Differences in Delirium Evaluation and Pharmacologic Management in Children With Developmental Delay: A Retrospective Case-Control Study.

Delirium is associated with increased mortality and cost, decreased neurocognition, and decreased quality of life in the pediatric intensive care unit (PICU) population. The Cornell Assessment for Pediatric Delirium (CAPD) is used in PICUs for delirium screening but lacks specificity in children with developmental delay (DD). Within a cohort of children receiving pharmacologic treatment for intensive care unit (ICU) delirium, we compared delirium scoring and medication management between children with and without DD. We hypothesized that CAPD scores and treatment decisions would differ between DD and neurotypical (NT) patients. In this retrospective case-control study, we queried the medical record of patients admitted to our PICU with respiratory failure from June 2018 to March 2022 who received antipsychotics typically used for ICU delirium. Antipsychotics prescribed for home use were excluded. Nonparametric statistics compared demographics, CAPD scores, medication choice, dosing (mg/kg), and medication continuation after discharge between those with and without DD based on the ICD-10 codes. Twenty-one DD admissions and 59 NT admissions were included. Groups did not significantly differ by demographics, LOS, drug, or initial dosage. DD patients had higher median CAPD scores at admission (17 vs 13; P = .02) and treatment initiation (18 vs 16.5; P = .05). Providers more frequently escalated doses in DD patients (13/21 vs 21/59; P = .04) and discharged them home on new antipsychotics (7/21 vs 5/59; P = .01). DD patients experience delirium screening and management differently than NT counterparts. Providers should be aware of baseline elevated scores in DD patients and carefully attend to indications for dosage escalation. Further work is needed to understand if prolonged duration, even after hospital discharge, benefits patients, or represents potential disparity in care.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease.

Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (-19.4 mL/100 g/min) and OEF (-8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, -0.9 mL/100 g/min; P = .024; OEF, -3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

The Development of Neuroimaging Biomarkers for Cognitive Decline in Sickle Cell Disease.

Sickle cell disease (SCD) is complicated by neurologic complications including vasculopathy, hemorrhagic or ischemic overt stroke, silent cerebral infarcts and cognitive dysfunction. Patients with SCD, even in the absence of vasculopathy or stroke, have experience cognitive dysfunction that progresses with age. Transcranial Doppler ultrasound and structural brain MRI are currently used for primary and secondary stroke prevention, but laboratory or imaging biomarkers do not currently exist that are specific to the risk of cognitive dysfunction in patients with SCD. Recent investigations have used advanced MR sequences assessing cerebral hemodynamics, white matter microstructure and functional connectivity to better understand the pathophysiology of cognitive decline in SCD, with the long-term goal of developing neuroimaging biomarkers to be used in risk prediction algorithms and to assess the efficacy of treatment options for patients with SCD.

GRAPES: Trivia game increases sickle cell disease knowledge in patients and providers and mitigates healthcare biases.

BACKGROUND: Patients with sickle cell disease (SCD) endure healthcare biases that are partially due to a lack of disease-specific education among healthcare providers. Furthermore, there is a paucity of age-appropriate health education materials for patients with SCD. To address this gap, we created the GRAPES tool (Game to Raise Awareness for Patient/Provider/Public Education of SCD; www.tinyurl.com/GRAPESgame) and hypothesized that utilization of the GRAPES tool will improve patient and provider SCD knowledge and mitigate healthcare bias. PROCEDURE: The GRAPES tool is an online, single-player trivia game. A feasibility study was conducted in pediatric patients with SCD at age 10 years or older and registered nurses. All participants were assessed for change in SCD-relevant knowledge and satisfaction post-gameplay. Providers were assessed for change in attitudes toward patients with SCD post-gameplay. RESULTS: Twenty-five patients and 25 providers were enrolled. All participants (P < 0.001), and specifically within the patient (P = 0.019) and provider (P < 0.001) cohorts, showed increased SCD knowledge post-gameplay. Both patients and providers reported high satisfaction with GRAPES. Provider negative attitudes were reduced (P = 0.007) post-gameplay without change in positive attitudes (P = 0.959). Providers demonstrated post-gameplay reduced (P = 0.001) belief that patients' changing behavior around providers indicates inappropriate drug-seeking behavior. CONCLUSIONS: This study demonstrates the feasibility and acceptability of the GRAPES tool as a potential digital, behavioral intervention to provide educational materials for patients and their providers in different clinical settings, improve knowledge about SCD, and decrease stigma against patients with SCD in the healthcare setting.

Cognitive Dysfunction After Analgesia and Sedation: Out of the Operating Room and Into the Pediatric Intensive Care Unit.

In the midst of concerns for potential neurodevelopmental effects after surgical anesthesia, there is a growing awareness that children who require sedation during critical illness are susceptible to neurologic dysfunctions collectively termed pediatric post-intensive care syndrome, or PICS-p. In contrast to healthy children undergoing elective surgery, critically ill children are subject to inordinate neurologic stress or injury and need to be considered separately. Despite recognition of PICS-p, inconsistency in techniques and timing of post-discharge assessments continues to be a significant barrier to understanding the specific role of sedation in later cognitive dysfunction. Nonetheless, available pediatric studies that account for analgesia and sedation consistently identify sedative and opioid analgesic exposures as risk factors for both in-hospital delirium and post-discharge neurologic sequelae. Clinical observations are supported by animal models showing neuroinflammation, increased neuronal death, dysmyelination, and altered synaptic plasticity and neurotransmission. Additionally, intensive care sedation also contributes to sleep disruption, an important and overlooked variable during acute illness and post-discharge recovery. Because analgesia and sedation are potentially modifiable, understanding the underlying mechanisms could transform sedation strategies to improve outcomes. To move the needle on this, prospective clinical studies would benefit from cohesion with regard to datasets and core outcome assessments, including sleep quality. Analyses should also account for the wide range of diagnoses, heterogeneity of this population, and the dynamic nature of neurodevelopment in age cohorts. Much of the related preclinical evidence has been studied in comparatively brief anesthetic exposures in healthy animals during infancy and is not generalizable to critically ill children. Thus, complementary animal models that more accurately "reverse translate" critical illness paradigms and the effect of analgesia and sedation on neuropathology and functional outcomes are needed. This review explores the interactive role of sedatives and the neurologic vulnerability of critically ill children as it pertains to survivorship and functional outcomes, which is the next frontier in pediatric intensive care.

Behavioral and cognitive functioning in individuals with Cantú syndrome.

Cantú syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore-forming subunits of ATP-sensitive potassium (KATP ) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self-reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross-sectional manner, we invited 35 individuals (1-69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age-related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale-2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (≥25%), but this percentage decreased markedly in adults.

Arterial Ischemic Stroke Secondary to Cardiac Disease in Neonates and Children.

OBJECTIVE: We describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease. METHODS: We identified children with cardiac causes of AIS enrolled in the International Pediatric Stroke Study registry from January 2003 to July 2014. Isolated patent foramen ovale was excluded. Peri-procedural AIS (those occurring during or within 72 hours of cardiac surgery, cardiac catheterization, or mechanical circulatory support) and spontaneous AIS that occurred outside of these time periods were compared. RESULTS: We identified 672 patients with congenital or acquired cardiac disease as the primary risk factor for AIS. Among these, 177 patients (26%) had peri-procedural AIS and 495 patients (74%) had spontaneous AIS. Among non-neonates, spontaneous AIS occurred at older ages (median 4.2 years, interquartile range 0.97 to 12.4) compared with peri-procedural AIS (median 2.4 years, interquartile range 0.35 to 6.1, P < 0.001). About a third of patients in both groups had a systemic illness at the time of AIS. Patients who had spontaneous AIS were more likely to have a preceding thrombotic event (16 % versus 9 %, P = 0.02) and to have a moderate or severe neurological deficit at discharge (67% versus 33%, P = 0.01) compared to those with peri-procedural AIS. CONCLUSIONS: Children with cardiac disease are at risk for AIS at the time of cardiac procedures but also outside of the immediate 72 hours after procedures. Many have acute systemic illness or thrombotic event preceding AIS, suggesting that inflammatory or prothrombotic conditions could act as a stroke trigger in this susceptible population.

Higher executive abilities following a blood transfusion in children and young adults with sickle cell disease.

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non-SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3-7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ2 (1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.

Large-Vessel Vasculopathy in Children With Sickle Cell Disease: A Magnetic Resonance Imaging Study of Infarct Topography and Focal Atrophy.

BACKGROUND: Large-vessel vasculopathy (LVV) increases stroke risk in pediatric sickle cell disease beyond the baseline elevated stroke risk in this vulnerable population. The mechanisms underlying this added risk and its unique impact on the developing brain are not established. METHODS: We analyzed magnetic resonance imaging and angiography scans of 66 children with sickle cell disease and infarcts by infarct density heatmaps and Jacobian determinants, a metric utilized to delineate focal volume change, to investigate if infarct location, volume, frequency, and cerebral atrophy differed among hemispheres with and without LVV. RESULTS: Infarct density heatmaps demonstrated infarct "hot spots" within the deep white matter internal border zone region in both LVV and non-LVV hemispheres, but with greater infarct density and larger infarct volumes in LVV hemispheres (2.2 mL versus 0.25 mL, P < 0.001). Additional scattered cortical infarcts in the internal carotid artery territory occurred in LVV hemispheres, but were rare in non-LVV hemispheres. Jacobian determinants revealed greater atrophy in gray and white matter of the parietal lobes of LVV compared with non-LVV hemispheres. CONCLUSION: Large-vessel vasculopathy in sickle cell disease appears to increase ischemic vulnerability in the borderzone region, as demonstrated by the increased frequency and extent of infarction within deep white matter, and increased risk of focal atrophy. Scattered infarctions across the LVV-affected hemispheres suggest additional stroke etiologies of vasculopathy (i.e., thromboembolism) in addition to chronic hypoxia-ischemia.

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

BACKGROUND: 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. METHODS: This was a retrospective cohort study of all children with SCD and moyamoya treated at two children's hospitals. Clinical events and imaging studies were reviewed. RESULTS: Twenty-seven children with SCD and confirmed moyamoya receiving chronic transfusion therapy were identified, of whom 12 underwent indirect cerebral revascularization. Two subjects had postoperative transient ischemic attacks and another had a subarachnoid blood collection, none of which caused permanent consequences. Two subjects had surgical wound infections. Among these 12 children, the rate of overt and silent infarct recurrence decreased from 13.4 infarcts/100 patient-years before revascularization to 0 infarcts/100 patient-years after revascularization (P = 0.0057); the postrevascularization infarct recurrence rate was also significantly lower than the overall infarct recurrence of 8.87 infarcts/100 patient-years in 15 children without cerebral revascularization (P = 0.025). CONCLUSIONS: The rate of overt and silent infarct recurrence was significantly lower following indirect cerebral revascularization. A prospective study of cerebral revascularization in children with SCD is needed.