Tzu Ching Wu

Hypothermia for acute ischaemic stroke

Ischaemic stroke is one of the leading causes of death and disability worldwide, and intravenous alteplase is the only proven effective treatment in the acute setting. Hypothermia has been shown to improve neurological outcomes after global ischaemia-hypoxia in comatose patients who have had cardiac arrest, and is one of the most extensively studied and powerful therapeutic strategies in acute ischaemic stroke. The protective mechanisms of therapeutic hypothermia affect the ischaemic cascade across several parallel pathways and, when coupled with reperfusion strategies, might yield synergistic benefits for patients who have had a stroke. Technological advances have allowed hypothermia to be induced rapidly, and the treatment has been used safely in acute stroke patients. Conclusive efficacy trials assessing therapeutic hypothermia combined with reperfusion therapies in acute ischaemic stroke are ongoing.

The Argatroban and Tissue-Type Plasminogen Activator Stroke Study Final Results of a Pilot Safety Study

Background and Purpose— Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. Methods— During standard-dose intravenous tPA, a 100-&mgr;g/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. Results— Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38–60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2–7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7–15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). Conclusions— The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00268762.

Increased blood-brain barrier permeability on perfusion CT might predict malignant middle cerebral artery infarction.

Background and Purpose— Perfusion CT has been used to assess the extent of blood–brain barrier breakdown. The purpose of this study was to determine the predictive value of blood–brain barrier permeability measured using perfusion CT for development of malignant middle cerebral artery infarction requiring hemicraniectomy (HC). Methods— We retrospectively identified patients from our stroke registry who had middle cerebral artery infarction and were evaluated with admission perfusion CT. Blood–brain barrier permeability and cerebral blood volume maps were generated and infarct volumes calculated. Clinical and radiographic characteristics were compared between those who underwent HC versus those who did not undergo HC. Results— One hundred twenty-two patients (12 HC, 110 no HC) were identified. Twelve patients who underwent HC had developed edema, midline shift, or infarct expansion. Infarct permeability area, infarct cerebral blood volume area, and infarct volumes were significantly different (P<0.018, P<0.0211, P<0.0001, P<0.0014) between HC and no HC groups. Age (P=0.03) and admission National Institutes of Health Stroke Scale (P=0.0029) were found to be independent predictors for HC. Using logistic regression modeling, there was an association between increased infarct permeability area and HC. The OR for HC based on a 5-, 10-, 15-, or 20-cm2 increase in infarct permeability area were 1.179, 1.390, 1.638, or 1.932, respectively (95% CI, 1.035 to 1.343, 1.071 to 1.804, 1.108 to 2.423, 1.146 to 3.255, respectively). Conclusion— Increased infarct permeability area is associated with an increased likelihood for undergoing HC. Because early HC for malignant middle cerebral artery infarction has been associated with better outcomes, the infarct permeability area on admission perfusion CT might be a useful tool to predict malignant middle cerebral artery infarction and need for HC.

Benefits of Stroke Treatment Using a Mobile Stroke Unit Compared With Standard Management The BEST-MSU Study Run-In Phase

Background and Purpose— Faster treatment with intravenous tissue-type plasminogen activator (tPA) is likely to improve outcomes. Optimizing prehospital triage by mobile stroke units (MSUs) may speed treatment times. The Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit (BEST-MSU) study was launched in May 2014 using the first MSU in the United States to compare stroke management using an MSU versus standard management (SM). Herein, we describe the results of the prespecified, nonrandomized run-in phase designed to obtain preliminary data on study logistics. Methods— The run-in phase consisted of 8 MSU weeks when all-patient care occurred on the MSU and 2 SM weeks when the MSU nurse met personnel on scene or at the emergency department to ensure comparability with MSU patients. Telemedicine was independently performed in 9 MSU cases. Results— Of 130 alerts, 24 MSU and 2 SM patients were enrolled. Twelve of 24 MSU patients received tPA on board; 4 were treated within 60 minutes of last seen normal, and 4 went on to endovascular treatment. There were no hemorrhagic complications. Four had primary intracerebral hemorrhage. Agreement on tPA eligibility between the onsite and telemedicine physician was 90%. Conclusions— The run-in phase provided a tPA treatment rate of 1.5 patients per week, assured us that treatment within 60 minutes of onset is possible, and enabled enrollment of patients on SM weeks. We also recognized the opportunity to assess the effect of the MSU on endovascular treatment and intracerebral hemorrhage. Challenges include the need to control biased patient selection on MSU versus SM weeks and establish inter-rater agreement for tPA treatment using telemedicine.

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

Rationale Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. Aims The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. Study Design This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. Outcomes The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Establishing the First Mobile Stroke Unit in the United States

Background and Purpose— Recently, the Mobile Stroke Unit (MSU) concept was introduced in Germany demonstrating prehospital treatment of more patients within the first hour of symptom onset. However, the details and complexities of establishing such a program in the United States are unknown. We describe the steps involved in setting up the first MSU in the United States. Methods— Implementation included establishing leadership, fund-raising, purchase and build-out, knitting a collaborative consortium of community stakeholders, writing protocols to ensure accountability, radiation safety, purchasing supplies, licensing, insurance, establishing a base station, developing a communication plan with city Emergency Medical Services, Emergency Medical Service training, staffing, and designing a research protocol. Results— The MSU was introduced after ≈1 year of preparation. Major obstacles to establishing the MSU were primarily obtaining funding, licensure, documenting radiation safety protocols, and establishing a smooth communication system with Emergency Medical Services. During an 8 week run-in phase, ≈2 patients were treated with recombinant tissue-type plasminogen activator per week, one-third within 60 minutes of symptom onset, with no complications. A randomized study to determine clinical outcomes, telemedicine reliability and accuracy, and cost effectiveness was formulated and has begun. Conclusion— The first MSU in the United States has been introduced in Houston, TX. The steps needed to accomplish this are described.

Prehospital Utility of Rapid Stroke Evaluation Using In-Ambulance Telemedicine: A Pilot Feasibility Study

Background and Purpose— Prehospital evaluation using telemedicine may accelerate acute stroke treatment with tissue-type plasminogen activator. We explored the feasibility and reliability of using telemedicine in the field and ambulance to help evaluate acute stroke patients. Methods— Ten unique, scripted stroke scenarios, each conducted 4 times, were portrayed by trained actors retrieved and transported by Houston Fire Department emergency medical technicians to our stroke center. The vascular neurologists performed remote assessments in real time, obtaining clinical data points and National Institutes of Health (NIH) Stroke Scale, using the In-Touch RP-Xpress telemedicine device. Each scripted scenario was recorded for a subsequent evaluation by a second blinded vascular neurologist. Study feasibility was defined by the ability to conduct 80% of the sessions without major technological limitations. Reliability of video interpretation was defined by a 90% concordance between the data derived during the real-time sessions and those from the scripted scenarios. Results— In 34 of 40 (85%) scenarios, the teleconsultation was conducted without major technical complication. The absolute agreement for intraclass correlation was 0.997 (95% confidence interval, 0.992–0.999) for the NIH Stroke Scale obtained during the real-time sessions and 0.993 (95% confidence interval, 0.975–0.999) for the recorded sessions. Inter-rater agreement using &kgr;-statistics showed that for live-raters, 10 of 15 items on the NIH Stroke Scale showed excellent agreement and 5 of 15 showed moderate agreement. Matching of real-time assessments occurred for 88% (30/34) of NIH Stroke Scale scores by ±2 points and 96% of the clinical information. Conclusions— Mobile telemedicine is reliable and feasible in assessing actors simulating acute stroke in the prehospital setting.

Optimizing Prediction Scores for Poor Outcome After Intra-Arterial Therapy in Anterior Circulation Acute Ischemic Stroke

Background and Purpose— Intra-arterial therapy (IAT) promotes recanalization of large artery occlusions in acute ischemic stroke. Despite high recanalization rates, poor clinical outcomes are common. We attempted to optimize a score that combines clinical and imaging variables to more accurately predict poor outcome after IAT in anterior circulation occlusions. Methods— Patients with acute ischemic stroke undergoing IAT at University of Texas (UT) Houston for large artery occlusions (middle cerebral artery or internal carotid artery) were reviewed. Independent predictors of poor outcome (modified Rankin Scale, 4–6) were studied. External validation was performed on IAT-treated patients at Emory University. Results— A total of 163 patients were identified at UT Houston. Independent predictors of poor outcome (P⩽0.2) were identified as score variables using sensitivity analysis and logistic regression. Houston Intra-Arterial Therapy 2 (HIAT2) score ranges 0 to 10: age (⩽59=0, 60–79=2, ≥80 years=4), glucose (<150=0, ≥150=1), National Institute Health Stroke Scale (⩽10=0, 11–20=1, ≥21=2), the Alberta Stroke Program Early CT Score (8–10=0, ⩽7=3). Patients with HIAT2≥5 were more likely to have poor outcomes at discharge (odds ratio, 6.43; 95% confidence interval, 2.75–15.02; P<0.001). After adjusting for reperfusion (Thrombolysis in Cerebral Infarction score ≥2b) and time from symptom onset to recanalization, HIAT2≥5 remained an independent predictor of poor outcome (odds ratio, 5.88; 95% confidence interval, 1.96–17.64; P=0.02). Results from the cohort of Emory (198 patients) were consistent; patients with HIAT2 score ≥5 had 6× greater odds of poor outcome at discharge and at 90 days. HIAT2 outperformed other previously published predictive scores. Conclusions— The HIAT2 score, which combines clinical and imaging variables, performed better than all previous scores in predicting poor outcome after IAT for anterior circulation large artery occlusions.

Pharmacological Deep Vein Thrombosis Prophylaxis Does Not Lead to Hematoma Expansion in Intracerebral Hemorrhage With Intraventricular Extension

Background and Purpose— Patients with intracerebral hemorrhage (ICH) are at high risk for development of deep venous thrombosis. Current guidelines state that low-dose subcutaneous low molecular weight heparin or unfractionated heparin may be considered at 3 to 4 days from onset. However, insufficient data exist on hematoma volume in patients with ICH before and after pharmacological deep venous thrombosis prophylaxis, leaving physicians with uncertainty regarding the safety of this practice. Methods— We identified patients from our stroke registry (June 2003 to December 2007) who presented with ICH only or ICH+intraventricular hemorrhage and received either low molecular weight heparin subcutaneously or unfractionated heparin within 7 days of admission and had a repeat CT scan performed within 4 days of starting deep venous thrombosis prophylaxis. We calculated the change in hematoma volume from the admission and posttreatment CTs. Hematoma volume was calculated using the ABC/2 method and intraventricular hemorrhage volumes were calculated using a published method of hand drawn regions of interest. Results— We identified 73 patients with a mean age of 63 years and median National Institutes of Health Stroke Scale score 11.5. The mean baseline total hematoma volume was 25.8 mL±23.2 mL. There was an absolute change in hematoma volume from pre- and posttreatment CT of −4.3 mL±11.0 mL. Two patients developed hematoma growth. Repeat analysis of patients given pharmacological deep venous thrombosis prophylaxis within 2 or 4 days after ICH found no increase in hematoma size. Conclusions— Pharmacological deep venous thrombosis prophylaxis given subcutaneously in patients with ICH and/or intraventricular hemorrhage in the subacute period is generally not associated with hematoma growth.

Neurofluctuation in patients with subcortical ischemic stroke

Objective: The purpose of this study was to assess the incidence of deterioration, fluctuation, and associated risk of poor outcome in patients with subcortical stroke (SCS). Methods: We conducted a prospective observational study, enrolling patients admitted with SCS based on their clinical examination and imaging studies. An NIH Stroke Scale evaluation was performed daily and whenever deterioration in examination was detected. Neurologic deterioration was defined as a motor score increase of at least 1 on the NIH Stroke Scale. Modified Rankin Scale scores at discharge were used to assess outcome. Results: Among 90 enrolled patients, 37 (41%) deteriorated, 75% of them in the first 24 hours after enrollment. Administration of tissue plasminogen activator was significantly associated with deterioration (hazard ratio 2.25; 95% confidence interval [CI]: 1.13–4.49) even after controlling for the association of deterioration with the early poststroke period. Deterioration conferred an increased risk of poor outcome (modified Rankin Scale scores 3–6) at discharge (relative risk: 1.80; 95% CI: 1.71–1.93). Reversion back to predeterioration deficits occurred in 38% of patients, and was associated with reduced risk of poor outcome at discharge (relative risk: 0.12; 95% CI: 0.02–0.83). Treatment with tissue plasminogen activator conferred better chances of spontaneous recovery to predeterioration deficits after initial deterioration (hazard ratio: 4.36; 95% CI: 1.36–14.01). Conclusion: More than 40% of patients with SCS deteriorate neurologically. Deterioration tends to occur early after stroke, spontaneously reverses in approximately one-third of cases, and poses an increased risk of poor outcome. Therapies are needed to prevent, arrest, or reverse deterioration in patients with SCS.