Intracerebral hemorrhage in patients treated with intravenous thrombolysis for acute ischemic stroke

Background. Nearly 30000 people suffer a stroke in Sweden every year. Stroke is the third most common cause of death after heart disease and cancer carrying a 17% mortality rate at three months. It is the most common cause of neurological disability in adults. Intravenous thrombolysis with alteplase is the only approved pharmacological therapy for acute ischemic stroke, improving neurological and functional outcome in one third of all treated patients. Meanwhile, thrombolytic treatment can in itself cause intracerebral hemorrhage. The aim of this thesis was to study risk factors associated with this complication, in a large cohort of ischemic stroke patients treated with intravenous alteplase. Methods. All studies were based on patient data contained within the Safe Implementation of Treatments of Stroke - International Stroke Thrombolysis Register (SITS-ISTR). The main outcomes of interest were symptomatic intracerebral hemorrhage (SICH) by SITS-MOST, ECASS II and NINDS definitions, functional status at 3 months (modified Rankin Scale), and death at 7 days and 3 months. Study 1. We aimed to develop a clinical scoring algorithm predicting the risk of SICH, using data from 31627 patients. Baseline and demographic factors associated with SICH were entered into a logistic regression model. Adjusted odds ratios (OR) were converted into points, summated to produce a risk score. We identified 9 predictors of SICH: stroke severity, plasma glucose, blood pressure, age, body weight, stroke onset to treatment time, aspirin or combined aspirin and clopidogrel, and history of hypertension. The overall rate of SICH was 1,8%. The score ranged from 0 to 12 points, showing a >70-fold increase in the rate of SICH for patients with a score ≥10 points (14,3%) compared to 0 points (0,2%), with an acceptable predictive performance, AUC-ROC = 0,70. We concluded that the SITS SICH Score is able to predict large thrombolysis-related SICH associated with severe clinical deterioration. Study 2. The SEDAN score is another prediction algorithm for SICH. We assessed its predictive performance for two definitions of SICH. Odds ratios for SICH per one-point increase of the score were obtained using logistic regression. The predictive capability for SICH per ECASS II was moderate at AUC-ROC = 0,66. With rising scores, there was a moderate increase in risk for SICH ECASS II (OR 1,7 per point, p<0,001), SICH rates between 1,6% for 0 points and 16,9% for ≥5 points. Prediction of SICH per SITS-MOST was weaker, AUC-ROC = 0,60, rates between 0,8% for 0 points and 5,4% for ≥5 points. We concluded that the predictive performance of the SEDAN was moderate for SICH per ECASS II and low for SICH per SITS-MOST. Study 3. The European license for alteplase contraindicates its use in stroke patients treated with warfarin. Conversely, American guidelines accept it in patients with an international normalized ratio (INR) ≤1,7. We studied the influence of warfarin on SICH, arterial recanalization, functional outcome and mortality in 768 patients with baseline warfarin treatment and INR≤1,7. They were older, had more comorbidities, and more severe strokes compared to patients without warfarin. There were no differences in SICH rates, mortality or functional outcome between warfarin and non-warfarin patients after adjustment for differences in age, stroke severity and co-morbidities. Arterial recanalization defined as the disappearance of a baseline hyperdense cerebral artery sign at 22-36 hour imaging was increased in warfarin patients at 63% vs 55%, p=0,022. Study 4. Hemorrhage following stroke thrombolysis can occur in brain parenchyma remote from acutely ischemic tissue (PHr), as well as in local relation to the infarct (PH). We investigated the risk factors, mortality and functional outcome in patients with the poorly understood complication of PHr, as well as PH, and concomitant occurrence of both. We compared baseline data in 970 patients (2,2%) with PHr, 2325 patients (5,3%) with local PH, and 39761 patients (91,4%) without PH or PHr. Independent risk factors were obtained by multivariate logistic regression. Increasing age and blood pressure were the only strong risk factors for PHr. High stroke severity, atrial fibrillation, CT hyperdense cerebral artery sign, i e factors indicating large artery occlusion, were associated with local PH. Functional independence at 3 months was more common in PHr than PH (34% vs 24%, p<0,001), 3 month mortality was lower (34% vs 39%, p<0,001). PH and PHr were equally often symptomatic. The better outcome in PHr is explained by PHr occurring in patients with milder strokes. We concluded that the differences in risk factors likely indicate an influence of underlying small vessel disease in PHr, and large vessel occlusion in PH

External Validation of the SEDAN Score for Prediction of Intracerebral Hemorrhage in Stroke Thrombolysis

Background and Purpose— The SEDAN score is a prediction rule for assessment of the risk of symptomatic intracerebral hemorrhage (SICH) per the European Cooperative Acute Stroke Study (ECASS) II definition in patients with acute ischemic stroke treated with intravenous thrombolysis. We assessed the performance of the score in predicting SICH per the ECASS II and Safe Implementation of Treatments in Stroke Monitoring Study (SITS-MOST) definitions in the SITS–International Stroke Thrombolysis Register (SITS-ISTR). Methods— We calculated the SEDAN score in 34 251 patients with complete data, enrolled into the SITS-ISTR. The risk for SICH by both definitions was calculated per score category. Odds ratios for SICH per point increase of the score were obtained using logistic regression. The predictive performance was assessed using area under the curve of the receiver operating characteristic (AUC-ROC). Results— The predictive capability for SICH per ECASS II was moderate at AUC-ROC=0.66. With rising scores, there was a moderate increase in risk for SICH per ECASS II (odds ratio, 1.65 per point; 95% confidence interval, 1.59–1.72; P <0.001), with SICH rates between 1.6% for 0 points and 16.9% for ≥5 points, average 5.1%. The predictive capability for SICH per SITS–MOST was weaker, AUC-ROC=0.60, with lower increase per score point (odds ratio, 1.36 per point; 95% confidence interval, 1.28–1.46; P <0.001), and SICH rates between 0.8% for 0 points and 5.4% for ≥5 points, average 1.8%. Conclusions— In this very large data set, the predictive and discriminatory performances of the SEDAN score were only moderate for SICH per ECASS II and low for SICH per SITS–Monitoring Study

Minor stroke due to large artery occlusion. When is intravenous thrombolysis not enough? Results from the SITS International Stroke Thrombolysis Register

Purpose: Beyond intravenous thrombolysis, evidence is lacking on acute treatment of minor stroke caused by large artery occlusion. To identify candidates for additional endovascular therapy, we aimed to determine the frequency of non-haemorrhagic early neurological deterioration in patients with intravenous thrombolysis-treated minor stroke caused by occlusion of large proximal and distal cerebral arteries. Secondary aims were to establish risk factors for non-haemorrhagic early neurological deterioration and report three-month outcomes in patients with and without non-haemorrhagic early neurological deterioration. Method: We analysed data from the SITS International Stroke Thrombolysis Register on 2553 patients with intravenous thrombolysis-treated minor stroke (NIH Stroke Scale scores 0–5) and available arterial occlusion data. Non-haemorrhagic early neurological deterioration was defined as an increase in NIH Stroke Scale score ≥4 at 24 h, without parenchymal hematoma on follow-up imaging within 22–36 h. Findings: The highest frequency of non-haemorrhagic early neurological deterioration was seen in 30% of patients with terminal internal carotid artery or tandem occlusions (internal carotid artery + middle cerebral artery) (adjusted odds ratio: 10.3 (95% CI 4.3–24.9), p &#60; 0.001) and 17% in extracranial carotid occlusions (adjusted odds ratio 4.3 (2.5–7.7), p &#60; 0.001) versus 3.1% in those with no occlusion. Proximal middle cerebral artery-M1 occlusions had non-haemorrhagic early neurological deterioration in 9% (adjusted odds ratio 2.1 (0.97–4.4), p = 0.06). Among patients with any occlusion and non-haemorrhagic early neurological deterioration, 77% were dead or dependent at three months. Conclusions: Patients with minor stroke caused by internal carotid artery occlusion, with or without tandem middle cerebral artery involvement, are at high risk of disabling deterioration, despite intravenous thrombolysis treatment. Acute vessel imaging contributes usefully even in minor stroke to identify and consider endovascular treatment, or intensive monitoring at a comprehensive stroke centre, for patients at high risk of neurological deterioration

Are you suffering from a large arterial occlusion? Please raise your arm!

Background and purpose: Triage tools to identify candidates for thrombectomy are of utmost importance in acute stroke. No prognostic tool has yet gained any widespread use. We compared the predictive value of various models based on National Institutes of Health Stroke Scale (NIHSS) subitems, ranging from simple to more complex models, for predicting large artery occlusion (LAO) in anterior circulation stroke. Methods: Patients registered in the SITS international Stroke Register with available NIHSS and radiological arterial occlusion data were analysed. We compared 2042 patients harbouring an LAO with 2881 patients having no/distal occlusions. Using binary logistic regression, we developed models ranging from simple 1 NIHSS-subitem to full NIHSS-subitems models. Sensitivities and specificities of the models for predicting LAO were examined. Results: The model with highest predictive value included all NIHSS subitems for predicting LAO (area under the curve (AUC) 0.77), yielding a sensitivity and specificity of 69% and 76%, respectively. The second most predictive model (AUC 0.76) included 4-NIHSS-subitems (level of consciousness commands, gaze, facial and arm motor function) yielding a sensitivity and specificity of 67% and 75%, respectively. The simplest model included only deficits in arm motor-function (AUC 0.72) for predicting LAO, yielding a sensitivity and specificity of 67% and 72%, respectively. Conclusions: Although increasingly more complex models yield a higher discriminative performance for predicting LAO, differences between models are not large. Assessing grade of arm dysfunction along with an established stroke-diagnosis model may serve as a surrogate measure of arterial occlusion-status, thereby assisting in triage decisions

Modeling the Decay in Probability of Receiving Endovascular Thrombectomy on the Basis of Time From Stroke Onset

Background American Heart Association guidelines specify infarct core volume as 1 determinant of eligibility for endovascular thrombectomy. Therefore, it is important to understand how time‐dependent infarct core growth translates to a patient's declining probability of thrombectomy eligibility. Modeling the probability that a patient with suspected large‐vessel occlusion would qualify for thrombectomy on the basis of their expected time from stroke onset to treatment can help inform the optimal prehospital emergency transport protocols, maximizing the likelihood of an excellent patient outcome. Methods We extended a published physiological model of infarct core growth to derive a decay curve of thrombectomy eligibility (based on a given infarct core volume threshold) as a function of time from stroke onset. We then adapted an existing model of the time‐dependent probability of an excellent outcome to incorporate this decay curve. Using the adapted model, we determined the optimal prehospital emergency transport protocols in Alberta, Canada, and compared these with the protocols that assumed all patients were thrombectomy eligible. Results The probability of qualifying for thrombectomy decays exponentially as time elapses from stroke onset. We found that the area where mothership is the optimal transport protocol increased by 18.6% after incorporating our decay curve of thrombectomy eligibility into the underlying optimization model. The benefit of mothership versus drip‐and‐ship also increased in the areas where mothership was favored, and in areas where drip‐and‐ship was favored, the benefit of drip‐and‐ship weakened. We also performed a number of sensitivity analyses to observe how these results change on the basis of our assumptions for model parameters. Conclusion This methodology provides a novel, physiology‐based approach to derive a thrombectomy eligibility curve. These models are necessary to better optimize prehospital transport decisions and consequently improve outcomes of patients with suspected large‐vessel occlusion

Intima-Media Thickness and Pulsatility Index of Common Carotid Arteries in Acute Ischaemic Stroke Patients with Diabetes Mellitus

Ultrasonographic parameters such as the common carotid artery (CCA) pulsatility index (PI) and CCA intima-media thickness (IMT) have been associated with an increased mortality and risk of recurrent stroke, respectively. We hypothesized that these ultrasonographic parameters may be useful for monitoring diabetic patients after an acute stroke. We analysed retrospective data of consecutive acute ischaemic stroke patients from the ASTRAL registry who underwent pre-cerebral ultrasonographic evaluation within 7 days of symptom onset. We compared clinical, demographic, radiological and ultrasonographic parameters in diabetic versus non-diabetic patients (univariable and multivariable analyses) and the association of these parameters with CCA PI and CCA IMT. We analysed 1507 carotid duplex ultrasound examinations from patients with a median age of 74 years. Cardiovascular co-morbidities, including hypertension, hypercholesterolemia, obstructive sleep apnoea syndrome, higher body-mass index (BMI) and peripheral artery disease, were associated with diabetes mellitus (DM). Diabetics were more often under antiplatelet therapy and had atrial fibrillation at admission. Diabetic patients showed an increased CCA PI and IMT in line with more atherosclerotic changes on acute CTA compared to non-diabetic patients. Taking IMT as the dependent variable in a second analysis, DM, higher age, hypertension, smoking and CCA PI were associated with higher IMT. Taking CCA PI as the dependent variable in a third analysis, DM, higher age and higher NIHSS at admission were associated with higher CCA PI values. Increased IMT was also associated with higher PI. We show that CCA PI and IMT are higher in diabetic patients in the first week after an initial stroke

An adaptive finite element method for detonation waves: towards reaction time limit zero

In the present paper we investigate a new adaptive finite element method for detonation waves as an example of hyperbolic systems with stiff source terms. As a unified approach to such problems we consider an implicit and L-stable streamline diffusion finite element method with good shock-capturing features. Moreover, being a Galerkin-type method; it admits residual-based weighted a-posteriori error estimation of asymptotically optimal order. On one hand, this error control allows for a simple balancing strategy to get reasonable streamline diffusion parameters. And on the other hand it paves a way to efficient and mathematically rigorous self-adaptive mesh selection strategies, both in space and time. For the error control, we avoid the use of global stability constants by solving the dual problem explicitly, but in an inexpensive way on a coarse grid. All present methods are substantiated by a series of numerical tests. We restrict ourselves to the case of one space dimension, but all ingredients of the scheme extend easily (in principle) to higher space dimensions. Some numerical results show that, using an appropriate mesh and balanced parameters, the streamline diffusion finite element method is able to reproduce the Chapman Jouguet speed of detonations and their ZND wave structure even in case of very small reaction times #tau#. Further examples show that such meshes are obtainable by our adaptive iterative procedure, if the initial mesh is not too bad. Our scheme generally consumes about 40-50 elements per time step only. The question how to obtain such a resonable initial mesh in case of a very small #tau# is left to further investigation. (orig.)Available from TIB Hannover: RR 1606(98-27) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Impact of Transcranial Doppler Ultrasound on Logistics and Outcomes in Stroke Thrombolysis: Results from the SITS-ISTR

Background and Purpose-Diagnostic transcranial Doppler ultrasound (TCD) is commonly used in patients with acute stroke before or during treatment with intravenous thrombolysis (IVT). We aimed to assess how much TCD delays IVT initiation and whether TCD influences outcomes. Methods-We analyzed data from the SITS-ISTR (Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register) collected from December 2002 to December 2011. Outcomes were door-To-needle time, symptomatic intracerebral hemorrhage, functional outcome per the modified Rankin Scale, and mortality at 3 months. Results-In hospitals performing any TCD pre-IVT, 1701 of 11 265 patients (15%) had TCD before IVT initiation. Door-To-needle time was higher in patients with pre-IVT TCD (74 versus 60 minutes; P<0.001). At hospitals performing any TCD during IVT infusion, of 9044 patients with IVT, 747 were examined with TCD during IVT. No treatment delay was seen with TCD during IVT. After multivariate adjustment, TCD during IVT was independently associated with modestly increased excellent functional outcome (modified Rankin Scale, 0-1; adjusted odds ratio, 1.28; 95% confidence interval, 1.06-1.55; P=0.012) and lower mortality (adjusted odds ratio, 0.73; 95% confidence interval, 0.55-0.95; P=0.022). Conclusions-We recommend that TCD, if performed, should be done during IVT infusion, to avoid treatment delay. The association of hyperacute TCD with beneficial outcomes suggests potential impact on patient management, which warrants further study

Intravenous thrombolysis in stroke mimics: results from the SITS International Stroke Thrombolysis Register.

BACKGROUND AND PURPOSE: Patients with stroke mimics (SM), i.e. conditions with stroke-like symptoms, may risk harm if treated with intravenous thrombolysis (IVT). Current guidelines state low risk of intracerebral hemorrhage based on studies comprising a total of <400 SM cases. We aimed to compare safety and outcomes following IVT between patients with acute ischaemic stroke and mimicking conditions. METHODS: We included IVT-treated ischaemic stroke patients in the SITS International Stroke Thrombolysis Register 2003-2017, examined with magnetic resonance imaging 22-36 h after treatment. Outcomes were parenchymal hematoma (PH) after treatment, symptomatic intracerebral hemorrhage (SICH) per Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST), Second European Co-operative Stroke Study (ECASS II) and National Institutes of Neurological Disorders and Stroke Study (NINDS) criteria, death and modified Rankin Scale score (mRS) at 3 months. RESULTS: Of 10 436 patients, 429 mimics (4.1%) were identified. The most common types were functional (30.8%), migraine (17.5%) and seizure (14.2%). Patients with mimics had fewer cerebrovascular risk factors and lower median National Institutes of Health Stroke Scale score [7 (interquartile range, 5-10) vs. 8 (5-14), P < 0.001]. Among mimics versus stroke patients, PH was seen in 1.2% vs. 5.1% (P < 0.001), SICH NINDS in 0.5% vs. 3.9% (P < 0.001), SICH ECASS II in 0.2% vs. 2.1% (P = 0.007) and SICH SITS-MOST in 0% vs. 0.5% (P = 0.28). Modified Rankin Scale score 0-1 at 3 months was present in 84.1% vs. 57.7% (P < 0.001) and death within 3 months in 2.6% vs. 5.4% (P = 0.028) of mimics and stroke patients, respectively. CONCLUSIONS: This large observational study indicated that PH and SICH following IVT in patients with SM are uncommon