Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany - A national case collection.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0-3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

Sonographic evaluation of hemorrhagic transformation and arterial recanalization in acute hemispheric ischemic stroke.

BACKGROUND AND PURPOSE: We conducted this prospective study to evaluate the time course of hemorrhagic transformation (HT) and arterial recanalization in the early phase of ischemic stroke using transcranial sonography (TCS). METHODS: Fifty-five patients with acute ischemic hemispheric stroke <32 hours after symptom onset were studied. A 2-MHz sector probe was used to evaluate brain tissue by TCS and basal cerebral arteries by transcranial color-coded sonography. Follow-up investigations were performed up to 6 days. Lesion size and localization were determined by cranial computed tomography. RESULTS: Of 20 patients with HT, 18 displayed by computed tomography could be identified by TCS. In 1 patient, TCS provided a wrong positive result, and in another 2 patients with small cortical HT, a wrong negative result was provided (sensitivity 90.0%, specificity 97.4%). HT was detected in the first 60 hours after symptom onset in 62.5% of patients treated with tissue plasminogen activator in comparison to 33.3% without thrombolysis. Recanalization of middle cerebral artery occurred earlier in tissue plasminogen activator-treated patients compared to those without tissue plasminogen activator treatment (in the first 60 hours after symptom onset: 78.5% vs 50.0%, respectively; P=0.34). There was a significant time difference between middle cerebral artery recanalization and HT occurrence (n=13, median time interval: 20 vs 60 hours; P=0.035). CONCLUSIONS: Transcranial ultrasound is a useful bedside method to depict and closely monitor HT in patients with acute hemispheric stroke. The strong influence of tissue plasminogen activator treatment on HT could be demonstrated. HT development is dependent on the time of artery recanalization.

Ultrasound perfusion imaging: determination of thresholds for the identification of critically disturbed perfusion in acute ischemic stroke--a pilot study.

Ultrasound harmonic imaging of perfusion after ultrasound contrast agent (UCA) bolus injection (BHI) can detect cerebral perfusion deficits. In a pilot study, we evaluated the ability of time-intensity curve (TIC) measurements to differentiate between normal and hypoperfused brain areas in acute ischemic stroke. Ten patients with symptoms of acute middle cerebral artery infarction were investigated (SONOS 5500, Harmonic Imaging 1.6/3.8 MHz, diencephalic plane, 10 cm investigation depth, SonoVue 2.4 mL bolus). Peak signal increase (PSI), time-to-peak intensity (TPI) and area under the curve (AUC) were calculated for 60 regions-of-interest (ROIs) in each patient. Reference methods: Perfusion- and diffusion-weighted MRI (PWI/DWI) within 4 h before/after BHI (PWI threshold: 4 s). Receiver operating characteristics (ROC) analysis defined cut-off values for each TIC variable to distinguish between normal and affected brain areas as defined by PWI/DWI. In five patients, PWI showed a perfusion delay >4 s; seven patients had a DWI lesion. In three patients, both PWI and DWI findings showed pathology; one patient had a normal MRI of the insonation plane. Cut-off values for PWI delay: PSI: 5.53% (sensitivity .98, specificity .89); TPI: 4.04 s (sensitivity .74, specificity .69) and AUC: .63 (sensitivity .94, specificity .58). Referred to the mean value in unaffected brain areas the relative thresholds were 17.6%, 109.5% and 16.1%, respectively. Regarding DWI, only for PSI, a significant cut-off value was defined: 10.86%, sensitivity .84, specificity .60 (34.6% of mean). In conclusion, these thresholds distinguish between normal and affected brain areas in acute ischemic stroke.

Transcranial sonographic monitoring of hemorrhagic transformation in patients with acute middle cerebral artery infarction.

BACKGROUND AND PURPOSE: Previous studies indicate the potential of transcranial sonography (TCS) to detect cerebrovascular disease. The authors conducted this patient study to evaluate the diagnostic potential of gray-scale TCS in depicting hemorrhagic transformation (HT) in the early phase of middle cerebral artery infarction. METHODS: TCS was performed in 32 patients with acute ischemic stroke in the middle cerebral artery territory less than 12, 24 +/- 4, 72 +/- 6, and 120 +/- 12 hours after symptom onset (SONOS 5500, S4 probe, 16 cm investigation depth). Hemorrhagic transformation was identified as hyperechogenicity in the MCA territory, and the echogenicity of these areas was assessed. In addition, the dislocation of the third ventricle (midline shift, MLS) was assessed by TCS. Size and localization of infarction were determined by cranial computed tomography (CCT). RESULTS: In 10 of 11 patients, TCS detected HT as confirmed by CCT. In 1 patient, TCS provided a false-positive result. In another patient, TCS was unable to detect the hemorrhage (sensitivity, 91%; specificity, 95%). The echointensity of HT increased over time. MLS measurement failed to predict fatal outcome in 1 patient. CONCLUSIONS: TCS is a promising tool for depicting HT in patients with acute hemispheric stroke and might be suitable for monitoring purposes.

Comparison of different mathematical models to analyze diminution kinetics of ultrasound contrast enhancement in a flow phantom.

Ultrasound (US) energy leads to intensity- and frequency-dependent destruction of US contrast agent (UCA) microbubbles. When applying repeated US pulses, this phenomenon can be detected as contrast diminution over time. Contrast diminution kinetics depend on the replenishment of UCA into the sample volume. Thus, it is related to organ perfusion. To analyze the contrast diminution kinetics following pulsed harmonic US application (SONOS 5500, 1.8-3.6 MHz, MI: 1.6, frame rates: 2, 4, and 6.67 Hz), we performed an in vitro study using SonoVue continuous infusion. Seven flow rates (4.5, 9, 13.5, 18, 22.5, 27 and 36 mL/min) were tested. Based on our results, three mathematical models (linear intensity decrease, exponential decay, and an exponential destruction/reperfusion model) describing diminution kinetics were compared. In 113 (89.7%) of 126 trials, a signal decrease was observed after US application. At higher flow rates (18 to 36 mL/min), curve fitting was not possible for the exponential models. For the linear model, intensity decrease depended significantly on the flow rate (p < or = 0.005, n = 7). A logistic model was fitted to the data, defining the slope in the dynamic range of quasilinear dependence for the different frame rates, as well as the inflection point: The higher the frame rate, the higher the flow rate at the point of inflection. For the exponential model, the contrast half-life was dependent on the flow rate (r = 0.95, p = 0.03, n = 6) only at the highest frame rate (6.67 Hz). The perfusion coefficient derived from the destruction/reperfusion model was not significantly related to the flow rate. In conclusion, the linear intensity decrease correlates well with the flow rate (i.e., flow velocity) and defines optimum frame rates for diminution imaging at different flow velocities. The exponential models, which required curve-fitting procedures, were determined to be inappropriate to describe flow in our phantom.