Development and Validation of a Model for Endotracheal Intubation and Mechanical Ventilation Prediction in PICU Patients.

OBJECTIVES: To develop and externally validate an intubation prediction model for children admitted to a PICU using objective and routinely available data from the electronic medical records (EMRs). DESIGN: Retrospective observational cohort study. SETTING: Two PICUs within the same healthcare system: an academic, quaternary care center (36 beds) and a community, tertiary care center (56 beds). PATIENTS: Children younger than 18 years old admitted to a PICU between 2010 and 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data was extracted from the EMR. PICU stays with at least one mechanical ventilation event (≥ 24 hr) occurring within a window of 1-7 days after hospital admission were included in the study. Of 13,208 PICU stays in the derivation PICU cohort, 1,175 (8.90%) had an intubation event. In the validation cohort, there were 1,165 of 17,841 stays (6.53%) with an intubation event. We trained a Categorical Boosting (CatBoost) model using vital signs, laboratory tests, demographic data, medications, organ dysfunction scores, and other patient characteristics to predict the need of intubation and mechanical ventilation using a 24-hour window of data within their hospital stay. We compared the CatBoost model to an extreme gradient boost, random forest, and a logistic regression model. The area under the receiving operating characteristic curve for the derivation cohort and the validation cohort was 0.88 (95% CI, 0.88-0.89) and 0.92 (95% CI, 0.91-0.92), respectively. CONCLUSIONS: We developed and externally validated an interpretable machine learning prediction model that improves on conventional clinical criteria to predict the need for intubation in children hospitalized in a PICU using information readily available in the EMR. Implementation of our model may help clinicians optimize the timing of endotracheal intubation and better allocate respiratory and nursing staff to care for mechanically ventilated children.

Mechanical Power Is Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: Mechanical power (MP) transferred from the ventilator to the lungs has been proposed as a summary variable that may impact mortality in children with acute respiratory distress syndrome (ARDS). To date, no study has shown an association between higher MP and mortality in children with ARDS. DESIGN: Secondary analysis of a prospective observational study. SETTING: Single-center, tertiary, academic PICU. PATIENTS: Five hundred forty-six intubated children with ARDS enrolled between January 2013 and December 2019 receiving pressure-controlled ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Higher MP was associated with increased mortality (adjusted hazard ratio [HR] 1.34 per 1 sd increase, 95% CI 1.08-1.65; p = 0.007). When assessing the contribution of individual components of MP, only positive end-expiratory pressure (PEEP) was associated with mortality (HR 1.32; p = 0.007), whereas tidal volume, respiratory rate, and driving pressure (ΔP = [peak inspiratory pressure (PIP)-PEEP]) were not. Finally, we tested whether there remained an association when specific terms were removed from the MP equation by calculating MP from static strain (remove ΔP), MP from dynamic strain (remove PEEP), and mechanical energy (remove respiratory rate). MP from static strain (HR 1.44; p < 0.001), MP from dynamic strain (HR 1.25; p = 0.042), and mechanical energy (HR 1.29; p = 0.009) were all associated with mortality. MP was associated with ventilator-free days only when using MP normalized to predicted body weight, but not when using measured weight. CONCLUSIONS: Higher MP was associated with mortality in pediatric ARDS, and PEEP appears to be the component most consistently driving this association. As higher PEEP is used in sicker patients, the association between MP and mortality may reflect a marker of illness severity rather than MP itself being causal for mortality. However, our results support future trials testing different levels of PEEP in children with ARDS as a potential means to improve outcome.

Plasma Nucleosomes Are Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown. DESIGN: We performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome. SETTING: Large academic tertiary-care PICU. PATIENTS: Intubated children meeting Berlin criteria for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome. CONCLUSIONS: Plasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.

Apnea Testing Using Continuous Positive Airway Pressure When Determining Death by Neurologic Criteria in Children: Retrospective Analysis of Potential Adverse Events.

OBJECTIVES: To determine the prevalence of adverse events during apnea testing for determination of death by neurologic criteria using continuous positive airway pressure in children. DESIGN: Single-center retrospective descriptive study. SETTING: Academic children's hospital. PATIENTS: Children evaluated for death by neurologic criteria in the PICU from 2013 to 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For each patient evaluated for death by neurologic criteria, we abstracted the number of apnea tests performed, vital signs and arterial blood gases during apnea testing, and outcome from the medical record. Adverse events were defined as oxygen-hemoglobin desaturation (arterial oxygen saturation < 85%), hypotension, or other significant event (e.g. arrhythmia, cardiac arrest) based on documentation in the medical record. We determined which adverse events resulted in early termination of the apnea test. We used oxygenation index, ventilator variables, and presence of vasopressors to determine preapnea test cardiopulmonary dysfunction. Seventy-two patients (age 7 yr [2.7-13.2 yr]; 48% male) underwent 121 apnea tests. Nine patients (12%) had 13 potential apnea tests deferred due to concern for cardiopulmonary instability as determined by the attending physician. Patients who underwent apnea testing had an oxygenation index of 3.5 (2.5-4.8) and were receiving vasopressors at the time of 108 apnea tests (89%). Hypotension was reported during seven apnea tests (6%) and resulted in the early termination of one apnea test (<1%). No other adverse events were reported. One hundred and twenty apnea tests (99%) were consistent with death by neurologic criteria. CONCLUSIONS: Apnea testing following a protocol that uses continuous positive airway pressure for apneic oxygenation has a low rate of adverse events in children meeting prerequisite criteria and determined by a pediatric intensivist to be physiologically appropriate for testing.

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Measuring Training Disruptions Using an Informatics Based Tool.

OBJECTIVE: Training disruptions, such as planned curricular adjustments or unplanned global pandemics, impact residency training in ways that are difficult to quantify. Informatics-based medical education tools can help measure these impacts. We tested the ability of a software platform driven by electronic health record data to quantify anticipated changes in trainee clinical experiences during the COVID-19 pandemic. METHODS: We previously developed and validated the Trainee Individualized Learning System (TRAILS) to identify pediatric resident clinical experiences (i.e. shifts, resident provider-patient interactions (rPPIs), and diagnoses). We used TRAILS to perform a year-over-year analysis comparing pediatrics residents at a large academic children's hospital during March 15-June 15 in 2018 (Control #1), 2019 (Control #2), and 2020 (Exposure). RESULTS: Residents in the exposure cohort had fewer shifts than those in both control cohorts (P < .05). rPPIs decreased an average of 43% across all PGY levels, with interns experiencing a 78% decrease in Continuity Clinic. Patient continuity decreased from 23% to 11%. rPPIs with common clinic and emergency department diagnoses decreased substantially during the exposure period. CONCLUSIONS: Informatics tools like TRAILS may help program directors understand the impact of training disruptions on resident clinical experiences and target interventions to learners' needs and development.

Characteristics of Emergency Room and Hospital Encounters Resulting From Consumer Home Monitors.

BACKGROUND AND OBJECTIVES: Consumer home monitors (CHM), which measure vital signs, are popular products marketed to detect airway obstruction and arrhythmia. Yet, they lack evidence of infant death prevention, demonstrate suboptimal accuracy, and may result in false alarms that prompt unnecessary acute care visits. To better understand the hospital utilization and costs of CHM, we characterized emergency department (ED) and hospital encounters associated with CHM use at a children's hospital. METHODS: We used structured query language to search the free text of all ED and admission notes between January 2013 and December 2019 to identify clinical documentation discussing CHM use. Two physicians independently reviewed the presence of CHM use and categorized encounter characteristics. RESULTS: Evidence of CHM use contributed to the presentation of 36 encounters in a sample of over 300 000 encounters, with nearly half occurring in 2019. The leading discharge diagnoses were viral infection (13, 36%), gastroesophageal reflux (8, 22%) and false positive alarm (6, 17%). Median encounter duration was 20 hours (interquartile range: 3 hours to 2 days; max 10.5 days) and median cost of encounters was $2188 (interquartile range: $255 to $7632; max $84 928). CONCLUSIONS: Although the annual rate of CHM-related encounters was low and did not indicate a major public health burden, for individual families who present to the ED or hospital for concerns related to CHMs, there may be important adverse financial and emotional consequences.

Attributing Patients to Pediatric Residents Using Electronic Health Record Features Augmented with Audit Logs.

OBJECTIVE: Patient attribution, or the process of attributing patient-level metrics to specific providers, attempts to capture real-life provider-patient interactions (PPI). Attribution holds wide-ranging importance, particularly for outcomes in graduate medical education, but remains a challenge. We developed and validated an algorithm using EHR data to identify pediatric resident PPIs (rPPIs). METHODS: We prospectively surveyed residents in three care settings to collect self-reported rPPIs. Participants were surveyed at the end of primary care clinic, emergency department (ED), and inpatient shifts, shown a patient census list, asked to mark the patients with whom they interacted, and encouraged to provide a short rationale behind the marked interaction. We extracted routine EHR data elements, including audit logs, note contribution, order placement, care team assignment, and chart closure, and applied a logistic regression classifier to the data to predict rPPIs in each care setting. We also performed a comment analysis of the resident-reported rationales in the inpatient care setting to explore perceived patient interactions in a complicated workflow. RESULTS: We surveyed 81 residents over 111 shifts and identified 579 patient interactions. Among EHR extracted data, time-in-chart was the best predictor in all three care settings (primary care clinic: odds ratio [OR] = 19.36, 95% confidence interval [CI]: 4.19-278.56; ED: OR = 19.06, 95% CI: 9.53-41.65' inpatient: OR = 2.95, 95% CI: 2.23-3.97). Primary care clinic and ED specific models had c-statistic values > 0.98, while the inpatient-specific model had greater variability (c-statistic = 0.89). Of 366 inpatient rPPIs, residents provided rationales for 90.1%, which were focused on direct involvement in a patient's admission or transfer, or care as the front-line ordering clinician (55.6%). CONCLUSION: Classification models based on routinely collected EHR data predict resident-defined rPPIs across care settings. While specific to pediatric residents in this study, the approach may be generalizable to other provider populations and scenarios in which accurate patient attribution is desirable.

Association Between Mobile Telephone Interruptions and Medication Administration Errors in a Pediatric Intensive Care Unit.

Importance: Incoming text messages and calls on nurses' mobile telephones may interrupt medication administration, but whether such interruptions are associated with errors has not been established. Objective: To assess whether a temporal association exists between mobile telephone interruptions and subsequent errors by pediatric intensive care unit (PICU) nurses during medication administration. Design, Setting, and Participants: A retrospective cohort study was performed using telecommunications and electronic health record data from a PICU in a children's hospital. Data were collected from August 1, 2016, through September 30, 2017. Participants included 257 nurses and the 3308 patients to whom they administered medications. Exposures: Primary exposures were incoming telephone calls and text messages received on the institutional mobile telephone assigned to the nurse in the 10 minutes leading up to a medication administration attempt. Secondary exposures were the nurse's PICU experience, work shift (day vs night), nurse to patient ratio, and level of patient care required. Main Outcomes and Measures: Primary outcome, errors during medication administration, was a composite of reported medication administration errors and bar code medication administration error alerts generated when nurses attempted to give medications without active orders for the patient whose bar code they scanned. Results: Participants included 257 nurses, of whom 168 (65.4%) had 6 months or more of PICU experience; and 3308 patients, of whom 1839 (55.6%) were male, 1539 (46.5%) were white, and 2880 (87.1%) were non-Hispanic. The overall rate of errors during 238 540 medication administration attempts was 3.1% (95% CI, 3.0%-3.3%) when nurses were uninterrupted by incoming telephone calls and 3.7% (95% CI, 3.4%-4.0%) when they were interrupted by such calls. During day shift, the odds ratios (ORs) for error when interrupted by calls (compared with uninterrupted) were 1.02 (95% CI, 0.92-1.13; P = .73) among nurses with 6 months or more of PICU experience and 1.22 (95% CI, 1.00-1.47; P = .046) among nurses with less than 6 months of experience. During night shift, the ORs for error when interrupted by calls were 1.35 (95% CI, 1.16-1.57; P < .001) among nurses with 6 months or more of PICU experience and 1.53 (95% CI, 1.16-2.03; P = .003) among nurses with less than 6 months of experience. Nurses administering medications to 1 or more patients receiving mechanical ventilation and arterial catheterization while caring for at least 1 other patient had an increased risk of error (OR, 1.21; 95% CI, 1.03-1.42; P = .02). Incoming text messages were not associated with error (OR, 0.97; 95% CI, 0.92-1.02; P = .22). Conclusions and Relevance: This study's findings suggest that incoming telephone call interruptions may be temporally associated with medication administration errors among PICU nurses. Risk of error varied by shift, experience, nurse to patient ratio, and level of patient care required.

A Model for Clinical Informatics Education for Residents: Addressing an Unmet Need.

Opportunities for education in clinical informatics exist throughout the spectrum of formal education extending from high school to postgraduate training. However, physicians in residency represent an underdeveloped source of potential informaticians. Despite the rapid growth of accredited fellowship programs since clinical informatics became a board-eligible subspecialty in 2011, few resident physicians are aware of their role at the intersection of clinical medicine and health information technology or associated opportunities. In an effort to educate and engage residents in clinical informatics, Children's Hospital of Philadelphia has developed a three-pronged model: (1) an elective rotation with hands-on project experience; (2) a longitudinal experience that offers increased exposure and mentorship; and (3) a resident founded and led working group in clinical informatics. We describe resident participation in these initiatives and lessons learned, as well as resident perceptions of how these components have positively influenced informatics knowledge and career choices. Since inception of this model, five residents have pursued the clinical informatics fellowship. This educational model supports resident involvement in hospital-wide informatics efforts with tangible projects and promotes wider engagement through educational opportunities commensurate with the resident's level of interest.

Influence of simulation on electronic health record use patterns among pediatric residents.

Objective: Electronic health record (EHR) simulation with realistic test patients has improved recognition of safety concerns in test environments. We assessed if simulation affects EHR use patterns in real clinical settings. Materials and Methods: We created a 1-hour educational intervention of a simulated admission for pediatric interns. Data visualization and information retrieval tools were introduced to facilitate recognition of the patient's clinical status. Using EHR audit logs, we assessed the frequency with which these tools were accessed by residents prior to simulation exposure (intervention group, pre-simulation), after simulation exposure (intervention group, post-simulation), and among residents who never participated in simulation (control group). Results: From July 2015 to February 2017, 57 pediatric residents participated in a simulation and 82 did not. Residents were more likely to use the data visualization tool after simulation (73% in post-simulation weeks vs 47% of combined pre-simulation and control weeks, P <. 0001) as well as the information retrieval tool (85% vs 36%, P < .0001). After adjusting for residents' experiences measured in previously completed inpatient weeks of service, simulation remained a significant predictor of using the data visualization (OR 2.8, CI: 2.1-3.9) and information retrieval tools (OR 3.0, CI: 2.0-4.5). Tool use did not decrease in interrupted time-series analysis over a median of 19 (IQR: 8-32) weeks of post-simulation follow-up. Discussion: Simulation was associated with persistent changes to EHR use patterns among pediatric residents. Conclusion: EHR simulation is an effective educational method that can change participants' use patterns in real clinical settings.

Controlling testing volume for respiratory viruses using machine learning and text mining.

Viral testing for pediatric inpatients with respiratory symptoms is common, with considerable associated charges. In an attempt to reduce testing volumes, we studied whether data available at the time of admission could aid in identifying children with low likelihood of having a particular viral origin of their symptoms, and thus safely forgo broad viral testing. We collected clinical data for 1,685 pediatric inpatients receiving respiratory virus testing from 2010-2012. Machine-learning on the data allowed us to construct pre-test models predicting whether a patient would test positive for a particular virus. Text mining improved the predictions for one viral test. Cost-sensitive models optimized for test sensitivity showed reasonable test specificities and an ability to reduce test volume by up to 46% for single viral tests. We conclude that diverse forms of data in the electronic medical record can be used productively to build models that help physicians reduce testing volumes.

Symbiosis as a source of selectable epigenetic variation: taking the heat for the big guy.

Evolutionary developmental biology is based on the principle that evolution arises from hereditable changes in development. Most of this new work has centred on changes in the regulatory components of the genome. However, recent studies (many of them documented in this volume) have shown that development also includes interactions between the organism and its environment. One area of interest concerns the importance of symbionts for the production of the normal range of phenotypes. Many, if not most, organisms have 'outsourced' some of their developmental signals to a set of symbionts that are expected to be acquired during development. Such intimate interactions between species are referred to as codevelopment, the production of a new individual through the coordinated interactions of several genotypically different species. Within the past 2 years, several research programmes have demonstrated that such codevelopmental schemes can be selected. We will focus on symbioses in coral reef cnidarians symbiosis, pea aphids and cactuses, wherein the symbiotic system provides thermotolerance for the composite organism.

Lhx2 selector activity specifies cortical identity and suppresses hippocampal organizer fate.

The earliest step in creating the cerebral cortex is the specification of neuroepithelium to a cortical fate. Using mouse genetic mosaics and timed inactivations, we demonstrated that Lhx2 acts as a classic selector gene and essential intrinsic determinant of cortical identity. Lhx2 selector activity is restricted to an early critical period when stem cells comprise the cortical neuroepithelium, where it acts cell-autonomously to specify cortical identity and suppress alternative fates in a spatially dependent manner. Laterally, Lhx2 null cells adopt antihem identity, whereas medially they become cortical hem cells, which can induce and organize ectopic hippocampal fields. In addition to providing functional evidence for Lhx2 selector activity, these findings show that the cortical hem is a hippocampal organizer.

Haematological malignancies developing in previously healthy individuals who received haematopoietic growth factors: report from the Research on Adverse Drug Events and Reports (RADAR) project.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1-5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed.