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OBJECTIVES To define the clinical characteristics of hospitalized children with moderate traumatic brain injury and identify factors associated with deterioration to severe traumatic brain injury. DESIGN Retrospective cohort study. SETTING Tertiary Children's Hospital with Level 1 Trauma Center designation. PATIENTS Inpatient children less than 18 years old with an International Classification of Diseases code for traumatic brain injury and an admission Glasgow Coma Scale score of 9-13. MEASUREMENTS AND RESULTS We queried the National Trauma Data Bank for our institutional data and identified 177 patients with moderate traumatic brain injury from 2010 to 2017. These patients were then linked to the electronic health record to obtain baseline and injury characteristics, laboratory data, serial Glasgow Coma Scale scores, CT findings, and neurocritical care interventions. Clinical deterioration was defined as greater than or equal to 2 recorded values of Glasgow Coma Scale scores less than or equal to 8 during the first 48 hours of hospitalization. Thirty-seven patients experienced deterioration. Children who deteriorated were more likely to require intubation (73% vs 26%), have generalized edema, subdural hematoma, or contusion on CT scan (30% vs 8%, 57% vs 37%, 35% vs 16%, respectively), receive hypertonic saline (38% vs 7%), undergo intracranial pressure monitoring (24% vs 0%), were more likely to be transferred to inpatient rehabilitation following hospital discharge (32% vs 5%), and incur greater costs of care ($25,568 vs $10,724) (all p < 0.01). There was no mortality in this cohort. Multivariable regression demonstrated that a higher Injury Severity Score, a higher initial international normalized ratio, and a lower admission Glasgow Coma Scale score were associated with deterioration to severe traumatic brain injury in the first 48 hours (p < 0.05 for all). CONCLUSIONS A substantial subset of children (21%) presenting with moderate traumatic brain injury at a Level 1 pediatric trauma center experienced deterioration in the first 48 hours, requiring additional resource utilization associated with increased cost of care. Deterioration was independently associated with an increased international normalized ratio higher Injury Severity Score, and a lower admission Glasgow Coma Scale score.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Objective: The purpose of this report is to provide insight from pediatric stakeholders with a shared desire to facilitate a revision of the current United States regulatory pathways for the development of pediatric healthcare devices. Methods: On August 5, 2020, a group of innovators, engineers, professors and clinicians met to discuss challenges and opportunities for the development of new medical devices for pediatric health and the importance of creating a regulatory environment that encourages and accelerates the research and development of such devices. On January 6, 2021, this group joined regulatory experts at a follow-up meeting. Results: One of the primary issues identified was the need to present decision-makers with opportunities that change the return-on-investment balance between adult and pediatric devices to promote investment in pediatric devices. Discussion/Conclusion: Several proposed strategies were discussed, and these strategies can be divided into two broad categories: 1. Removal of real and perceived barriers to pediatric device innovation; 2. Increasing incentives for pediatric device innovation.

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.

Background and Aims Intracranial compliance refers to the relationship between a change in intracranial volume and the resultant change in intracranial pressure (ICP). Measurement of compliance is useful in managing cardiovascular and respiratory failure; however, there are no contemporary means to assess intracranial compliance. Knowledge of intracranial compliance could complement ICP and cerebral perfusion pressure (CPP) monitoring in patients with severe traumatic brain injury (TBI) and may enable a proactive approach to ICP management. In this proof-of-concept study, we aimed to capitalize on the physiologic principles of intracranial compliance and vascular reactivity to CO2, and standard-of-care neurocritical care monitoring, to develop a method to assess dynamic intracranial compliance. Methods Continuous ICP and end-tidal CO2 (ETCO2) data from children with severe TBI were collected after obtaining informed consent in this Institutional Review Board-approved study. An intracranial pressure-PCO2 Compliance Index (PCI) was derived by calculating the moment-to-moment correlation between change in ICP and change in ETCO2. As such, “good” compliance may be reflected by a lack of correlation between time-synched changes in ICP in response to changes in ETCO2, and “poor” compliance may be reflected by a positive correlation between changes in ICP in response to changes in ETCO2. Results A total of 978 h of ICP and ETCO2 data were collected and analyzed from eight patients with severe TBI. Demographic and clinical characteristics included patient age 7.1 ± 5.8 years (mean ± SD); 6/8 male; initial Glasgow Coma Scale score 3 [3–7] (median [IQR]); 6/8 had decompressive surgery; 7.1 ± 1.4 ICP monitor days; ICU length of stay (LOS) 16.1 ± 6.8 days; hospital LOS 25.9 ± 8.4 days; and survival 100%. The mean PCI for all patients throughout the monitoring period was 0.18 ± 0.04, where mean ICP was 13.7 ± 2.1 mmHg. In this cohort, PCI was observed to be consistently above 0.18 by 12 h after monitor placement. Percent time spent with PCI thresholds > 0.1, 0.2, and 0.3 were 62% [24], 38% [14], and 23% [15], respectively. The percentage of time spent with an ICP threshold > 20 mmHg was 5.1% [14.6]. Conclusions Indirect assessment of dynamic intracranial compliance in TBI patients using standard-of-care monitoring appears feasible and suggests a prolonged period of derangement out to 5 days post-injury. Further study is ongoing to determine if the PCI—a new physiologic index, complements utility of ICP and/or CPP in guiding management of patients with severe TBI. Electronic supplementary material The online version of this article (10.1007/s12028-020-01004-3) contains supplementary material, which is available to authorized users.

AIM: The mathematical method used to calculate chest compression (CC) rate during cardiopulmonary resuscitation varies in the literature and across device manufacturers. The objective of this study was to determine the variability in calculated CC rates by applying four published methods to the same dataset. METHODS: This study was a secondary investigation of the first 200 pediatric cardiac arrest events with invasive arterial line waveform data in the ICU-RESUScitation Project (NCT02837497). Instantaneous CC rates were calculated during periods of uninterrupted CCs. The defined minimum interruption length affects rate calculation (e.g., if an interruption is defined as a break in CCs ≥ 2 seconds, the lowest possible calculated rate is 30 CCs/min). Average rates were calculated by four methods: 1) rate with an interruption defined as ≥ 1 second; 2) interruption ≥ 2 seconds; 3) interruption ≥ 3 seconds; 4) method #3 excluding top and bottom quartiles of calculated rates. American Heart Association Guideline-compliant rate was defined as 100–120 CCs/min. A clinically important change was defined as ± 5 CCs/min. The percentage of events and epochs (30 second periods) that changed Guideline-compliant status was calculated. RESULTS: Across calculation methods, mean CC rates (118.7 – 119.5/min) were similar. Comparing all methods, 14 events (7%) and 114 epochs (6%) changed Guideline-compliant status. CONCLUSION: Using four published methods for calculating CC rate, average rates were similar, but 7% of events changed Guideline-compliant status. These data suggest that a uniform calculation method (interruption ≥ 1 second) should be adopted to decrease variability in resuscitation science.

OBJECTIVE: To identify whether a high Pao(2) (hyperoxemia) at the time of presentation to the PICU is associated with in-hospital mortality. DESIGN: Single-center observational study. SETTING: Quaternary-care PICU. PATIENTS: Encounters admitted between January 1, 2009, and December 31, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Encounters with a measured Pao(2) were included. To account for severity of illness upon presentation, we calculated a modified Pediatric Risk of Mortality IV score excluding Pao(2) for each encounter, calibrated for institutional data. Logistic regression was used to determine whether hyperoxemia (Pao(2) ≥ 300 torr [39.99 kPa]) in the 12 hours surrounding PICU admission was associated with in-hospital mortality. We reperformed our analysis using a cutoff for hyperoxemia obtained by comparisons of observed versus predicted mortality when encounters were classified by highest Pao(2) in 50 torr (6.67 kPa) bins. Results are reported as adjusted odds ratios with 95% CIs. Of 23,719 encounters, 4,093 had a Pao(2) recorded in the period −6 to +6 hours after admission. Two hundred seventy-four of 4,093 (6.7%) had in-hospital mortality. The prevalence of hyperoxemia increased with rising modified Pediatric Risk of Mortality IV and was not associated with mortality in multivariable models (adjusted odds ratio, 1.38; 95% CI, 0.98–1.93). When using a higher cutoff of hyperoxemia derived from comparison of observed versus predicted rates of mortality of greater than or equal to 550 torr (73.32 kPa), hyperoxemia was associated with mortality (adjusted odds ratio, 2.78; 95% CI, 2.54–3.05). CONCLUSIONS: A conventional threshold for hyperoxemia at presentation to the PICU was not associated with in-hospital mortality in a model using a calibrated acuity score. Extreme states of hyperoxemia (≥ 73.32 kPa) were significantly associated with in-hospital mortality. Prospective research is required to identify if hyperoxemia before and/or after PICU admission contributes to poor outcomes.

Background. In 2009, the Pediatric Emergency Care Applied Research Network (PECARN) published evidence-based guidelines for the risk-stratification of children at risk of clinically important traumatic brain injury (ciTBI). Machine learning approaches may allow for risk-stratification of patients with higher diagnostic accuracy, allowing for decreased utilization of computerized tomography (CT) in low-risk patients. Methods. We performed a secondary analysis of a public use dataset from a multicenter prospective study performed by PECARN between the years 2004-2006 from 25 North American emergency departments who presented within 24 hours of trauma, retaining only those patients with Glasgow Coma Scale scores of 14-15. Patients who were missing outcome data or who were paralyzed, intubated or sedated at the …

Key Points Question What factors are associated with increasing hospital costs for patients with bronchiolitis? Findings In this cross-sectional study of 385 883 bronchiolitis hospitalizations, children hospitalized in later years received more costly and intensive care without objective evidence of increasing severity of illness. Substantial changes in coding practices were observed, with an increasing proportion of patients diagnosed with respiratory failure between 2010 and 2019. Meaning This study suggests that future research on trends in bronchiolitis should account for changes in the patterns of diagnostic coding., Importance Increasing hospital costs for bronchiolitis have been associated with increasing patient complexity and mechanical ventilation. However, the associations of illness severity and diagnostic coding practices with bronchiolitis hospitalization costs have not been examined. Objective To investigate the association of patient complexity, illness severity, and diagnostic coding practices with bronchiolitis hospitalization costs. Design, Setting, and Participants This retrospective cross-sectional study included 385 883 infants aged 24 months or younger who were hospitalized with bronchiolitis at 39 hospitals in the Pediatric Health Information System database from January 1, 2010, to December 31, 2019. Exposure Hospitalization for bronchiolitis. Main Outcomes and Measures Inflation-adjusted standardized unit cost (expressed in dollar units) per hospitalization over time. A nested subgroup analysis was performed to further examine factors associated with changes in cost. Results A total of 385 883 bronchiolitis hospitalizations were studied; the patients had a mean (SD) age of 7.5 (6.4) months and included 227 309 of 385 883 boys (58.9%) and 253 870 of 385 883 publicly insured patients (65.8%). Among patients hospitalized with bronchiolitis, the median standardized unit cost per hospitalization increased significantly during the study period (from $5636 [95% CI, $5558-$5714] in 2010 to $6973 [95% CI, $6915-$7030] in 2019; P, This cross-sectional study of more than 385 000 children hospitalized with bronchiolitis investigates the association of the complexity of a patient’s condition, illness severity, and diagnostic coding practices with bronchiolitis hospitalization costs.

BACKGROUND: Acute Kidney Disease (AKD) is defined as impaired kidney function present for < 90 days with or without an acute kidney injury (AKI) event. Adults with AKD have an increased risk for progression to chronic kidney disease (CKD) and mortality. There are no data on the epidemiology of AKD in children after transplant. The aim of this study was to evaluate the incidence and risk factors for AKI, AKD, and CKD in children after transplantation. METHODS: This is a retrospective cohort study of all children undergoing non-kidney solid organ transplant between 2011–2019 at UPMC Children’s Hospital of Pittsburgh. AKI and AKD were defined using the Kidney Disease Improving Global Outcomes criteria. Patients with a new estimated glomerular filtration rate < 60 ml/min/1.73m(2) persisting for > 3 months met criteria for new CKD. Variables associated with AKI, AKD, and CKD were analyzed. RESULTS: Among 338 patients 37.9% met criteria for severe AKI, 13% for AKD, and 8% for a new diagnosis of CKD. Stage 3 AKI was independently associated with AKD (OR: 5.35; 95% CI: 2.23–12.86). Severe AKI was not associated with new onset CKD whereas AKD was associated with new onset CKD (OR: 29.74; CI: 11.22–78.82). CONCLUSION: AKD may be superior to AKI in predicting risk of CKD in children after non-kidney solid organ transplantation.

IntroductionRapid, continuous implementation of credible scientific findings and regulatory approvals is often slow in large, diverse health systems. The COVID-19 pandemic created a new threat to this common “slow to learn and adapt” model in healthcare. We describe how UPMC committed to a rapid learning health system (LHS) model to respond to the COVID-19 pandemic.MethodsAn observational cohort study was conducted among 11,429 hospitalized patients from 22 hospitals (PA, NY) with a primary diagnosis of COVID-19 infection (March 19, 2020 – June 6, 2021). Sociodemographic and clinical data were captured from UPMC electronic medical record (EMR) systems. Patients were grouped into four time-defined patient “waves” based on nadir of daily hospital admissions, with wave 3 (September 20, 2020 – March 10, 2021) split at its zenith due to high volume with steep acceleration and deceleration. Outcomes included changes in clinical practice (e.g., use of corticosteroids, antivirals, and other therapies) in relation to timing of internal system analyses, scientific publications, and regulatory approvals, along with 30-day rate of mortality over time.ResultsMean (SD) daily number of hospital admissions was 26 (28) with a maximum 7-day moving average of 107 patients. System-wide implementation of the use of dexamethasone, remdesivir, and tocilizumab occurred within days of release of corresponding seminal publications and regulatory actions. After adjustment for differences in patient clinical profiles over time, each month of hospital admission was associated with an estimated 5% lower odds of 30-day mortality (adjusted OR = 0.95, 95% confidence interval: 0.92 – 0.97, p < .001).ConclusionsIn our large LHS, near real-time changes in clinical management of COVID-19 patients happened promptly as scientific publications and regulatory approvals occurred throughout the pandemic. Alongside these changes, patients with COVID-19 experienced lower adjusted 30-day mortality following hospital admission over time.

Severe sepsis in immunocompromised children is associated with increased mortality. This paper describes the epidemiology landscape, clinical acuity, and outcomes for severe sepsis in pediatric intestinal (ITx) and multi-visceral (MVTx) transplant recipients requiring admission to the pediatric intensive care unit (PICU). Severe sepsis episodes were retrospectively reviewed in 51 ITx and MVTx patients receiving organs between 2009 and 2015. Twenty-nine (56.8%) patients had at least one sepsis episode (total of 63 episodes) through December 2016. Bacterial etiologies accounted for 66.7% of all episodes (n = 42), occurring a median of 122.5 days following transplant (IQR 59-211.8 days). Multidrug-resistant organisms (MDROs) accounted for 73.8% of bacterial infections; extended spectrum beta-lactamase producers, vancomycin-resistant enterococcus, and highly-resistant Pseudomonas aeruginosa were the most commonly identified. Increased mechanical ventilation and vasoactive requirements were noted in MDRO episodes (OR 3.03, 95% CI 1.09-8.46 and OR 3.07, 95% CI 1.09-8.61, respectively; p

OBJECTIVES: To determine the changes in ICU admissions, ventilatory support, length of stay, and cost for patients with bronchiolitis in the United States. METHODS: Retrospective cross-sectional study of the Pediatric Health Information Systems database. All patients age RESULTS: Of 203 859 admissions for bronchiolitis, 39 442 (19.3%) were admitted to an ICU, 6751 (3.3%) received IMV, and 9983 (4.9%) received NIV. ICU admissions for bronchiolitis doubled from 11.7% in 2010 to 24.5% in 2019 (P < .001 for trend), whereas ICU admissions for all children in Pediatric Health Information Systems CONCLUSIONS: The proportions of children with bronchiolitis admitted to an ICU and receiving NIV have substantially increased, whereas the proportion receiving IMV is unchanged over the past decade. Further study is needed to better understand the factors underlying these temporal patterns.

Multiple studies among adults have suggested a non-linear relationship between arterial partial pressure of oxygen (PaO2) and clinical outcomes. Meta-analyses in this population suggest that high levels of supplemental oxygen resulting in hyperoxia are associated with mortality. This mini-review focuses on the non-neonatal pediatric literature examining the relationship between PaO2 and mortality. While only one pilot pediatric randomized-controlled trials exists, over the past decade, there have been at least eleven observational studies examining the relationship between PaO2 values and mortality in critically ill children. These analyses of mixed-case pediatric ICU populations have generally reported a parabolic (“u-shaped”) relationship between PaO2 and mortality, similar to that seen in the adult literature. However, the estimates of the point at which hyperoxemia becomes deleterious have varied widely (300–550 mmHg). Where attempted, this effect has been robust to analyses restricted to the first PaO2 value obtained, those obtained within 24 h of admission, anytime during admission, and the number of hyperoxemic blood gases over time. These findings have also been noted when using various methods of risk-adjustment (accounting for severity of illness scores or complex chronic conditions). Similar relationships were found in the majority of studies restricted to patients undergoing care after cardiac arrest. Taken together, the majority of the literature suggests that there is a robust parabolic relationship between PaO2 and risk-adjusted pediatric ICU mortality, but that the exact threshold at which hyperoxemia becomes deleterious is unclear, and likely beyond the typical target value for most clinical indications. Findings suggest that clinicians should remain judicious and thoughtful in the use of supplemental oxygen therapy in critically ill children.

The objective of this study was to characterize the population pharmacokinetics of fentanyl and identify factors that contribute to exposure variability in critically ill pediatric patients. We conducted a single-center, retrospective cohort study using electronic record data and remnant blood samples in the setting of a mixed medical/surgical intensive care unit (ICU) at a quaternary children’s hospital. Children with a predicted ICU length of stay of at least 3 days and presence of an indwelling central venous or arterial line were included. Serum fentanyl measurements were performed for 278 unique remnant samples from 66 patients. Both one- and two-compartment models were evaluated to describe fentanyl disposition. Covariates were introduced into the model in a forward/backward, stepwise approach and included age, sex, race, weight, cytochrome P450 (CYP) 3A5 genotype, and the presence of CYP3A4 or CYP3A5 inducers or inhibitors. Simulations were performed using the successful model to depict the influence of inducers on fentanyl concentrations. A two-compartment base model best described the data. There was good agreement between observed and predicted concentrations in the final model. The typical fentanyl clearance for 70 kg (reference weight) and 20.1 kg (median weight) patients were 34.6 and 13.6 L/h, respectively. The magnitude of the unexplained random inter-individual variability was high for both clearance (60.7%) and apparent volume of the central compartment (V1) (107.2%). Coadministration of the known CYP3A4/5 inducers fosphenytoin and/or phenobarbital was associated with significantly increased fentanyl clearance. Simulations demonstrate that the effect of inducer administration was most pronounced following discontinuation of a fentanyl infusion. In this study we show the feasibility and utility of using electronic record data and remnant blood samples to successfully construct population pharmacokinetic models for a heterogeneous cohort of critically ill children. A clinically relevant effect of concomitant CYP3A4/5 inducers was identified. Scaling this population pharmacokinetic approach is necessary to craft precision approaches to fentanyl administration for critically ill children.

Objective: Legitimate opioid prescriptions have been identified as a risk factor for opioid misuse in pediatric patients. In 2014, Pennsylvania legislation expanded a prescription drug monitoring program (PDMP) to curb inappropriate controlled substance prescriptions. The authors’ objective was to describe recent opioid prescribing trends at a large, pediatric health system situated in a region with one of the highest opioid-related death rates in the United States and examine the impact of the PDMP on prescribing trends. Design: Quasi-experimental assessment of trends of opioid e-prescriptions, from 2012 to 2017. Multivariable Poisson segmented regression examined the effect of the PDMP. Period prevalence comparison of opioid e-prescriptions across the care continuum in 2016. Results: There were 62,661 opioid e-prescriptions identified during the study period. Combination opioid/non-opioid prescriptions decreased, while oxycodone prescriptions increased. Seasonal variation was evident. Of 110,884 inpatient encounters, multivariable regression demonstrated lower odds of an opioid being prescribed at discharge per month of the study period (p < 0.001) and a significant interaction between passage of the PDMP legislation and time (p = 0.03). Black patients had lower odds of receiving an opioid at discharge compared to white patients. Inpatients had significantly greater odds of receiving an opioid compared to emergency department (Prevalence Odds Ratio 7.1 [95% confidence interval: 6.9-7.3]; p < 0.001) and outpatient (398.9 [355.5-447.5]; p < 0.001) encounters. Conclusion: In a large pediatric health system, oxycodone has emerged as the most commonly prescribed opioid in recent years. Early evidence indicates that a state-run drug monitoring program is associated with reduced opioid prescribing. Additional study is necessary to examine the relationship between opioid prescriptions and race.

Objective To identify trends in pediatric emergency department (ED) utilization following the COVID-19 pandemic. Methods We performed a cross-sectional study from 37 geographically diverse US children's hospitals. We included ED encounters between January 1, 2010 and December 31, 2020, transformed into time-series data. We constructed ensemble forecasting models of the most common presenting diagnoses and the most common diagnoses leading to admission, using data from 2010 through 2019. We then compared the most common presenting diagnoses and the most common diagnoses leading to admission in 2020 to the forecasts. Results 29,787,815 encounters were included, of which 1,913,085 (6.4%) occurred during 2020. ED encounters during 2020 were lower compared to prior years, with a 65.1% decrease in April relative to 2010–2019. In forecasting models, encounters for depression and diabetic ketoacidosis remained within the 95% confidence interval [CI]; fever, bronchiolitis, hyperbilirubinemia, skin/subcutaneous infections and seizures occurred within the 80–95% CI during the portions of 2020, and all other diagnoses (abdominal pain, otitis media, asthma, pneumonia, trauma, upper respiratory tract infections, and urinary tract infections) occurred below the predicted 95% CI. Conclusion Pediatric ED utilization has remained low following the COVID-19 pandemic, and below forecasted utilization for most diagnoses. Nearly all conditions demonstrated substantial declines below forecasted rates from the prior decade and which persisted through the end of the year. Some declines in non-communicable diseases may represent unmet healthcare needs among children. Further study is warranted to understand the impact of policies aimed at curbing pandemic disease on children.

Importance In early 2020, the United States declared a public health emergency in response to coronavirus disease 2019 (COVID-19) and implemented a variety of social distancing measures. The association between the COVID-19 pandemic and the number of pediatric admissions is unclear. Objective To determine the changes in patterns of pediatric admissions in 2020 compared with the prior decade. Design, Setting, and Participants This cross-sectional study included 49 US hospitals contributing to the Pediatric Health Information Systems database. Inpatient admissions were transformed into time-series data, and ensemble forecasting models were generated to analyze admissions across a range of diagnoses in 2020 compared with previous years. The setting was inpatient admissions. All patients discharged between January 1, 2010, and June 30, 2020, from an inpatient hospital encounter were included. Main Outcomes and Measures Number of hospital admissions by primary diagnosis for each encounter. Results Of 5 424 688 inpatient encounters among 3 372 839 patients (median [interquartile range] age, 5.1 [0.7-13.3] years; 2 823 748 [52.1%] boys; 3 171 224 [58.5%] White individuals) at 49 hospitals, 213 571 (3.9%) were between January 1, 2020, and June 30, 2020. There was a decrease in the number of admissions beginning in March 2020 compared with the period from 2010 to 2019. At the nadir, admissions in April 2020 were reduced 45.4% compared with prior years (23 798 in April 2020 compared with a median [interquartile range] of 43 550 [42 110-43 946] in April 2010-2019). Inflation-adjusted hospital charges decreased 27.7% in the second quarter of 2020 compared with prior years ($4 327 580 511 in 2020 compared with a median [interquartile range] of $5 983 142 102 [$5 762 690 022-$6 324 978 456] in 2010-2019). Seasonal patterns were evident between 2010 and 2019 for a variety of common pediatric conditions, including asthma, atrial septal defects, bronchiolitis, diabetic ketoacidosis, Kawasaki syndrome, mental health admissions, and trauma. Ensemble models were able to discern seasonal patterns in admission diagnoses and accurately predicted admission rates from July 2019 until December 2019 but not from January 2020 to June 2020. All diagnoses except for birth decreased below the model 95% CIs between January 2020 and June 2020. Conclusions and Relevance In this cross-sectional study, pediatric admissions to US hospitals decreased in 2020 across an array of pediatric conditions. Although some conditions may have decreased in incidence, others may represent unmet needs in pediatric care during the COVID-19 pandemic.

This cross-sectional study assesses potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence and estimating the prevalence of potentially actionable prescribing decisions., Key Points Question What is the opportunity for genotype-guided prescribing among pediatric patients in the US? Findings In this serial cross-sectional study of annual prescribing data at 16 health systems representing approximately 2.9 million pediatric patients per year from 2011 to 2017, the annual prevalence of exposure to at least 1 Clinical Pharmacogenetics Implementation Consortium level A drug ranged from 7987 to 10 629 per 100 000 pediatric patients, with increasing prevalence before reaching a plateau in 2014. The medications with the highest potential for actionability were analgesics (oxycodone, codeine, and tramadol), the antiemetic ondansetron, and antidepressants (citalopram, escitalopram, and amitriptyline). Meaning These findings suggest that ample opportunity exists for genotype-guided prescribing among pediatric patients in the US, especially for drugs metabolized by CYP2D6 or CYP2C19., Importance Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. Objective To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. Design, Setting, and Participants This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children’s hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Exposures Prescription of 38 level A medications based on electronic health records. Main Outcomes and Measures Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Results Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. Conclusions and Relevance These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.

A relationship between Pao2 and mortality has previously been observed in single-center studies. We performed a retrospective cohort study of the Pediatric Health Information System plus database including patients less than or equal to 21 years old admitted to a medical or cardiac ICU who received invasive ventilation within 72 hours of admission. We trained and validated a multivariable logistic regression mortality prediction model with very good discrimination (C-statistic, 0.86; 95% CI, 0.79-0.92; area under the precision-recall curve, 0.39) and acceptable calibration (standardized mortality ratio, 0.96; 95% CI, 0.75-1.23; calibration belt p = 0.07). Maximum Pao2 measurements demonstrated a parabolic ("U-shaped") relationship with PICU mortality (Box-Tidwell p < 0.01). Maximum Pao2 was a statistically significant predictor of risk-adjusted mortality (standardized odds ratio, 1.27; 95% CI, 1.23-1.32; p < 0.001). This analysis is the first multicenter pediatric study to identify a relationship between the extremes in Pao2 values and PICU mortality. Clinicians should remain judicious in the use of oxygen when caring for children.

BACKGROUND:Recent decision rules for the management of febrile infants support the identification of infants at higher risk of serious bacterial infections (SBIs) without the performance of routine lumbar puncture. We derive and validate a model to identify febrile infants ≤60 days of age at low risk for SBIs using supervised machine learning approaches.METHODS:We conducted a secondary analysis of a multicenter prospective study performed between December 2008 and May 2013 of febrile infants. Our outcome was SBI, (culture-positive urinary tract infection, bacteremia, and/or bacterial meningitis). We developed and validated 4 supervised learning models: logistic regression, random forest, support vector machine, and a single-hidden layer neural network.RESULTS:A total of 1470 patients were included (1014 >28 days old). One hundred thirty-eight (9.3%) had SBIs (122 urinary tract infections, 20 bacteremia, and 8 meningitis; 11 with concurrent SBIs). Using 4 features (urinalysis, white blood cell count, absolute neutrophil count, and procalcitonin), we demonstrated with the random forest model the highest specificity (74.9, 95% confidence interval: 71.5%–78.2%) with a sensitivity of 98.6% (95% confidence interval: 92.2%–100.0%) in the validation cohort. One patient with bacteremia was misclassified. Among 1240 patients who received a lumbar puncture, this model could have prevented 849 (68.5%) such procedures.CONCLUSIONS:We derived and internally validated a supervised learning model for the risk-stratification of febrile infants. Although computationally complex, lacking parameter cutoffs, and in need of external validation, this strategy may allow for reductions in unnecessary procedures, hospitalizations, and antibiotics while maintaining excellent sensitivity.

Supplemental Digital Content is available in the text., Introduction: To compare encounter estimates and demographics of pediatric patients (

PURPOSE: To identify if triage hypothermia (

OBJECTIVES Neurologic complications occur in up to 40% of adult abdominal solid organ transplant recipients and are associated with increased mortality. Comparable pediatric data are sparse. This study describes the occurrence of neurologic and behavioral complications (neurobehavioral complications) in pediatric abdominal solid organ transplant recipients. We examine the association of these complications with length of stay, mortality, and tacrolimus levels. DESIGN The electronic health record was interrogated for inpatient readmissions of pediatric abdominal solid organ transplant recipients from 2009 to 2017. A computable composite definition of neurobehavioral complication, defined using structured electronic data for neurologic and/or behavioral phenotypes, was created. SETTING Quaternary children's hospital with an active transplant program. PATIENTS Pediatric abdominal solid organ transplant recipients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Computable phenotypes demonstrated a specificity 98.7% and sensitivity of 63.0% for identifying neurobehavioral complications. There were 1,542 readmissions among 318 patients, with 65 (20.4%) having at least one admission with a neurobehavioral complication (total 109 admissions). Median time from transplant to admission with neurobehavioral complication was 1.2 years (interquartile range, 0.52-2.28 yr). Compared to encounters without an identified neurobehavioral complication, encounters with a neurobehavioral complication were more likely to experience ICU admission (odds ratio, 3.9; 2.41-6.64; p < 0.001), have longer ICU length of stay (median 10.3 vs 2.2 d; p < 0.001) and hospital length of stay (8.9 vs 4.3 d; p < 0.001), and demonstrate higher maximum tacrolimus level (12.3 vs 9.8 ng/mL; p = 0.001). Patients with a neurobehavioral complication admission were more likely to die (odds ratio, 5.04; 1.49-17.09; p = 0.009). In a multivariable analysis, type of transplant, ICU admission, and tacrolimus levels were independently associated with the presence of a neurobehavioral complication. CONCLUSIONS Common electronic health record variables can be used to accurately identify neurobehavioral complications in the pediatric abdominal solid organ transplant population. Late neurobehavioral complications are associated with increased hospital resource utilization, mortality, and tacrolimus exposure. Additional studies are required to delineate the relationship between maximum tacrolimus level and neurobehavioral complications to guide therapeutic drug monitoring and dosing.

Rationale: While recent research has shown an overall beneficial impact of surrounding green space on general health, there are contradictory and non-conclusive results regarding the relation between residential green space and the development of respiratory and allergic diseases. Aims: This study aims to evaluate the associations of residential land cover (green, grey, and agricultural space) with childhood allergic and respiratory diseases. A secondary analysis was also conducted to investigate the effects of proximity to different types of forests (deciduous, coniferous, and mixed) and health outcomes. Methods: Data from over eight-thousand children, aged 3-14 years, were obtained from nine European population-based studies participating in the HEALS consortium (“Health and Environment-wide Associations based on Large population Surveys”, www.healseu.eu). Information on lifetime occurrence of wheezing, asthma, rhinitis and eczema, family lifestyle and socio-demographic characteristics were collected through parental-administered questionnaires. Land-cover within a 500 m buffer from children’s home addresses was computed using data from the Coordination of Information on the Environment (CORINE) inventory. Logistic regression models were fitted to estimate the associations of the health outcomes with CORINE land-cover features within each study, adjusting for sex, age, body mass index, maternal education, parental smoking, and parental history of allergy. The pooled effects across studies were estimated using meta-analyses. Results: The results from the meta-analyses showed that a 10% increase in green space coverage was significantly associated with an increased risk of wheezing (odds ratio [95% confidence interval]: 1.059 [1.008-1.114]), asthma (1.092 [1.011-1.178]) and rhinitis (1.081 [1.008-1.160]), but not eczema (1.009 [0.957-1.064]). The estimates did not depend on gender and age and were confirmed using different buffer radii and after controlling for outdoor residential NO2 and PM10 levels. A lower risk of respiratory symptoms in subjects exposed to residential agricultural space was also observed, but did not reach statistical significance. Grey (urban) space was not associated with any of the considered outcomes. In secondary analyses, living close to forests of conifers, but not other forest types, was significantly associated with greater odds of wheezing (3.95 [2.08-7.49]), asthma (2.54 [1.10-5.82]) and rhinitis (3.39 [1.83-6.30]). Conclusions: Our findings provide further evidence that exposure to green space is associated with increased risk of wheezing, asthma, and allergic rhinitis in childhood. Moreover, our results suggest that living in proximity to coniferous forests may influence the onset of respiratory diseases probably due to the exposures to pollen, moulds and biogenic volatile organic compounds.

After years of mainly expert discussions (not only in the Slovak legal environment), the concept of and legislation on re-export offer a sort of solution provided for in the Act no. 306/2016 Coll. Said act amends the key legislation in this field, namely the Act no. 362/2011 Coll. on Medicinal Products and Medical Devices and on the amendment of certain acts, as amended (hereinafter referred to as the “Act on Medicinal Products”) and the Act no. 363/2011 Coll. on the Scope and Conditions of Payments for Medicinal Products, Medical Devices and Dietetic Foods from Public Health Insurance and on the amendment of certain acts, as amended (hereinafter referred to as the “Act on Payments”). The topic of the paper belongs in the area of medicinal products and pharmaceutical services, it offers, however, significant overlaps in the area of the constitutional, administrative and European law and is aimed at multidisciplinary research into the issue of the reverse export (re-export) of medicinal products. Besides these laws, also the Constitution of the Slovak Republic (“SR”) and the sources of the European Law have to be taken into account in relation to the subject in question. The main aim of legislation in this area of law was restriction on the re-export of selected products and protection of patients from adverse impacts of such business activity. The aim of the paper is the authors’ effort to analyse the issue of the re-export of medicinal products within the context of the adopted Act no. 306/2016 Coll., whose legislative solution is inevitable for the protection of life and health of the population of the Slovak Republic.

OBJECTIVE This study examines temporal trends in treatment-related outcomes surrounding a diabetic ketoacidosis (DKA) performance improvement intervention consisting of mandated intensive care unit admission and implementation of a standardized management pathway, and identifies physical and biochemical characteristics associated with outcomes in this population. METHODS A retrospective cohort of 1225 children with DKA were identified in the electronic health record by international classification of diseases codes and a minimum pH less than 7.3 during hospitalization at a quaternary children's hospital between April, 2009 and May, 2016. Multivariable regression examined predictors and trends of hypoglycemia, central venous line placement, severe hyperchloremia, head computed tomography (CT) utilization, treated cerebral edema and hospital length of stay (LOS). RESULTS The incidence of severe hyperchloremia and head CT utilization decreased during the study period. Among patients with severe DKA (presenting pH

OBJECTIVE: Mechanical ventilation of patients with ARDS should balance lung and diaphragm protective principles, which may be difficult to achieve in routine clinical practice. Through a Phase I clinical trial, we sought to determine whether a computerized decision support (CDS) based protocol (Real-time Effort Driven ventilator management (REDvent)) is feasible to implement, results in improved acceptance for lung and diaphragm protective ventilation and improves clinical outcomes over historical controls. DESIGN: Interventional non-blinded pilot study SETTING: Pediatric Intensive Care Unit PATIENTS: Mechanically ventilated children with ARDS INTERVENTIONS: A CDS tool was tested which prioritized lung protective management of ΔP (PIP-PEEP), PEEP/FiO(2), and ventilator rate. Esophageal manometry was used to maintain patient effort in a physiologic range. Protocol acceptance was reported, and enrolled patients were matched 4:1 with respect to age, initial OI, and percentage of immune compromise to historical control patients for outcome analysis. MEASUREMENTS AND MAIN RESULTS: Thirty-two patients were included. Acceptance of protocol recommendations was over 75%. 128 matched historical controls were used for analysis. Compared to historical controls, patients treated with REDvent received lower ΔP and V(T), and higher PEEP when FiO(2) was > 0.60. REDvent was associated with 6 more ventilator free days, shorter duration until the first spontaneous breathing trial and 3 fewer days on MV amongst survivors (all p = < 0.05) in comparison to historical controls, while maintaining no difference in the rate of reintubation. CONCLUSIONS: A CDS based protocol prioritizing lung protective ventilation balanced with reduction of controlled ventilation to maintain physiologic levels of patient effort can be implemented and may be associated with shorter duration of ventilation.

Pediatric neurocritical care is a growing subspecialty of pediatric intensive care that focuses on the management of acute neurological diseases in children. A brief history of the field of pediatric neurocritical care is provided. Neuromonitoring strategies for children are reviewed. Management of major categories of acute childhood central neurologic diseases are reviewed, including treatment of diseases associated with intracranial hypertension, seizures and status epilepticus, stroke, central nervous system infection and inflammation, and hypoxic-ischemic injury.

Key Points Question Is severe hyperoxemia (arterial oxygen tension ≥300 mm Hg) associated with mortality among critically ill children? Findings In this cohort study of 23 719 intensive care encounters from 2009 to 2018 at a children’s hospital, 6250 patients had at least 1 measured arterial oxygen tension value. After adjusting for covariates, severe hyperoxemia appeared to be independently associated with in-hospital mortality, and a stepwise increase in the adjusted odds of mortality was observed with more episodes of severe hyperoxemia. Meaning Severe hyperoxemia appeared to be associated with mortality in a large, single-center cohort of critically ill children; prospective data are needed to assess causality., Importance A high Pao2, termed hyperoxemia, is postulated to have deleterious health outcomes. To date, the association between hyperoxemia during the ongoing management of critical illness and mortality has been incompletely evaluated in children. Objective To examine whether severe hyperoxemia events are associated with mortality among patients admitted to a pediatric intensive care unit (PICU). Design, Setting, and Participants A retrospective cohort study was conducted over a 10-year period (January 1, 2009, to December 31, 2018); all 23 719 PICU encounters at a quaternary children’s hospital with a documented arterial blood gas measurement were evaluated. Exposures Severe hyperoxemia, defined as Pao2 level greater than or equal to 300 mm Hg (40 kPa). Main Outcomes and Measures The highest Pao2 values during hospitalization were dichotomized according to the definition of severe hyperoxemia and assessed for association with in-hospital mortality using logistic regression models incorporating a calibrated measure of multiple organ dysfunction, extracorporeal life support, and the total number of arterial blood gas measurements obtained during an encounter. Results Of 23 719 PICU encounters during the inclusion period, 6250 patients (13 422 [56.6%] boys; mean [SD] age, 7.5 [6.6] years) had at least 1 measured Pao2 value. Severe hyperoxemia was independently associated with in-hospital mortality (adjusted odds ratio [aOR], 1.78; 95% CI, 1.36-2.33; P, This cohort study examines whether severe hyperoxemia events are associated with mortality among children admitted to a pediatric intensive care unit.

OBJECTIVES: To explore the perceptions of parents of pediatric patients in a pediatric intensive care unit (PICU) regarding real-time open electronic health record (EHR) data displayed in patient rooms. DESIGN: Cross-sectional qualitative interview study SETTING: PICU in a large Midwestern tertiary-care children’s hospital. SUBJECTS: Parents of patients in a PICU (n=33). MEASUREMENTS AND MAIN RESULTS: Qualitative data were collected through in-person semi-structured, individual and small-group interviews. Data were collected from March to July 2016, with approval from the study hospital’s institutional review board. Data were analyzed using inductive thematic analysis. Results included positive effects of accessing real-time open EHR data on family empowerment, situation awareness, potential error detection, understanding of medical data, and facilitating discussions during rounds. Concerns were reported regarding privacy of information as well as potential misinterpretation of displayed data. We identified several ways to improve this collaborative technology to make it more family-centered. CONCLUSIONS: This study suggests that a new health information technology system providing continuous access to open EHR data may be an effective way to empower and engage parents in the PICU, but potential drawbacks were also noted. The results also provide insights into the collaborative use of health information technology in the PICU setting.

Our objective was to determine if C-reactive protein (CRP) and ferritin values alone and in combination are associated with mortality among hospitalized children. All hospitalized patients at our institution with a CRP or ferritin assay in 2015 and 2016 were included. Area under the receiver operating curves (AUROC) were examined, optimal cut-points determined, and patients were stratified into low-, intermediate-, or high-risk groups based on elevation of zero, one, or both biomarkers. A total of 14 928 CRP and 653 ferritin values were obtained, with both obtained for 172 patients. AUROC for maximum CRP value was 0.76 (0.68-0.85) with a cut-point of 7.1 mg/dL for in-hospital mortality and 0.90 (0.83-0.98) for maximum ferritin with a cut-point of 373 ng/mL. Elevation of both ferritin and CRP was associated with the highest inpatient mortality (21.7%) and greatest organ dysfunction, followed by either biomarker alone. Additional prospective study of these biomarkers in combination is warranted.

Membrane transporters regulate the trafficking of endogenous and exogenous molecules across biological barriers and within the neurovascular unit. In traumatic brain injury (TBI), they moderate the dynamic movement of therapeutic drugs and injury mediators among neurons, endothelial cells and glial cells, thereby becoming important determinants of pathogenesis and effective pharmacotherapy after TBI. There are three ways transporters may impact outcomes in TBI. First, transporters likely play a key role in the clearance of injury mediators. Second, genetic association studies suggest transporters may be important in the transition of TBI from acute brain injury to a chronic neurological disease. Third, transporters dynamically control the brain penetration and efflux of many drugs and their distribution within and elimination from the brain, contributing to pharmacoresistance and possibly in some cases pharmacosensitivity. Understanding the nature of drugs or candidate drugs in development with respect to whether they are a transporter substrate or inhibitor is relevant to understand whether they distribute to their target in sufficient concentrations. Emerging data provide evidence of altered expression and function of transporters in humans after TBI. Genetic variability in expression and/or function of key transporters adds an additional dynamic, as shown in recent clinical studies. In this review, evidence supporting the role of individual membrane transporters in TBI are discussed as well as novel strategies for their modulation as possible therapeutic targets. Since data specifically targeting pediatric TBI are sparse, this review relies mainly on experimental studies using adult animals and clinical studies in adult patients.

Introduction Although positive airway pressure (PAP) effectively treats obstructive sleep apnea (OSA), adherence remains suboptimal for many patients. One factor that may influence a patient’s decision to use PAP is a prevailing concern that use of unsanitized PAP equipment may serve as a reservoir for pathogens that cause respiratory tract infections (RTI). Conversely, untreated OSA could also have long-term consequences, including impaired immune function, raising the possibility that PAP therapy could reduce RTI risk. The objective of this study is to compare RTI patterns before and after initiation of PAP in persons with OSA, and examine clinical characteristics that may influence RTI risk. Methods Patients with at least 2 years of continuous primary care at Michigan Medicine preceding and following their OSA diagnosis (N=480) were considered eligible for analyses. Medical charts were reviewed to determine pre- and post-PAP RTI frequency and characteristics during this time frame. Change in RTI frequency was examined with paired T-tests. Results Male:female ratio was 1:1, mean age 56 years, mean apnea hypopnea index was 10, N=85/480 had documented good PAP compliance (defined as ≥ 4h/night, 70% of the nights). Among 480 patients, total RTI frequency pre and post PAP therapy were 170 and 144 respectively (p=0.11). Data collection is ongoing. Conclusion These preliminary data suggest that use of PAP is not associated with increased risk of respiratory infections. Further data regarding clinical characteristics that may influence RTI risk in OSA patients will be informed by ongoing data collection and planned multivariable analyses. Support Dr. Gavidia is supported by a Training in Clinical and Basic Neuroscience T32 (NIH/NINDS T32 NS 007222)