practice, key acute care decisions are associated with stroke subtype (ICH/ischemic) and whether these decisions are independently associated with survival. METHODS: We extracted data describing all stroke patients included in a UK quality register between 1 April 2013 and 31 March 2014. Key care decisions in our analyses were transfer to higher level care on admission and palliation in the first 72 h. We used multivariable regression models to test for associations between stroke subtype (ICH/ischemic), key care decisions, and survival. RESULTS: A total of 65,818 patients were included in the final analysis. After ICH (n = 7020/65,818, 10.7%), 10.5% were palliated on the day of admission and 19.3% by 72 h (vs. 0.7% and 3.3% for ischemic stroke). Although a greater proportion were admitted directly to higher level care after ICH (3.7% vs. 1.5% for ischemic stroke), ICH was not independently associated with the decision to admit to higher level care (adjusted odds ratio (OR): 1.12, 95% confidence interval (95%CI): 0.95-1.31, p = 0.183). However, ICH was strongly associated with the decision to commence palliative care on the day of admission (OR: 7.27, 95%CI: 6.31-8.37, p < 0.001). Palliative care was independently associated with risk of death by 30 days regardless of stroke subtype. CONCLUSIONS: When compared to ischemic stroke, patients with ICH are much more likely to commence palliative care during the first 72 h of their care, independent of level of consciousness, age, and premorbid health.

Clinical risk scores for predicting stroke-associated pneumonia: A systematic review.

PURPOSE: Several risk stratification scores for predicting stroke-associated pneumonia have been derived. We aimed to evaluate the performance and clinical usefulness of such scores for predicting stroke-associated pneumonia. METHOD: A systematic literature review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, with application of the Quality Assessment of Diagnostic Accuracy-2 tool. Published studies of hospitalised adults with ischaemic stroke, intracerebral haemorrhage, or both, which derived and validated an integer-based clinical risk score, or externally validated an existing score to predict occurrence of stroke-associated pneumonia, were considered and independently screened for inclusion by two reviewers. FINDINGS: We identified nine scores, from eight derivation cohorts. Age was a component of all scores, and the NIHSS score in all except one. Six scores were internally validated and five scores were externally validated. The A2DS2 score (Age, Atrial fibrillation, Dysphagia, Severity [NIHSS], Sex) was the most externally validated in 8 independent cohorts. Performance measures were reported for eight scores. Discrimination tended to be more variable in the external validation cohorts (C statistic 0.67-0.83) than the derivation cohorts (C statistic 0.74-0.85). DISCUSSION: Overall, discrimination and calibration were similar between the different scores. No study evaluated influence on clinical decision making or prognosis. CONCLUSION: The clinical prediction scores varied in their simplicity of use and were comparable in performance. Utility of such scores for preventive intervention trials and in clinical practice remains uncertain and requires further study.

Study design and population pharmacokinetic analysis of a phase II dose-ranging study of interleukin-1 receptor antagonist.

Interleukin-1 receptor antagonist, a naturally-occurring antagonist to the pro-inflammatory cytokine Interleukin-1, is already in clinical use. In experimental models of stroke, Interleukin-1 receptor antagonist in cerebrospinal fluid has been associated with cerebral neuroprotection and in a phase I clinical trial in patients with subarachnoid haemorrhage it crosses the blood-cerebrospinal fluid barrier. The aims of the current work were to design a dose-ranging clinical study in patients and to analyse the plasma and cerebrospinal fluid data obtained using a population pharmacokinetic modelling approach. The study was designed using prior information: a published population pharmacokinetic model and associated parameter estimates. Simulations were carried out to identify combinations of intravenous bolus and 4 h infusion doses that could achieve a concentration of 100 ng/ml in cerebrospinal fluid within approximately 30 min. The most informative time points for plasma and cerebrospinal fluid were obtained prospectively; optimisation identified five sampling time points that were included in the 15 time points in the present study design. All plasma and cerebrospinal fluid concentration data from previous and current studies were combined for updated analysis. The result of the simulations showed that a dosage regimen of 500 mg intravenous bolus and 10 mg/kg/h could achieve the target concentration, however four other regimens that represent a stepwise increase in maximum concentration were also selected. Analysis of the updated data showed improvement in parameter accuracy and predictive performance of the model; the percentage relative standard errors for fixed and random-effects parameters were <15 and 35% respectively. A dose-ranging study was successfully designed using modelling and simulation.