Lars Kellert

Results of Intravenous Thrombolysis Within 4.5 to 6 Hours and Updated Results Within 3 to 4.5 Hours of Onset of Acute Ischemic Stroke Recorded in the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR): An Observational Study

IMPORTANCE Pooled analysis of randomized controlled trials of intravenous thrombolysis shows no statistically significant benefit beyond 4.5 hours, with the possible advantage perhaps offset by risk. OBJECTIVE To compare the outcomes of patients who were treated within 4.5 to 6 hours or within 3 to 4.5 hours of the onset of an ischemic stroke with the outcomes of patients who were treated within 3 hours in the SITS-ISTR. DESIGN An observational study based on SITS-ISTR data during the period from 2002 to 2011. SETTING Acute and emergency care. PARTICIPANTS Of 29 618 patients with acute ischemic stroke, 283 (1.0%) were treated within 4.5 to 6 hours of onset, 4056 (13.7%) were within 3 to 4.5 hours of onset, and 25 279 (85.4%) were treated within 3 hours of onset, in compliance with other European Union approval criteria. EXPOSURE Intravenous thrombolysis with alteplase. MAIN OUTCOMES AND MEASURES Functional independence (modified Rankin Scale score of 0-2) and mortality at 3 months and symptomatic intracerebral hemorrhage (SICH). P values are based on comparisons between patients treated within 4.5 to 6 hours or within 3 to 4.5 hours of onset against patients treated within 3 hours of onset. RESULTS Results are presented as within 4.5 to 6 hour vs within 3 to 4.5 hours vs within 3 hours. Median time from stroke onset to treatment was 295 vs 210 minutes vs 138 minutes (P < .01), median age was 65 vs 67 vs 68 years (P < .01), and median baseline National Institutes of Health Stroke Scale score was 9 vs 9 vs 12 (P < .01). Rate of functional independence was 61.3% (P = .40) vs 62.7% (P < .01) vs 58.4%; mortality rate was 11.8% (P = .99) vs 11.1% (P = .21) vs 11.8%; and rate of SICH was 2.6% (P = .17) vs 1.8% (P = .27) vs 1.5%. Multivariate analysis detected no significant difference in SICH (P > .05), mortality (P > .05), or independence (P > .05). Time from stroke onset to treatment as a continuous variable was significantly associated with higher rates of SICH and poor 3-month outcome after adjustment for age and National Institutes of Health Stroke Scale score. CONCLUSIONS AND RELEVANCE The treatment remains safe and effective for patients treated within 3 to 4.5 hours compared with patients treated within 3 hours. Our selected group of patients treated within 4.5 to 6 hours of stroke onset did not have worse outcomes than patients treated within 3 hours. An inevitable limitation of our observational study is the possible nonequivalence of the cohorts, particularly the 4.5- to 6-hour cohort relative to the other 2 cohorts.

Endovascular Stroke Therapy Tirofiban Is Associated With Risk of Fatal Intracerebral Hemorrhage and Poor Outcome

Background and Purpose— To investigate the relationship between severe bleeding complications and outcome after mechanical thrombectomy with or without glycoprotein-IIb/IIIa inhibitor tirofiban treatment. Methods— The study included prospectively collected data of consecutive patients with acute ischemic stroke in whom mechanical thrombectomy was perfomed in the years 2006 to 2011. Results— Of 162 patients, 128 patients had anterior circulation stroke, and 34 patients had posterior circulation stroke. Additional treatment with tirofiban was given to 30 of 128 patients with anterior circulation stroke and to 20 of 34 patients with posterior circulation stroke. Treatment with tirofiban did not influence recanalization rates. Fatal intracerebral hemorrhage occurred more frequently in tirofiban-treated patients in the entire cohort (12.0% vs 2.7%; P=0.03) and in tirofiban-treated patients with anterior circulation stroke (13.3% vs 3.1%; P=0.05). Logistic regression found age (odds ratio, 1.17; 95% confidence interval, 1.00–1.37; P=0.05) and tirofiban treatment (odds ratio, 3.03; 95% confidence interval, 1.50–4.05; P=0.04) to be independent predictors for fatal intracerebral hemorrhage. Tirofiban treatment was also an independent predictor for poor outcome (odds ratio, 6.60; 95% confidence interval, 1.06–41.52; P=0.04) in addition to National Institute of Health Stroke Scale (odds ratio, 1.08; 95% confidence interval, 1.00–1.17; P=0.05). Conclusions— In endovascular stroke therapy, additional treatment with the glycoprotein-IIb/IIIa inhibitor tirofiban is associated with increased risk of fatal intracerebral hemorrhage and poor outcome.

Cerebral Oxygen Transport Failure?: Decreasing Hemoglobin and Hematocrit Levels After Ischemic Stroke Predict Poor Outcome and Mortality: STroke: RelevAnt Impact of hemoGlobin, Hematocrit and Transfusion (STRAIGHT)—an Observational Study

Background and Purpose— Although conceivably relevant for penumbra oxygenation, the optimal levels of hemoglobin (Hb) and hematocrit (Hct) in patients with acute ischemic stroke are unknown. Methods— We identified patients from our prospective local stroke database who received intravenous thrombolysis based on multimodal magnet resonance imaging during the years 1998 to 2009. A favorable outcome at 3 months was defined as a modified Rankin Scale score ⩽2 and a poor outcome as a modified Rankin Scale score ≥3. The dynamics of Hemoglobin (Hb), Hematocrit (Hct), and other relevant laboratory parameters as well as cardiovascular risk factors were retrospectively assessed and analyzed between these 2 groups. Results— Of 217 patients, 114 had a favorable and 103 a poor outcome. In a multivariable regression model, anemia until day 5 after admission (odds ratio [OR]=2.61; 95% CI, 1.33 to 5.11; P=0.005), Hb nadir (OR=0.81; 95% CI, 0.67 to 0.99; P=0.038), and Hct nadir (OR=0.93; 95% CI, 0.87 to 0.99; P=0.038) remained independent predictors for poor outcome at 3 months. Mortality after 3 months was independently associated with Hb nadir (OR=0.80; 95% CI, 0.65 to 0.98; P=0.028) and Hb decrease (OR=1.34; 95% CI, 1.01 to 1.76; P=0.04) as well as Hct decrease (OR=1.12; 95% CI, 1.01 to 1.23; P=0.027). Conclusions— Poor outcome and mortality after ischemic stroke are strongly associated with low and further decreasing Hb and Hct levels. This decrease of Hb and Hct levels after admission might be more relevant and accessible to treatment than are baseline levels.

Low hemoglobin is associated with poor functional outcome after non-traumatic, supratentorial intracerebral hemorrhage

IntroductionThe impact of anemia on functional outcome and mortality in patients suffering from non-traumatic intracerebral hemorrhage (ICH) has not been investigated. Here, we assessed the relationship between hemoglobin (HB) levels and clinical outcome after ICH.MethodsOne hundred and ninety six patients suffering from supratentorial, non-traumatic ICH were extracted from our local stroke database (June 2004 to June 2006). Clinical and radiologic computed tomography data, HB levels on admission, mean HB values and nadir during hospital stay were recorded. Outcome was assessed at discharge and 3 months using the modified Rankin score (mRS).ResultsForty six (23.5%) patients achieved a favorable functional outcome (mRS ≤ 3) and 150 (76.5%) had poor outcome (mRS 4 - 6) at discharge. Patients with poor functional outcome had a lower mean HB (12.3 versus 13.7 g/dl, P < 0.001) and nadir HB (11.5 versus 13.0 g/dl, P < 0.001). Ten patients (5.1%) received red blood cell (RBC) transfusions. In a multivariate logistic regression model, the mean HB was an independent predictor for poor functional outcome at three months (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.58-0.92, P = 0.007), along with National Institute of Health Stroke Scale (NIHSS) at admission (OR 1.17, 95% CI 1.11 - 1.24, P < 0.001), and age (OR 1.08, 95% CI 1.04 - 1.12, P < 0.001).ConclusionsWe report an association between low HB and poor outcome in patients with non-traumatic, supratentorial ICH. While a causal relationship could not be proven, previous experimental studies and studies in brain injured patients provide evidence for detrimental effects of anemia on brain metabolism. However, the potential risk of anemia must be balanced against the risk of harm from red blood cell infusion.

Blood Pressure Variability after Intravenous Thrombolysis in Acute Stroke Does Not Predict Intracerebral Hemorrhage but Poor Outcome

Background: The relevance of blood pressure variability (BPV) in the development of intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) in acute stroke still remains uncertain. Methods: 427 consecutive patients treated with IVT in the years 2007–2009 were studied. Blood pressure (BP) values were analyzed from admission to follow-up imaging scan and described as mean, maximum, minimum, standard deviation (SD), difference between maximum and minimum, successive variation (SV) and maximum SV. ICH was categorized based on radiologic criteria and symptomatic ICH (sICH) was defined as ICH plus worsening of the National Institute of Health Stroke Scale by ≧4 points or leading to death. Three-month outcome was described by means of the modified Rankin Scale. Results: We observed any ICH in 51 (11.9%) and sICH in 10 (2.3%) patients. Systolic and diastolic BP profiles, including mean, maximum, minimum, SD, difference between maximum and minimum, SV and maximum SV, did not differ between ICH-negative, ICH-positive and sICH patients. In univariate analysis, high systolic BPV was associated with sICH (p = 0.03). A logistic regression model to predict ICH only found early CT findings (OR = 2.74, 95% CI = 1.47–5.11, p < 0.01) as independently associated with ICH. Poor 3-month outcome was independently predicted by age (OR = 0.96, 95% CI = 0.94–0.97, p < 0.001), NIHSS on admission (OR = 0.84, 95% CI = 0.80–0.87, p < 0.001), ICH (OR = 0.29, 95% CI = 0.13–0.66, p < 0.01) and high systolic BPV (OR = 1.68, 95% CI = 1.05–2.69, p < 0.05). Conclusions: We demonstrate that high BPV in patients receiving IVT leads to poor outcome but does not increase the risk of ICH/sICH.

Improved Clinical Outcome after Acute Basilar Artery Occlusion since the Introduction of Endovascular Thrombectomy Devices

Background: Thrombectomy devices are increasingly used for intra-arterial recanalization therapy in stroke. We analyzed whether the use of these devices modified the outcome of patients with acute basilar occlusion (BAO) at our institution. Methods: Between 1998 and 2012, one hundred forty-seven consecutive patients with acute BAO received recanalization therapy. In July 2009, for the first time, a thrombectomy device was used and hence the cohort was split into two chronological groups: BAO-1 (before July 2009) and BAO-2 (after July 2009). All patients were treated at a dedicated neurological ICU following institutional standard operating procedures. A good clinical outcome was defined as a modified Rankin scale score of 0-2 after 3 months. Univariate and multivariate analyses were applied using outcome parameters as dependent variables and baseline variables with a significant p value in univariate tests as independent variables. Results: One hundred eleven patients (BAO-1) were treated before and 36 were treated after July 2009 (BAO-2). Patients in the BAO-1 and BAO-2 groups had similar neurological deficits on admission as expressed by the Glasgow Coma Scale (BAO-1: median 4, IQR 5, vs. BAO-2: median 4.5, IQR 8, p = 0.41) and the proportion of patients who were presented intubated and ventilated was similar in both groups as well (49.5 vs. 47.7%, p = 0.85). Bridging concepts with intravenous recombinant tissue plasminogen activator (rtPA) were applied in 18.9% (BAO-1) versus 63.9% (BAO-2, p < 0.001) of cases, whereas glycoprotein IIb/IIIa antagonists were used significantly more frequently in the BAO-1 cohort (57.7 vs. 33.3%, p = 0.034). Thrombectomies were performed in 20 patients (55.5%) of the BAO-2 group but in none of the BAO-1 cohort. Complete recanalization (TICI 3) was achieved in 45.1% (BAO-1) versus 66.7% (BAO-2, p = 0.062) of patients. A good clinical outcome was observed in 13.5% of the BAO-1 group and 30.6% of the BAO-2 cohort (p = 0.026); mortality was 57.7% in the earlier group and 36.1% in the later group (p = 0.034). The frequency of symptomatic intracranial hemorrhage was similar in both groups (8.1% BAO-1 vs. 2.8% BAO-2, p = 0.45). Treatment in the BAO-2 cohort was an independent predictor of good clinical outcome (OR 2.56; 95% CI 1.01-6.78) and mortality (OR 0.36; 95% CI 0.15-0.86) in an adjusted logistic regression model. Conclusion: Our results show improved outcomes in patients in the BAO-2 cohort. The treatment approach in this group was an independent predictor of both good outcome and mortality. Especially in patients with BAO - where endovascular treatment strategies are common clinical practice - bridging protocols with rtPA and modern thrombectomy devices should be used more frequently.

The impact of low hemoglobin levels and transfusion on critical care patients with severe ischemic stroke

PURPOSE Optimal management of hemoglobin (Hb) and red blood cell transfusion (RBCT) in neurologic intensive care unit (NICU) patients has not been determined yet. Here we aimed to investigate the impact of anemia and transfusion activity in patients who had acute ischemic stroke. MATERIALS AND METHODS A retrospective analysis of clinical, laboratory, and outcome data of patients with severe acute ischemic stroke treated on our NICU between 2004 and 2011 was performed. RESULTS Of 109 patients, 97.2% developed anemia and 33% received RBCT. Significant correlations were found between NICU length of stay (NICU LOS) and lowest (nadir) Hb (correlation coefficient, -0.42, P < .001), Hb decrease (0.52, P < .001), nadir hematocrit (Hct; -0.43, P < .001), and Hct decrease (0.51, P < .001). Duration of mechanical ventilation (MV) was strongly associated with both nadir Hb (-0.41, P < .001) and decrease (0.42, P < .001) and nadir Hct (-0.43, P < .001) and decrease (0.40, P < .001). Red blood cell transfusion correlated with NICU LOS (0.33, P < .001) and with duration of MV (0.40, P < .001). None of these hematologic parameters correlated with in-hospital mortality or 90-day outcome. The linear regression model showed number of RBCT (0.29, P = .008), nadir Hb (-0.18, P = .049), Hb decrease (0.33, P < .001), nadir Hct (-0.18, P = .03), and Hct decrease (0.29, P < .001) to be independent predictors of NICU LOS. Duration of MV was also independently predicted by number of RBC transfusions (0.29, P < .001), nadir Hb (-0.20, P = .02), Hb decrease (0.25, P = .002), nadir Hct (-0.21, P = .015), and Hct decrease (0.26, P < .001). CONCLUSIONS Low and further decreasing Hb and Hct levels as well as RBCT activity are associated with prolonged NICU stay and duration of MV but not with mortality or long-term outcome. Our findings do not justify using a more aggressive transfusion practice at present.

Frequency of Increased Blood Pressure Levels During Systemic Thrombolysis and Risk of Intracerebral Hemorrhage

Background and Purpose— Significantly increased blood pressure (BP) is common in patients receiving intravenous thrombolysis (IVT). We aimed to investigate frequency of pre- and post-treatment elevated BP and its relation to intracerebral hemorrhage (ICH) and symptomatic ICH (sICH), respectively. Methods— Data for patients treated with intravenous thrombolysis in the years 2007 to 2009 were retrospectively extracted from our prospectively conducted local stroke database. All documented BP levels from admission to follow-up imaging scan were analyzed. BP protocol violations were defined as systolic BP >185mm Hg and/or diastolic BP >110 mm Hg. sICH was defined as ICH plus worsening of the National Institute of Health Stroke Scale ≥4 points. Results— BP protocol violation before IVT emerged in 12.6% and during the course of IVT in 40.1% of 427 patients. sICH occurred in 10 (2.3%) and ICH in general occurred in 51 (11.9%) of 427 patients. Proportions of BP protocol violations were similar in patients without ICH, with any ICH, and with sICH (3.1% versus 2.8% versus 3.2%). Systolic BP levels and mean arterial pressure did not differ between patients without ICH, patients with any ICH, and patients with sICH. In the multivariate analysis, only early CT findings independently predicted ICH (OR, 2.39; 95% CI, 1.25–4.61; P=0.009). Conclusions— BP protocol violations are common before and during the course of IVT, but neither the frequency of BP protocol violations nor the BP levels predicted ICH or sICH in univariate or multivariate analyses.

Loss of Penumbra by Impaired Oxygen Supply Decreasing Hemoglobin Levels Predict Infarct Growth after Acute Ischemic Stroke

Background: The association of mortality and poor outcome with reduced levels of hemoglobin (Hb) and hematocrit (Hct) in patients admitted for ischemic stroke was recently demonstrated. The mechanisms behind this have remained unclear. Aims: Here, we aimed to investigate a putative association between low Hb and Hct levels and infarct growth. Methods: All consecutive patients who received intravenous thrombolysis based on multimodal magnetic resonance imaging during the years 1998–2009 were screened. Laboratory data as well as admission magnetic resonance images and follow-up computed tomography scans of 257 patients were assessed. Overall, data of 100 patients were of sufficient quality and further analyzed. Results: Decrease in Hb and Hct as well as perfusion-weighted imaging volume, mismatch volume, and final infarct size on follow-up computed tomography were associated with infarct growth. A linear regression model revealed Hb decrease (β = 0.23, p = 0.02) to be a predictor of infarct growth, independent of mismatch volume (β = 0.27, p = 0.004) and minimum sodium (β = -0.21, p = 0.03), and adjusted to the non-predicting variables age, National Institute of Health Stroke Scale score, maximum leucocytes and C-reactive protein, blood glucose, and Hct decrease. Conclusion: Hb levels that decrease after admission independently predict infarct growth in thrombolyzed stroke patients. The clinical implications of this relationship remain to be investigated.

Stent Retriever Thrombectomy in Patients Who Are Ineligible for Intravenous Thrombolysis: A Multicenter Retrospective Observational Study

BACKGROUND AND PURPOSE: Intravenous thrombolysis with rtPA is the standard of care for patients with acute ischemic stroke within 4.5 hours after symptom onset. However, a considerable number of patients are ineligible for IV thrombolysis due to various contraindications. Recent studies have proved the superiority of mechanical thrombectomy for patients with large-vessel occlusions in combination with IV rtPA compared with IV rtPA alone. We aimed to demonstrate the efficacy of mechanical thrombectomy for patients who are ineligible for IV rtPA. MATERIALS AND METHODS: Patients from the stroke registries of 4 dedicated centers who were treated with mechanical thrombectomy from January 2010 to October 2014 were retrospectively evaluated. Inclusion criteria were the following: acute stroke due to proved large-artery occlusion, ineligibility for IV thrombolysis, and a timeframe of ≤4.5 hours between stroke and the start of mechanical thrombectomy. Recanalization success, periprocedural complications, clinical outcome, and hemorrhages were evaluated. RESULTS: One hundred thirty endovascular recanalization procedures were identified. The locations were the following: proximal ICA in 17 (13.1%), terminus ICA in 25 (19.2%), M1 segment in 77 (59.2%), and M2 segment in 11 (8.5%). TICI 2b/3 results were achieved in 101 (77.7%), and an mRS score of 0–2 in 47 patients (37.9%). There was a significant correlation between TICI 2b/3 results and good clinical outcomes (87.2% versus 6.8%; P = .048). A good clinical result was most frequent when recanalization was achieved within 4.5 hours (37/74 = 50% versus 10/50 = 20.0%; P = .001). Symptomatic hemorrhage occurred in 13.1% of patients; mortality was 24.2%. Periprocedural complications were recorded in 10 patients (7.7%). CONCLUSIONS: Mechanical thrombectomy can achieve good clinical outcomes in patients with acute large-artery occlusion ineligible for IV thrombolysis, in particular when recanalization is reached early.