Daniel Strbian

Reducing in-hospital delay to 20 minutes in stroke thrombolysis

Objectives: Efficacy of thrombolytic therapy for ischemic stroke decreases with time elapsed from symptom onset. We analyzed the effect of interventions aimed to reduce treatment delays in our single-center observational series. Methods: All consecutive ischemic stroke patients treated with IV alteplase (tissue plasminogen activator [tPA]) were prospectively registered in the Helsinki Stroke Thrombolysis Registry. A series of interventions to reduce treatment delays were implemented over the years 1998 to 2011. In-hospital delays were analyzed as annual median door-to-needle time (DNT) in minutes, with interquartile range. Results: A total of 1,860 patients were treated between June 1995 and June 2011, which included 174 patients with basilar artery occlusion (BAO) treated mostly beyond 4.5 hours from symptom onset. In the non-BAO patients, the DNT was reduced annually, from median 105 minutes (65–120) in 1998, to 60 minutes (48–80) in 2003, further on to 20 minutes (14–32) in 2011. In 2011, we treated with tPA 31% of ischemic stroke patients admitted to our hospital. Of these, 94% were treated within 60 minutes from arrival. Performing angiography or perfusion imaging doubled the in-hospital delays. Patients with in-hospital stroke or arriving very soon from symptom onset had longer delays because there was no time to prepare for their arrival. Conclusions: With multiple concurrent strategies it is possible to cut the median in-hospital delay to 20 minutes. The key is to do as little as possible after the patient has arrived at the emergency room and as much as possible before that, while the patient is being transported.

Off-Label Thrombolysis Is Not Associated With Poor Outcome in Patients With Stroke

Background and Purpose— Numerous contraindications included in the license of alteplase, most of which are not based on scientific evidence, restrict the portion of patients with acute ischemic stroke eligible for treatment with alteplase. We studied whether off-label thrombolysis was associated with poorer outcome or increased rates of symptomatic intracerebral hemorrhage compared with on-label use. Methods— All consecutive patients with stroke treated with intravenous thrombolysis from 1995 to 2008 at the Helsinki University Central Hospital were registered (n=1104). After excluding basilar artery occlusions (n=119), the study population included 985 patients. Clinical outcome (modified Rankin Scale 0 to 2 versus 3 to 6) and symptomatic intracerebral hemorrhage according to 3 earlier published criteria were analyzed with a logistic regression model adjusting for 21 baseline variables. Results— One or more license contraindications to thrombolysis was present in 51% of our patients (n=499). The most common of these were age >80 years (n=159), mild stroke National Institutes of Health Stroke Scale score <5 (n=129), use of intravenous antihypertensives prior to treatment (n=112), symptom-to-needle time >3 hours (n=95), blood pressure >185/110 mm Hg (n=47), and oral anticoagulation (n=39). Age >80 years was the only contraindication independently associated with poor outcome (OR, 2.18; 95% CI, 1.27 to 3.73) in the multivariate model. None of the contraindications were associated with an increased risk of symptomatic intracerebral hemorrhage. Conclusions— Off-license thrombolysis was not associated with poorer clinical outcome, except for age >80 years, nor with increased rates of symptomatic intracerebral hemorrhage. The current extensive list of contraindications should be re-evaluated when data from ongoing randomized trials and observational studies become available.

The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia.

The blood-brain barrier (BBB) is the principal regulator of blood-borne substance entry into the brain parenchyma. Therefore, BBB leakage, which leads to cerebral edema and influx of toxic substances, is common in pathological conditions such as cerebral ischemia, inflammation, trauma, and tumors. The leakage of BBB after ischemia-reperfusion injury has long been considered to be biphasic, although a considerable amount of discrepancies as for the timing of the second opening does exist among the studies. This led us to evaluate systematically and quantitatively the dynamics of BBB leakage in a rat model of 90-min ischemia-reperfusion, using gadolinium-enhanced (small molecule) magnetic resonance imaging and fluorescent dye Evans Blue (large molecule). BBB leakage was assessed at the following time points after reperfusion: 25 min, 2, 4, 6, 12, 18, 24, 36, 48, and 72 h, and 1, 2, 3, 4, and 5 weeks. We observed BBB leakage for both gadolinium and Evans Blue as early as 25 min after reperfusion. Thereafter, BBB remained open for up to 3 weeks for Evans Blue and up to 5 weeks for gadolinium. Our results show that BBB leakage after ischemia-reperfusion injury in the rat is continuous and long-lasting, without any closure up to several weeks. This is the first systematic and extensive study fully demonstrating BBB leakage dynamics following transient brain ischemia and the findings are of major clinical and experimental interest.

Predicting outcome of IV thrombolysis–treated ischemic stroke patients The DRAGON score

Objective: To develop a functional outcome prediction score, based on immediate pretreatment parameters, in ischemic stroke patients receiving IV alteplase. Methods: The derivation cohort consists of 1,319 ischemic stroke patients treated with IV alteplase at the Helsinki University Central Hospital, Helsinki, Finland. We evaluated the predictive value of parameters associated with the 3-month outcome and developed the score according to the magnitude of logistic regression coefficients. We assessed accuracy of the model with bootstrapping. External validation was performed in a cohort of 330 patients treated at the University Hospital Basel, Basel, Switzerland. We assessed the score performance with area under the receiver operating characteristic curve (AUC-ROC). Results: The DRAGON score (0–10 points) consists of (hyper)Dense cerebral artery sign/early infarct signs on admission CT scan (both = 2, either = 1, none = 0), prestroke modified Rankin Scale (mRS) score >1 (yes = 1), Age (≥80 years = 2, 65–79 years = 1, <65 years = 0), Glucose level at baseline (>8 mmol/L [>144 mg/dL] = 1), Onset-to-treatment time (>90 minutes = 1), and baseline National Institutes of Health Stroke Scale score (>15 = 3, 10–15 = 2, 5–9 = 1, 0–4 = 0). AUC-ROC was 0.84 (0.80–0.87) in the derivation cohort and 0.80 (0.74–0.86) in the validation cohort. Proportions of patients with good outcome (mRS score 0–2) were 96%, 88%, 74%, and 0% for 0–1, 2, 3, and 8–10 points, respectively. Proportions of patients with miserable outcome (mRS score 5–6) were 0%, 2%, 5%, 70%, and 100% for 0–1, 2, 3, 8, and 9–10 points, respectively. External validation showed similar results. Conclusions: The DRAGON score is valid at our site and was reliable externally. It can support clinical decision-making, especially when invasive add-on strategies are considered. The score was not studied in patients with basilar artery occlusion. Further external validation is warranted.

Symptomatic intracranial hemorrhage after stroke thrombolysis: The SEDAN Score

A study was undertaken to develop a score for assessing risk for symptomatic intracranial hemorrhage (sICH) in ischemic stroke patients treated with intravenous (IV) thrombolysis.

Mast cells as early responders in the regulation of acute blood–brain barrier changes after cerebral ischemia and hemorrhage

The inflammatory response triggered by stroke has been viewed as harmful, focusing on the influx and migration of blood-borne leukocytes, neutrophils, and macrophages. This review hypothesizes that the brain and meninges have their own resident cells that are capable of fast host response, which are well known to mediate immediate reactions such as anaphylaxis, known as mast cells (MCs). We discuss novel research suggesting that by acting rapidly on the cerebral vessels, this cell type has a potentially deleterious role in the very early phase of acute cerebral ischemia and hemorrhage. Mast cells should be recognized as a potent inflammatory cell that, already at the outset of ischemia, is resident within the cerebral microvasculature. By releasing their cytoplasmic granules, which contain a host of vasoactive mediators such as tumor necrosis factor-α, histamine, heparin, and proteases, MCs act on the basal membrane, thus promoting blood–brain barrier (BBB) damage, brain edema, prolonged extravasation, and hemorrhage. This makes them a candidate for a new pharmacological target in attempts to even out the inflammatory responses of the neurovascular unit, and to stabilize the BBB after acute stroke.

Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation

We previously observed degranulated mast cells (MC) in association with perivascular brain edema formation during focal cerebral ischemia. Brain MC are typically located perivascularly and contain potent fast-acting vasoactive and proteolytic substances. We examined in a rat model of transient middle cerebral artery occlusion (MCAO) whether, in the early phase of ischemia, MC regulate microcirculation, the blood–brain barrier (BBB) permeability, and edema formation. First, animals received MC inhibitor (cromoglycate), MC-degranulating drug (compound 48/80), or saline. Thereafter, we performed transient MCAO in gene-manipulated MC-deficient rats and their wild-type (WT) littermates, calculating brain swelling, visualizing BBB leakage by intravenously administered Evans blue albumin, and determining neutrophil infiltration with light microscopy. Cerebral blood flow, monitored by laser-Doppler flowmetry in separate experiments, was similar among pharmacological treatments. Ischemic swelling resulted in increased hemispheric volume of 13.4% ± 1.0% in controls, 8.1% ± 0.4% (39% reduction) after cromoglycate, and 25.2% ± 2.0% (89% increase) after compound 48/80 (P < 0.05). Early ischemic BBB leakage was reduced by 51% after cromoglycate, and 50% enhanced by compound 48/80 (P < 0.05). The cromoglycate group showed 37% less postischemic neutrophil infiltration than did controls (P < 0.05). Furthermore, MC-deficient rats responded to focal ischemia with 58% less brain swelling (6.7% ± 1.2%) than did their WT littermates (15.8% ± 1.4%, P < 0.05). Blood-brain barrier damage was 47% lower in MC-deficient rats than in the WT (P < 0.05). Neutrophil infiltration after MCAO was decreased 47% in MC-deficient rats in comparison to WT (P < 0.05). Pharmacological MC inhibition thus appears to deserve further investigation regarding reduction of brain swelling and inflammation early after stroke.

Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis

Objectives: To assess the impact of symptomatic intracerebral hemorrhage (sICH) on outcome of thrombolysis-treated ischemic stroke patients, as additional to recognized prognosticators. Methods: The study cohort included 985 ischemic stroke patients treated with IV thrombolysis at the Helsinki University Central Hospital (1995–2008). In a multivariable model adjusted for baseline stroke severity, age, onset-to-treatment time, baseline glucose, hyperdense cerebral artery sign, and early infarct signs on baseline imaging, and prior modified Rankin Scale (mRS), we calculated risk ratios (RRs) of patients with sICH (separately per Safe Implementation of Thrombolysis in Stroke[SITS]–Monitoring Study, European Cooperative Acute Stroke Study II [ECASS-II], and National Institute of Neurological Disorders and Stroke [NINDS] definitions) for poor 3-month outcome (mRS 3–6) and mortality. Receiver operating characteristic (ROC) curve and integrated discrimination improvement (IDI) evaluated impact of sICH on outcome. Internal cross-validation of the model was done with bootstrap statistics. Results: The frequency of sICH was 2.1% (SITS), 7.0% (ECASS-II), and 9.4% (NINDS). RRs for poor and fatal outcome, respectively, were 1.7 and 4.8 (SITS), 1.6 and 3.8 (ECASS-II), and 1.6 and 3.4 (NINDS). In IDI analyses, sICH improved prediction model for 3-month mRS of 3–6 and 4–6, respectively, by 1.4% and 3.0% (SITS), 4.0% and 5.9% (ECASS-II), and 4.7% and 6.1% (NINDS). In case of 3-month mRS 5–6 and mortality, it was 6.1% and 5.3% (SITS), 11.3% and 9.3% (ECASS-II), and 10.3% and 8.0% (NINDS). ROC analysis revealed similar results. Conclusions: Patients with sICH have increased risk of poor and fatal outcome. Compared with recognized stroke prognosticators, contribution of sICH is smaller. Definition-wise, ECASS-II- and NINDS-based sICH contribute relatively more; ECASS-II has the largest contribution to worst outcomes.

SMASH-U: A Proposal for Etiologic Classification of Intracerebral Hemorrhage

Background and Purpose— The purpose of this study was to provide a simple and practical clinical classification for the etiology of intracerebral hemorrhage (ICH). Methods— We performed a retrospective chart review of consecutive patients with ICH treated at the Helsinki University Central Hospital, January 2005 to March 2010 (n=1013). We classified ICH etiology by predefined criteria as structural vascular lesions (S), medication (M), amyloid angiopathy (A), systemic disease (S), hypertension (H), or undetermined (U). Clinical and radiological features and mortality by SMASH-U (Structural lesion, Medication, Amyloid angiopathy, Systemic/other disease, Hypertension, Undetermined) etiology were analyzed. Results— Structural lesions, namely cavernomas and arteriovenous malformations, caused 5% of the ICH, anticoagulation 14%, and systemic disease 5% (23 liver cirrhosis, 8 thrombocytopenia, and 17 various rare conditions). Amyloid angiopathy (20%) and hypertensive angiopathy (35%) were common, but etiology remained undetermined in 21%. Interrater agreement in classifying cases was high (&kgr;, 0.89; 95% CI, 0.82–0.96). Patients with structural lesions had the smallest hemorrhages (median volume, 2.8 mL) and best prognosis (3-month mortality 4%), whereas anticoagulation-related ICHs were largest (13.4 mL) and most often fatal (54%). Overall, median ICH survival was 5½ years, varying strongly by etiology (P<0.001). After adjustment for baseline characteristics, patients with structural lesions had the lowest 3-month mortality rates (OR, 0.06; 95% CI, 0.01–0.37) and those with anticoagulation (OR, 1.9; 1.0–3.6) or other systemic cause (OR, 4.0; 1.6–10.1) the highest. Conclusions— In our patients, performing the SMASH-U classification was feasible and interrater agreement excellent. A plausible etiology was determined in most patients but remained elusive in one in 5. In this series, SMASH-U based etiology was strongly associated with survival.

Thrombolysis of basilar artery occlusion: Impact of baseline ischemia and time

To evaluate the impact of extensive baseline ischemic changes on functional outcome after thrombolysis of basilar artery occlusion (BAO), and to study the effect of time to treatment in the absence of such findings.