Biomarker Assessment of a High-Risk, Data-Driven Pediatric Sepsis Phenotype Characterized by Persistent Hypoxemia, Encephalopathy, and Shock.

OBJECTIVES: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. We sought to the determine reproducibility of the data-driven "persistent hypoxemia, encephalopathy, and shock" (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk strata. DESIGN: We retrained and validated a random forest classifier using organ dysfunction subscores in the 2012-2018 electronic health record (EHR) dataset used to derive the PHES phenotype. We used this classifier to assign phenotype membership in a test set consisting of prospectively (2003-2023) enrolled pediatric septic shock patients. We compared profiles of the PERSEVERE family of biomarkers among those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk strata. SETTING: Twenty-five PICUs across the United States. PATIENTS: EHR data from 15,246 critically ill patients with sepsis-associated MODS split into derivation and validation sets and 1,270 pediatric septic shock patients in the test set of whom 615 had complete biomarker data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The area under the receiver operator characteristic curve of the modified classifier to predict PHES phenotype membership was 0.91 (95% CI, 0.90-0.92) in the EHR validation set. In the test set, PHES phenotype membership was associated with both increased adjusted odds of complicated course (adjusted odds ratio [aOR] 4.1; 95% CI, 3.2-5.4) and 28-day mortality (aOR of 4.8; 95% CI, 3.11-7.25) after controlling for age, severity of illness, and immunocompromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and were more likely to be stratified as high risk based on PERSEVERE biomarkers predictive of death and persistent MODS. CONCLUSIONS: The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlapped with higher risk strata based on prospectively validated biomarker approaches.

Learning competing risks across multiple hospitals: one-shot distributed algorithms.

OBJECTIVES: To characterize the complex interplay between multiple clinical conditions in a time-to-event analysis framework using data from multiple hospitals, we developed two novel one-shot distributed algorithms for competing risk models (ODACoR). By applying our algorithms to the EHR data from eight national children's hospitals, we quantified the impacts of a wide range of risk factors on the risk of post-acute sequelae of SARS-COV-2 (PASC) among children and adolescents. MATERIALS AND METHODS: Our ODACoR algorithms are effectively executed due to their devised simplicity and communication efficiency. We evaluated our algorithms via extensive simulation studies as applications to quantification of the impacts of risk factors for PASC among children and adolescents using data from eight children's hospitals including the Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, Children's Hospital of Colorado covering over 6.5 million pediatric patients. The accuracy of the estimation was assessed by comparing the results from our ODACoR algorithms with the estimators derived from the meta-analysis and the pooled data. RESULTS: The meta-analysis estimator showed a high relative bias (∼40%) when the clinical condition is relatively rare (∼0.5%), whereas ODACoR algorithms exhibited a substantially lower relative bias (∼0.2%). The estimated effects from our ODACoR algorithms were identical on par with the estimates from the pooled data, suggesting the high reliability of our federated learning algorithms. In contrast, the meta-analysis estimate failed to identify risk factors such as age, gender, chronic conditions history, and obesity, compared to the pooled data. DISCUSSION: Our proposed ODACoR algorithms are communication-efficient, highly accurate, and suitable to characterize the complex interplay between multiple clinical conditions. CONCLUSION: Our study demonstrates that our ODACoR algorithms are communication-efficient and can be widely applicable for analyzing multiple clinical conditions in a time-to-event analysis framework.

Institutional Variability in Respiratory Support Use for Pediatric Critical Asthma: A Multicenter Retrospective Study.

Rationale: Over 20,000 children are hospitalized in the United States for asthma every year. Although initial treatment guidelines are well established, there is a lack of high-quality evidence regarding the optimal respiratory support devices for these patients.Objectives: The objective of this study was to evaluate institutional and temporal variability in the use of respiratory support modalities for pediatric critical asthma.Methods: We conducted a retrospective cohort study using data from the Virtual Pediatrics Systems database. Our study population included children older than 2 years old admitted to a VPS contributing pediatric intensive care unit from January 2012 to December 2021 with a primary diagnosis of asthma or status asthmaticus. We evaluated the percentage of encounters using a high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), noninvasive bilevel positive pressure ventilation (NIV), and invasive mechanical ventilation (IMV) for all institutions, then divided institutions into quintiles based on the volume of patients. We created logistic regression models to determine the influence of institutional volume and year of admission on respiratory support modality use. We also conducted time-series analyses using Kendall's tau.Results: Our population included 77,115 patient encounters from 163 separate institutions. Institutional use of respiratory modalities had significant variation in HFNC (28.3%, interquartile range [IQR], 11.0-49.0%; P < 0.01), CPAP (1.4%; IQR, 0.3-4.3%; P < 0.01), NIV (8.6%; IQR, 3.5-16.1%; P < 0.01), and IMV (5.1%; IQR, 3.1-8.2%; P < 0.01). Increased institutional patient volume was associated with significantly increased use of NIV (odds ratio [OR], 1.33; 1.29-1.36; P < 0.01) and CPAP (OR, 1.20; 1.15-1.25; P < 0.01), and significantly decreased use of HFNC (OR, 0.80; 0.79-0.81; P < 0.01) and IMV (OR, 0.82; 0.79-0.86; P < 0.01). Time was also associated with a significant increase in the use of HFNC (11.0-52.3%; P < 0.01), CPAP (1.6-5.4%; P < 0.01), and NIV (3.7-21.2%; P < 0.01), whereas there was no significant change in IMV use (6.1-4.0%; P = 0.11).Conclusions: Higher-volume centers are using noninvasive positive pressure ventilation more frequently for pediatric critical asthma and lower frequencies of HFNC and IMV. Treatment with HFNC, CPAP, and NIV for this population is increasing in the last decade.

Noninvasive Respiratory Support for Pediatric Critical Asthma: A Multicenter Cohort Study.

BACKGROUND: Noninvasive respiratory support (NRS) for pediatric critical asthma includes CPAP; bi-level positive airway pressure (BPAP); and heated, humidified, high-flow nasal cannula (HFNC). We used the Virtual Pediatric System database to estimate NRS by prescribing rates for pediatric critical asthma and characterize patient clinical features and in-patient outcomes by the initial NRS device applied. METHODS: We performed a retrospective cohort study from 125 participating pediatric ICUs among children 2-17 years of age hospitalized for critical asthma and prescribed NRS from 2017 through 2021. The primary outcomes were NRS modality prescribing rates and trends. Secondary outcomes were descriptive and included demographics, comorbidities, severity of illness indices, and NRS failure rates (defined as escalation from the initial NRS modality to invasive ventilation, HFNC to BPAP or CPAP, or CPAP to BPAP). RESULTS: Of the 10,083 encounters studied, the initial NRS modalities prescribed varied widely by hospital center (HFNC: 69.7 ± 29.6%; BPAP: 27.2 ± 7.1%; CPAP: 3.1 ± 5.9%). The mean rates of HFNC use increased from 59.7% in 2017 to 71.9% in 2021 (+2.5%/y). In contrast, BPAP (-1.6%/y) and CPAP (-0.8%/y) utilization declined throughout the study period. Older children who were obese and with a higher Pediatric Risk of Mortality III-Probability of Mortality score were more frequently prescribed BPAP and CPAP compared with HFNC. Those children on HFNC experienced higher noninvasive respiratory support failure rates versus BPAP (7.3% vs 2.4%; P < .001) but a lower subsequent invasive ventilation rate versus BPAP (0.8% vs 2.4%; P < .001). CONCLUSIONS: In this multi-center cohort study, we observed that children with critical asthma are increasingly exposed to HFNC compared with BPAP and CPAP. Rates of HFNC failure were greater than those of BPAP failure, but a majority were transitioned to BPAP without subsequent invasive ventilation. The next steps include prospective trials, including practical end points such as patient comfort and optimal delivery of nebulized treatments to distinguish device superiority and suitable NRS utilization.

Wide Institutional Variability in the Treatment of Pediatric Critical Asthma: A Multicenter Retrospective Study.

OBJECTIVES: Children with status asthmaticus refractory to first-line therapies of systemic corticosteroids and inhaled beta-agonists often receive additional treatments. Because there are no national guidelines on the use of asthma therapies in the PICU, we sought to evaluate institutional variability in the use of adjunctive asthma treatments and associations with length of stay (LOS) and PICU use. DESIGN: Multicenter retrospective cohort study. SETTING: Administrative data from the Pediatric Health Information Systems (PHIS) database. PATIENTS: All inpatients 2-18 years old were admitted to a PHIS hospital between 2013 and 2021 with a diagnostic code for asthma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study included 213,506 inpatient encounters for asthma, of which 29,026 patient encounters included care in a PICU from 39 institutions. Among these PICU encounters, large variability was seen across institutions in both the number of adjunctive asthma therapies used per encounter (min: 0.6, median: 1.7, max: 2.5, p < 0.01) and types of adjunctive asthma therapies (aminophylline, ipratropium, magnesium, epinephrine, and terbutaline) used. The center-level median hospital LOS ranged from 1 (interquartile range [IQR]: 1, 3) to 4 (3, 6) days. Among all the 213,506 inpatient encounters for asthma, the range of asthma admissions that resulted in PICU admission varied between centers from 5.2% to 47.3%. The average number of adjunctive therapies used per institution was not significantly associated with hospital LOS ( p = 0.81) nor the percentage of encounters with PICU admission ( p = 0.47). CONCLUSIONS: Use of adjunctive therapies for status asthmaticus varies widely among large children's hospitals and was not associated with hospital LOS or the percentage of encounters with PICU admission. Wide variance presents an opportunity for standardizing care with evidence-based guidelines to optimize outcomes and decrease adverse treatment effects and hospital costs.

Critical Care Utilization in Children With Cancer: U.S. Pediatric Health Information System Database Cohort 2012-2021.

OBJECTIVES: To determine changes in pediatric oncology hospitalizations requiring intensive care over the period 2012-2021. DESIGN: Retrospective study of hospital admission. SETTING: Registry data from 36 children's hospitals in the U.S. Pediatric Health Information Systems database. PATIENTS: Children 18 years or younger admitted to any of 36 hospitals with an oncology diagnosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were a total of 55,827 unique patients accounted for 281,221 pediatric oncology hospitalizations over the 10-year period, and 16.6% of hospitalizations included admission to the PICU. Hospitalizations and PICU admissions steadily increased over this decade. Between 2012 and 2016, 15.1% of oncology hospitalizations were admitted to the PICU compared with 18.0% from 2017 to 2021 (difference 2.9% [95% CI, 2.6-3.2%] p ≤ 0.0001). Support with invasive mechanical ventilation also increased over time with 3.7% during 2012-2016 compared with 4.1% from 2017 to 2021 (difference 0.4% [95% CI, 0.2-0.5%] p ≤ 0.0001). Similar results were seen with cardiorespiratory life support using extracorporeal membrane oxygenation (difference 0.05% [95% CI, 0.02-0.07%] p = 0.0002), multiple vasoactive agent use (difference 0.3% [95% CI, 0.2-0.4%] p < 0.0001), central line placement (difference 5.3% [95% CI, 5.1-5.6%], p < 0.001), and arterial line placement (difference 0.4% [95% CI, 0.3-0.4%], p < 0.001). Year-on-year case fatality rate was unchanged over time (1.3%), but admission to the PICU during the second 5 years, compared with the first 5 years, was associated with lower odds of mortality (difference 0.7% [95% CI, 0.3-1.1%]) (odds ratio 0.82 [95% CI, 0.75-0.90%] p < 0.001). CONCLUSIONS: The percentage of pediatric oncology hospitalizations resulting in PICU admission has increased over the past 10 years. Despite the increasing use of PICU admission and markers of acuity, and on comparing 2017-2021 with 2012-2016, there are lower odds of mortality.

Suicide and Self-Harm in Adolescents During the COVID-19 Pandemic: A U.S. Virtual Pediatric Systems, LLC, Database Study of PICU Admissions, 2016-2021.

OBJECTIVES: To characterize the epidemiology of suicide and self-harm among adolescents admitted to PICUs during the first 2 years of the COVID-19 pandemic in the United States. DESIGN: Descriptive analysis of a large, multicenter, quality-controlled database (Virtual Pediatric Systems [VPS]), and of a national public health dataset (U.S. Centers for Disease Control and Prevention web-based Wide-ranging ONline Data for Epidemiology Research [CDC WONDER]). SETTING: The 69 PICUs participating in the VPS database that contributed data for the entire the study period, January 1, 2016, to December 31, 2021. PATIENTS: Adolescents older than 12 years to younger than 18 years old admitted to a participating PICU during the study period with a diagnosis involving self-harm or a suicide attempt (VPS sample), or adolescent suicide deaths over the same period (CDC WONDER sample). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 10,239 suicide deaths and 7,692 PICU admissions for self-harm, including 5,414 admissions in the pre-pandemic period (Q1-2016 to Q1-2020) and 2,278 in the pandemic period (Q2-2020 to Q4-2021). Compared with the pre-pandemic period, there was no increase in the median (interquartile range) number of suicide deaths per quarter (429 [399-453] vs. 416 [390-482]) or PICU admissions for self-harm per quarter (315 [289-353] vs. 310 [286-387]) during the pandemic period, respectively. There was an increase in the ratio of self-harm PICU admissions to all-cause PICU admissions per quarter during the pandemic (1.98 [1.43-2.12]) compared with the pre-pandemic period per quarter (1.59 [1.46-1.74]). We also observed a significant decrease in all-cause PICU admissions per quarter early in the pandemic compared with the pre-pandemic period (16,026 [13,721-16,297] vs. 19,607 [18,371-20,581]). CONCLUSIONS: The number of suicide deaths and PICU admissions per quarter for self-harm remained relatively constant during the pandemic, while the number of all-cause PICU admissions per quarter decreased compared with the pre-pandemic period. The resultant higher ratio of self-harm admissions to all-cause PICU admissions may have contributed to the perception that more adolescents required critical care for mental health-related conditions early in the pandemic.

Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes-an international multicentre retrospective study.

Background: Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. Methods: We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n = 383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n = 1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24 h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. Findings: LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p < 0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04-3.34) in the European cohort and 1.6 (1.2-2.2) in the U.S. cohort. Interpretation: We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Funding: Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Outcomes of a respiratory therapist driven high flow nasal cannula management protocol for pediatric critical asthma patients.

INTRODUCTION: This study aimed to determine if a respiratory therapist (RT)-driven high flow nasal cannula (HFNC) protocol could decrease duration of HFNC use, pediatric intensive care unit (PICU) and hospital length of stay (LOS), and duration of continuous albuterol use in pediatric patients with critical asthma. METHODS: This was a quality improvement project performed at a quaternary academic PICU. Patients admitted to the PICU between 2 and 18 years of age with a diagnosis of asthma requiring continuous albuterol and HFNC were included. Implementation of an RT-driven HFNC protocol [Plan-Do-Study-Act (PDSA) 1] occurred in October 2017. Additional interventions included weaning continuous albuterol and HFNC simultaneously (PDSA 2; March 2019), adjusting HFNC wean rate (PDSA 3; July 2020), and a HFNC holiday (PDSA 4; October 2021). HFNC duration was the primary outcome. Secondary outcomes included LOS data and continuous albuterol duration. Noninvasive ventilation (NIV), invasive mechanical ventilation (IMV), and 7-day PICU and hospital readmission rates were used as balancing measures. RESULTS: A total of 410 patients were included. Patient demographics and adjunct therapy use did not differ among the groups. After PDSA 2, mean HFNC duration decreased (26.8-18.1 h). Mean PICU LOS decreased (41-31.8 h). Mean hospital LOS also decreased (86.5-68 h). These outcomes remained stable during PDSA 3 and 4. Continuous albuterol duration and NIV use were unchanged, while IMV use decreased. CONCLUSIONS: An RT-driven HFNC protocol led to decreased length of HFNC and PICU and hospital LOS for pediatric patients with critical asthma without an increase in adverse events.

External validation and biomarker assessment of a high-risk, data-driven pediatric sepsis phenotype characterized by persistent hypoxemia, encephalopathy, and shock.

Objective: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. Data-driven phenotyping approaches that leverage electronic health record (EHR) data hold promise given the widespread availability of EHRs. We sought to externally validate the data-driven 'persistent hypoxemia, encephalopathy, and shock' (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk-strata. Design: We trained and validated a random forest classifier using organ dysfunction subscores in the EHR dataset used to derive the PHES phenotype. We used the classifier to assign phenotype membership in a test set consisting of prospectively enrolled pediatric septic shock patients. We compared biomarker profiles of those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk-strata. Setting: 25 pediatric intensive care units (PICU) across the U.S. Patients: EHR data from 15,246 critically ill patients sepsis-associated MODS and 1,270 pediatric septic shock patients in the test cohort of whom 615 had biomarker data. Interventions: None. Measurements and Main Results: The area under the receiver operator characteristic curve (AUROC) of the new classifier to predict PHES phenotype membership was 0.91(95%CI, 0.90-0.92) in the EHR validation set. In the test set, patients with the PHES phenotype were independently associated with both increased odds of complicated course (adjusted odds ratio [aOR] of 4.1, 95%CI: 3.2-5.4) and 28-day mortality (aOR of 4.8, 95%CI: 3.11-7.25) after controlling for age, severity of illness, and immuno-compromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and overlapped with high risk-strata based on PERSEVERE biomarkers predictive of death and persistent MODS. Conclusions: The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlap with higher risk-strata based on validated biomarker approaches.

Predicting Duration of Invasive Mechanical Ventilation in the Pediatric ICU.

BACKGROUND: Timely ventilator liberation can prevent morbidities associated with invasive mechanical ventilation in the pediatric ICU (PICU). There currently exists no standard benchmark for duration of invasive mechanical ventilation in the PICU. This study sought to develop and validate a multi-center prediction model of invasive mechanical ventilation duration to determine a standardized duration of invasive mechanical ventilation ratio. METHODS: This was a retrospective cohort study using registry data from 157 institutions in the Virtual Pediatric Systems database. The study population included encounters in the PICU between 2012-2021 involving endotracheal intubation and invasive mechanical ventilation in the first day of PICU admission who received invasive mechanical ventilation for > 24 h. Subjects were stratified into a training cohort (2012-2017) and 2 validation cohorts (2018-2019/2020-2021). Four models to predict the duration of invasive mechanical ventilation were trained using data from the first 24 h, validated, and compared. RESULTS: The study included 112,353 unique encounters. All models had observed-to-expected (O/E) ratios close to one but low mean squared error and R2 values. The random forest model was the best performing model and achieved an O/E ratio of 1.043 (95% CI 1.030-1.056) and 1.004 (95% CI 0.990-1.019) in the validation cohorts and 1.009 (95% CI 1.004-1.016) in the full cohort. There was a high degree of institutional variation, with single-unit O/E ratios ranging between 0.49-1.91. When stratified by time period, there were observable changes in O/E ratios at the individual PICU level over time. CONCLUSIONS: We derived and validated a model to predict the duration of invasive mechanical ventilation that performed well in aggregated predictions at the PICU and the cohort level. This model could be beneficial in quality improvement and institutional benchmarking initiatives for use at the PICU level and for tracking of performance over time.

Machine learning models to predict and benchmark PICU length of stay with application to children with critical bronchiolitis.

OBJECTIVE: To create models for prediction and benchmarking of pediatric intensive care unit (PICU) length of stay (LOS) for patients with critical bronchiolitis. HYPOTHESIS: We hypothesize that machine learning models applied to an administrative database will be able to accurately predict and benchmark the PICU LOS for critical bronchiolitis. DESIGN: Retrospective cohort study. PATIENTS: All patients less than 24-month-old admitted to the PICU with a diagnosis of bronchiolitis in the Pediatric Health Information Systems (PHIS) Database from 2016 to 2019. METHODOLOGY: Two random forest models were developed to predict the PICU LOS. Model 1 was developed for benchmarking using all data available in the PHIS database for the hospitalization. Model 2 was developed for prediction using only data available on hospital admission. Models were evaluated using R2 values, mean standard error (MSE), and the observed to expected ratio (O/E), which is the total observed LOS divided by the total predicted LOS from the model. RESULTS: The models were trained on 13,838 patients admitted from 2016 to 2018 and validated on 5254 patients admitted in 2019. While Model 1 had superior R2 (0.51 vs. 0.10) and (MSE) (0.21 vs. 0.37) values compared to Model 2, the O/E ratios were similar (1.18 vs. 1.20). Institutional median O/E (LOS) ratio was 1.01 (IQR 0.90-1.09) with wide variability present between institutions. CONCLUSIONS: Machine learning models developed using an administrative database were able to predict and benchmark the length of PICU stay for patients with critical bronchiolitis.

The MPRINT Hub Data, Model, Knowledge and Research Coordination Center: Bridging the gap in maternal-pediatric therapeutics research through data integration and pharmacometrics.

Maternal and pediatric populations have historically been considered "therapeutic orphans" due to their limited inclusion in clinical trials. Physiologic changes during pregnancy and lactation and growth and maturation of children alter pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Precision therapy in these populations requires knowledge of these effects. Efforts to enhance maternal and pediatric participation in clinical studies have increased over the past few decades. However, studies supporting precision therapeutics in these populations are often small and, in isolation, may have limited impact. Integration of data from various studies, for example through physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling or bioinformatics approaches, can augment the value of data from these studies, and help identify gaps in understanding. To catalyze research in maternal and pediatric precision therapeutics, the Obstetric and Pediatric Pharmacology and Therapeutics Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub. Herein, we provide an overview of the status of maternal-pediatric therapeutics research and introduce the Indiana University-Ohio State University MPRINT Hub Data, Model, Knowledge and Research Coordination Center (DMKRCC), which aims to facilitate research in maternal and pediatric precision therapeutics through the integration and assessment of existing knowledge, supporting pharmacometrics and clinical trials design, development of new real-world evidence resources, educational initiatives, and building collaborations among public and private partners, including other NICHD-funded networks. By fostering use of existing data and resources, the DMKRCC will identify critical gaps in knowledge and support efforts to overcome these gaps to enhance maternal-pediatric precision therapeutics.

Characteristics and Outcomes of Critically Ill Children With Multisystem Inflammatory Syndrome.

OBJECTIVES: To characterize the prevalence of pediatric critical illness from multisystem inflammatory syndrome in children (MIS-C) and to assess the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain on outcomes. DESIGN: Retrospective cohort study. SETTING: Database evaluation using the Virtual Pediatric Systems Database. PATIENTS: All children with MIS-C admitted to the PICU in 115 contributing hospitals between January 1, 2020, and June 30, 2021. MEASUREMENTS AND MAIN RESULTS: Of the 145,580 children admitted to the PICU during the study period, 1,338 children (0.9%) were admitted with MIS-C with the largest numbers of children admitted in quarter 1 (Q1) of 2021 ( n = 626). The original SARS-CoV-2 viral strain and the D614G Strain were the predominant strains through 2020, with Alpha B.1.1.7 predominating in Q1 and quarter 2 (Q2) of 2021. Overall, the median PICU length of stay (LOS) was 2.7 days (25-75% interquartile range [IQR], 1.6-4.7 d) with a median hospital LOS of 6.6 days (25-75% IQR, 4.7-9.3 d); 15.2% received mechanical ventilation with a median duration of mechanical ventilation of 3.1 days (25-75% IQR, 1.9-5.8 d), and there were 11 hospital deaths. During the study period, there was a significant decrease in the median PICU and hospital LOS and a decrease in the frequency of mechanical ventilation, with the most significant decrease occurring between quarter 3 and quarter 4 (Q4) of 2020. Children admitted to a PICU from the general care floor or from another ICU/step-down unit had longer PICU LOS than those admitted directly from an emergency department. CONCLUSIONS: Overall mortality from MIS-C was low, but the disease burden was high. There was a peak in MIS-C cases during Q1 of 2021, following a shift in viral strains in Q1 of 2021. However, an improvement in MIS-C outcomes starting in Q4 of 2020 suggests that viral strain was not the driving factor for outcomes in this population.

The Heparin-Antithrombin Product: A Novel Value for Pediatric Extracorporeal Anticoagulation.

Hematologic complications are a source of morbidity and mortality for patients receiving extracorporeal membrane oxygenation (ECMO) support. There is no consensus strategy for monitoring anticoagulation for children supported with ECMO. This study evaluated a novel measurement of anticoagulation for children on ECMO. This was a single-center observational study of children supported with ECMO from 2015 to 2020. Each patient's current unfractionated heparin dose was multiplied by the current antithrombin III (AT) level to obtain a novel anticoagulation value, the heparin-antithrombin product (HAP). This value was compared with the heparin dose, AT, and activated clotting time (ACT) to predict anti-Xa value using linear correlation and decision tree methods. Data were obtained from 128 patients supported with ECMO. The HAP value was more highly correlated with anti-Xa level than heparin dose, AT level, and ACT. This correlation was highest in the neonatal population (r = .7). The variable importance metrics from the regression tree and random forest models both identified the HAP value as the most influential predictor variable for anti-Xa value. The HAP value is more highly correlated with the anti-Xa level than heparin dose, AT level, or ACT. Further research is needed to evaluate the effectiveness of the HAP value as a measurement of anticoagulation for children on ECMO.

School Closures in the United States and Severe Respiratory Illnesses in Children: A Normalized Nationwide Sample.

OBJECTIVES: To determine the association between nationwide school closures and prevalence of common admission diagnoses in the pediatric critical care unit. DESIGN: Retrospective cohort study. SETTING: National database evaluation using the Virtual Pediatric Systems LLC database. PATIENTS: All patients admitted to the PICU in 81 contributing hospitals in the United States. MEASUREMENTS AND MAIN RESULTS: Diagnosis categories were determined for all 110,418 patients admitted during the 20-week study period in each year (2018, 2019, and 2020). Admission data were normalized relative to statewide school closure dates for each patient using geographic data. The "before school closure" epoch was defined as 8 weeks prior to school closure, and the "after school closure" epoch was defined as 12 weeks following school closure. For each diagnosis, admission ratios for each study day were calculated by dividing 2020 admissions by 2018-2019 admissions. The 10 most common diagnosis categories were examined. Significant changes in admission ratios were identified for bronchiolitis, pneumonia, and asthma. These changes occurred at 2, 8, and 35 days following school closure, respectively. PICU admissions decreased by 82% for bronchiolitis, 76% for pneumonia, and 76% for asthma. Nonrespiratory diseases such as diabetic ketoacidosis, status epilepticus, traumatic injury, and poisoning/ingestion did not show significant changes following school closure. CONCLUSIONS: School closures are associated with a dramatic reduction in the prevalence of severe respiratory disease requiring PICU admission. School closure may be an effective tool to mitigate future pandemics but should be balanced with potential academic, economic, mental health, and social consequences.

The association of postoperative dexmedetomidine with pain, opiate utilization, and hospital length of stay in children post-Chiari malformation decompression.

OBJECTIVE: The aim of this study was to determine the association of postoperative dexmedetomidine with markers of pain in children undergoing Chiari malformation decompression. The authors hypothesized that patients receiving dexmedetomidine postoperatively would have decreased cumulative opiate use. They further hypothesized that there would be no difference in median pain scores, outcomes, or medication adverse events. METHODS: An IRB-approved retrospective cohort study of patients undergoing Chiari malformation decompression from December 1, 2015, to December 31, 2018, was performed. Patients aged 0-21 years who underwent intradural Chiari malformation decompression at a single institution were included. Data for those who used dexmedetomidine postoperatively were compared with those who did not use dexmedetomidine. The primary outcome was cumulative opiate use throughout hospitalization. Secondary outcomes included pain scores, ancillary medication use, adverse events, hospital and ICU length of stay, readmission rates, and hospital cost. RESULTS: The authors reviewed the records of 172 patients who underwent Chiari malformation decompression. Of those patients, 86 received dexmedetomidine postoperatively and 86 did not. Demographics were not different between the groups. Patients who received dexmedetomidine postoperatively received more doses of dexamethasone and were also more frequently exposed to dexmedetomidine intraoperatively (p = 0.028). Patients who received dexmedetomidine postoperatively used fewer morphine equivalents during their admission (1.02 mg/kg vs 1.43 mg/kg, p = 0.003). The patients who received dexmedetomidine postoperatively also had lower median pain scores on postoperative day 0 (0 vs 2, p < 0.001), lower median pain scores throughout the entire admission (1 vs 2, p < 0.001), and lower maximum pain scores recorded (6 vs 8, p = 0.005). Adjusting for steroid dose number and intraoperative dexmedetomidine exposure, postoperative dexmedetomidine remained associated with lower opiate dosing, lower pain scores on postoperative day 0, lower scores throughout hospital stay, and lower maximum pain scores. Patients who received dexmedetomidine had shorter hospital lengths of stay by 19 hours (p < 0.001). There were no statistically significant differences in medication adverse events or hospital costs between the two groups. CONCLUSIONS: Postoperative dexmedetomidine use was associated with decreased opiate use, lower pain scores, and shorter hospital length of stay in this cohort. Dexmedetomidine may be considered as a safe adjuvant medication that may have opiate-sparing effects for this patient population.

Reducing Unnecessary Nitric Oxide Use: A Hospital-Wide, Respiratory Therapist-Driven Quality Improvement Project.

BACKGROUND: We sought to evaluate the institutional use of inhaled nitric oxide (INO) and to create a pathway to reduce waste using the Institute for Healthcare Improvement's model for improvement. Our aim was to reduce the use of INO by 20% within 8 months. METHODS: This was a prospective, respiratory therapist-driven, quality improvement project. We implemented a hospital-wide INO utilization protocol that was developed by neonatology, pediatric critical care, cardiac critical care, and respiratory therapy. INO use and respiratory therapist input for protocol failures were derived from the electronic medical record and were used to generate improvement opportunities. Monthly total hospital use of INO (in hours) was used as the primary outcome measure. Median hourly use per subject (evaluated in groups of 7 subjects) was used as a secondary outcome measure. New sildenafil dosing was tabulated for pre- and post-INO weaning protocol intervention as a balancing measure. Subjects included all patients in the hospital who were given INO therapy during the specified timeframe. RESULTS: Hospital-wide total hours were reduced from 1,515 h/month to 930 h/month. This hospital-wide reduction of 39% equates to a cost-avoidance of approximately $912,000 per year based on 2018 costs of INO of $130 per hour. Median hours of INO per subject decreased from 88 h to 50 h. Sildenafil was started in 18 of 98 subjects (18%) in the pre-intervention period and in 12 of 109 subjects (11%) in the post-intervention period (P = .27). CONCLUSIONS: A hospital-wide, multi-professional initiative led to a reduction in unnecessary INO use, resulting in decreased subject exposure and associated cost avoidance.