Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region.

Background Earlier tPA treatment for acute ischemic stroke increases efficacy, prompting national efforts to reduce door-to-needle times (DNTs). We utilized lean process improvement methodology to develop a streamlined IV tPA protocol. Methods In early 2011, a multi-disciplinary team analyzed the steps required to treat acute ischemic stroke patients with IV tPA, utilizing value stream analysis (VSA). We directly compared the tPA-treated patients in the “pre-VSA” epoch to the “post-VSA” epoch with regard to baseline characteristics, protocol metrics, and clinical outcomes. Results The VSA revealed several tPA protocol inefficiencies: routing of patients to room, then to CT, then back to room; serial processing of work flow; and delays in waiting for lab results. On 3/1/2011, a new protocol incorporated changes to minimize delays: routing patients directly to head CT prior to patient room, utilizing parallel process work-flow, and implementing point-of-care labs. In the pre-and post-VSA epochs, 132 and 87 patients were treated with IV tPA, respectively. Compared to pre-VSA, DNTs and percent of patients treated ≤60 minutes from hospital arrival were improved in the post-VSA epoch: 60 min vs. 39 min (p<0.0001) and 52% vs. 78% (p<0.0001), respectively, with no change in symptomatic hemorrhage rate. Conclusions Lean process improvement methodology can expedite time-dependent stroke care, without compromising safety.

Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; < .001) and decreased Hb S (from 39.7% to 24.3%; < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; = .004) and OEF (from 34.4% to 31.2%; < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA ( < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.

Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density ( < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.

Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.

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Background Early identification of dysphagia is associated with lower rates of pneumonia after acute stroke. The Barnes-Jewish Hospital-Stroke Dysphagia Screen (BJH-SDS) was previously developed as a simple bedside screen performed by nurses for sensitive detection of dysphagia and was previously validated against the speech pathologist’s clinical assessment for dysphagia. In this study, acute stroke patients were prospectively enrolled to assess the accuracy of the BJH-SDS when tested against the gold-standard test for dysphagia, the video-fluoroscopic swallow study (VFSS). Methods Acute stroke patients were prospectively enrolled at a large tertiary care inpatient stroke unit. The nurse performed the BJH-SDS at the bedside. After providing consent, patients then underwent VFSS for determination of dysphagia and aspiration. The VFSS was performed by a speech pathologist who was blinded to the results of the BJH-SDS. Sensitivity and specificity were calculated. Pneumonia rates were assessed across the five year period over which the BJH-SDS was introduced into the Stroke Unit. Results A total of 225 acute stroke patients were enrolled. Sensitivity and specificity of the screen to detect dysphagia were 94% and 66%, respectively. Sensitivity and specificity of the screen to detect aspiration were 95% and 50%, respectively. No increase in pneumonia was identified during implementation of the screen (p=0.33). Conclusion The BJH-SDS, validated against video-fluoroscopy, is a simple bedside screen for sensitive identification of dysphagia and aspiration in the stroke population.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19—severe acute respiratory syndrome coronavirus 2—gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1–7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1–7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.