Mark Barber

Hemostatic Function and Progressing Ischemic Stroke D-dimer Predicts Early Clinical Progression

Background and Purpose— Early clinical progression of ischemic stroke is common and is associated with increased risk of death and dependency. We hypothesized that activation of the coagulation system is an important contributor in some cases of deterioration. We aimed to characterize alterations in circulating hemostatic markers in patients with progressing stroke. Methods— Consecutive acute ischemic stroke admissions were recruited. Progressing stroke was defined by deterioration in components of the Scandinavian Stroke Scale. Hemostatic markers (coagulation factors VIIc, VIIIc, and IXc, prothrombin fragments 1+2 [F1+2], thrombin–antithrombin complexes [TAT], D-dimer, fibrinogen, von Willebrand factor [vWF] and tissue plasminogen activator) were measured within 24 hours of symptom recognition. Results— Fifty-four (25%) of the 219 patients met criteria for progressing stroke. F1+2 (median 1.28 versus 1.06 nmol/L, P = 0.01), TAT (5.28 versus 4.07 μg/L, P < 0.01), D-dimer (443 versus 194 ng/mL, P < 0.001) and vWF (216 versus 198 IU/dL, P < 0.05) levels were higher in these patients than in stable/improving patients. In logistic regression analysis, with all important clinical and laboratory variables included, only natural log D-dimer (odds ratio [OR]: 1.87; 95% confidence interval [CI]: 1.38 to 2.54; P = 0.0001) and mean arterial blood pressure (OR: 1.26 per 10 mm Hg change; 95% CI: 1.05 to 1.51; P = 0.01) remained independent predictors of progressing stroke. Conclusions— There is evidence of excess thrombin generation and fibrin turnover in patients with progressing ischemic stroke. Measurement of D-dimer levels can identify patients at high risk for stroke progression. Further research is required to determine whether such patients benefit from acute interventions aimed at modifying hemostatic function.

Elevated Troponin Levels Are Associated with Sympathoadrenal Activation in Acute Ischaemic Stroke

Background: It has been hypothesised that elevated serum troponin levels in acute stroke are due to myocardial damage caused by sympathoadrenal activation, which, in turn, may be due particularly to insular damage. We aimed to determine the factors associated with troponin elevation in ischaemic stroke and the prognostic value of this finding. Methods: We studied 222 consecutive acute ischaemic stroke admissions. Serum troponin I and catecholamines were measured. Ischaemic damage on brain computed tomography (CT) scan was graded using the Alberta Stroke Program Early CT Score (ASPECTS). Electrocardiograms were classified using the Minnesota Code and the European Society of Cardiology/American College of Cardiology criteria for acute myocardial infarction. The Rankin scale was recorded at 30 days. Results: Forty-five patients (20%) had troponin I >0.2 µg/l. These troponin-positive patients had higher epinephrine levels (median 0.27 vs. 0.17 nmol/l; p = 0.0002) and were more likely to have electrocardiograms coded as definite or possible acute myocardial infarction (odds ratio 3.35; 95% CI 1.26–8.93), compared with those with troponin ≤0.2 µg/l, in univariate analysis. There were no significant associations between troponin I score and ASPECTS or insular damage on brain CT. In logistic regression analyses, elevated troponin was significantly associated with age, elevated serum creatinine and epinephrine; however, increased troponin was not an independent predictor of death or dependency (Rankin >2) at 30 days. Conclusions: Raised troponin I is associated with elevation of circulating epinephrine in acute ischaemic stroke. Activation of the sympathoadrenal system may be an important contributor to myocardial damage in these patients. Increased troponin is not associated with insular damage and does not independently predict poor outcome.

Associations of Inflammatory and Haemostatic Biomarkers with Poor Outcome in Acute Ischaemic Stroke

Background: Many inflammatory and haemostatic biomarkers show associations with acute ischaemic stroke outcome, but few studies compare a large range of markers. Methods: We assessed clinical status and 16 biomarkers within 24 h of onset in 180 consecutive acute ischaemic stroke patients. Results: A total of 94 patients had a poor outcome (dead or dependent at 30 days). C-reactive protein (CRP), IL-6, and fibrin D-dimer showed the strongest univariate associations with poor outcome (>2-fold increase; p < 0.01). When all biomarkers were included with clinical variables in a multivariable model, only D-dimer (OR 1.54; 95% CI 1.09–2.17), CRP (OR 1.31; 95% CI 1.03–1.68) and Scandinavian Stroke Scale (OR 0.91; 95% CI 0.88–0.95) were associated with poor outcome. Conclusions:D-dimer and CRP are independently associated with poor outcome in acute ischaemic stroke. More data is required to expand our understanding of these potential relationships with outcome.

Validity and Reliability of Estimating the Scandinavian Stroke Scale Score from Medical Records

Background: Reliable estimation of severity of neurological impairments early after stroke is essential for research and audit of acute stroke care. Obtaining this information prospectively requires significant resources. We wished to assess the reliability of estimating the Scandinavian Stroke Scale (SSS) score retrospectively from routine hospital admission records. Methods: Acute stroke admissions to a large urban hospital were examined and had their SSS scored by an experienced physician within 4 h of the examination performed by the medical admissions team. Two examiners (a trained research nurse and a second physician), blinded to the patients’ clinical condition, later independently estimated retrospective SSS scores using information documented in the medical admission notes. Results: Fifty patients were recruited [median age 73 years (interquartile range 61, 79)]. Weighted kappa statistics for agreement between domains of the face-to-face and retrospective SSS were as follows: consciousness 0.73, eye movements 0.60, arm motor power 0.83, hand motor power 0.71, leg motor power 0.81, orientation 0.81, speech 0.80, and facial palsy 0.53. The intraclass correlation coefficient for face-to-face and retrospective SSS composite scores was 0.97 (95% CI 0.96–0.98), p < 0.0001. Interobserver reliability for the different components of the retrospective SSS was excellent (kappa values greater than 0.75) apart from consciousness (0.71) and eye movements (0.58). Conclusions: The composite SSS score and most of its individual components can be reliably estimated retrospectively from routine hospital admission records. This method is potentially useful both in observational studies and in case-mix adjustment for audit purposes.

d-Dimer Predicts Early Clinical Progression in Ischemic Stroke: Confirmation Using Routine Clinical Assays

Background and Purpose— Plasma d-dimer levels, measured using a research laboratory assay, independently predict progressing ischemic stroke. We wished to confirm these findings using commercially available assays and to provide data to allow the design of intervention studies. Methods— We studied 219 consecutive acute ischemic stroke admissions of whom 54 (25%) met criteria for progressing stroke. Results— There were strong correlations between d-dimer results as measured by the Biopool AB, MDA and VIDAS assays; correlation coefficients r=0.91 to 0.94; all P<0.001. In binary logistic regression analyses, d-dimer, as measured by the 3 different assays, was an independent predictor of progressing stroke (odds ratios, 1.87 to 2.45; all P<0.001). This confirms the results of our original analysis (Biopool AB) using 2 commercial d-dimer assays, demonstrating the potential usefulness of d-dimer in providing early prognostic information after ischemic stroke in different clinical settings. We also provide information on the performance of the 3 assays in predicting progressing stroke at a variety of cutoff values. Conclusions— Ischemic stroke patients at high risk of early progression can be identified using commercial d-dimer measurements. This could allow selection of high-risk patients for inclusion in randomized trials of early antithrombotic treatments.

Prognostic value of blood interleukin-6 in the prediction of functional outcome after stroke: A systematic review and meta-analysis

We aimed to quantify the association of blood interleukin-6 (IL-6) concentrations with poor outcome after stroke and its added predictive value over clinical information. Meta-analysis of 24 studies confirmed this association with a weighted mean difference of 3.443 (1.592-5.294) pg/mL, despite high heterogeneity and publication bias. Individual participant data including 4112 stroke patients showed standardized IL-6 levels in the 4th quartile were independently associated with poor outcome (OR=2.346 (1.814-3.033), p<0.0001). However, the additional predictive value of IL-6 was moderate (IDI=1.5%, NRI=5.35%). Overall these results indicate an unlikely translation of IL-6 into clinical practice for this purpose.

Poor outcome in primary intracerebral haemorrhage: results of a matched comparison

Background: Primary intracerebral haemorrhage (PICH) is associated with a poorer outcome than cerebral infarction. This study aimed to determine whether this is explained by the clinical severity of stroke. Methods: An observational study of outcome in consecutive admissions with acute PICH and ischaemic stroke was undertaken. A nested case-control analysis, matched on a 1:2 basis for age, pre-stroke disability, early neurological impairment (Scandinavian Stroke Scale; SSS), and Oxfordshire Community Stroke Project classification was then performed. Follow up was at 30 days and at hospital discharge. Results: Overall, 679 subjects were included in the analysis. Of these, 53 (8%) had PICH; this group had more severe initial neurological impairment (day 3 SSS 28 v 45 points, p<0.001) and a higher prevalence of total anterior circulation strokes (55% v 21%, p<0.001) than did the group admitted with ischaemic strokes. Outcomes were poorer in the PICH group, with 36% inpatient mortality and 68% of survivors having a day 30 modified Rankin Scale (MRS) of at least 3 (compared with 13% and 52%, respectively, in the ischaemic stroke group). Following matching for baseline clinical characteristics, the PICH group had a higher mortality, but this was not statistically significant; the day 30 MRS and institutionalisation rates in survivors were similar in the matched haemorrhage and infarct groups. Conclusions: Compared with ischaemic stroke, PICH is associated with higher mortality and increased disability in survivors. The severity of clinical stroke is a major contributor to these poor outcomes; baseline characteristics, however, do not fully explain outcome differences.

Predictors of early neurological deterioration after ischaemic stroke: a case-control study.

Background: Early neurological deterioration after ischaemic stroke (stroke in progression) is reported to be common and associated with poor outcome or death. The causes of progressing stroke are, however, uncertain. Objective: To determine whether prior drug treatment (with anticoagulant or antiplatelet agents) or early adverse physiological features (pyrexia, hypoxia, dehydration or hyperglycaemia) are associated with progressing ischaemic stroke. Methods: The study used a case-control design. From a database of 873 consecutive acute stroke admissions, 196 cases of progressing ischaemic stroke (defined by point deterioration in components of the Scandinavian Stroke Scale or death over the first 72 h after hospital admission) were matched to 196 controls on the basis of age and stroke type. Univariate and conditional logistic regression techniques were used to explore predictors of progressing stroke. Results: Cases and controls were well matched for baseline stroke severity. Warfarin use prior to admission was associated with a reduced risk of progressing stroke [odds ratio (OR) 0.10, p = 0.005]. Prior antiplatelet use was not related. A previous history of diabetes (OR 2.11, p = 0.039) and elevated systolic blood pressure on admission (OR 1.01 for each 1 mm Hg rise, p = 0.017) predicted progressing stroke. Although there were no differences in time to presentation or to brain imaging, a visible causative lesion on CT scanning was more common in the progressing stroke group (OR 2.30, p = 0.022). We found no evidence that adverse physiological features were associated with progressing stroke. Outcomes were worse in the progressing stroke group with 70% being dead or dependent by 30 days compared to 55% in the control group (p = 0.002). Conclusion: Prior warfarin use may be protective against progressing ischaemic stroke. A previous history of diabetes along with elevated admission systolic blood pressure predict deterioration. We found no evidence for an association between adverse physiological features and progressing stroke.

Augmented visual feedback of movement performance to enhance walking recovery after stroke: study protocol for a pilot randomised controlled trial

BackgroundIncreasing evidence suggests that use of augmented visual feedback could be a useful approach to stroke rehabilitation. In current clinical practice, visual feedback of movement performance is often limited to the use of mirrors or video. However, neither approach is optimal since cognitive and self-image issues can distract or distress patients and their movement can be obscured by clothing or limited viewpoints. Three-dimensional motion capture has the potential to provide accurate kinematic data required for objective assessment and feedback in the clinical environment. However, such data are currently presented in numerical or graphical format, which is often impractical in a clinical setting. Our hypothesis is that presenting this kinematic data using bespoke visualisation software, which is tailored for gait rehabilitation after stroke, will provide a means whereby feedback of movement performance can be communicated in a more meaningful way to patients. This will result in increased patient understanding of their rehabilitation and will enable progress to be tracked in a more accessible way.MethodsThe hypothesis will be assessed using an exploratory (phase II) randomised controlled trial. Stroke survivors eligible for this trial will be in the subacute stage of stroke and have impaired walking ability (Functional Ambulation Classification of 1 or more). Participants (n = 45) will be randomised into three groups to compare the use of the visualisation software during overground physical therapy gait training against an intensity-matched and attention-matched placebo group and a usual care control group. The primary outcome measure will be walking speed. Secondary measures will be Functional Ambulation Category, Timed Up and Go, Rivermead Visual Gait Assessment, Stroke Impact Scale-16 and spatiotemporal parameters associated with walking. Additional qualitative measures will be used to assess the participant’s experience of the visual feedback provided in the study.DiscussionResults from the trial will explore whether the early provision of visual feedback of biomechanical movement performance during gait rehabilitation demonstrates improved mobility outcomes after stroke and increased patient understanding of their rehabilitation.Trial registrationCurrent Controlled Trials ISRCTN79005974

Stroke patients admitted within normal working hours are more likely to achieve process standards and to have better outcomes

Background The presence of a ‘weekend’ effect has been shown across a range of medical conditions, but has not been consistently observed for patients with stroke. Aims We investigated the impact of admission time on a range of process and outcome measures after stroke. Methods Using routine data from National Scottish data sets (2005–2013), time of admission was categorised into weekday, weeknight and weekend/public holidays. The main process measures were swallow screen on day of admission (day 0), brain scan (day 0 or 1), aspirin (day 0 or 1), admission to stroke unit (day 0 or 1), and thrombolysis administration. After case-mix adjustment, multivariable logistic regression was used to estimate the OR for mortality and discharge to home/usual place of residence. Results There were 52 276 index stroke events. Compared to weekday, the adjusted OR (95%CI) for early stroke unit admission was 0.81 (0.77 to 0.85) for weeknight admissions and 0.64 (0.61 to 0.67) for weekend/holiday admissions; early brain scan 1.30 (0.87 to 1.94) and 1.43 (0.95 to 2.18); same day swallow screen 0.86 (0.81 to 0.91) and 0.85 (0.81 to 0.90); thrombolysis 0.85 (0.75 to 0.97) and 0.85 (0.75 to 0.97), respectively. Seven-day mortality, 30-day mortality and 30-day discharge for weekend admission compared to weekday was 1.17 (1.05 to 1.30); 1.08 (1.00 to 1.17); and 0.90 (0.85 to 0.95), respectively. Conclusions Patients with stroke admitted out of hours and at weekends or public holidays are less likely to be managed according to current guidelines. They experience poorer short-term outcomes than those admitted during normal working hours, after correcting for known independent predictors of outcome and early mortality.