Michael M. Binkley

Increased complications of chronic erythrocytapheresis compared with manual exchange transfusions in children and adolescents with sickle cell disease

Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion‐induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions.

Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease

Objective To determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen utilization (CMRO2) in children with SCD. Methods Participants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO2. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps. Results Fifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min, p < 0.001), OEF (42.7% vs 28.8%, p < 0.001), and CMRO2 (3.7 vs 2.5 mL/100 g/min, p < 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO2 in this region, which encompassed the CBF nadir, was low relative to all white matter (p < 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort. Conclusions 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.

Reduction in Overt and Silent Stroke Recurrence Rate Following Cerebral Revascularization Surgery in Children with Sickle Cell Disease and Severe Cerebral Vasculopathy

Children with sickle cell disease (SCD) and moyamoya may benefit from indirect cerebral revascularization surgery in addition to chronic blood transfusion therapy for infarct prevention. We sought to compare overt and silent infarct recurrence rates in children with SCD undergoing revascularization.

Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia

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 (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, 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; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .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 (P < .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 infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow

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 (P < .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.

Reduced Order Modeling and Experimental Investigation of Acoustic Particle Manipulation in Complex 3D Geometries

A reduced order computational model and imaging experiments are presented as a combined method to investigate migration and trapping of microscale particles within an ultrasonic droplet generator. Use of two-dimensional (2D) cross-sectional representations of the three-dimensional (3D) device enables observation of acoustic focusing phenomena that are otherwise visually inaccessible. Our approach establishes relationships between system operating parameters and particle retention due to acoustic radiation forces that arise during atomization of heterogeneous particle suspensions. The droplet generator consists of a piezoelectric transducer for ultrasonic actuation, a resonant fluid-filled chamber, and an array of microscopic pyramidal nozzles. 2D visualization chips were produced through anodic bonding of glass to microfluidic reservoirs deep reactive ion etched in silicon. Open nozzle orifices of the 3D microarray were sealed in its 2D representation to facilitate filling and testing. Finite element analysis was used to model the harmonic response of the 2D assembly from 500 kHz to 2 MHz. The average nozzle tip pressure amplitude across the 2D array was then used to identify operating frequencies that correspond to optimal droplet ejection from the 3D device (ejection modes). The pressure field at these resonant frequencies predicts the equilibrium distribution of polymeric beads suspended in the reservoirs of the 2D chips. To qualitatively assess the accuracy of the model results, visualization experiments were performed at the first three ejection modes of the system (fn1 ≈ 620–680 kHz, fn2 ≈ 1.14 MHz, and fn3 ≈ 1.63 MHz) using 10 μm polystyrene beads. The model demonstrates a remarkable ability to capture the overall shape, as well as specific details of the terminal particle distributions, defined as the state with no further movement toward a pressure node or antinode. Finally, time course trials of acoustic focusing of heterogeneous particle suspensions were used to observe the influence of particle volume on the magnitude of the acoustic radiation force. A mixture of 5 μm and 20 μm diameter polystyrene beads was subjected to a standing acoustic field in the 2D chips. Particle position was recorded at 5 ms intervals until an equilibrium distribution was achieved. As expected, the larger beads focused much more rapidly than smaller beads, acquiring their final positions in seconds (versus 10s of seconds for the 5 μm particles). The method and results reported here serve as building blocks toward translation of an existing ultrasonic droplet generator into a high-throughput particle separation and isolation platform.Copyright