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Rationale: Interventional clinical trials involving children with septic shock would benefit from an efficient preenrollment stratification strategy.Objectives: To test the predictive value of interleukin (IL)-8 for 28-day mortality in pediatric septic shock.Methods: A training data set (n = 40) identified a serum IL-8 of greater than 220 pg/ml as having a 75% sensitivity and specificity for predicting 28-day mortality. This cutoff was then subjected to a series of validation steps.Measurements and Main Results: Subjects were drawn from two large, independent pediatric septic shock databases. Prospective application of the IL-8 cutoff to validation data set 1 (n = 139) demonstrated 78% sensitivity and 64% specificity for 28-day mortality. A serum IL-8 level of 220 pg/ml or less, however, had a negative predictive value for 28-day mortality of 95% in validation data set 1, which was subsequently applied to an independently generated data set of children with septic shock (validation set 2, n = 193). A serum IL-8 level of 220 pg/ml or less had a negative predictive value for 28-day mortality of 94% when applied to validation set 2.Conclusions: A serum IL-8 level of 220 pg/ml or less, obtained within 24 hours of admission, predicts a high likelihood of survival in children with septic shock. We propose that IL-8 can be used to exclude such patients from interventional clinical trials and ultimately derive a study population with a more favorable risk to benefit ratio when subjected to a study agent. [ABSTRACT FROM AUTHOR]

Introduction: Septic-shock-associated acute kidney injury (SSAKI) carries high morbidity in the pediatric population. Effective treatment strategies are lacking, in part due to poor detection and prediction. There is a need to identify novel candidate biomarkers of SSAKI. The objective of our study was to determine whether microarray data from children with septic shock could be used to derive a panel of candidate biomarkers for predicting SSAKI.Methods: A retrospective cohort study compared microarray data representing the first 24 hours of admission for 179 children with septic shock with those of 53 age-matched normal controls. SSAKI was defined as a >200% increase of baseline serum creatinine, persistent to 7 days after admission.Results: Patients with SSAKI (n = 31) and patients without SSAKI (n = 148) were clinically similar, but SSAKI carried a higher mortality (45% vs. 10%). Twenty-one unique gene probes were upregulated in SSAKI patients versus patients without SSAKI. Using leave-one-out cross-validation and class prediction modeling, these probes predicted SSAKI with a sensitivity of 98% (95% confidence interval (CI) = 81 to 100) and a specificity of 80% (95% CI = 72 to 86). Serum protein levels of two specific genes showed high sensitivity for predicting SSAKI: matrix metalloproteinase-8 (89%, 95% CI = 64 to 98) and elastase-2 (83%, 95% CI = 58 to 96). Both biomarkers carried a negative predictive value of 95%. When applied to a validation cohort, although both biomarkers carried low specificity (matrix metalloproteinase-8: 41%, 95% CI = 28 to 50; and elastase-2: 49%, 95% CI = 36 to 62), they carried high sensitivity (100%, 95% CI = 68 to 100 for both).Conclusions: Gene probes upregulated in critically ill pediatric patients with septic shock may allow for the identification of novel candidate serum biomarkers for SSAKI prediction. [ABSTRACT FROM AUTHOR]

Objectives: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed., Design: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022., Setting: Ten PICUs in the United States., Patients: Children with septic shock 1 week to 18 years old admitted to the PICU., Interventions: None., Measurements and Main Results: Seventy-nine of 363 patients (22%) had D3 severe AKI, defined as Kidney Disease Improving Global Outcomes stage 2 or higher. Patients were assigned a probability of D3 severe AKI using the PERSEVERE-II AKI model. The model predicted D3 severe AKI with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.85-0.93), sensitivity of 77% (95% CI, 66-86%), specificity of 88% (95% CI, 84-92%), positive predictive value of 65% (95% CI, 54-74%), and negative predictive value of 93% (95% CI, 89-96%). These data represent an increase in post-test probability of D3 severe AKI with a positive test from 22% to 65%, and a prevalence threshold of 28%. On multivariable regression, the PERSEVERE-II AKI prediction model demonstrated greater adjusted odds ratio (aOR) for D3 severe AKI (aOR, 11.2; 95% CI, 4.9-25.3) and lesser aOR for failure of D3 renal recovery from early AKI (aOR, 0.31; 95% CI, 0.13-0.69)., Conclusions: The PERSEVERE-II AKI model demonstrates consistently robust performance for prediction of new or persistent D3 severe AKI in children with septic shock. A major limitation is that actual D3 severe AKI prevalence is below the prevalence threshold for the test, and thus future work should focus on evaluating use in enriched populations., Competing Interests: Dr. Stanski’s institution received funding from the National Institute of General Medical Sciences (NIGMS); she disclosed that they hold a provisional patent for the Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (AKI) Prediction Model. Drs. Stanski, Cvijanovich, Fitzgerald, Thomas, Weiss, Atreya, Lautz, and Kaplan received support for article research from the National Institutes of Health. Dr. Cvijanovich’s institution received funding from the Cincinnati Children’s Hospital Medical Center, the Nationwide Children’s Hospital, the Boston Children’s Hospital, and the Collaborative Pediatric Critical Care Research Network. Dr. Fitzgerald received funding from the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK119463, P50DK114786) and the Commonwealth of Pennsylvania Department of Health Cure Grant. Dr. Jain received funding from AltaThera Pharmaceuticals. Dr. Lautz received funding from the NIGMS (K08GM148957-01, R21GM150093-01, and L40GM134527-03). Dr. Atreya’s institution received funding from the Cincinnati Children’s Research Foundation; he disclosed that they hold a provisional patent for the integrated PERSEVERE and endothelial biomarker risk model to predict sepsis-associted acute kidney injury (PERSEVEREnce SA-AKI model); and he received funding through the Procter K to R Scholar program awarded by the Cincinnati Children’s Research Foundation and the NIGMS (R21GM151703 and R21GM15009). Dr. Weiss received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD102396, R01HD101528) and the U.S. Centers for Disease Control and Prevention (75D30123C17693). Dr. Zingarelli’s institution received funding from the NIGMS (R01 GM115973, R21 GM151734, 1R21GM150093, and R01GM145698); she received funding from the National Heart, Lung, and Blood Institute (R01 HL141229); and she disclosed that they are editor of the Shock journal. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches., Methods: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme., Results: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes., Conclusions: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill., (© 2024. The Author(s).)

Introduction: Adolescents with elevated body mass index are at increased risk for comorbidities such as dyslipidemia, diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease. Guideline-based screening can identify impacted patients early, allowing for lifestyle modifications and other treatments to improve long-term health. Unfortunately, only 20% of pediatric patients with obesity receive recommended screening., Methods: A multidisciplinary quality improvement team designed and implemented a project to improve comorbidity screening utilizing the Model for Improvement. Provider education and incentive, clinical decision support, and regular performance feedback were chosen as interventions. Screening rates were tracked on a statistical process control chart., Results: From March through December of 2022, 9547 pediatric patients aged 10 years and up with body mass index greater than or equal to the 95 th percentile were seen for preventive care visits. Screening rates for comorbidities increased from a baseline of 19.5%-58% and were sustained for over 3 months. Numerous patients at risk for chronic disease were identified., Conclusions: Evidence-based clinical decision support, along with provider education and engagement, can effectively increase screening rates for comorbidities in pediatric patients with obesity., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: This work was supported by grant R21HD096402 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (Dr. Sanchez-Pinto). Drs. Atreya and Sanchez-Pinto received funding from R21GM151703. Cincinnati Children’s Hospital Medical Center (CCHMC) and the estate of the late Dr. Hector Wong hold patents for the pediatric sepsis biomarker risk model (PERSEVERE) for risk stratification of pediatric sepsis patients and gene expression-based adaptive endotypes. Dr. Atreya received funding from the National Institute of Child Health and Human Development (NICHD) (R21HD096402) and the National Institute of General Medical Sciences, he disclosed he holds patents for the pediatric sepsis biomarker risk model (PERSEVERE) for risk stratification of pediatric sepsis patients and gene expression-based adaptive endotypes. Drs. Atreya, Bennett, Faustino, Lufti, and Sanchez-Pinto received support for article research from the National Institutes of Health (NIH). Dr. Bennett’s institution received funding from the NICHD, the National Center for Advancing Translational Sciences, and the National Heart, Lung, and Blood Institute. Drs. Faustino and Sanchez-Pinto’s institutions received funding from the NIH. Dr. Cvijanovich’s institution received funding from CCHMC, Boston Children’s Hospital, the Centers for Disease Control, and Nationwide Children’s Hospital. Dr. Thomas received funding from Bayer AG. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background and Objectives: Medication reconciliation is a complex, but necessary, process to prevent patient harm from medication discrepancies. Locally, the steps of medication reconciliation are completed consistently; however, medication errors still occur, which suggest process inaccuracies. We focused on removal of unnecessary medications as a proxy for accuracy. The primary aim was to increase the percentage of patients admitted to the pediatric hospital medicine service with at least 1 medication removed from the home medication list by 10% during the hospital stay by June of 2022., Methods: Using the Model for Improvement, a multidisciplinary team was formed at a children's hospital, a survey was completed, and multiple Plan-Do-Study-Act cycles were done focusing on: 1. simplifying electronic health record processes by making it easier to remove medications; 2. continuous resident education about the electronic health record processes to improve efficiency and address knowledge gaps; and 3. auditing charts and real-time feedback. Data were monitored with statistical process control charts., Results: The project exceeded the goal, improving from 35% to 48% of patients having at least 1 medication removed from their home medication list. Improvement has sustained for 12 months., Conclusions: The combination of interventions including simplifying workflow, improving education, and enhancing accountability resulted in more patients with medications removed from their home medication list., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Surge demands for annual influenza vaccines challenge healthcare systems. Mass immunizations differ from the traditional care model. The coronavirus 2019 (COVID-19) pandemic challenged current care models with amplified demand and infection risks while challenging the organization to create new and improve existing processes., Methods: Using the Model for Improvement, the team set out to (1) safely meet a surge in vaccination demand and (2) adopt pandemic-driven innovations into routine immunization practice., Results: This free-standing pediatric system delivered 87,000 COVID-19 vaccines (~1.3% state total). It administered over 50% of COVID-19 vaccines using new mass immunization processes, including 37,000 adult vaccines before pediatric authorization. In the 2021-2022 influenza season, it used the new or improved immunization processes to deliver 22% of influenza vaccines., Conclusions: Pandemic-driven adaptation for the COVID-19 vaccine substantially increased the efficiency of influenza vaccination processes but did not result in a clear increase in influenza vaccine administration rates., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Free thyroxine (fT4) is often ordered when not indicated. The goal of the current study was to use quality improvement tools to identify and implement an optimal approach to reduce inappropriate fT4 testing throughout a large pediatric hospital system., Methods: After reviewing evidence-based guidelines and best practices, a thyroid-stimulating hormone with reflex to fT4 test and an outpatient thyroid order panel with clinical decision support at order entry, along with several rounds of provider education and feedback, were implemented. Outpatient and inpatient order sets and system preference lists were reviewed with subject matter experts and revised when appropriate. Tracking metrics were identified. Automated monthly run charts and statistical process control charts were created using data retrieved from the electronic health record. Charts established baseline data, balancing measure data, monitored the impact of interventions, and identified future interventions., Results: Over a 44-month period, among nonendocrinology providers, a reduction in fT4 and thyroid-stimulating hormone co-orders from 67% to 15% and an increase in reflex fT4 tests from 0% to 77% was obtained in inpatient and outpatient settings. Direct cost savings as a result of performing 5179 fewer fT4 tests over 3 years was determined to be $45 800., Conclusions: After implementation of a reflex fT4 test, a novel order panel with clinical decision support, provider education, and changes to ordering modes, a large and sustainable reduction in fT4 tests that was associated with significant cost savings was achieved among nonendocrinology providers., (Copyright © 2024 by the American Academy of Pediatrics.)

Introduction/background: Unmet need for seasonal influenza vaccination administration to pediatric patients exists at national and local levels. Vaccination during the perioperative period remains controversial, though opportunity exists to meet vaccination need through perioperative programs. The initial SMART Aim of this quality improvement initiative was to establish and increase seasonal influenza vaccination rate in eligible patients during in person preoperative clinic visits in a pediatric perioperative surgical home (PSH) to 10%. Informed by each prior season's experience, we increased our SMART Aim target for vaccinations in seasons two and three to 15 and 18%, respectively., Methods: Following the Model for Improvement methodology, the PSH team developed and implemented a perioperative pediatric influenza vaccination program. Across three influenza seasons, key interventions included updates to organizational perioperative vaccination policy, obtaining material influenza vaccination supplies, development of EHR tools, PSH staff education, and communication with patient-families. Rate of eligible patients receiving influenza vaccination at their PSH clinic appointment was tracked over time. Influenza vaccination rates were reported monthly during Season 1, then weekly during seasons two and three. The balancing measure was same day surgery case cancellations related to influenza vaccination given at PSH clinic appointment. Statistical analysis methods utilized include Shewart's control chart and statistical process control (SPC) standards. Special cause variation was determined by eight or more consecutive data points above or below the centerline., Results: The influenza vaccination rates in each of the three influenza seasons exceeded vaccination rate goals of 10, 15, and 18%, respectively. A total of 695 vaccines have been administered since program inception. No same day surgical case cancellations were observed as balancing measure., Conclusions: Over three consecutive influenza vaccination seasons, we safely established and met vaccination rate goals of 10, 15, and 18% to eligible patients during preoperative clinic visits within a pediatric PSH system. Through iterative PDSA cycles, we continue to identify opportunities for future improvement. This suggests that the perioperative period presents opportunity for seasonal influenza vaccination with potential program expansion to include routine vaccines of childhood., (© 2023 John Wiley & Sons Ltd.)

Objectives: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (acute kidney injury), and use of continuous renal replacement therapy (CRRT) in pediatric septic shock., Design: Ongoing multicenter prospective observational cohort., Setting: Thirteen PICUs in the United States (2003-2023)., Patients: Six hundred and eighty-one children with septic shock., Interventions: None., Measurements and Main Results: Cumulative percent PFB between days 1 and 7 (days 1-7 %PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of greater than or equal to two organ dysfunctions by day 7. Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II biomarkers were used to assign mortality probability and categorize patients into high mortality ( n = 91), intermediate mortality ( n = 134), and low mortality ( n = 456) risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis-associated acute kidney injury on day 3, and use of CRRT, demonstrated that time-dependent variable days 1-7%PFB was independently associated with an increased hazard of complicated course. Risk-stratified analyses revealed that each 10% increase in days 1-7 %PFB was associated with increased hazard of complicated course only among patients with high mortality risk strata (adjusted hazard ratio 1.24 (95% CI, 1.08-1.43), p = 0.003). However, this association was not causally mediated by PERSEVERE-II biomarkers., Conclusions: Our data demonstrate the influence of cumulative %PFB on the risk of complicated course in pediatric septic shock. Contrary to our previous report, this risk was largely driven by patients categorized as having a high mortality risk based on PERSEVERE-II biomarkers. Incorporation of such prognostic enrichment tools in randomized trials of restrictive fluid management or early initiation of de-escalation strategies may inform targeted application of such interventions among at-risk patients., Competing Interests: Dr. Atreya and Cincinnati Children’s Hospital (CCHMC) hold a provisional patent for a unified biomarker model—PERSEVERENCE that incorporates Pediatric Sepsis Biomarker Risk Model (PERSEVERE) and endothelial dysfunction markers to predict the risk of multiple organ dysfunctions in sepsis. Dr. Atreya received funding through the Cincinnati Children’s Research Foundation (CCRF) Procter-Scholar Award. Dr. Stanski and CCHMC hold a provisional patent for the use of PERSEVERE biomarkers in sepsis-associated acute kidney injury. Dr. Stanski is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (KL2TR001426). Dr. Atreya, Dr. Stanski, and CCHMC hold a provisional patent for PERSEVERENCE sepsis-associated acute kidney injury model to identify high-risk patients for microvascular modulating therapies. Dr. Fitzgerald, Dr. Weiss, Dr. Haileselassie, Dr. Quasney, and Dr. Alder received funding from the NIH., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Abstract: Background: Multiple-organ dysfunction syndrome disproportionately contributes to pediatric sepsis morbidity. Humanin (HN) is a small peptide encoded by mitochondrial DNA and thought to exert cytoprotective effects in endothelial cells and platelets. We sought to test the association between serum HN (sHN) concentrations and multiple-organ dysfunction syndrome in a prospectively enrolled cohort of pediatric septic shock. Methods: Human MT-RNR2 ELISA was used to determine sHN concentrations on days 1 and 3. The primary outcome was thrombocytopenia-associated multiorgan failure (TAMOF). Secondary outcomes included individual organ dysfunctions on day 7. Associations across pediatric sepsis biomarker (PERSEVERE)-based mortality risk strata and correlation with platelet and markers of endothelial activation were tested. Results: One hundred forty subjects were included in this cohort, of whom 39 had TAMOF. The concentration of sHN was higher on day 1 relative to day 3 and among those with TAMOF phenotype in comparison to those without. However, the association between sHN and TAMOF phenotype was not significant after adjusting for age and illness severity in multivariate models. In secondary analyses, sHN was associated with presence of day 7 sepsis-associated acute kidney injury ( P = 0.049). Furthermore, sHN was higher among those with high PERSEVERE-mortality risk strata and correlated with platelet counts and several markers of endothelial activation. Conclusion: Future investigation is necessary to validate the association between sHN and sepsis-associated acute kidney injury among children with septic shock. Furthermore, mechanistic studies that elucidate the role of HN may lead to therapies that promote organ recovery through restoration of mitochondrial homeostasis among those critically ill., Competing Interests: B.Z. and Cincinnati Children's Hospital Medical Center hold a provisional patent for serum humanin as a biomarker in trauma and sepsis. The remaining authors report no conflicts of interest., (Copyright © 2023 by the Shock Society.)

Background: Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI). Here, we prospectively assess sRAI performance in a separate cohort., Methods: A secondary analysis of a prospective, multicenter, observational study of children with septic shock admitted to the pediatric intensive care unit from 1/2019 to 12/2022. The primary outcome was severe AKI (≥ KDIGO Stage 2) on Day 3 (D3 severe AKI), and we compared predictive performance of the sRAI (calculated on Day 1) to the original RAI and serum creatinine elevation above baseline (D1 SCr > Baseline +). Original renal angina fulfillment (RAI +) was defined as RAI ≥ 8; sepsis renal angina fulfillment (sRAI +) was defined as RAI ≥ 20 or RAI 8 to < 20 with platelets < 150 × 10 3 /µL., Results: Among 363 patients, 79 (22%) developed D3 severe AKI. One hundred forty (39%) were sRAI + , 195 (54%) RAI + , and 253 (70%) D1 SCr > Baseline + . Compared to sRAI-, sRAI + had higher risk of D3 severe AKI (RR 8.9, 95%CI 5-16, p < 0.001), kidney replacement therapy (KRT) (RR 18, 95%CI 6.6-49, p < 0.001), and mortality (RR 2.5, 95%CI 1.2-5.5, p = 0.013). sRAI predicted D3 severe AKI with an AUROC of 0.86 (95%CI 0.82-0.90), with greater specificity (74%) than D1 SCr > Baseline (36%) and RAI + (58%). On multivariable regression, sRAI + retained associations with D3 severe AKI (aOR 4.5, 95%CI 2.0-10.2, p < 0.001) and need for KRT (aOR 5.6, 95%CI 1.5-21.5, p = 0.01)., Conclusions: Prediction of severe AKI in pediatric septic shock is important to improve outcomes, allocate resources, and inform enrollment in clinical trials examining potential disease-modifying therapies. The sRAI affords more accurate and specific prediction than context-free SCr elevation or the original RAI in this population., (© 2023. The Author(s).)

Abstract: Background: Endothelial activation is a key driver of multiple organ dysfunction syndrome (MODS). Soluble endoglin (sENG) is expressed by mature and progenitor endothelial cells and thought to have angiogenic properties. We sought to determine the association between sENG and pediatric sepsis-associated MODS. Methods: Prospective observational study of pediatric septic shock. Primary outcome of interest was complicated course-a composite of death by (or) MODS on day 7 of illness. Secondary outcomes included individual organ dysfunctions. Endothelial biomarkers including sENG were measured using multiplex Luminex assays among patients with existing data on the Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) data. Multivariable regression was used to test the independent association between sENG and clinical outcomes. Serum sENG concentrations across PERSEVERE-II mortality risk strata and correlations with established markers of endothelial dysfunction were determined. Results: Three hundred six critically ill children with septic shock were included. Serum sENG concentrations were higher among those with primary and secondary outcomes of interest, with the exception of acute neurological dysfunction. Soluble endoglin was independently associated with increased odds of complicated course (adjusted odds ratio, 1.53; 95% confidence interval, 1.02-2.27; P = 0.038) and acute renal dysfunction (adjusted odds ratio, 1.84; 95% confidence interval, 1.18-2.876; P = 0.006). Soluble endoglin demonstrated graded responses across PERSEVERE-II risk strata and was positively correlated with endothelial biomarkers, except angiopoietin-1. Conclusions: Serum sENG is independently associated with complicated course and acute renal dysfunction in pediatric septic shock. Future studies are required to validate our observational data, and mechanistic studies are necessary to elucidate whether endoglin plays an organ-specific role in the development or resolution of acute renal dysfunction in sepsis., Competing Interests: The author reports no conflicts of interest., (Copyright © 2023 by the Shock Society.)

Background: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI., Methods: Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of ≥ Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI among prespecified subgroups based on PERSEVERE-II risk., Results: A total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr., Conclusions: Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children., (© 2023. The Author(s).)

Background: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction., Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified., Results: A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype., Conclusions: We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies., (© 2023. The Author(s).)

Introduction: Cystitis and pyelonephritis are common bacterial infections in infants and children, and initial treatment is usually empirical. Antimicrobial stewardship advocates using narrow-spectrum antibiotics with consideration for local resistance patterns. Narrow-spectrum antibiotic use is critical in addressing the global issue of bacterial antimicrobial resistance, associated with approximately 5 million annual deaths., Methods: The antimicrobial stewardship committee developed a guideline for diagnosing and managing urinary tract infections and distributed it to all primary care providers. A standardized order set provided clinical decision support regarding appropriate first-line antibiotic therapy. A chief complaint of dysuria prompted the use of the order set. Prescription rates for the most common antimicrobials were tracked on a control chart., Results: From March 2018 through March 2020, there were 4,506 antibiotic prescriptions for urinary tract infections. Utilization of the recommended first-line therapy, cephalexin, increased from 27.5% to 74.8%. Over the same period, trimethoprim-sulfamethoxazole, no longer recommended due to high local resistance, decreased from 31.8% to 8.1%. Providers have maintained these prescribing patterns since the conclusion of the project., Conclusion: Using clinical decision support as a standardized order set can sustainably improve the use of first-line antimicrobials for treating pediatric urinary tract infections., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Healthcare institutions are placing greater emphasis on equitable care. To accurately track and validate equity metrics, Akron Children's Hospital evaluated how key fields are collected, analyzed, and visualized throughout the organization. Standardized recommendations in this area vary, and this investigation provided specific ways to advance analytics in this field. In addition, the technical infrastructure needed a comprehensive evaluation to increase confidence in using demographic data., Methods: First, we reviewed how staff are trained to collect data at registration. Next, the electronic health record team standardized race and ethnicity fields with federal definitions. We found that fields were not consistently accessible across reporting tools. However, when present, all fields are sourced from the same electronic health record field. Finally, 6 months of encounters were analyzed and validated, with limitations to a seldom-populated Race 2 field., Results: We compared data, including and excluding null values, to provide concise recommendations for standard visualizations. We uncovered many consistencies and a few inconsistencies that informed the next steps., Conclusions: The results informed 7 recommendations to align Akron Children's Hospital's advancement in analytics for health equity data: standardize race and ethnicity fields across all reporting tools, add Child Opportunity Index 2.0 to the enterprise data warehouse, utilize data at the time of the patient's encounter, include null fields (patient refused, unknown, and not specified) in analysis, increase reporting capabilities for social determinants of health (SDOH), standardize multiracial data visualizations, and optimize reliable upstream data collection to increase reliability for all health equity measures., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Providing high-quality care in the appropriate setting to optimize value is a worthy goal of an efficient health system. Consequences of managing nonurgent complaints in the emergency department (ED) have been described including inefficiency, loss of the primary care-patient relationship, and delayed care for other ED patients. The purpose of this initiative was to redirect nonurgent patients arriving in the ED to their primary care office for a same-day visit, and the SMART AIM was to increase redirected patients from 0% of those eligible to 30% in a 12-month period., Methods: The setting was a pediatric ED (PED) and primary care office of a tertiary care pediatric medical system. The initiative utilized the electronic health record to identify and mediate the redirection of patients to the patient's primary care office after ED triage. The primary measurement was the percentage of eligible patients redirected. Additional measures included health benefits during the primary care visit (vaccines, well-visits) and a balancing measure of patients returned to the PED., Results: The SMART AIM of >30% redirection was achieved and sustained with a final redirection rate of 46%. In total, 216 of 518 eligible patients were redirected, with zero untoward outcomes. The encounter time for redirected patients was similar for those who remained in the PED, and additional health benefits were appreciated for redirected patients., Conclusions: This initiative redirected nonurgent patients efficiently from a PED setting to their primary care office. The process is beneficial to patients and families and supports the patient-centered medical home. The balancing measure of no harm done to patients who accepted redirect reinforced the reliability of PED triage. The benefits achieved through the project highlight the value of the primary care-patient relationship and the continued need to improve access for patients and families., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Environmental contamination contributes to hospital associated infections, particularly those caused by multi-drug resistant organisms (MDRO). This study investigated bioburden presence on surfaces in a critical care center's patient rooms following typical environmental services (EVS) practices and following intervention with hybrid hydrogen peroxide™ (HHP™) fogging., Methods: Upon patient discharge, following standard cleaning or cleaning with ultraviolet (UV) light use, patient rooms were sampled by swabbing for adenosine triphosphate (ATP) and aerobic colony counts (ACC) from five preset locations. Rooms were then fogged via HHP technology using chemical indicators and Geobacillus stearothermophilus biological indicators for sporicidal validation monitoring. Following fogging, rooms were sampled again, and results were compared., Results: A 98% reduction in ACC was observed after fogging as compared to post EVS practices both with and without UV light use. No statistical difference was seen when comparing cleaning to cleaning with UV light use. Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa were identified following EVS practices and not detected following HHP fogging. ATP samples were reduced 88% by fogging application. Chemical and biological indicators confirmed correct application of HHP fogging, as seen through its achievement of a 6-log reduction of bacterial spores., Conclusion: HHP fogging is a thorough and efficacious technology which, when applied to critical care patient rooms, significantly reduces bioburden on surfaces, indicating potential benefits for implementation as part of infection prevention measures., (© 2022. The Author(s).)

Background: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock., Methods: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter., Results: Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables-ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1-contributed to the models' predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively., Conclusions: The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics., (© 2022. The Author(s).)

Background: Pediatric acute care utilization decreased dramatically during the coronavirus disease 2019 (COVID-19) pandemic. This study examined the association between the Child Opportunity Index (COI), a multidimensional neighborhood measure of childhood opportunity, and changes in acute care utilization at US pediatric hospitals during the COVID-19 pandemic compared with the previous 3 years., Methods: This observational study used administrative data across 41 US-based pediatric hospitals. Children aged 0 to 17 years with emergency department (ED) encounters during the study period were included. The COVID-19 pandemic time period (March 15, 2020-March 14, 2021) was the primary exposure. The primary outcome was the relative volume drop in ED encounters and observation/inpatient admissions through the ED by COI quintile., Results: Of 12 138 750 encounters, 3 705 320 (30.5%) were among the very low COI quintile. Overall, there was a 46.8% relative volume reduction in the pandemic period compared with the prepandmic period. This drop in volume occurred disproportionately among the very low COI quintile (51.1%) compared with the very high COI quintile (42.8%). The majority of clinical diagnosis groups demonstrated larger relative volume drops among the very low COI quintile., Conclusions: Acute care utilization decreased the most among children from very low COI neighborhoods, narrowing previously described acute care utilization disparities. Additional study of patient perspectives on health care needs and access during this period is required to understand these changes., (Copyright © 2022 by the American Academy of Pediatrics.)

Objectives: Our goal with this initiative was to reduce discharge opioid prescriptions while maintaining optimal pain management through the use of standardized pain prescribing guidelines for pediatric patients after orthopedic surgical procedures., Methods: Through analysis of established yet inconsistent prescribing practices, we created a 4-tiered guideline for pediatric orthopedic postoperative pain management prescription ordering. Following the Model for Improvement methodology including iterative plan-do-study-act cycles, the team created an electronic medical record order set to be used at discharge from the hospital. The provider compliance with this order set was monitored and analyzed over time by using provider-level and aggregate control charts. A secondary measure of opioid prescriptions (morphine milligram Eq [MME] dosage per patient) was tracked over time. The balancing measure was the analysis of unanticipated opioid prescription refills., Results: Greater than 90% compliance with the guidelines was achieved and sustained for 20 months. This resulted in a 54% reduction in opioids prescribed during the improvement period (baseline = 71 MME per patient; postintervention = 33 MME per patient) and has been sustained for 12 months. The percentage of unanticipated opioid prescription refills did not significantly change from the period before the institution of the guidelines and after institution of the guidelines (2017 = 3%; 2019 = 3%)., Conclusions: The creation of these guidelines has led to a significant reduction in the number of opioids prescribed while maintaining effective postoperative pain management., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Exposure to environmental lead continues to be a significant public health concern. Elevated blood lead levels can lead to neurocognitive delays and other adverse health outcomes. Unfortunately, screening rates in most communities remain low. This quality improvement project aimed to improve universal screening at 12 months of age and increase screening rates from 71% to 95%. The project team also aimed to improve risk-based screening at 24 months of age to increase screening rates from 41% to 70%., Methods: This project utilized the Model for Improvement. After identifying key drivers, the team designed, tested, and adopted a series of interventions to improve lead screening. Dynamic order sets were developed that pre-checked the lead order, if appropriate, based on the patient's age, previous results, and risk factors. Sites received regular feedback on their screening rates., Results: The percentage of patients receiving universal lead screening at their 12-month well visit increased from 71% to 96%. 70% of 2-year-olds were at risk for lead exposure based on ZIP code and insurance provider. Development of dynamic orders for patients at risk increased screening rates from 41% to 74% at the 24-month well visit., Conclusions: Utilization of clinical decision support tools within an electronic health record can significantly increase the percentage of children screened for lead toxicity. Similar tools could identify patients due for other screens or interventions, resulting in improved care and patient outcomes., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Sepsis-associated acute kidney injury (AKI) is a common diagnosis in children that is associated with poor outcomes. The lack of therapeutic options once present makes early identification of at-risk patients essential. The renal angina index (RAI) has been previously validated to predict severe AKI in heterogeneous populations of critically ill children. The performance of this score specifically in children with septic shock is unknown., Methods: A secondary analysis of a multicenter, prospective, observational study of 379 children with septic shock to determine the ability of the RAI to predict severe AKI at day 3, and to assess for the potential need for recalibration of the RAI in this unique subset of patients., Results: At the original cutoff of ≥8, the RAI predicted day 3 severe AKI with an area under the receiving operating characteristic (AUROC) curve 0.90 (95% confidence interval [CI]: 0.86 to 93), 95% sensitivity, and 54% specificity. A Youden's index identified a higher optimal cutoff of ≥20 (sensitivity 83%, specificity 80%), and day 1 platelet count <150 × 10 3 /μl was an independent predictor of severe AKI (adjusted odds ratio: 3.2; 95% CI: 1.7 to 6.3; P  < 0.001). Recalibration of the RAI to include platelet count and this new threshold restored the sensitivity of the original ≥8 threshold (95%), while improving its specificity (69%)., Conclusions: The RAI appears to be a sensitive and reliable tool for prediction of severe AKI in children with septic shock, although the use of a recalibrated sepsis-specific RAI using a higher cutoff and platelet count may be beneficial., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Objectives: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis. We sought to validate this association in children with septic shock and in a juvenile murine model of sepsis., Design: Prospectively enrolled cohort of children with septic shock; experimental mice., Setting: Seventeen participating institutions; research laboratory., Patients and Subjects: Five-hundred twenty-two children with septic shock; juvenile (14 d old) and adult (10-14 wk) mice with constitutive proprotein convertase subtilisin/kexin type 9 null and wildtype control mice (C57BL/6)., Interventions: Proprotein convertase subtilisin/kexin type 9 single-nucleotide polymorphisms, serum proprotein convertase subtilisin/kexin type 9, and lipid profiles in patients. Cecal slurry murine model of sepsis; survival studies in juvenile and adult mice, assessment of lipoprotein fractions, bacterial burden, and inflammation in juvenile mice., Measurements and Main Results: PCSK9 loss-of-function genetic variants were independently associated with increased odds of complicated course and mortality in children with septic shock. PCSK9, low-density lipoprotein, and high-density lipoprotein concentrations were lower among patients with complicated course relative to those without. PCSK9 concentrations negatively correlated with proinflammatory cytokine interleukin-8. Proprotein convertase subtilisin/kexin type 9 loss-of-function decreased survival in juvenile mice, but increased survival in adult mice with sepsis. PCSK9 loss-of-function resulted in low lipoproteins and decreased hepatic bacterial burden in juvenile mice., Conclusions: In contrast to the adult host, proprotein convertase subtilisin/kexin type 9 loss-of-function is detrimental to the juvenile host with septic shock. PCSK9 loss-of-function, in the context of low lipoproteins, may result in reduced hepatic bacterial clearance in the juvenile host with septic shock. Our data indicate that children should be excluded in sepsis clinical trials involving proprotein convertase subtilisin/kexin type 9 inhibitors.

Background: With the regionalization of specialty care, there is an increasing need for interfacility transport from local to regional hospitals. There are very limited data on rates of cardiopulmonary resuscitation (CPR) during medical transport and relationship between transport-specific factors, such as transport program type and need of CPR during transport of critically ill patients. We present the first, multicenter, international report of CPR during medical transport using the large Ground and Air Medical qUality Transport (GAMUT) database., Methods: We retrospectively reviewed the GAMUT database from January 2014 to March 2017 for CPR during transport. We determined the overall CPR rate and CPR rates for adult, pediatric, and neonatal transport programs. The rate of CPR per total transports was expressed as percentage, and then, Spearman's rho nonparametric associations were determined between CPR and other quality metrics tracked in the GAMUT database. Examples include advanced airway presence, waveform capnography usage, average mobilization time from the start of referral until en route, 1 st attempt intubation success rate, and DASH1A intubation success (definitive airway sans hypoxia/hypotension on 1 st attempt). Data were analyzed using chi-square tests, and in the presence of overall significance, post hoc Bonferroni adjusted z tests were performed., Results: There were 72 programs that had at least one CPR event during the study period. The overall CPR rate was 0.42% (777 CPR episodes/184,272 patient contacts) from 115 programs reporting transport volume and CPR events from the GAMUT database during the study period. Adult, pediatric, and neonatal transport programs ( n  = 57, 40 and 16, respectively) had significantly different CPR rates ( P < 0.001) i.e., 0.68% (555/82,094), 0.18% (138/76,430), and 0.33% (73/21,823), respectively. Presence of an advanced airway and mobilization time was significantly associated with CPR episodes ( P < 0.001) (Rs = +0.41 and Rs  = -0.60, respectively). Other transport quality metrics such as waveform capnography, first attempt intubation, and DASH1A success rate were not significantly associated with CPR episodes., Conclusion: The overall CPR rate during medical transport is 0.42%. Adult, pediatric, and neonatal program types have significantly different overall rates of CPR. Presence of advanced airway and mobilization time had an association with the rate of CPR during transport., Competing Interests: All authors declare no conflicts of interest., (Copyright © 2020 Utpal S. Bhalala et al.)

Objectives: Improve medication-related variable ICU costs by increasing value related to a locally identified high-frequency/high-cost medication, IV acetaminophen., Design: Structured quality improvement initiative using the Institute for Healthcare Improvement's Model for Improvement., Setting: Twenty-three-bed tertiary PICU., Patients: All patients admitted to the PICU receiving IV acetaminophen during the study period of 2015-2018., Interventions: PICU staff survey, education to close nurse/provider knowledge gap, optimization of order sets and electronic health record order entry, improving oral/enteral medication transition, and optimization of pharmacy dispensing., Measurements and Main Results: The primary outcome of interest was IV acetaminophen doses per patient day reported as a 12-month rolling average. Baseline IV acetaminophen prescribing prior to the study period was initially 0.55 doses per patient day, and in 2014, there were 3,042 doses administered. IV acetaminophen is $43 per dose. The rolling 12-month average post intervention was 0.33 doses per patient day. Enteral and rectal doses increased from 0.42 to 0.58 doses per patient day. Opioid utilization varied throughout the study. A 40% reduction in IV acetaminophen equated to a $35,507 cost savings in a single year., Conclusions: IV acetaminophen is prescribed with high frequency and impacts variable PICU costs. Value can be improved by optimizing IV acetaminophen prescribing.

Rationale: Acute kidney injury (AKI), a common complication of sepsis, is associated with substantial morbidity and mortality and lacks definitive disease-modifying therapy. Early, reliable identification of at-risk patients is important for targeted implementation of renal protective measures. The updated Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) is a validated, multibiomarker prognostic enrichment strategy to estimate baseline mortality risk in pediatric septic shock. Objectives: To assess the association between PERSEVERE-II mortality probability and the development of severe, sepsis-associated AKI on Day 3 (D 3 SA-AKI) in pediatric septic shock. Methods: We performed secondary analysis of a prospective observational study of children with septic shock in whom the PERSEVERE biomarkers were measured to assign a PERSEVERE-II baseline mortality risk. Measurements and Main Results: Among 379 patients, 65 (17%) developed severe D 3 SA-AKI. The proportion of patients developing severe D 3 SA-AKI increased directly with increasing PERSEVERE-II risk category, and increasing PERSEVERE-II mortality probability was independently associated with increased odds of severe D 3 SA-AKI after adjustment for age and illness severity (odds ratio, 1.4; 95% confidence interval, 1.2-1.7; P  < 0.001). Similar associations were found between increasing PERSEVERE-II mortality probability and the need for renal replacement therapy. Lower PERSEVERE-II mortality probability was independently associated with increased odds of renal recovery among patients with early AKI. A newly derived model incorporating the PERSEVERE biomarkers and Day 1 AKI status predicted severe D 3 SA-AKI with an area under the received operating characteristic curve of 0.95 (95% confidence interval, 0.92-0.98). Conclusions: Among children with septic shock, the PERSEVERE biomarkers predict severe D 3 SA-AKI and identify patients with early AKI who are likely to recover.

Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis have limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rational development, testing, and targeting of new therapies. We previously developed the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate mortality risk and proposed its use as a prognostic enrichment tool in sepsis clinical trials; prognostic enrichment selects patients based on mortality risk independent of treatment. Here, we show that PERSEVERE has excellent performance in a diverse cohort of children with septic shock with potential for use as a predictive enrichment strategy; predictive enrichment selects patients based on likely response to treatment. We demonstrate that the PERSEVERE biomarkers are reliably associated with mortality in mice challenged with experimental sepsis, thus providing an opportunity to test precision medicine strategies in the preclinical setting. Using this model, we tested two clinically feasible therapeutic strategies, guided by the PERSEVERE-based enrichment, and found that mice identified as high risk for mortality had a greater bacterial burden and could be rescued by higher doses of antibiotics. The association between higher pathogen burden and higher mortality risk was corroborated among critically ill children with septic shock. This bedside to bench to bedside approach provides proof of principle for PERSEVERE-guided application of precision medicine in sepsis., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Confirmation of endotracheal tube (ETT) tip position and timely identification and correction of malposition is an essential component of care for endotracheally intubated and mechanically ventilated children. We evaluated the ability of a prototype optoacoustic medical device to determine ETT tip position. We hypothesized that the precision of optoacoustic assessment of ETT tip position would be comparable to chest radiography., Methods: We recruited children aged newborn to 16 y who were admitted to the pediatric ICU requiring tracheal intubation and undergoing a chest radiograph for clinical purposes. After positioning each child on a chest radiograph plate, a sterile optical fiber, temporarily inserted through the ETT, emitted laser pulses perpendicular to the fiber and to the ETT, generating acoustic (ultrasound) waves in overlying tissue when the tip of the fiber passed beneath an acoustic sensor in the sternal notch. The distance from the ETT tip to the peak acoustic signal was used to calculate the distance from the ETT tip to the carina, which was compared with the same distance calculated by the radiologist reading the chest radiograph. Pearson's correlation coefficient, paired t tests, a Bland-Altman plot were used to compare the measures ( P < .05 was considered statistically significant)., Results: Twenty-six subjects were enrolled: 15 (57.7%) were male, median (interquartile range) age, weight, and height were 9 months (4-24), 9.6 kg (5.7-13.0), and 75 cm (62-90), respectively. All ETTs were cuffed (internal diameter range 3.0-5.0 mm). The relationship between optoacoustic and chest radiograph measurements was strong (r = 0.91, P < .001). Bias was 0.1 cm with narrow limits of agreement between measures (0.58 cm and 0.76 cm)., Conclusions: The optoacoustic prototype accurately determined ETT tip position and was comparable in precision to chest radiograph., (Copyright © 2018 by Daedalus Enterprises.)

Emergency medical services and critical care transport teams are relatively new parts of the American healthcare delivery system. Although most healthcare providers regularly interact with these groups and rely upon their almost ubiquitous availability, few know how these services developed or what sort of infrastructure currently exists to maintain them. This article provides a focused overview of the history and present practices of both emergency medical services and critical care transport teams, with a concentrated look at the implementation of these services in the pediatric population. Within this context, we also consider current challenges and future opportunities for both groups and conclude with ways to become involved in the improvement of out-of-hospital pediatric critical care., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Adherence to guidelines for endotracheal tube (ETT) insertion depth may not be sufficient to prevent malposition or harm to the patient. To obtain an estimate of ETT malpositioning, we evaluated initial postintubation chest radiographs and hypothesized that many ETTs in multiple intubation settings would be malpositioned despite adherence to Pediatric Advanced Life Support and Neonatal Resuscitation Program guidelines., Methods: In a random subset (randomization table) of 2,000 initial chest radiographs obtained from January 1, 2009, to May 5, 2012, we recorded height, weight, age, sex, ETT inner diameter, and cm marking at the lip from the electronic health record. Chest radiographs of poor quality and with spinal or skeletal deformities were excluded. We defined adherence to Pediatric Advanced Life Support or Neonatal Resuscitation Program guidelines as the difference between predicted and actual ETT markings at the lip as ± 0.25, ± 0.50, or ± 1.0 cm for ETTs of 2.5-4, 4.5-6.0, or >6.5 mm inner diameter, respectively. We defined the proper position as the ETT tip being below the thoracic inlet (superior border of the clavicular heads) and ≥1 cm above the carina. Descriptive statistics reported demographics, guideline adherence, and malposition incidence. The chi-square test was used to assess relationships among intubation setting, malposition, and depth guideline adherence ( P < .05, significant)., Results: We reviewed 507 records, 477 of which met inclusion criteria and had sufficient data for analysis. Fifty-six percent of the subjects were male, with median (interquartile range) age 15.2 (3.4-59.4) months, and 330 ETTs (69%) were malpositioned: 39 above the thoracic inlet, and 291 < 1 cm above the carina. Of 79 ETTS (17%) that adhered to depth guidelines, 56 (74%) were malpositioned. Three-hundred seventy-three ETTs (83%) did not meet guidelines. Two-hundred sixty-four (68%) were malpositioned. The intubation setting did not influence malposition or guideline adherence ( P = .54)., Conclusions: In infants and children, a high proportion of ETTs were malpositioned on the first postintubation chest radiograph, with little influence of guideline adherence., (Copyright © 2018 by Daedalus Enterprises.)

Background: Children admitted to the general care floor sometimes require acute escalation of care and rapid transfer (RT) to the PICU shortly after admission. In this study, we aim to investigate the characteristics of RTs and the impact RTs have on patient outcomes, including PICU length of stay (LOS), mortality, and emergency transfer defined as critical care interventions occurring within 1 hour on either side of transfer to the PICU., Methods: We conducted a 2-year, single-center, retrospective analysis including all patients admitted to the general care floor of a tertiary children's hospital that were subsequently transferred to the PICU, with attention to those transferred within 4 hours of admission, meeting criteria as RTs. Patient-level data and outcomes were tracked. Statistical summaries were stratified by RT or non-RT strata and between-strata comparisons were performed. Significant univariate factors were entered into a multivariate logistic regression model and reduced with statistical significance required for final model inclusion., Results: Of 450 patients with an unplanned PICU transfer, 105 (23.3%) experienced RTs. Significant factors in the reduced multivariate logistic regression model associated with decreased risk for RT were increased baseline Pediatric Overall Performance Category ( P = .046) and PICU origin of admission ( P = .012). RT patients had shorter PICU LOSs (2.8 vs 5.5 days, P < .001) compared with non-RT patients despite a higher rate of emergency transfer (15.2% vs 7.5%, P = .018) and no difference in mortality ( P = .741)., Conclusions: In this study, we demonstrate RTs have an increase in emergency transfer rate but no apparent risk of increased PICU LOS or mortality., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Introduction: Tracheal intubation (TI) is a lifesaving critical care skill. Failed TI attempts, however, can harm patients. Critical care transport (CCT) teams function as the first point of critical care contact for patients being transported to tertiary medical centers for specialized surgical, medical, and trauma care. The Ground and Air Medical qUality in Transport (GAMUT) Quality Improvement Collaborative uses a quality metric database to track CCT quality metric performance, including TI. We sought to describe TI among GAMUT participants with the hypothesis that CCT would perform better than other prehospital TI reports and similarly to hospital TI success., Methods: The GAMUT Database is a global, voluntary database for tracking consensus quality metric performance among CCT programs performing neonatal, pediatric, and adult transports. The TI-specific quality metrics are "first attempt TI success" and "definitive airway sans hypoxia/hypotension on first attempt (DASH-1A)." The 2015 GAMUT Database was queried and analysis included patient age, program type, and intubation success rate. Analysis included simple statistics and Pearson chi-square with Bonferroni-adjusted post hoc z tests (significance = p < 0.05 via two-sided testing)., Results: Overall, 85,704 patient contacts (neonatal n [%] = 12,664 [14.8%], pediatric n [%] = 28,992 [33.8%], adult n [%] = 44,048 [51.4%]) were included, with 4,036 (4.7%) TI attempts. First attempt TI success was lowest in neonates (59.3%, 617 attempts), better in pediatrics (81.7%, 519 attempts), and best in adults (87%, 2900 attempts), p < 0.001. Adult-focused CCT teams had higher overall first attempt TI success versus pediatric- and neonatal-focused teams (86.9% vs. 63.5%, p < 0.001) and also in pediatric first attempt TI success (86.5% vs. 75.3%, p < 0.001). DASH-1A rates were lower across all patient types (neonatal = 51.9%, pediatric = 74.3%, adult = 79.8%)., Conclusions: CCT TI is not uncommon, and rates of TI and DASH-1A success are higher in adult patients and adult-focused CCT teams. TI success rates are higher in CCT than other prehospital settings, but lower than in-hospital success TI rates. Identifying factors influencing TI success among high performers should influence best practice strategies for TI.

Objective: Critical care transport (CCT) supports regionalization of medical care. Focus on the quality of CCT care prompted the development of the Ground and Air Medical qUality in Transport (GAMUT) Quality Improvement collaborative database which tracks consensus quality metrics. The Institute of Medicine recommends benchmarking of comparative data to accelerate improvement. Herein, we report the strategies and rationale for GAMUT QI Collaborative benchmarking., Methods: The GAMUT database includes >350 programs internationally with >200,000 annual patient contacts. Evidence-based literature review performed in May 2016 and October 2017 identified benchmarking strategies were evaluated and summarized, specific to the GAMUT metrics. Statistical analyses include simple statistics and weighted expectation calculations for benchmark examples (Pearson chi-square with Bonferroni adjusted post-hoc z tests)., Results: Evidence-based literature search yielded 70 articles, and 31 were selected for inclusion in our evidence table. 5 evidence-based benchmark strategies were considered: average (mean), average (median), adjusted benchmark (based on expected outcome), Achievable Benchmark of Care (ABC), and Delphi. ABC threshold establishes a higher target (90th percentile) forcing more programs to achieve higher performance., Conclusion: Benchmarking is not well-suited for a single strategy and requires customized consideration based on each metric, though adjusted benchmark and ABC generally set higher performance benchmarks., (Copyright © 2018 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Background: The American Academy of Pediatrics Section on Transport recommends the use of portable ventilators during the transport of patients with advanced airways. We sought to identify knowledge gaps and evaluate the effectiveness of a transport ventilator competency boot camp., Methods: Electronic health records of children requiring ventilatory support during air and ground interfacility transport from January 1 through December 31, 2015, were reviewed to determine when manual ventilation was used in lieu of a portable ventilator, and simulations were constructed from commonly occurring scenarios. All registered respiratory therapists trained in air and ground critical-care transports participated. Demographic data were collected. We assessed performance on 3 facilitated simulated scenarios using a ventilator connected to a low-fidelity pediatric mannequin attached to breathing simulator. Scores were based on the participants' ability to correctly perform pre-use checks, select and optimize ventilator settings, set alarms, and complete safety checks. A 60-min interactive education intervention was conducted between the pre- and post-assessments. The pre-assessment, intervention, and post-assessment were conducted 6 weeks apart. De-identified assessments were scored, and results were shared after study completion. Descriptive statistics reported participant demographics. Paired t tests compared before and after assessments. Statistical significance was established at P < .05., Results: A total of 172 electronic health records were reviewed. Manual ventilation was used more frequently in toddlers requiring pressure control ventilation; noninvasive ventilation was rarely used. A total of 17 registered respiratory therapists participated; 18% were male, 41% had 6-9 years of tenure and 5 years of experience with our transport team. Completing ventilator pre-use check and engaging alarms provided the most opportunity for improvement. Improvements were greater with the use of noninvasive ventilation ( P = .006) than pressure control ventilation ( P = .10) and volume control ventilation use ( P = .07)., Conclusions: Quality data were useful in identifying areas requiring knowledge and competency assessment. Re-assessment results validated the need to conduct education and competency assessment at defined intervals., (Copyright © 2018 by Daedalus Enterprises.)

Objective: We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes., Design: Observational cohort study including existing and newly enrolled participants., Setting: Multiple PICUs., Patients: Children with septic shock., Interventions: None., Measurements and Main Results: We measured the 100 endotyping genes at day 1 and day 3 of illness in 375 patients. We determined if endotype assignment changes over time, and whether changing endotype is associated with corticosteroid response and outcomes. We used multivariable logistic regression to adjust for illness severity, age, and comorbidity burden. Among the 132 subjects assigned to endotype A on day 1, 56 (42%) transitioned to endotype B by day 3. Among 243 subjects assigned to endotype B on day 1, 77 (32%) transitioned to endotype A by day 3. Assignment to endotype A on day 1 was associated with increased odds of mortality. This risk was modified by the subsequent day 3 endotype assignment. Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A., Conclusions: A substantial proportion of children with septic shock transition endotypes during the acute phase of illness. The risk of poor outcome and the response to corticosteroids change with changes in endotype assignment. Patients persisting as endotype A are at highest risk of poor outcomes.

Objective: Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock., Design: Retrospective analysis of a pediatric septic shock database., Setting: Twenty-nine PICUs in the United States., Patients: Eight hundred ninety children 10 years and younger with septic shock., Interventions: None., Measurements and Main Results: We considered the minimum, maximum, and mean chloride values during the initial 7 days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration greater than or equal to 110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of greater than or equal to two organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 patients (25%) with a complicated course and 93 mortalities (10%). Seventy patients had a minimum chloride greater than or equal to 110 mmol/L, 179 had a mean chloride greater than or equal to 110 mmol/L, and 514 had a maximum chloride greater than or equal to 110 mmol/L. A minimum chloride greater than or equal to 110 mmol/L was associated with increased odds of complicated course (odds ratio, 1.9; 95% CI, 1.1-3.2; p = 0.023) and mortality (odds ratio, 3.7; 95% CI, 2.0-6.8; p < 0.001). A mean chloride greater than or equal to 110 mmol/L was also associated with increased odds of mortality (odds ratio, 2.1; 95% CI, 1.3-3.5; p = 0.002). The secondary analysis yielded similar results., Conclusion: Hyperchloremia is independently associated with poor outcomes among children with septic shock.

Introduction: Critical Care Transport teams use various strategies to maintain temperature sensitive drugs and equipment at optimal temperature. The purpose of this study was to examine the effectiveness of current passive refrigeration of temperature sensitive transport medications/equipment., Methods: Initially, we performed a retrospective review of transport durations. Subsequently, an experimental paradigm was created using a temperature probe inside of the transport cooler packs utilizing various configurations and initial starting temperatures with high and low "in range" temperature margins of 8°C (max) and 2°C (min)., Results: The mean round-trip transport time was 2.5 hours and over 15% of transports last longer than 4 hours. At a starting temperature of -3.9°C, the cooler and ice pack maintained "in range" temperatures for 3 hours. When the ice pack starting temperature was -12.9°C, high temperatures excursions weren't experienced until 6 hours 55 minutes, but initially low excursions fell below for up to 3 hours. iSTAT ® cartridges remained within range between 1-4 hours at cooler and ice pack starting temperature of -3.9°C., Conclusion: The current system of passive refrigeration does not appear to be sufficient for safely storing medications or point-of-care testing equipment for our transport services. This might reveal a flaw in the existing practices around medication refrigeration in transport., (Copyright © 2017 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Rationale: We previously derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate baseline mortality risk in children with septic shock. The PERSEVERE biomarkers are serum proteins selected from among the proteins directly related to 80 mortality risk assessment genes. The initial approach to selecting the PERSEVERE biomarkers left 68 genes unconsidered., Objectives: To determine if the 68 previously unconsidered genes can improve upon the performance of PERSEVERE and to provide biological information regarding the pathophysiology of septic shock., Methods: We reduced the number of variables by determining the biological linkage of the 68 previously unconsidered genes. The genes identified through variable reduction were combined with the PERSEVERE-based mortality probability to derive a risk stratification model for 28-day mortality using classification and regression tree methodology (n = 307). The derived tree, PERSEVERE-XP, was then tested in a separate cohort (n = 77)., Measurements and Main Results: Variable reduction revealed a network consisting of 18 mortality risk assessment genes related to tumor protein 53 (TP53). In the derivation cohort, PERSEVERE-XP had an area under the receiver operating characteristic curve (AUC) of 0.90 (95% confidence interval, 0.85-0.95) for differentiating between survivors and nonsurvivors. In the test cohort, the AUC was 0.96 (95% confidence interval, 0.91-1.0). The AUC of PERSEVERE-XP was superior to that of PERSEVERE., Conclusions: PERSEVERE-XP combines protein and mRNA biomarkers to provide mortality risk stratification with possible clinical utility. PERSEVERE-XP significantly improves on PERSEVERE and suggests a role for TP53-related cellular division, repair, and metabolism in the pathophysiology of septic shock.