Sustainability of a Pediatric Neurointensive Care Unit Model Within a Mixed Pediatric Intensive Care Unit and Its Effect on Nursing Sentiment.

ABSTRACT: BACKGROUND: Pediatric neurocritical care (PNCC) and pediatric neurointensive care units (neuro-PICU) are growing fields. Although some institutions have established independent neuro-PICUs meeting most Neurocritical Care Society (NCS) standards for neurocritical care units, many centers lack the resources to do so. We describe an alternative neuro-PICU model as a designated unit within a mixed pediatric intensive care unit (PICU) and its effects on nursing sentiment. METHODS: We established a 6-bed neuro-PICU within a 36-bed noncardiac PICU. Charge nurses were tasked with admitting PNCC patients into these beds. For nursing expertise, we used a core group of 12 PNCC specialty nurses and instituted PNCC nursing education to PICU nurses. We observed the number of PNCC patients admitted to neuro-PICU beds and surveyed charge nurses to identify barriers to assigning patients. We surveyed PICU nursing staff to explore sentiment regarding PNCC before and after establishing the neuro-PICU. Nursing criteria were compared with NCS standards. RESULTS: In the 40-month period, our PICU saw 2060 PNCC admissions. Overall, occupied neuro-PICU beds housed PNCC patients 74.1% of the time. The biggest barriers to patient placement were too many competing placement requests, not enough neuro-PICU beds when specialty census was high, and difficulty assigning one nurse to two PNCC patients. In surveys after establishing the neuro-PICU, compared to before, experienced nurses reported being more interested in obtaining Emergency Neurological Life Support certification (94.2% vs 80.6%, P = .0495), and inexperienced nurses reported being more familiar with PNCC clinical pathways (53.5% vs 31.7%, P = .0263). Most NCS criteria related to nursing organization were met. CONCLUSIONS: Focused neuro-PICUs should be developed to complement advances in the field of PNCC. Alternative neuro-PICU models are possible and can increase nursing interest in further education and awareness of clinical pathways, but barriers exist that require institutional commitment to nursing development to sustain the delivery of specialized care to this population.

Agreement between noninvasive oscillometric and invasive intra-arterial blood pressure in children with ruptured brain arteriovenous malformations.

BACKGROUND: Divergence between intra-arterial catheters blood pressure (ABP) and noninvasive oscillometry (NIBP) may affect the care of children with brain arteriovenous malformations (bAVMs). We described the agreement between ABP and NIBP in these children. METHODS: We conducted a retrospective review of patients admitted to the pediatric intensive care unit between 2017 and 2023 with bAVM rupture. Paired ABP and NIBP measurements were collected. Bland-Altman analyses were used to assess agreement. Correlation analysis was conducted between higher ABP and divergence between systolic BP (SBP) measurements. Hypertension was defined as mean arterial pressure (MAP) exceeding age-based 95th percentile. RESULTS: Thirty-four patients with 1901 BP pairs were observed. Bias overall was acceptable, but standard deviation (SD) was high. The best agreement of MAP was in non-hypertensive (bias 1.23 mmHg, SD 8.03 mmHg) and radial arterial catheters (bias 1.83 mmHg, SD 9.08 mmHg) subgroups. Bias for SBP was higher in hypertension (10.98 mmHg) and in infratentorial bAVMs (7.42 mmHg), suggesting poorer agreement in these subgroups. There were significant correlations between intra-arterial MAP and SBP divergence (R = +0.346, p<.001) and between intra-arterial SBP and SBP divergence (R = +0.677, p<.001), suggesting divergence widens with higher BP. Around 25 % of measurement pairs diverged to where one measurement crossed the clinical threshold for treatment, while the other did not, with ABP being more frequently higher than NIBP. CONCLUSIONS: There is good agreement between ABP and NIBP, particularly in non-hypertensive ranges and with radial arterial catheters. Measurements, however, diverge in hypertension. Further research must define age-based thresholds, validate methods of BP measurement, and determine the effect of BP reduction on outcomes in these children.

Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity.

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Multidisciplinary Consensus on Curricular Priorities for Pediatric Neurocritical Care Nursing Education: A Modified Delphi Study in the United States.

BACKGROUND: Nurses are vital partners in the development of pediatric neurocritical care (PNCC) programs. Nursing expertise is acknowledged to be an integral component of high-quality specialty patient care in the field, but little guidance exists regarding educational requirements to build that expertise. We sought to obtain expert consensus from nursing professionals and physicians on curricular priorities for specialized PNCC nursing education in pediatric centers across the United States. METHODS: We used a modified Delphi study technique surveying a multidisciplinary expert panel of nursing professionals and physicians. Online surveys were distributed to 44 panelists over three rounds to achieve consensus on curricular topics deemed essential for PNCC nursing education. During each round, panelists were asked to rate topics as essential or not essential, as well as given opportunities to provide feedback and suggest changes. Feedback was shared anonymously to the panelist group throughout the process. RESULTS: From 70 initial individual topics, the consensus process yielded 19 refined topics that were confirmed to be essential for a PNCC nursing curriculum by the expert panel. Discrepancies existed regarding how universally to recommend topics of advanced neuromonitoring, such as brain tissue oxygenation; specialized neurological assessments, such as the serial neurological assessment in pediatrics or National Institutes of Health Stroke Scale; and some disease-based populations. Panelists remarked that not all centers see specific diseases, and not all centers currently employ advanced neuromonitoring technologies and skills. CONCLUSIONS: We report 19 widely accepted curricular priorities that can serve as a standard educational base for PNCC nursing. Developing education for nurses in PNCC will complement PNCC programs with targeted nursing expertise that extends comprehensive specialty care to the bedside. Further work is necessary to effectively execute educational certification programs, implement nursing standards in the field, and evaluate the impact of nursing expertise on patient care and outcomes.

Post-discharge outcomes of hospitalized children diagnosed with acute SARS-CoV-2 or MIS-C.

Introduction: Hospitalized children diagnosed with SARS-CoV-2-related conditions are at risk for new or persistent symptoms and functional impairments. Our objective was to analyze post-hospital symptoms, healthcare utilization, and outcomes of children previously hospitalized and diagnosed with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C). Methods: Prospective, multicenter electronic survey of parents of children <18 years of age surviving hospitalization from 12 U.S. centers between January 2020 and July 2021. The primary outcome was a parent report of child recovery status at the time of the survey (recovered vs. not recovered). Secondary outcomes included new or persistent symptoms, readmissions, and health-related quality of life. Multivariable backward stepwise logistic regression was performed for the association of patient, disease, laboratory, and treatment variables with recovered status. Results: The children [n = 79; 30 (38.0%) female] with acute SARS-CoV-2 (75.7%) or MIS-C (24.3%) had a median age of 6.5 years (interquartile range 2.0-13.0) and 51 (64.6%) had a preexisting condition. Fifty children (63.3%) required critical care. One-third [23/79 (29.1%)] were not recovered at follow-up [43 (31, 54) months post-discharge]. Admission C-reactive protein levels were higher in children not recovered vs. recovered [5.7 (1.3, 25.1) vs. 1.3 (0.4, 6.3) mg/dl, p = 0.02]. At follow-up, 67% overall had new or persistent symptoms. The most common symptoms were fatigue (37%), weakness (25%), and headache (24%), all with frequencies higher in children not recovered. Forty percent had at least one return emergency visit and 24% had a hospital readmission. Recovered status was associated with better total HRQOL [87 (77, 95) vs. 77 (51, 83), p = 0.01]. In multivariable analysis, lower admission C-reactive protein [odds ratio 0.90 (95% confidence interval 0.82, 0.99)] and higher admission lymphocyte count [1.001 (1.0002, 1.002)] were associated with recovered status. Conclusions: Children considered recovered by their parents following hospitalization with SARS-CoV-2-related conditions had less symptom frequency and better HRQOL than those reported as not recovered. Increased inflammation and lower lymphocyte count on hospital admission may help to identify children needing longitudinal, multidisciplinary care. Clinical Trial Registration: ClinicalTrials.gov (NCT04379089).

High Variability in the Duration of Chest Compression Interruption is Associated With Poor Outcomes in Pediatric Extracorporeal Cardiopulmonary Resuscitation.

OBJECTIVES: To determine the association between chest compression interruption (CCI) patterns and outcomes in pediatric patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR). DESIGN: Cardiopulmonary resuscitation (CPR) data were collected using defibrillator-electrode and bedside monitor waveforms from pediatric ECPR cases between 2013 and 2021. Duration and variability of CCI during cannulation for ECPR was determined and compared with survival to discharge using Fishers exact test and logistic regressions with cluster-robust se s for adjusted analyses. SETTING: Quaternary care children's hospital. PATIENTS: Pediatric patients undergoing ECPR. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 41 ECPR events, median age was 0.7 years (Q1, Q3: 0.1, 5.4), 37% (15/41) survived to hospital discharge with 73% (11/15) of survivors having a favorable neurologic outcome. Median duration of CPR from start of ECPR cannulation procedure to initiation of extracorporeal membrane oxygenation (ECMO) flow was 21 minutes (18, 30). Median duration of no-flow times associated with CCI during ECMO cannulation was 11 seconds (5, 28). Following planned adjustment for known confounders, survival to discharge was inversely associated with maximum duration of CCI (odds ratio [OR] 0.91 [0.86-0.95], p = 0.04) as well as the variability in the CCI duration (OR 0.96 [0.93-0.99], p = 0.04). Cases with both above-average CCI duration and higher CCI variability ( sd > 30 s) were associated with lowest survival (12% vs. 54%, p = 0.009). Interaction modeling suggests that lower variability in CCI is associated with improved survival, especially in cases where average CCI durations are higher. CONCLUSIONS: Shorter duration of CCI and lower variability in CCI during cannulation for ECPR were associated with survival following refractory pediatric cardiac arrest.

Pediatric Moyamoya Revascularization Perioperative Care: A Modified Delphi Study.

BACKGROUND: Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities. METHODS: Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement. RESULTS: Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery. CONCLUSIONS: In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

Study of Legionella pneumophila treatment with copper in drinking water by single cell-ICP-MS.

Legionella pneumophila is a persistent opportunistic pathogen that poses a significant threat to domestic water systems. Previous studies suggest that copper (Cu) is an effective antimicrobial in water systems. A rapid and sensitive quantification method is desired to optimize the conditions of L. pneumophila treatment by Cu and to better understand the interaction mechanisms between Cu and cells. In this study, we developed a highly sensitive single cell (SC)-ICP-MS method to monitor L. pneumophila cell concentration and track their uptake of Cu. The SC-ICP-MS method showed excellent sensitivity (with a cell concentration detection limit of 1000 cells/mL), accuracy (good agreement with conventional hemocytometry method), and precision (relative standard deviation < 5%) in drinking water matrix. The cupric ions (Cu2+) treatment results indicated that the total L. pneumophila cell concentration, Cu mass per cell, colony-forming unit counting, and Cu concentration in supernatant all exhibited a dose-dependent trend, with 800-1200 µg/L reaching high disinfection rates in drinking water. The investigation of percentages of viable and culturable, viable but nonculturable (VBNC), and lysed cells suggested there always were VBNC present at any Cu concentration. Experimental results of different Cu2+ treatment times further suggested that L. pneumophila cells developed an antimicrobial resistant mechanism with the prolonged Cu exposure. This is the first quantification study on the interactions of Cu and L. pneumophila in drinking water using SC-ICP-MS.

Knowledge and Practice Gaps in Pediatric Neurocritical Care Nursing: Lessons Learned From a Specialized Educational Boot Camp.

OBJECTIVES: Pediatric neurocritical care (PNCC) is a quickly growing subspecialty within pediatric critical care medicine. Standards for care, education, and application of neuromonitoring technologies in PNCC are still being developed. We sought to identify and improve knowledge deficits in neurocritical care with an educational boot camp for nurses. SETTING: Quaternary children's hospital with 36 PICU beds. DESIGN: Preinterventional and postinterventional study. METHODS: A 2-day boot camp course covering neurologic and neurosurgical topics pertinent to PNCC was provided to 46 pediatric acute and critical care nurses divided into three cohorts over 3 years. Participant characteristics were collected, and precourse and postcourse knowledge assessments were administered. RESULTS: Regarding participant characteristics, neither critical care registered nurse certification nor years of nursing experience were associated with better precourse baseline knowledge. Knowledge gaps spanned bedside neurologic assessments, physiologic goals in brain injury, and side effects of neurocritical care medications. In postcourse assessments, all participants showed improvement in scores, and most participants sustained improvements after 6 months. Nurses reported significant improvement in self-reported confidence in caring for the PNCC population. We also observed shorter ICU lengths of stay, decreased hospital incident reports, and decreased time to stroke imaging, although these programmatic metrics cannot be credited to nursing education alone. CONCLUSIONS: PNCC programs should include nursing expertise in the field. However, topics specific to PNCC may not be adequately addressed by existing general critical care nursing education and certification. A multimodal educational boot camp can be an effective method to improve nursing knowledge in PNCC. Our results demonstrate that specialty nursing education in PNCC is both innovative and feasible, with the potential to improve patient care. Further research is needed to determine the benefits of specialty education on quality of care and clinical outcomes.

Performance of a Provider-Assigned Functional Outcome Score in Critically Ill Children.

OBJECTIVES: Determine agreement between Pediatric Cerebral Performance Category (PCPC) scores integrated into clinical workflow and traditional investigator-assigned scores. DESIGN: Longitudinal study. SETTING: A single-center quaternary-care academic institution. SUBJECTS: Children admitted to the PICU between November 2019 and April 2020. INTERVENTIONS: Providers assigned PCPC scores as part of daily workflow. Investigators assigned scores using retrospective chart review. MEASUREMENTS AND MAIN RESULTS: Of 803 patients admitted to the PICU, 782 survived and were included. Admission and discharge scores were recorded in 95% and 90% of patients, respectively. Agreement between provider- and investigator-assigned scores was excellent, with a weighted kappa of 0.87 (95% CI, 0.84-0.90) and 0.80 (95% CI, 0.76-0.84) for admission and discharge. CONCLUSIONS: Provider-assigned PCPC scores, documented as standard of care, are largely concordant with retrospective investigator-assigned scores. Measurement of cognitive functional status can be successfully integrated into daily provider workflow for use in the clinical, quality improvement, and research arenas.

Novel Serum Biomarkers Associated With Pediatric Hepatic Encephalopathy: A Systematic Review.

BACKGROUND: The pathophysiology of pediatric hepatic encephalopathy (HE) is not well understood. Various serum biomarkers associated with HE may provide insight into its pathology, but their use and interpretation in clinical practice for diagnosis and prognostication remain undetermined. We sought to investigate reported correlations of serum biomarkers with presence and degree of HE in children. METHODS: We conducted a systematic review of studies examining novel serum biomarkers and cytokines in association with HE that included children on PubMed, Embase, Lilacs, and Scopus. We utilized Covidence for abstract and text review by 2 independent reviewers for each study. RESULTS: We reviewed 2824 unique publications; 15 met criteria for inclusion. Categories of biomarkers reported were inflammatory cytokines, products of amino acid metabolism, trace elements and vitamins, and hepatic and neuro biomarkers. Of 19 individual biomarkers, only 5 were measured in more than 1 study. Elevations in interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were most commonly reported as associated with HE. Notably, we observed lower average IL-6 and TNF-alpha levels in pediatric-only studies compared to mixed age studies. Overall, high bias and poor applicability to our review question was observed. We encountered low numbers of studies with pediatric focus, and few conducted with low bias study designs. CONCLUSION: Investigated biomarkers span a large range of categories and suggest potentially useful correlations with HE. Further well-designed prospective biomarker research is necessary to better elucidate the pathogenesis of HE in children and improve early detection and clinical care.

Proceedings of the First Pediatric Coma and Disorders of Consciousness Symposium by the Curing Coma Campaign, Pediatric Neurocritical Care Research Group, and NINDS: Gearing for Success in Coma Advancements for Children and Neonates.

This proceedings article presents the scope of pediatric coma and disorders of consciousness based on presentations and discussions at the First Pediatric Disorders of Consciousness Care and Research symposium held on September 14th, 2021. Herein we review the current state of pediatric coma care and research opportunities as well as shared experiences from seasoned researchers and clinicians. Salient current challenges and opportunities in pediatric and neonatal coma care and research were identified through the contributions of the presenters, who were Jose I. Suarez, MD, Nina F. Schor, MD, PhD, Beth S. Slomine, PhD Erika Molteni, PhD, and Jan-Marino Ramirez, PhD, and moderated by Varina L. Boerwinkle, MD, with overview by Mark Wainwright, MD, and subsequent audience discussion. The program, executively planned by Varina L. Boerwinkle, MD, Mark Wainwright, MD, and Michelle Elena Schober, MD, drove the identification and development of priorities for the pediatric neurocritical care community.

Effect of clevidipine on intracranial pressure in pediatric neurosurgical patients: a single-center retrospective review.

OBJECTIVE: Hemodynamic management in pediatric neurosurgical patients is essential for maintaining cerebral perfusion pressure (CPP), avoiding hemorrhage, and preventing secondary neurological injury. Antihypertensive infusions approved for pediatrics are not widely studied in the pediatric neurosurgical population and may have adverse effects on intracranial pressure (ICP), contributing to reduced CPP. Clevidipine is an ultra-rapid-acting intravenous antihypertensive agent used for hemodynamic control in adult surgical patients. In pediatric patients, clevidipine is safe and effective in controlling blood pressure in the perioperative period, although studies evaluating its effect on ICP in neurosurgical patients are lacking. The objective of this research was to evaluate the effect of clevidipine on ICP in pediatric neurosurgical patients. METHODS: This single-center retrospective study involved patients admitted to the pediatric ICU between January 1, 2017, and December 31, 2020. Patients eligible for inclusion had ICP monitoring devices and received clevidipine infusion for a minimum of 6 hours postoperatively, with at least one ICP measurement pre- and postinfusion. Excluded patients had an elevated preinfusion ICP > 20 mm Hg. The primary outcome was the average change in ICP from preinfusion baseline to hours 6 to < 12, 12 to < 24, and 24 to < 48 of clevidipine infusion. Secondary outcomes included frequency of ICP measurements > 20 mm Hg, CPP measurements < 50 mm Hg, treatment failure defined by a need for concurrent antihypertensive infusion, and frequency of elevated serum triglycerides > 200 mg/dL. Descriptive data were expressed as frequency with percentage or median with interquartile range as appropriate. Analysis of continuous outcome variable data involved Mann-Whitney U-tests with an alpha significance of 0.05. RESULTS: Data from 47 patients were included in the analysis. The average change in ICP from preinfusion baseline to 48 hours was < 1 mm Hg. Of 3025 total postinfusion ICP measurements in 47 patients, 67 measurements (2.2%) in 13 patients (28%) were > 20 mm Hg. CPP measurements < 50 mm Hg occurred in 16 of 45 patients (36%). Three patients (6.4%) required use of a secondary antihypertensive medication infusion, and 5 of 14 patients (36%) had serum triglycerides > 200 mg/dL. CONCLUSIONS: Use of clevidipine had minimal effect on ICP. The results of this study suggest that clevidipine is effective at safely maintaining ICP and CPP measurements without detrimental adverse effects in pediatric neurosurgical patients.

Exploring Trends in Neuromonitoring Use in a General Pediatric ICU: The Need for Standardized Guidance.

Neuromonitoring has become more standardized in adult neurocritical care, but the utility of different neuromonitoring modalities in children remains debated. We aimed to describe the use of neuromonitoring in critically ill children with and without primary neurological diseases. We conducted a retrospective review of patients admitted to a 32-bed, non-cardiac PICU during a 12-month period. Neuro-imaging, electroencephalogram (EEG), cerebral oximetry (NIRS), automated pupillometry, transcranial doppler (TCD), intracranial pressure (ICP) monitoring, brain tissue oxygenation (PbtO2), primary diagnosis, and outcome were extracted. Neuromonitoring use by primary diagnosis and associations with outcome were observed. Of 1946 patients, 420 received neuro-imaging or neuromonitoring. Primary non-neurological diagnoses most frequently receiving neuromonitoring were respiratory, hematologic/oncologic, gastrointestinal/liver, and infectious/inflammatory. The most frequently used technologies among non-neurological diagnoses were neuro-imaging, EEG, pupillometry, and NIRS. In the multivariate analysis, pupillometry use was associated with mortality, and EEG, NIRS, and neuro-imaging use were associated with disability. Frequencies of TCD and PbtO2 use were too small for analysis. Neuromonitoring is prevalent among various diagnoses in the PICU, without clear benefit on outcomes when used in an ad hoc fashion. We need standard guidance around who, when, and how neuromonitoring should be applied to improve the care of critically ill children.

Establishing pteridine metabolism in a progressive isogenic breast cancer cell model - part II.

INTRODUCTION: Determining the biological significance of pteridines in cancer development and progression remains an important step in understanding the altered levels of urinary pteridines seen in certain cancers. Our companion study revealed that several folate-derived pteridines and lumazines correlated with tumorigenicity in an isogenic, progressive breast cancer cell model, providing direct evidence for the tumorigenic origin of pteridines. OBJECTIVES: This study sought to elucidate the pteridine biosynthetic pathway in a progressive breast cancer model via direct pteridine dosing to determine how pteridine metabolism changes with tumorigenicity. METHODS: First, MCF10AT breast cancer cells were dosed individually with 15 pteridines to determine which pteridines were being metabolized and what metabolic products were being produced. Second, pteridines that were significantly metabolized were dosed individually across the progressive breast cancer cell model (MCF10A, MCF10AT, and MCF10ACA1a) to determine the relationship between each metabolic reaction and breast cancer tumorigenicity. RESULTS: Several pteridines were found to have altered metabolism in breast cancer cell lines, including pterin, isoxanthopterin, xanthopterin, sepiapterin, 6-biopterin, lumazine, and 7-hydroxylumazine (p < 0.05). In particular, isoxanthopterin and 6-biopterin concentrations were differentially expressed (p < 0.05) with respect to tumorigenicity following dosing with pterin and sepiapterin, respectively. Finally, the pteridine biosynthetic pathway in breast cancer cells was proposed based on these findings. CONCLUSIONS: This study, along with its companion study, demonstrates that pteridine metabolism becomes disrupted in breast cancer tumor cells. This work highlights several key metabolic reactions within the pteridine biosynthetic pathway that may be targeted for further investigation and clinical applications.

Continuing Care For Critically Ill Children Beyond Hospital Discharge: Current State of Follow-up.

OBJECTIVES: Survivors of the PICU face long-term morbidities across health domains. In this study, we detail active PICU follow-up programs (PFUPs) and identify perceptions and barriers about development and maintenance of PFUPs. METHODS: A web link to an adaptive survey was distributed through organizational listservs. Descriptive statistics characterized the sample and details of existing PFUPs. Likert responses regarding benefits and barriers were summarized. RESULTS: One hundred eleven respondents represented 60 institutions located in the United States (n = 55), Canada (n = 3), Australia (n = 1), and the United Kingdom (n = 1). Details for 17 active programs were provided. Five programs included broad PICU populations, while the majority were neurocritical care (53%) focused. Despite strong agreement on the need to assess and treat morbidity across multiple health domains, 29% were physician only programs, and considerable variation existed in services provided by programs across settings. More than 80% of all respondents agreed PFUPs provide direct benefits and are essential to advancing knowledge on long-term PICU outcomes. Respondents identified "lack of support" as the most important barrier, particularly funding for providers and staff, and lack of clinical space, though successful programs overcome this challenge using a variety of funding resources. CONCLUSIONS: Few systematic multidisciplinary PFUPs exist despite strong agreement about importance of this care and direct benefit to patients and families. We recommend stakeholders use our description of successful programs as a framework to develop multidisciplinary models to elevate continuity across inpatient and outpatient settings, improve patient care, and foster collaboration to advance knowledge.

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Quantification of silver nanoparticle interactions with yeast Saccharomyces cerevisiae studied using single-cell ICP-MS.

Silver nanoparticles (AgNPs) have been used in many fields due to their anticancer, antimicrobial, and antiviral potential. Single-cell ICP-MS (SC-ICP-MS) is an emerging technology that allows for the rapid characterization and quantification of a metal analyte across a cell population in a single analysis. In this study, a new rapid and sensitive SC-ICP-MS method was developed to quantitatively study the interactions of AgNPs with yeast Saccharomyces cerevisiae. The method can quantify the cell concentration, silver concentration per cell, and profile the nanoparticle distribution in a yeast cell population. AgNP dosing time, concentration, and AgNP size were quantitatively evaluated for their effects on AgNP-yeast cell interactions. The results showed that the initial uptake of AgNPs was rapid and primarily driven by the mass of Ag per cell. The optimal dosing particle concentrations for highest uptake were approximately 1820, 1000, and 300 AgNPs/cell for 10, 20, and 40 nm AgNPs, respectively. Furthermore, this study also validated a washing method for the application to a microorganism for the first time and was used to quantitatively determine the amount of cell surface-adsorbed AgNPs and intracellular AgNPs. These results indicated that the mass (Ag in ag/cell) ratios of intracelluar vs cell surface-adsorbed AgNPs were similar for different AgNP sizes. This high throughput and ultrasensitive SC-ICP-MS method is expected to have many potential applications, such as optimization of methods for green synthesis of AgNPs, nanotoxicity studies, and drug delivery. This is the first quantification study on the interactions of AgNPs and S. cerevisiae using SC-ICP-MS.

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C.

BACKGROUND: Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). METHODS: Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. RESULTS: Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. CONCLUSIONS: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.