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Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship.In a pooled, patient-level analysis of EXTEND-IA trials and SELECT study, we employed a mediation analysis framework to quantify infarct growth and cerebral edema(midline shift) mediation effect on successful reperfusion(mTICI≥2b) association with functional outcome(mRS distribution). Further, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift.542/665(81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful vs unsuccessful reperfusion. Median(IQR) infarct growth was 12.3(1.8-48.4)ml and median(IQR) midline shift was 0(0,2.2)mm. Of 249(37%) demonstrating a midline shift of ≥1mm, median(IQR) shift was 2.75(1.89, 4.21)mm). Successful reperfusion was associated with reductions in both predefined mediators; infarct growth (β, -1.19; 95%CI, -1.51to-0.88;p0.001) and midline shift (aOR:0.36,95%CI:0.23-0.57,p0.001). Successful reperfusion association with improved functional outcome (acOR:2.68; 95%CI:1.86-3.88,p0.001), became insignificant (acOR:1.39, 95%CI:0.95-2.04,p=0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect. Analysis considering alternative hypothesis demonstrated consistent results.In this mediation analysis from a pooled, patient-level cohort, a significant proportion(~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect and identify novel therapeutic targets to further enhance reperfusion benefits. This article is protected by copyright. All rights reserved.

Background: Hematoma enlargement (HE) after intracerebral hemorrhage (ICH) is a therapeutic target for improving outcomes. Hemostatic therapies to prevent HE may be more effective the earlier they are attempted. An understanding of HE in first 1 to 2 hours specifically in the prehospital setting would help guide future treatment interventions in this time frame and setting. Methods: Patients with spontaneous ICH within 4 hours of symptom onset were prospectively evaluated between May 2014 and April 2020 as a prespecified substudy within a multicenter trial of prehospital mobile stroke unit versus standard management. Baseline computed tomography scans obtained 6 mL if baseline ICH volume was < 20 mL and 33% increase if baseline volume >20 mL. The association between time from symptom onset to baseline computed tomography (hours) and HE was investigated using Wilcoxon rank-sum test when time was treated as a continuous variable and using Fisher exact test when time was categorized. Kruskal-Wallis and Wilcoxon rank-sum tests evaluated differences in baseline volumes and HE. Univariable and multivariable logistic regression analyses were conducted to identify factors associated with HE and variable selection was performed using cross-validated L1-regularized (Lasso regression). This study adhered to STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology) for cohort studies. Results: One hundred thirty-nine patients were included. There was no difference between baseline ICH volumes obtained 2 hours (n=45) from symptom onset (median [interquartile range], 13 mL [6–24] versus 14 mL [6–30] versus 12 mL [4–19]; P =0.65). However, within the same 3 time epochs, initial hematoma growth (volume/time from onset) was greater with earlier baseline scanning (median [interquartile range], 17 mL/hour [9–35] versus 9 mL/hour [5–23]) versus 4 mL/hour [2–7]; P 2 hours; P =0.02). HE did not occur between the scans repeated at 1 hour and 24 hours. No association between baseline variables and HE was detected in multivariable analyses. Conclusions: HE in the next hour occurs in 28% of ICH patients with baseline imaging within the first hour after symptom onset, and in 17% of those with baseline imaging between 1 and 2 hours. These patients would be a target for ultraearly hemostatic intervention.

Mobile stroke units (MSUs) are specialized ambulances equipped with the personnel, equipment, and imaging capability to diagnose and treat acute stroke in the prehospital setting. Over the past decade, MSUs have proliferated throughout the world, particularly in European and US cities, culminating in the formation of an international consortium. Randomized trials have demonstrated that MSUs increase stroke thrombolysis rates and reduce onset-to-treatment times but until recently it was uncertain if these advantages would translate into better patient outcomes. In 2021, 2 pivotal, large, controlled clinical trials, B_PROUD and BEST-MSU, demonstrated that as compared with conventional emergency care, treatment aboard MSUs was safe and led to improved functional outcomes in patients with stroke. Further, the observed benefit of MSUs appeared to be primarily driven by the higher frequency of ultra-early thrombolysis within the golden hour. Nevertheless, questions remain regarding the cost-effectiveness of MSUs, their utility in nonurban settings, and optimal infrastructure. In addition, in much of the world, MSUs are currently not reimbursed by insurers nor accepted as standard care by regulatory bodies. As MSUs are now established as one of the few proven acute stroke interventions with an effect size that is comparable to that of intravenous thrombolysis and stroke units, stroke leaders and organizations should work with emergency medical services, governments, and community stakeholders to determine how MSUs might benefit individual communities, and their optimal organization and financing. Future research to explore the effect of MSUs on intracranial hemorrhage and thrombectomy outcomes, cost-effectiveness, and novel models including the use of rendezvous transports, helicopters, and advanced neuroimaging is ongoing. Recommended next steps for MSUs include reimbursement by insurers, integration with ambulance networks, recognition by program accreditors, and inclusion in registries that monitor care quality.

Background: Neuroinflammation is ubiquitous in acute stroke and worsens outcome. However, the precise timing of the inflammatory response is unknown, hindering the design of acute anti-inflammatory therapeutic interventions. We sought to identify the onset of the neuroinflammatory cascade using a mobile stroke unit. Methods: The study is a proof-of-concept, cohort investigation of ultra-early blood- and extracellular vesicle–derived markers of neuroinflammation and outcome in acute stroke. Blood was obtained, prehospital, on an mobile stroke unit. Outcomes were biomarker concentrations, modified Rankin Scale score, and National Institutes of Health Stroke Scale score. Results: Forty-one adults were analyzed, including 15 patients treated on the mobile stroke unit between August 2021 and April 2022, and 26 healthy controls to establish biomarker reference levels. Median patient age was 74 (range, 36–97) years, 60% were female, and 80% White. Ten (67%) were diagnosed as stroke, with 8 (53%) confirmed and 2 likely transient ischemic attack or stroke averted by thrombolysis; 5 were stroke mimics. For strokes, median initial National Institutes of Health Stroke Scale score was 11 (range, 4–19) and 6 (75%) received tPA (tissue-type plasminogen activator). Blood was obtained a median of 58 (range, 36–133) minutes after symptom onset. Within 36 minutes after stroke, plasma IL-6 (interleukin-6), neurofilament light chain, UCH-L1 (ubiquitin C-terminal hydrolase L1), and GFAP (glial fibrillary acidic protein) were elevated by as much as 10 times normal. In EVs, MMP-9 (matrix metalloproteinase-9), CXCL4 (chemokine (C-X-C motif) ligand 4), CRP (C-reactive protein), IL-6, OPN (osteopontin), and PECAM1 (platelet and endothelial cell adhesion molecule 1) were elevated. Inflammatory markers increased rapidly in the first 2 hours and continued rising for 24 hours. Conclusions: The neuroinflammatory cascade was found to be activated within 36 to 133 minutes after stroke and progresses rapidly. This is earlier than observed previously in humans and suggests injury from neuroinflammation occurs faster than had been surmised. These findings could inform development of acute immunomodulatory stroke therapies and lead to new diagnostic tools and improved outcomes.

Background: Neuroinflammation is ubiquitous in acute stroke and worsens outcome. However, the precise timing of the inflammatory response is unknown, hindering the design of acute anti-inflammatory therapeutic interventions. We used a mobile stroke unit (MSU) to identify the onset of the neuroinflammatory cascade within minutes of symptom onset. Methods: The study is a prospective, cohort investigation of ultra-early blood- and extracellular vesicle (EV)-derived markers of neuroinflammation and outcome in acute stroke. Blood was obtained on the MSU with head CT, and from healthy controls. Plasma biomarkers were analyzed with ELISA, SIMOA and ECL. EVs were isolated with HSP pull down. Confirmed strokes, mimics and healthy controls were compared. Variables included demographics, mRS, NIHSS and discharge disposition. Results: Forty one adults were analyzed, including 15 patients treated on the MSU between August 2021 and April 2022, and 26 controls. For MSU patients, median age was 74 (range 36-97) years, 60% were female, and 80% white. Ten (67%) were diagnosed as stroke, with 8 (53%) confirmed and 2 likely TIA or stroke averted by thrombolysis; 5 were stroke mimics. For strokes, median initial NIHSS score was 11 (range 4-19) and 6 (75%) received tPA. Blood was obtained a median of 58 (range 36-133) minutes after symptom onset. Within 36 minutes after stroke, plasma interleukin-6 (IL-6), neurofilament light chain (NfL), ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were elevated by as much as 10 times normal. In EVs, matrix metalloproteinase-9 (MMP-9), chemokine (C-X-C motif) ligand 4 (CXCL4), C-reactive protein (CRP), IL-6, osteopontin (OPN) and platelet and endothelial cell adhesion molecule 1 (PECAM1) were elevated. Inflammatory markers increased rapidly in the first two hours, and continued rising for 24 hours. Conclusions: This study found the inflammatory cascade is activated as early as 36 minutes after stroke, and progresses rapidly. This is earlier than observed previously in humans, and suggests injury from neuroinflammation may occur faster than had been surmised. The findings may inform development of immunomodulatory therapies for acute stroke, and lead to new diagnostic tools and improved outcomes.

Background: Few data exists on acute stroke treatment in patients with pre-existing disability (PD) since they are usually excluded from clinical trials. Methods: A pre-specified subgroup analysis of tPA-eligible patients with PD enrolled in a prospective multicenter trial of Mobile Stroke Units (MSUs) vs standard management by emergency medical services (EMS). All patients had baseline mRS scores. Co-primary outcomes were mean utility-weighted modified Rankin Scale score (uw-mRS) and return to baseline mRS at 90 days. Linear and logistic regression models compared outcomes in patients with vs without PD, and patients with PD treated by MSU vs EMS. Time metrics, safety, quality of life, and health-care utilization were also compared. Results: Of 1047 patients, 254 had baseline mRS >= 2 (159 MSU, 95 EMS; 31% mRS 2, 52% mRS 3, 17% mRS 4). Compared to patients without disability, patients with PD were older, had higher NIHSS, more comorbidities, less often lived at home, were treated slower, and had less thrombectomy. Patients with PD had worse 90-day uw-mRS (0.39 vs 0.80), higher mortality, more health-care utilization and worse quality of life than patients without PD. However, rates of symptomatic intracranial hemorrhage and final diagnoses of stroke mimics were similar between groups, and 52% of patients with PD returned to their baseline mRS. Patients with PD treated within the first hour had better 90-day uw-mRS than those treated later (0.48 vs 0.36, p=0.01). Comparing patients with PD treated by MSU vs EMS, time from last-known-well to tPA bolus was shorter (82 vs 111 min), and 24% vs 0% were treated in the first hour. Among patients with PD, MSU patients had non-significantly better 90-day uw-mRS (0.41 vs 0.35, p=0.09) and higher rate of returning to baseline mRS (56% vs 44%, p=0.09) than EMS patients. There was no interaction between either time to treatment (p=0.24) or MSU vs EMS group assignment (p= 0.42), 90-day uw-mRS, and PD vs no disability status. Conclusion: Although outcomes after stroke are less favorable in patients with vs without PD, in a large, controlled trial, we found no interaction between baseline disability and the benefit of MSU treatment. Our data support the earliest treatment of acute stroke patients regardless of premorbid functional status.

Introduction: Stroke is a leading cause of long-term disability in the U.S., and 90% of stroke survivors have residual movement impairment. Inpatient and outpatient rehabilitation is critical for restoring functionality and quality of life among survivors. However, there are few studies evaluating the patterns and predictors of rehabilitation use among stroke survivors. Methods: This study used 947 tPA-eligibe patients from an observational, prospective, multicenter, clinical trial in the U.S., who had complete 1 year follow-up utilization data, collected quarterly as self-reported surveys. We determined the occurrence and length of stay for inpatient rehabilitation, and occurrence and number of visits for outpatient rehabilitation. Logistic and linear regressions were used to examine predictors associated with these occurrences and intensities. Results: The majority of rehabilitation use occurred during the first quarter with 19% and 33% of patients using inpatient and outpatient rehabilitation respectively, and rehabilitation use fell considerably over the rest of the year (Table 1). Higher disability at baseline (mRS≥2 and not living at home) reduced rehabilitation use, and higher disability at discharge increased rehabilitation use. Being uninsured reduced rehabilitation use. Other socio-demographic characteristics (such as age, gender and race-ethnicity), baseline comorbidities, and type and timeliness of therapies after stroke did not have an effect on rehabilitation use. Conclusion: Rehabilitation use is highest during the first 3 months after discharge. Patients with higher discharge disability are more in need of rehabilitation, hence receive it. Patients already disabled at baseline are often excluded, probably due to a combination of rehabilitation entry requirements and perceived lack of potential benefits. Access barriers, such as lack of insurance reduced rehabilitation use suggesting an unmet need among stroke survivors.

Objective: To serially quantify the blood coagulation within hematoma of patients with hyper-acute intracerebral hemorrhagic (ICH) stroke using non-invasive quantitative susceptibility mapping (QSM) MRI. Introduction: A blood clot is a combination of aggregated red blood cells, fibrin, platelets, hemosiderin, and other cell debris. An accurate evaluation of clot formation within hematoma could advance the clinical management of hematoma expansion, blood pressure management, and reversal of anticoagulants. Post-ICH hemolysis changes the heme iron oxidation state from oxy to deoxyhemoglobin (deoxy-Hb) resulting in unpaired iron electrons on aggregated RBC’s deoxy-Hb inducing magnetic susceptibility (χ). Therefore, a region with a higher number of aggregated RBC deoxy-Hb molecules, the dominant component of clots, will exhibit a higher positive χ susceptibility. We hypothesized that coagulated blood within hematoma will exhibit a higher positive χ in comparison to the non-clotted which can be quantified using quantitative susceptibility mapping (QSM), which is an advanced MRI image-processing algorithm. Methods: For proof of concept, we measured susceptibilities of 5 human blood phantoms with various percentages of the clot. Twenty-four patients with acute spontaneous ICH were enrolled and serially imaged 3 times within 12-24 (T1), 36-48 (T2), and 60-72(T3) hours of last known well (LNW). A 3D anatomical and multi-echo gradient echo images were obtained using a 3T MRI system. Hematoma and edema volumes were segmented and used as a region of interest (ROI). The rate of coagulation was assessed by measuring the change in susceptibilities within the hematoma. Results: The blood phantom exhibited a linear relationship between the percent coagulation and χ (R 2 =0.91). The QSM maps showed a significant increased in hematoma susceptibility over time (T1=0.29 ± 0.04, T2=0.36 ± 0.04, T3= 0.45 ± 0.04 ppm, p Conclusion: In conclusion, we present novel surrogate imaging markers of coagulation within the hematoma of ICH.

Introduction: While the goal of IV tissue plasminogen activator (TPA) is to prevent infarction, few data exist on averted stroke. Methods: Secondary analysis of a multicenter trial from 2014-2020 comparing outcomes between patients treated for stroke by mobile stroke unit (MSU) vs standard care (SC). The analytical cohort were patients with suspected stroke treated with IV TPA. The primary outcome was a time-defined averted stroke diagnosis, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours. The secondary outcome was a tissue-defined averted stroke diagnosis, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours and no acute infarction/hemorrhage on imaging. We used multivariable logistic regression to evaluate associations between study exposures (demographics, comorbidities, stroke characteristics) and outcomes. Results: Among 1009 patients with a median last known well-to-TPA time of 87 minutes, 276 patients (27%) had a time-defined averted stroke (31% MSU, 21% SC) and 159 patients (16%) had a tissue-defined averted stroke (18% MSU, 11% SC). Factors independently associated with time-defined averted stroke were younger age (OR, 0.98; 95% CI, 0.96-0.99), female sex (0R, 0.51; 95% CI, 0.36-0.74), hyperlipidemia (OR, 1.81, 95% CI, 1.24-2.64), normal premorbid function (0R, 2.22; 95% CI, 1.37-3.67), lower glucose (OR, 0.996; 95% CI, 0.993-0.999), lower MAP (OR, 0.991; 95% CI, 0.983-0.998), MSU care (OR, 1.77; 95% CI, 1.21-2.62), lower NIH stroke scale (OR, 0.89; 95% CI, 0.86-0.93), and no large vessel occlusion (LVO) (OR, 0.52; 95% CI, 0.32-0.83). For tissue-based averted stroke, younger age, female sex, hyperlipidemia, lower MAP, MSU treatment, lower NIH stroke scale, and no LVO were significantly associated. Conclusion: In a modern acute stroke trial, one-in-four patients treated with TPA for stroke recovered within 24 hours and one-in-six had no demonstrable brain injury on imaging. Younger age, female sex, hyperlipidemia, lower MAP, MSU care, lower stroke severity, and no LVO may increase the odds of averting stroke.

Several approaches have been developed to optimize prehospital systems for acute stroke given poor access and significant delays to timely treatment. Specially equipped ambulances that directly initiate treatment, known as Mobile Stroke Units (MSUs), have rapidly proliferated across the world. This review provides a comprehensive summary on the efficacy of MSUs in acute stroke, its various applications beyond thrombolysis, as well as the establishment, optimal setting and cost-effectiveness of incorporating an MSU into healthcare systems.MSUs speed stroke treatment into the first "golden hour" when better outcomes from thrombolysis are achieved. While evidence for the positive impact of MSUs on outcomes was previously unavailable, two recent landmark controlled trials, B_PROUD and BEST-MSU, show that MSUs result in significantly lesser disability compared to conventional ambulance care. Emerging literature prove the significant impact of MSUs. Adaptability however remains limited by significant upfront financial investment, challenges with reimbursements and pending evidence on their cost-effectiveness.

Randomized clinical trials of acute stroke have led to major advances in acute stroke therapy over the past decade. Despite these successes, recruitment in acute trials is often difficult. We outline challenges in recruitment for acute stroke trials and present potential solutions, which can increase the speed and decrease the cost of identifying new treatments for acute stroke. One of the largest opportunities to increase the speed of enrollment and make trials more generalizable is expansion of inclusion criteria whose impact on expected recruitment can be assessed by epidemiologic and registry databases. Another barrier to recruitment besides the number of eligible patients is availability of study investigators limited to business hours, which may be helped by financial support for after-hours call. The wider use of telemedicine has accelerated quicker stroke treatment at many hospitals and has the potential to accelerate research enrollment but requires training of clinical investigators who are often inexperienced with this approach. Other potential solutions to enhance recruitment include rapid prehospital notification of clinical investigators of potential patients, use of mobile stroke units, advances in the process of emergency informed consent, storage of study medication in the emergency department, simplification of study treatments and data collection, education of physicians to improve equipoise and enthusiasm for randomization of patients within a trial, and clear recruitment plans, and even potentially coenrollment, when there are competing trials at sites. Without successful recruitment, scientific advances and clinical benefit for acute stroke patients will lag.

Background Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard m...

Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR (Stroke Treatment Academic Industry Roundtable) conferences identified both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in workshop no. 1 Top Priorities for Neuroprotection sought to redefine the neuroprotection paradigm and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term brain cytoprotection or cerebroprotection to replace the term neuroprotection when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although “time is still brain,” tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a tissue window to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term target window to suggest therapies that target the different elements of the neurovascular unit at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised, and enhanced the STAIR preclinical recommendations for developing new treatments in 2 phases: an exploratory qualification phase and a definitive validation phase. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood-brain barrier. Before clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multicenter, collaborative testing, for example, network trials. In the absence of a proven cerebroprotective agent to use as a gold standard, however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.

Acute ischemic stroke (AIS) due to cerebral artery occlusion is often treated by thrombolytics or antithrombotic drugs. Thromboelastography (TEG) is a noninvasive test that provides a dynamic overview of the coagulation process. TEG may help guide thrombolytic and antithrombotic therapy in AIS. This article aims to highlight the potential use of TEG in AIS patients by reviewing available studies. We conducted a literature review, including PubMed and Cochrane library databases. The following keywords were used to find relevant studies: thromboelastography, TEG, acute ischemic stroke, stroke, coagulopathy, antiplatelet, and anticoagulant treatment. We identified 142 papers and after abstract review, we included 24 studies in this report. TEG identified a hypercoagulable state in AIS patients represented by short R, K, and greater α angle in all papers included. Modification of TEG parameters induced by intravenous thrombolysis was inconsistent but prolonged lysis (increased LY30) and weaker clots (lower maximum amplitude) were most frequent. TEG detected hypo-coagulopathy induced by dual antiplatelet therapy as well as antiplatelet drug resistance, with ticagrelor and aspirin having greater inhibition of platelet activity. A prolonged R-value seems to be the most reliable TEG parameter in detecting the anticoagulant effect of factor Xa inhibitor treatment. TEG might represent a useful point-of-care test for emergency decision-making in AIS patients and a tool for individualized treatment options. This hypothesis needs validation in a large cohort of prospectively studied AIS patients.

Bone marrow mononuclear cells (MNCs) attenuate secondary degeneration and enhance recovery in stroke animal models. In a nonrandomized clinical trial, we imaged 37 patients with stroke: 17 patients treated with MNCs (treated) and 20 patients who received standard of care (nontreated) at 1, 3, and 12 months onset of stroke on 3.0T MRI system. Three‐dimensional anatomical and diffusion tensor images were obtained. The integrity of the corticospinal tract was assessed by measuring absolute and relative fractional anisotropy (FA) and mean diffusivity (MD) in the rostral pons (RP), posterior limb of the internal capsule, and corona radiata by drawing regions of interest. Infarct volume and stroke severity, which was assessed via the NIH Stroke Scale (NIHSS), were higher in the MNC group compared with the nontreated patients, which is a major limitation. Overall, the relative FA (rFA) of the nontreated patients exhibited continued reduction and an increase in relative MD (rMD) from 1 to 12 months, whereas despite larger infarcts and higher severity, treated patients displayed an increase in rFA from 3 to 12 months and no change in rMD. Contrary to the nontreated group, the treated patients' rFA was also significantly correlated (P, Autologous bone‐marrow mononuclear cells were intravenously administered in patients with acute ischemic stroke as procedure outline in panel (A). The nontreated patients were recruited separately. Both groups were imaged three times over year and neuroimaging biomarkers were developed. Integrity of the ipsilesional and contralesional cortical spinal tracts (CST) were evaluated via diffusion tensor imaging (DTI), in the rostral pons (RP), posterior limb of internal capsule (PLIC), and corona radiata (CR) as illustrated in panel (B). The relative fractional anisotropy (rFA), an imaging marker of white matter integrity, was serially quantified in these three regions in each group as shown in panel (C1), (C2), and (C3). Despite larger infarct size and severity of the treated group, the rFA either increased or stabilized as compared to the nontreated patients.

BACKGROUND: Prehospital tissue plasminogen activator dosing in a mobile stroke unit (MSU) is estimated by the paramedic and nurse. We aimed to determine the accuracy of the estimated weight method compared with the actual weight of patients treated with tissue plasminogen activator on the MSU. METHODS: We prospectively collected the estimated weight used on the MSU for treatment and the first-documented hospital-measured weight (bed scale) within 24 hours of hospital arrival. Median absolute and percent difference in weights were calculated; less than 10% of difference in weights was considered acceptable. To compare the estimated and measured weights, we conducted a Wilcoxon signed rank test and Fisher exact test to explore the association between weight difference of greater than 10% and patient outcomes. RESULTS: Among 337 patients, median estimated and hospital-measured weights were 79.0 kg (interquartile range [IQR], 66.0-94.5) and 78.5 kg (IQR, 65.0-91.7), respectively. The median of the absolute value of the difference in estimated versus measured weight was 2.7 kg (IQR, 0.6-7.6; P < .0001). The median percent difference in weight was 3.6% (IQR, 0.8%-9.4%). The median difference between the tissue plasminogen activator dosage administered on the MSU and the recommended dose based on the actual weight was 1.3 mg (IQR, 0.06-4.8) in absolute value. In 56 patients (16.6% of the entire sample) with overestimation of weight by greater than 10%, there were no symptomatic intracerebral hemorrhages. There was no association between weight difference and discharge modified Rankin score (P = .59). CONCLUSION: Weight estimation on an MSU can lead to similar tissue plasminogen activator dosing for 83.4% of subjects compared with if dosing were determined based on actual weight. Weight overestimation or underestimation had no detected impact on tissue plasminogen activator outcomes.

We thank the Editors of JNIS for alerting us in advance to the concerns about SELECT2 raised by Jadhav1 and colleagues and appreciate the opportunity to explain the rationale for the study design and clarify the benefits of including perfusion imaging-based selection criteria. We are confident that SELECT2 will provide high-level, reliable data regarding the safety and efficacy of endovascular thrombectomy (EVT) for large core patients. The choice of imaging modality for identifying large core in acute ischemic stroke remains an area of considerable debate. Magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI), computed tomography (CT) or MR perfusion imaging and Alberta Stroke Program Early CT Score (ASPECTS) have all been proposed and studied. At present, there is no clear consensus on which imaging modality is best for identifying patients with large core. It is important to recognize that the early window randomized EVT trials used a broad range of imaging selection criteria. The imaging selection criteria for the initial five pivotal trials ranged from allowing patients to be enrolled regardless of the degree of early infarct signs,2 to studies that required a specific ASPECTS score range in addition to other imaging criteria,3–5 to EXTEND IA6 where the ASPECTS score was not considered, and CT perfusion (CTP) mismatch with a maximum estimated core size was required. All five trials were successful but with substantial variability in the treatment effect, leaving uncertainty as to the optimal imaging approach as well as whether there are patient subgroups who do not benefit. In fact, those utilizing perfusion mismatch criteria (EXTEND-IA, SWIFT PRIME) had higher rates of modified Rankin Scale (mRS) scores 0–2 and larger treatment effects, compared with other trials.2–6 Even if a treatment has a clear benefit in most patients, there can be important subgroups that do not …

ObjectiveTo evaluate the comparative safety and efficacy of direct endovascular thrombectomy (dEVT) compared to bridging therapy (BT; IV tissue plasminogen activator + EVT) and to assess whether BT potential benefit relates to stroke severity, size, and initial presentation to EVT vs non-EVT center.MethodsIn a prospective multicenter cohort study of imaging selection for endovascular thrombectomy (Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke [SELECT]), patients with anterior circulation large vessel occlusion (LVO) presenting to EVT-capable centers within 4.5 hours from last known well were stratified into BT vs dEVT. The primary outcome was 90-day functional independence (modified Rankin Scale [mRS] score 0–2). Secondary outcomes included a shift across 90-day mRS grades, mortality, and symptomatic intracranial hemorrhage. We also performed subgroup analyses according to initial presentation to EVT-capable center (direct vs transfer), stroke severity, and baseline infarct core volume.ResultsWe identified 226 LVOs (54% men, mean age 65.6 ± 14.6 years, median NIH Stroke Scale [NIHSS] score 17, 28% received dEVT). Median time from arrival to groin puncture did not differ in patients with BT when presenting directly (dEVT 1.43 [interquartile range (IQR) 1.13–1.90] hours vs BT 1.58 [IQR 1.27–2.02] hours, p = 0.40) or transferred to EVT-capable centers (dEVT 1.17 [IQR 0.90–1.48] hours vs BT 1.27 [IQR 0.97–1.87] hours, p = 0.24). BT was associated with higher odds of 90-day functional independence (57% vs 44%, adjusted odds ratio [aOR] 2.02, 95% confidence interval [CI] 1.01–4.03, p = 0.046) and functional improvement (adjusted common OR 2.06, 95% CI 1.18–3.60, p = 0.011) and lower likelihood of 90-day mortality (11% vs 23%, aOR 0.20, 95% CI 0.07–0.58, p = 0.003). No differences in any other outcomes were detected. In subgroup analyses, patients with BT with baseline NIHSS scores p = 0.006); this association was not evident for patients with NIHSS scores ≥15 (aOR 1.05, 95% CI 0.40–2.74, p = 0.92). Similarly, functional outcomes improvements with BT were detected in patients with core volume strata (ischemic core 3: aOR 2.10, 95% CI 1.02–4.33, p = 0.044 vs ischemic core ≥50 cm3: aOR 0.41, 95% CI 0.01–16.02, p = 0.64) and transfer status (transferred: aOR 2.21, 95% CI 0.93–9.65, p = 0.29 vs direct to EVT center: aOR 1.84, 95% CI 0.80–4.23, p = 0.15).ConclusionsBT appears to be associated with better clinical outcomes, especially with milder NIHSS scores, smaller presentation core volumes, and those who were “dripped and shipped.” We did not observe any potential benefit of BT in patients with more severe strokes.Trial Registration InformationClinicalTrials.gov Identifier: NCT02446587.Classification of EvidenceThis study provides Class III evidence that for patients with ischemic stroke from anterior circulation LVO within 4.5 hours from last known well, BT compared to dEVT leads to better 90-day functional outcomes.

Prevention of ischemic stroke relies on the use of antithrombotic medications comprising antiplatelet agents and anticoagulation. Stroke risk is particularly high in patients with cardiovascular disease. This review will focus on the role of antithrombotic therapies in the context of different types of cardiovascular disease. We will discuss oral antiplatelet medications and both IV and parental anticoagulants. Different kinds of cardiovascular disease contribute to stroke via distinct pathophysiological mechanisms, and the optimal treatment for each varies accordingly. We will explore the mechanism of stroke and evidence for antithrombotic therapy in the following conditions: atrial fibrillation, prosthetic heart values (mechanical and bioprosthetic), aortic arch atherosclerosis, congestive heart failure (CHF), endocarditis (infective and nonbacterial thrombotic endocarditis), patent foramen ovale (PFO), left ventricular assist devices (LVAD), and extracorporeal membrane oxygenation (ECMO). While robust data exist for antithrombotic use in conditions such as atrial fibrillation, optimal treatment in many situations remains under active investigation.

Background and Purpose: The optimal endovascular stroke therapy (EVT) care delivery structure is unknown. Here, we present our experience in creating an integrated stroke system (ISS) to expand EVT availability throughout our region while maintaining hospital and physician quality standards. Methods: We identified all consecutive patients with large vessel occlusion acute ischemic stroke treated with EVT from January 2014 to February 2019 in our health care system. In October 2017, we implemented the ISS, in which 3 additional hospitals (4 total) became EVT-performing hospitals (EPHs) and physicians were rotated between all centers. The cohort was divided by time into pre-ISS and post-ISS, and the primary outcome was time from stroke onset to EPH arrival. Secondary outcomes included hospital and procedural quality metrics. We performed an external validation using data from the Southeast Texas Regional Advisory Council. Results: Among 513 patients with large vessel occlusion acute ischemic stroke treated with EVT, 58% were treated pre-ISS and 43% post-ISS. Over the study period, EVT procedural volume increased overall but remained relatively low at the 3 new EPHs (P P P Conclusions: In our system, increasing EVT availability decreased time from stroke onset to EPH arrival. The ISS provides a framework to maintain quality in lower volume hospitals.

ImportanceThe role of endovascular thrombectomy is uncertain for patients presenting beyond 24 hours of the time they were last known well.ObjectiveTo evaluate functional and safety outcomes for endovascular thrombectomy (EVT) vs medical management in patients with large-vessel occlusion beyond 24 hours of last known well.Design, Setting, and ParticipantsThis retrospective observational cohort study enrolled patients between July 2012 and December 2021 at 17 centers across the United States, Spain, Australia, and New Zealand. Eligible patients had occlusions in the internal carotid artery or middle cerebral artery (M1 or M2 segment) and were treated with EVT or medical management beyond 24 hours of last known well.InterventionsEndovascular thrombectomy or medical management (control).Main Outcomes and MeasuresPrimary outcome was functional independence (modified Rankin Scale score 0-2). Mortality and symptomatic intracranial hemorrhage (sICH) were safety outcomes. Propensity score (PS)–weighted multivariable logistic regression analyses were adjusted for prespecified clinical characteristics, perfusion parameters, and/or Alberta Stroke Program Early CT Score (ASPECTS) and were repeated in subsequent 1:1 PS-matched cohorts.ResultsOf 301 patients (median [IQR] age, 69 years [59-81]; 149 female), 185 patients (61%) received EVT and 116 (39%) received medical management. In adjusted analyses, EVT was associated with better functional independence (38% vs control, 10%; inverse probability treatment weighting adjusted odds ratio [IPTW aOR], 4.56; 95% CI, 2.28-9.09; P P = .003). This association persisted after PS-based matching on (1) clinical characteristics and ASPECTS (EVT, 35%, vs control, 19%; aOR, 3.14; 95% CI, 1.02-9.72; P = .047); (2) clinical characteristics and perfusion parameters (EVT, 35%, vs control, 17%; aOR, 4.17; 95% CI, 1.15-15.17; P = .03); and (3) clinical characteristics, ASPECTS, and perfusion parameters (EVT, 45%, vs control, 21%; aOR, 4.39; 95% CI, 1.04-18.53; P = .04). Patients receiving EVT had lower odds of mortality (26%) compared with those in the control group (41%; IPTW aOR, 0.49; 95% CI, 0.27-0.89; P = .02).Conclusions and RelevanceIn this study of treatment beyond 24 hours of last known well, EVT was associated with higher odds of functional independence compared with medical management, with consistent results obtained in PS-matched subpopulations and patients with presence of mismatch, despite increased odds of sICH. Our findings support EVT feasibility in selected patients beyond 24 hours. Prospective studies are warranted for confirmation.

Background Intravenous recombinant tissue plasminogen activator is the only proven effective medication for the treatment of acute ischemic stroke. Two approaches that may augment recombinant tissue plasminogen activator thrombolysis and prevent arterial reocclusion are direct thrombin inhibition with argatroban and inhibition of the glycoprotein 2b/3a receptor with eptifibatide. Aim The multi-arm optimization of stroke thrombolysis trial aims to determine the safety and efficacy of intravenous therapy with argatroban or eptifibatide as compared with placebo in acute ischemic stroke patients treated with intravenous recombinant tissue plasminogen activator within 3 h of symptom onset. Sample size estimate A maximum of 1200 randomized subjects to test the superiority of argatroban or eptifibatide to placebo in improving 90-day modified Rankin scores. Methods and design Multiarm optimization of stroke thrombolysis is a multicenter, multiarm, adaptive, single blind, randomized controlled phase 3 clinical trial conducted within the National Institutes of Health StrokeNet clinical trial network. Patients treated with 0.9 mg/kg intravenous recombinant tissue plasminogen activator within 3 h of stroke symptom onset are randomized to receive intravenous argatroban (100 µg/kg bolus followed by 3 µg/kg/min for 12 h), intravenous eptifibatide (135 µg/kg bolus followed by 0.75 µg/kg/min infusion for 2 h) or IV placebo. Patients may receive endovascular thrombectomy per usual care. Study outcomes The primary efficacy outcome is improved modified Rankin score assessed at 90 days post-randomization. Discussion Multiarm optimization of stroke thrombolysis is an innovative and collaborative project that is the culmination of many years of dedicated efforts to improve outcomes for stroke patients.

BackgroundIt is unknown whether endovascular thrombectomy (EVT) is cost effective in large ischemic core infarcts.MethodsIn the prospective, multicenter, cohort study of imaging selection study (SELECT), large core was defined as computed tomography (CT) ASPECTSResultsFrom 361 patients enrolled in SELECT, 105 had large core on CT or CTP (EVT 62, MM 43). 19 (31%) EVT vs 6 (14%) MM patients achieved modified Rankin Scale (mRS) score 0–2 (OR 3.27, 95% CI 1.11 to 9.62, P=0.03) with a shift towards better mRS (cOR 2.12, 95% CI 1.05 to 4.31, P=0.04). Over the projected lifetime of patients presenting with large core, EVT led to incremental costs of $33 094 and a gain of 1.34 QALYs per patient, resulting in ICER of $24 665 per QALY. EVT has a higher NMB compared with MM at lower (EVT -$42 747, MM -$76 740) and upper (EVT $155 041, MM $57 134) WTP thresholds. PSA confirmed the results and CEAC showed 77% and 92% acceptability of EVT at the WTP of $50 000 and $100 000, respectively. EVT was associated with an increment of $29 225 in societal costs. The pivotal EVT trials (HERMES, DAWN, DEFUSE 3) were dominant in a sensitivity analysis at the same inputs, with societal cost-savings of $37 901, $86 164 and $22 501 and a gain of 1.62, 2.36 and 2.21 QALYs, respectively.ConclusionsIn a non-randomized prospective cohort study, EVT resulted in better outcomes in large core patients with higher QALYs, NMB and high cost-effectiveness acceptability rates at current WTP thresholds. Randomized trials are needed to confirm these results.Clinical trial registrationNCT02446587

IntroductionCerebral vasospasm (CVS) is the leading cause of mortality and morbidity following aneurysmal subarachnoid haemorrhage (aSAH). One of the recently implicated underlying mechanisms of CVS is inflammatory cascades. Specific feasibility objectives include determining the ability to recruit 30 participants over 24 months while at least 75% of them comply with at least 75% of the study protocol and being able to follow 85% of them for 3 months after discharge.Methods and analysisThis is a feasibility study for a randomised controlled trial. Eligible participants are adult patients who are 18 years of age and older with an aSAH confirmed by a brain CT scan, and CT angiography, or magnetic resonance angiography, or digital subtraction angiography who admitted to the emergency department within 12 hours of the ictus. Eligible subjects will be randomised 1:1 for the administration of either ibuprofen or a placebo, while both groups will concomitantly be treated by the standard of care for 2 weeks. Care givers, patients, outcome assessors and data analysts will be blinded. This will be the first study to investigate the preventive effects of a short-acting non-steroidal anti-inflammatory drug on CVS and the key expected outcome of this pilot study is the feasibility and safety assessment of the administration of ibuprofen in patients with aSAH. The objectives of the definitive trial would be to assess the effect of ibuprofen relative to placebo on mortality, CVS, delayed cerebral ischaemia, and level of disability at 3-month follow-up.Ethics and disseminationThis study is approved by Mashhad University of Medical Sciences ethical committee (IR.MUMS.MEDICAL.REC.1398.225). Results from the study will be submitted for publication regardless of whether or not there are significant findings.Trial registration numberISRCTN14611625.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials. Methods: We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence. Results: We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio [OR],0.73 [95% CI, 0.53–1.00]; moderate certainty; absolute risk reduction (ARR), −3.35%). Nimodipine (OR, 1.46 [95% CI, 1.07–1.99]; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 [95% CI, 1.14–12.18]; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 [95% CI, 0.22–0.68]; high certainty; ARR, −16.65%), nicardipine (OR, 0.48 [95% CI, 0.24–0.94]; moderate certainty; ARR, −13.70%), fasudil (OR, 0.55 [95% CI, 0.31–0.98]; moderate certainty; ARR, −11.54%), and magnesium (OR, 0.66 [95% CI, 0.46–0.94]; high certainty; ARR, −8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia. Conclusions: Nimodipine and cilostazol are likely the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42019122183.

Introduction: Mobile Stroke Units (MSUs) improve clinical outcome in patients treated with tPA compared to standard management by Emergency Medical Services (EMS), but the impact of MSUs on outcomes in patients with large vessel occlusions (LVOs) having endovascular thrombectomy (EVT) has yet to be determined. Methods: A pre-specified substudy of tPA-eligible stroke patients with LVOs on CT and/or CTA who were enrolled in the Benefits of Stroke Treatment Using a Mobile Stroke Unit (BEST-MSU), a prospective multicenter controlled trial comparing MSU with standard EMS management, was conducted. The primary outcome was the score on the 90-day utility-weighted modified Rankin Scale (uw-mRS). Secondary outcomes were rate of early neurologic recovery (30% improvement in NIHSS score) at 24 hours and functional independence (mRS 0-1) at 90 days. Results: A total of 295 patients were included, 169 in the MSU group and 126 in the EMS group. Baseline characteristics were comparable between the groups, with the exception of baseline NIHSS (MSU median 19.0 [IQR 13.0, 23.0] vs EMS 16.0 [11.0, 20.0], p=0.003). 92% MSU vs 87% EMS LVO patients received tPA, and 78% vs 85% went on to have EVT. MSU LVO patients had faster tPA bolus from symptom onset (65.0 min [50.5, 92.0] vs 96.0 [79.3, 130.0], p Conclusions: In tPA-eligible LVO stroke patients, MSU management was associated with better clinical outcomes compared with standard EMS management.

Introduction: Recruitment into hyperacute stroke trials is challenging but ultimately depends on on-call availability of treating investigators, study coordinators, and pharmacists. These data may not be considered in initial decision-making for site selection and estimates of site recruitment are frequently based upon registry data from sites that includes all clinical cases. Hypothesis: Site recruitment on a per month basis is associated with time open for enrollment. Methods: We surveyed all Multi-arm Optimization of Stroke (MOST) trial centers open for enrollment to determine which were open for trial recruitment during business hours during Monday through Friday only, business hours 7 days a week, extended hours beyond business hours, or 24 hours/7 days a week. We also surveyed about pharmacy availability. Descriptive statistics were used to compare the average monthly enrollment by survey responses. Results: Sites open for enrollment only during business hours, Monday through Friday recruited at a rate of 0.14 participants per month compared to 0.36 per month for sites that enroll 7 days a week (see graphic). Restriction of pharmacy availability to business hours Monday through Friday was associated with decreased recruitment rate as well. Conclusions: Ability to recruit trial participants 7 days a week should be the standard for site selection, successful acute stroke trial recruitment, and estimates of needed sites. Methods to increase financial support for hours outside of week-day business hours is a potential method to enhance recruitment into acute stroke trials.

Background: Limited data are available on endovascular thrombectomy (EVT) efficacy and safety in large vessel occlusion (LVO) patients presenting >24hr from last known well (LKW). We compared outcomes between patients receiving EVT and best medical management (MM) in a multicenter international cohort. Methods: Consecutive patients with anterior circulation LVO presenting >24h after LKW from 13 centers from 7/2012-4/2021 were analyzed. Multivariable models for 90d mRS distribution and symptomatic ICH were adjusted for age, NIHSS, glucose, IV tPA, transfer status, clot location, time from LKW, CT ASPECTS and ischemic core (rCBF6s volumes. Results: Of 240 patients with a median (IQR) LKW to presentation 28.3h (24.9-38.2), 153 (64%) received EVT. Baseline characteristics were similar except for NIHSS (EVT: 13 (8-20) vs MM: 17 (10-22), p=0.005), CT ASPECTS (EVT: 8(6-9) vs MM: 4(3-6), p Conclusions: EVT may be associated with better functional outcomes, despite numerically increased risk of sICH in patients presenting with anterior circulation LVO beyond 24 hours. Further prospective studies are warranted.

Introduction: Blood pressure fluctuations in the acute phase of large vessel occlusion (LVO) ischemic stroke are associated with infarct progression and poor outcomes. We evaluated the association of prehospital blood pressure variations on a Mobile Stroke Unit (MSU) with early neurological change. Methods: Prospectively-derived data were analyzed from tPA-eligible LVO patients treated and transported on the MSU, identified by hyperdense artery on CT or arterial occlusion on CTA. Patients were categorized by change in mean arterial pressure (ΔMAP) of > 10 mm Hg vs Δ MAP < 10 mmHg from arrival of MSU on-scene to arrival to the emergency department (ED). A sub-analysis of patients with ΔMAP > 10 mm Hg compared those whose MAP decreased by > 10 mm Hg vs those whose MAP increased by > 10 mm Hg. The primary outcome was 24-hour change in NIHSS. Groups were compared using Chi-square/Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Results: A total of 39 tPA-eligible LVO patients were identified, 19 with ΔMAP < 10mm Hg and 20 with ΔMAP > 10mm Hg. Baseline characteristics were comparable between groups including NIHSS (18.0 [11.0, 21.0] vs 20.0 [16.8, 25.8]) (Table 1). A similar percentage from each group received tPA and thrombectomy. Upon presentation to ED, 7/19 (37%) patients with ΔMAP < 10mm Hg had a 30% improvement in NIHSS, compared to 4/20 (20%) patients with ΔMAP >10mm Hg (p=0.417). The 24-hour change in NIHSS was also similar (ΔMAP < 10mm Hg = 7.0 [3.5, 12.0] vs ΔMAP > 10 mm Hg 10.0 [4.0, 16.0], p=0.517). Among patients with ΔMAP of 10mm Hg group, those with MAP decrease by > 10 mm Hg had a 10 point [7.0, 16.0] improvement in NIHSS vs 6.0 [2.5, 15.0] point improvement in those whose MAP increased by > 10 mm Hg (p=0.169). Conclusion: Though limited by a small sample size, prehospital blood pressure fluctuations in LVO stroke patients on a MSU were not associated with early clinical changes.

Background: The effect of anesthesia choice on endovascular thrombectomy (EVT) outcomes is unclear. Collateral status on perfusion imaging may help identify the optimal anesthesia choice. Methods: In a pooled patient level analysis of EXTEND-IA, EXTEND-IA TNK, EXTEND-IA TNK part II and SELECT, EVT Functional outcomes (mRS distribution) were compared between general anesthesia (GA) vs non-general anesthesia (non-GA). Further, we assessed the impact of collateral flow on perfusion imaging evaluated by hypoperfusion intensity ratio (HIR) - Tmax10 sec/Tmax6 sec) on the association between anesthesia type and EVT outcomes. Results: Of 731 treated with EVT, 305 (42%) received GA and 426 (58%) non-GA. The baseline characteristics were similar, except for presentation NIHSS (median [IQR] GA 18 [13-22], non-GA 16[11-20], p Conclusion: GA was associated with worse functional outcomes after EVT, particularly in patients with poor collaterals. These findings have implications for randomized trials of GA vs non-GA.

Objective To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA). Methods We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER. Results The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53). Conclusion BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.

BACKGROUND Reducing acute care readmissions from inpatient rehabilitation facilities (IRFs) is a healthcare reform goal. Stroke patients have higher acute readmission rates and persistent impairments, warranting second IRF hospitalization consideration. OBJECTIVE To provide evidence-based information to justify IRF readmission for patients with post-stroke impairments. MAIN OUTCOME MEASURE Variables that increase the likelihood of a second IRF hospitalization. DESIGN Retrospective cohort study. SETTING Seven-center rehabilitation network. PARTICIPANTS Stroke patients, readmitted to acute care, who returned or did not return to an in-network IRF between 1 October 2014-31 December 2017(n = 380). INTERVENTIONS Univariable analyses (Returned/Did Not Return to IRF) described demographics, stroke type and risk factors. Between group differences in readmission causes, motor impairments and functional independence measure (FIM) scores were examined. Return to IRF logistic regression model included variables with P

Background and Purpose— Timely access to endovascular thrombectomy (EVT) centers is vital for best acute ischemic stroke outcomes. Methods— US stroke-treating centers were mapped utilizing geo-mapping and stratified into non-EVT or EVT if they reported ≥1 acute ischemic stroke thrombectomy code in 2017 to Center for Medicare and Medicaid Services. Direct EVT-access, defined as the population with the closest facility being an EVT-center, was calculated from validated trauma-models adapted for stroke. Current 15- and 30-minute access were described nationwide and at state-level with emphasis on 4 states (TX, NY, CA, IL). Two optimization models were utilized. Model-A used a greedy algorithm to capture the largest population with direct access when flipping 10% and 20% non-EVT to EVT-centers to maximize access. Model-B used bypassing methodology to directly transport patients to the nearest EVT centers if the drive-time difference from the geo-centroid to hospital was within 15 minutes from the geo-centroid to the closest non-EVT center. Results— Of 1941 stroke-centers, 713 (37%) were EVT. Approximately 61 million (19.8%) Americans have direct EVT access within 15 minutes while 95 million (30.9%) within 30 minutes. There were 65 (43%) EVT centers in TX with 22% of the population currently within 15-minute access. Flipping 10% hospitals with top population density improved access to 30.8%, while bypassing resulted in 45.5% having direct access to EVT centers. Similar results were found in NY (current, 20.9%; flipping, 34.7%; bypassing, 50.4%), CA (current, 25.5%; flipping, 37.3%; bypassing, 53.9%), and IL (current, 15.3%; flipping, 21.9%; bypassing, 34.6%). Nationwide, the current direct access within 15 minutes of 19.8% increased by 7.5% by flipping the top 10% non-EVT to EVT-capable in all states. Bypassing non-EVT centers by 15 minutes resulted in a 16.7% gain in coverage. Conclusions— EVT-access within 15 minutes is limited to less than one-fifth of the US population. Optimization methodologies that increase EVT centers or bypass non-EVT to the closest EVT center both showed enhanced access. Results varied by states based on the population size and density. However, bypass showed more potential for maximizing direct EVT-access. National and state efforts should focus on identifying gaps and tailoring solutions to improve EVT-access.

Background and Purpose— The first of the 2 NINDS (National Institute of Neurological Disorders and Stroke) Study trials did not show a significant increase in early neurological improvement, defined as National Institutes of Health Stroke Scale (NIHSS) improvement by ≥4, with alteplase treatment. We hypothesized that early neurological improvement defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours. Methods— We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as ([admission NIHSS score−24-hour NIHSS score]×100/admission NIHSS score] and delta NIHSS as (admission NIHSS score−24-hour NIHSS score). We compared early neurological improvement using these definitions between alteplase versus placebo patients. We also used receiver operating characteristic curve to determine the predictive association of early neurological improvement with excellent 3-month functional outcomes (Barthel Index score of 95–100 and modified Rankin Scale score of 0–1), good 3-month functional outcome (modified Rankin Scale score of 0–2), and 3-month infarct volume. Results— There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared with the placebo group (28% versus 15%; P =0.045) but not median delta NIHSS (3 versus 2; P =0.471). Receiver operating characteristic curve comparison showed that percent change NIHSS (ROC percent ) was better than delta NIHSS (ROC delta ) and admission NIHSS (ROC admission ) with regards to excellent 3-month Barthel Index (ROC percent , 0.83; ROC delta , 0.76; ROC admission , 0.75), excellent 3-month modified Rankin Scale (ROC percent , 0.83; ROC delta , 0.74; ROC admission , 0.78), and good 3-month modified Rankin Scale (ROC percent , 0.83; ROC delta , 0.76; ROC admission , 0.78). Conclusions— In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.