Purpose: Pediatric and adult patients with sickle cell anemia (SCA) are at increased risk of stroke and cerebrovascular accident. In the general adult population, there is a relationship between arterial hemodynamics and pathology; however, this relationship in SCA patients remains to be elucidated. The aim of this work was to characterize circle of Willis hemodynamics in patients with SCA and quantify the impact of viscosity choice on pathophysiologically-relevant hemodynamics measures. Methods: Based on measured vascular geometries, time-varying flow rates, and blood parameters, detailed patient-specific simulations of the circle of Willis were conducted for SCA patients (n = 6). Simulations quantified the impact of patient-specific and standard blood viscosities on wall shear stress (WSS). Results: These results demonstrated that use of a standard blood viscosity introduces large errors into the estimation of pathophysiologically-relevant hemodynamic parameters. Standard viscosity models overpredicted peak WSS by 55% and 49% for steady and pulsatile flow, respectively. Moreover, these results demonstrated non-uniform, spatial patterns of positive and negative WSS errors related to viscosity, and standard viscosity simulations overpredicted the time-averaged WSS by 32% (standard deviation = 7.1%). Finally, differences in shear rate demonstrated that the viscosity choice alters the simulated near-wall flow field, impacting hemodynamics measures. Conclusions: This work presents simulations of circle of Willis arterial flow in SCA patients and demonstrates the importance and feasibility of using a patient-specific viscosity in these simulations. Accurately characterizing cerebrovascular hemodynamics in SCA populations has potential for elucidating the pathophysiology of large-vessel occlusion, aneurysms, and tissue damage in these patients.

Sickle cell disease (SCD) is the most common hemoglobinopathy in the United States and vaso-occlusive pain episodes (VOE) are the leading cause of hospitalizations and emergency department (ED) visits1. There are limited therapies for acute management of VOE that directly target the underlying etiology for sickle-related pain therefore treatment is largely symptomatic. Moderate-to-severe pain is typically treated with parenteral hydration, opioids, and hospitalization to achieve adequate pain control.

Background: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults. Methods: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE. Discussion: Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children. Trial registration: The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).

Youth living with chronic sickle cell disease (SCD) pain are at risk for psychosocial distress and high levels of pain catastrophizing that contribute to functional impairment. This study aimed to identify the unique long-term impact of pain catastrophizing on pain impairment among youth with SCD. Youth with chronic SCD pain (N = 63, 10–18 years old, 58.3% female, 95.1% Black or African American) were recruited within comprehensive SCD clinics and completed a battery of measures at baseline and 4-months follow-up. A linear hierarchical regression examined baseline demographic and clinical characteristics (child SCD genotype, age, and average pain intensity), psychosocial functioning (anxiety, depression), and pain catastrophizing as predictors of pain interference at 4-months follow-up. Pain catastrophizing was the only unique predictor of pain interference at 4-months follow-up. Among youth with chronic SCD pain, pain catastrophizing warrants greater consideration as an important predictor that influences pain management and overall functioning.

Background: Sickle cell disease (SCD) is characterized by severe acute pain episodes as well as risk for chronic pain. Digital delivery of SCD pain self-management support may enhance pain self-management skills and accessibility for youth. However, little is known about how youth with SCD and their caregivers engage with digital health programs. iCanCope with pain is a digital pain self-management platform adapted for youth with SCD and caregivers through a user-centered design approach. The program was delivered via a website (separate versions for youth and caregiver) and mobile app (youth only). Objective: We aimed to characterize patterns of user engagement with the iCanCope with SCD program among youth with SCD and their caregivers. Methods: A randomized controlled trial was completed across multiple North American SCD clinics. Eligible youth were aged 12-18 years, diagnosed with SCD, English-speaking, and experiencing moderate-to-severe pain interference. Eligible caregivers were English-speaking with a child enrolled in the study. Dyads were randomized to receive the iCanCope intervention or attention-control education for 8-12 weeks. This report focused on engagement among dyads who received the intervention. User-level analytics were captured. Individual interviews were conducted with 20% of dyads. Descriptive statistics characterized quantitative engagement. Content analysis summarized qualitative interview data. Exploratory analysis tested the hypothesis that caregiver engagement would be positively associated with child engagement. Results: The cohort included primarily female (60% [34/57] of youth; 91% [49/56] of caregivers) and Black (>90% of youth [53/57] and caregivers [50/56]) participants. Among 56 dyads given program access, differential usage patterns were observed: both the youth and caregiver engaged (16/56, 29%), only the youth engaged (24/56, 43%), only the caregiver engaged (1/56, 2%), and neither individual engaged (16/56, 29%). While most youth engaged with the program (40/57, 70%), most caregivers did not (39/56, 70%). Youth were more likely to engage with the app than the website (85% [34/57] versus 68% [23/57]), and the most popular content categories were goal setting, program introduction, and symptom history. Among caregivers, program introduction, behavioral plans, and goal setting were the most popular content areas. As hypothesized, there was a moderate positive association between caregiver and child engagement (χ21=6.6; P=.01; ϕ=0.34). Interviews revealed that most dyads would continue to use the program (11/12, 92%) and recommend it to others (10/12, 83%). The reasons for app versus website preference among youth were ease of use, acceptable time commitment, and interactivity. Barriers to caregiver engagement included high time burden and limited perceived relevance of content. Conclusions: This is one of the first studies to apply digital health analytics to characterize patterns of engagement with SCD self-management among youth and caregivers. The findings will be used to optimize the iCanCope with SCD program prior to release.

Caregivers of children with sickle cell disease (SCD) experience significant physical and emotional hardship with their child’s disease management. Little is known about the potential contributors to parenting stress in pediatric SCD. The present study aimed to identify child and caregiver biopsychosocial factors associated with disease-related parenting stress in pediatric SCD. Participants included 74 caregiver-youth dyads. Parenting stress was associated with increased child pain frequency, more missed school days, and increased healthcare utilization, and inversely correlated with caregiver mental health and social-emotional functioning. Parenting stress also partially explained the relationship between child pain frequency and healthcare utilization after controlling for parent depression and anxiety. Parenting stress may play a unique and critical role in pediatric SCD and underscore the impact parenting stress may have on youth in medical and academic settings. Further research is warranted to determine risk factors and appropriate interventions for parenting stress to improve comprehensive patient care.

Introduction: Pain and complications related to pediatric sickle cell disease (SCD) are associated with higher health care utilization. In other pediatric chronic conditions, psychosocial screening can help identify children and families at risk of increased health care utilization to guide resource allocation, address treatment needs, and improve care. This study aimed to investigate the utility of psychosocial screening in predicting increased health care utilization among youth with SCD. Methods: Youth with SCD (n = 74, 8–18 years) and their parents were recruited from comprehensive SCD clinics. Parents completed the Psychosocial Assessment Tool (PAT), which categorized family psychosocial risk into one of three categories: Universal (minimal distress), Targeted (elevated distress), and Clinical (persistent distress). Youth reported on their pain characteristics, and health care utilization was extracted from medical chart review. Differences in health care utilization were evaluated using analysis of variance (ANOVA) and moderation analyses. Results: Based on PAT risk, families were categorized into Universal (56.8%), Targeted (29.7%), and Clinical (13.5%) risk groups, with no significant group differences across demographic variables. Patients in the Targeted group reported significantly higher pain frequency than those in the Universal group (F[2, 66] = 3.7, p <.05). The association between pain frequency and health care utilization significantly varied on the basis of psychosocial risk, such that Clinical psychosocial risk strengthened the connection between pain frequency and health care utilization (β =.2, t = 2.1, p <.05). Conclusions: Integrating the PAT into routine clinical care may help health care providers identify families in need of greater psychosocial or medical support to further optimize SCD management.

OBJECTIVES: This study aimed to: (1) examine changes in pain, psychosocial functioning, and health care utilization among children and adolescents with sickle cell disease (SCD) over a 2-year period and (2) identify baseline biopsychosocial variables associated with the development and maintenance of chronic SCD pain at follow-up. MATERIALS AND METHODS: Forty-two youth (8 to 18 y old) with SCD completed a battery of self-report measures at baseline and 2-year follow-up. Analgesic, Anesthetic, and Addiction Clinical Trial Translational Innovations Opportunities and Networks and American Pain Society Pain Taxonomy (AAPT) diagnostic criteria were used to categorize patients into pain frequency groups at both timepoints: chronic (pain on most [≥15] d/mo for the past 6 mo, per AAPT diagnostic criteria), episodic (pain on 1 to 14 d/mo), or asymptomatic (0 d/mo). RESULTS: At baseline, 31% (n=13) had chronic pain, 50% (n=21) episodic pain, and 19% (n=8) were asymptomatic. At follow-up, 40.5% (n=17) had chronic pain, 52.4% (n=22) episodic pain, and 7.1% (n=3) were asymptomatic. Between baseline and 2-year follow-up, 12% (n=5) developed chronic SCD pain. Depressive symptoms and admissions for pain significantly increased over time for youth with chronic pain (Ps<0.05). An interaction effect revealed that baseline pain groups differed in their change in pain intensity over time (P<0.01). Baseline psychosocial factors (ie, higher functional disability, greater depressive symptoms, higher pain catastrophizing, and lower quality of life) were significantly associated with chronic pain at follow-up. DISCUSSION: Biopsychosocial factors may be associated with the development and maintenance of chronic SCD pain and their relative contributions warrant further study.

Background: This study aimed to evaluate the preliminary validation and application of a pain screening tool to identify biopsychosocial risk factors for chronic pain in pediatric sickle cell disease (SCD) and classify youth with SCD into prognostic risk groups. Method: Youth presenting to a pediatric SCD clinic completed the Pediatric Pain Screening Tool (PPST), a brief 9-item self-report questionnaire developed for rapid identification of risk in youth with pain complaints. Youth also completed a battery of standardized patient-reported outcomes, including pain characteristics, pain burden, functional disability, pain interference, depressive symptoms, pain catastrophizing, and fear of pain. Healthcare utilization was extracted from medical chart review. Results: Seventy-three 8- to 18-year-olds (94% Black, 57% female) with SCD participated. The PPST demonstrated discriminant validity that ranged from fair to excellent (area under the curves (AUC) = 0.74–0.93, P values < 0.001) for identifying significant pain frequency, disability, pain interference, and psychosocial distress. Receiver operating characteristic curve analyses indicated that previously established cutoff scores were appropriate for the SCD sample. Participants were classified into low-risk (28.8%), medium-risk (38.4%), and high-risk (32.9%) groups, with significant group differences across measures, F(18, 116) = 6.67, P < 0.001. The high-risk group reported significantly higher pain intensity, pain frequency, pain burden, functional disability, pain interference, and depressive symptoms relative to both low-risk and medium-risk groups (P values < 0.005). Conclusions: The high-risk group demonstrated a pain and psychosocial profile consistent with chronic SCD pain. The PPST may be useful for efficiently identifying youth with chronic SCD pain or those at risk of poor outcomes.

Objectives: Evaluate the implementation of cognitive-behavioral therapy (CBT) for chronic pain in a clinical setting by comparing youth with sickle cell disease (SCD) who initiated or did not initiate CBT. Design: Youth with SCD (ages 6–18; n = 101) referred for CBT for chronic pain were compared based on therapy attendance: Established Care; Early Termination; or Comparison (i.e., did not initiate CBT). Setting: Outpatient pediatric psychology and comprehensive SCD clinics in 3 locations at a southeastern children's hospital. Interventions: CBT delivery was standardized. Treatment plans were tailored to meet individualized needs. Main Outcome Measures: Healthcare utilization included pain-related inpatient admissions, total inpatient days, and emergency department reliance (EDR) at 12-months pre-post CBT. Patient-reported outcomes (PROs) included typical pain intensity, functional disability, and coping efficacy pre-post treatment. Results: Adjusting for age, genotype, and hydroxyurea, early terminators of CBT had increased rates of admissions and hospital days over time relative to comparisons; those who established care had faster reduction in admissions and hospital days over time relative to comparisons. EDR decreased by 0.08 over time for Established Care and reduced by 0.01 for every 1 completed session. Patients who completed pre- and post-treatment PROs reported decreases in typical pain intensity, functional disability, and improved coping efficacy. Conclusions: Establishing CBT care may support reductions in admissions for pain, length of stay, and EDR for youth with chronic SCD pain, which may be partially supported by patient-reported improvements in functioning, coping, and lower pain intensity following CBT. Enhancing clinical implementation of multidisciplinary treatments may optimize the health of these youth.