The Effect of a Collaborative Pediatric Emergency Readiness Improvement Intervention on Patients' Hospital Outcomes.

OBJECTIVE: We hypothesized that collaborative intervention to improve weighted pediatric readiness score (WPRS) will be associated with decreased pediatric intensive care (PICU) mortality, PICU and hospital length of stay. METHODS: This study analyzes the transfer of acutely ill and injured patients from general emergency departments (GEDs) to our institution. The intervention involved customized assessment reports focusing on team performance and systems improvement for pediatric readiness, sharing best practices and clinical resources, designation of a nurse PECC at each GED and ongoing interactions at 2 and 4 months. Data was collected from charts before and after the intervention, focusing on patients transferred to our pediatric emergency department (ED) or directly admitted to our PICU from the GEDs. Clinical outcomes such as PICU length of stay (LOS), hospital LOS, and PICU mortality were assessed. Descriptive statistics were used for demographics, and various statistical tests were employed to analyze the data. Bivariate analyses and multivariable models were utilized to examine patient outcomes and the association between the intervention and outcomes. RESULTS: There were 278 patients in the pre-intervention period and 314 patients in the post-intervention period. Multivariable analyses revealed a significant association between the change in WPRS and decreased PICU LOS (ß=-0.05 [95% CI: -0.09, -0.01), p=0.023), and hospital LOS (ß=-0.12 [95% CI: -0.21, -0.04], p=0.004), but showed no association between the intervention and other patient outcomes. CONCLUSIONS: In this cohort, improving pediatric readiness scores in GEDs was associated with significant improvements in PICU and hospital length of stay. Future initiatives should focus on disseminating pediatric readiness efforts to improve outcomes of critically ill children nationally. WHATS NEW: Improving pediatric readiness scores in general emergency departments is associated with improved downstream clinical outcomes demonstrated by reduced PICU and hospital length of stay.

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

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

Implementation of an Anterior Mediastinal Mass Pathway to Improve Time to Biopsy and Multidisciplinary Communication.

Background: Mediastinal masses in children with cancer present unique challenges, including the risk of respiratory and hemodynamic compromise due to the complex anatomy of the mediastinum. Multidisciplinary communication is often a challenge in the management of these patients. After a series of patients with mediastinal masses were admitted to Riley Hospital for Children Pediatric Intensive Care Unit, the time from presentation to biopsy and pathology was greater than expected. We aimed to reduce the time to biopsy by 25% and demonstrate improved multidisciplinary communication within 6 months of protocol implementation for patients presenting to Riley Hospital for Children Emergency Department with an anterior mediastinal mass. Methods: Quality improvement methodology created a pathway that included early multidisciplinary communication. The pathway includes communication between the emergency department and multiple surgical and medical teams via a HIPPA-compliant texting platform. Based on patient stability, imaging findings, and sedation risks, the approach and timing of the biopsy were determined. Results: The pathway has been used 20 times to date. We successfully reduced the time to biopsy by 38%, from 25.1 hours to 15.4 hours. There was no statistically significant reduction in time to pathology. The multidisciplinary team reported improved communication from a baseline Likert score of 3.24 to 4. Conclusions: By initiating early multidisciplinary communication, we reduced the time to biopsy and pathology results, improving care for our patients presenting with anterior mediastinal masses.

Revisiting Post-ICU Admission Fluid Balance Across Pediatric Sepsis Mortality Risk Strata: A Secondary Analysis of a Prospective Observational Cohort Study.

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.

Deep Sedation in Pediatric Patients With Single Ventricle Physiology Outside of the Operating Room.

Background: Advancements in palliative surgery of patients with single ventricle physiology have led to an increase in the need for deep sedation protocols for painful procedures. However, positive pressure ventilation during anesthesia can result in unfavorable cardiopulmonary interactions. This patient population may benefit from sedation from these painful procedures. Methods: This study aims to demonstrate the safety and efficacy of deep sedation by pediatric intensivists outside the operating room for children with single ventricle physiology. This is a single-center, retrospective chart review on consecutive pediatric patients with single ventricle physiology who received deep sedation performed by pediatric intensivists between 2013 and 2020. Results: Thirty-three sedations were performed on 27 unique patients. The median age was 3.7 years (25th%-75th%: 2.1-15.6). The majority of the sedations, 88% (29/33), were done on children with Fontan physiology and 12% (4/33) were status-post superior cavopulmonary anastomosis. The primary cardiac defect was hypoplastic left heart in 63% (17/27) of all sedation procedures. There were 24 chest tube placements and 9 cardioversions. Ketamine alone [median dose 1.5 mg/kg (range 0.8-3.7)], ketamine [median dose 1 mg/kg (range 0.1-2.1)] with propofol [median dose 2.3 mg/kg (range 0.7-3.8)], and ketamine [median dose 1.5 mg/kg (range 0.4-3.0)] with morphine [median dose 0.06 mg/kg (range 0.03-0.20)] were the most common sedation regimens used. Adverse events (AEs) occurred in 4 patients (15%), three of which were transient AEs. All sedation encounters were successfully completed. Conclusion: Procedural deep sedation can be safely and effectively administered to single ventricle patients by intensivist-led sedation teams in selective case.

SERUM HUMANIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE-ORGAN DYSFUNCTION SYNDROME.

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.

Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort.

Background: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions. Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme. Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes. Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative 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.

External validation of the modified sepsis renal angina index for prediction of severe acute kidney injury in children with septic shock.

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 × 103/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.

Predictors of Failure of Noninvasive Ventilation in Critically Ill Children.

Noninvasive ventilation (NIV) is a common modality employed to treat acute respiratory failure. Most data guiding its use is extrapolated from adult studies. We sought to identify clinical predictors associated with failure of NIV, defined as requiring intubation. This single-center retrospective observational study included children admitted to pediatric intensive care unit (PICU) between July 2014 and June 2016 treated with NIV, excluding postextubation. A total of 148 patients was included. Twenty-seven (18%) failed NIV. There was no difference between the two groups with regard to age, gender, comorbidities, or etiology of acute respiratory failure. Those that failed had higher admission pediatric risk of mortality ( p = 0.01) and pediatric logistic organ dysfunction ( p = 0.002) scores and higher fraction of inspired oxygen (FiO 2 ; p = 0.009) at NIV initiation. Failure was associated with lack of improvement in tachypnea. At 6 hours of NIV, the failure group had worsening tachypnea with a median increase in respiratory rate of 8%, while the success group had a median reduction of 18% ( p = 0.06). Multivariable Cox's proportional hazard models revealed FiO 2 at initiation and worsening respiratory rate at 1- and 6-hour significant risks for failure of NIV. Failure was associated with a significantly longer PICU length of stay (success [2.8 days interquartile range (IQR): 1.7, 5.5] vs. failure [10.6 days IQR: 5.6, 13.2], p < 0.001). NIV can be successfully employed to treat acute respiratory failure in pediatric patients. There should be heightened concern for NIV failure in hypoxemic patients whose tachypnea is unresponsive to NIV. A trend toward improvement should be closely monitored.

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

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

Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock.

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.

Bivalirudin or heparin for systemic anticoagulation during pediatric extracorporeal membrane oxygenation: Multicenter retrospective study.

BACKGROUND: The objective of this study is to evaluate the outcomes of unfractionated heparin (UFH) compared to bivalirudin anticoagulation in pediatric ExtraCorporeal Membrane Oxygenation (ECMO). METHODS: A multicenter retrospective study, that included pediatric patients <18 years of age, who were supported on ECMO between June 2017 and May 2020. Patients treated with UFH were matched 2:1 by age and type of ECMO support to the bivalirudin group. RESULTS: The bivalirudin group (75 patients) were matched to 150 patients treated with UFH. Baseline characteristics and comorbidities of the two groups were similar. Veno-Arterial ECMO was the most common mode (141/225 [63 %]) followed by extracorporeal cardiopulmonary resuscitation (48/225 [21 %]). Bivalirudin treatment was associated with lower odds of bleeding events (aOR 0.23, 95%CI 0.12-0.45, p < 0.001) and lower odds of thrombotic events (aOR 0.48, 95%CI 0.23-0.98, p = 0.045). Patients who received bivalirudin had lesser odds for transfusion with fresh frozen plasma, and platelets (aOR 0.26, CI 0.12-0.57, p ≤0.001 and aOR 0.28, CI 0.15-0.53, p < 0.001, respectively). After adjusting for the type of ECMO support and adjusting for age, bivalirudin was associated with a decrease in hospital mortality by 50 % compared to the UFH group (aOR 0.50, 95%CI 0.27-0.93, p = 0.028). Similarly, for neurological disability at time of discharge, bivalirudin was associated with higher odds of intact neurological outcomes compared to UFH (OR 1.99 [95%CI 1.13-3.51], p = 0.017). CONCLUSIONS: This study demonstrated that effective anticoagulation can be achieved with bivalirudin, which was associated with lesser odds of bleeding events and utilization of blood products. Bivalirudin, in comparison with UFH, was associated with greater odds of hospital survival and intact neurological function at the time of discharge. A prospective randomized trial is required to validate the results of this study.

SERUM SOLUBLE ENDOGLIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE ORGAN DYSFUNCTION SYNDROME.

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.

Factors Associated With Improved Pediatric Resuscitative Care in General Emergency Departments.

OBJECTIVES: To describe the quality of pediatric resuscitative care in general emergency departments (GEDs) and to determine hospital-level factors associated with higher quality. METHODS: Prospective observational study of resuscitative care provided to 3 in situ simulated patients (infant seizure, infant sepsis, and child cardiac arrest) by interprofessional GED teams. A composite quality score (CQS) was measured and the association of this score with modifiable and nonmodifiable hospital-level factors was explored. RESULTS: A median CQS of 62.8 of 100 (interquartile range 50.5-71.1) was noted for 287 resuscitation teams from 175 emergency departments. In the unadjusted analyses, a higher score was associated with the modifiable factor of an affiliation with a pediatric academic medical center (PAMC) and the nonmodifiable factors of higher pediatric volume and location in the Northeast and Midwest. In the adjusted analyses, a higher CQS was associated with modifiable factors of an affiliation with a PAMC and the designation of both a nurse and physician pediatric emergency care coordinator, and nonmodifiable factors of higher pediatric volume and location in the Northeast and Midwest. A weak correlation was noted between quality and pediatric readiness scores. CONCLUSIONS: A low quality of pediatric resuscitative care, measured using simulation, was noted across a cohort of GEDs. Hospital factors associated with higher quality included: an affiliation with a PAMC, designation of a pediatric emergency care coordinator, higher pediatric volume, and geographic location. A weak correlation was noted between quality and pediatric readiness scores.

Revisiting post-ICU admission fluid balance across pediatric sepsis mortality risk strata: A secondary analyses from a prospective observational cohort study.

Introduction: 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 (AKI), and use of renal replacement therapy (CRRT) in pediatric septic shock. Design: Ongoing multi-center prospective observational cohort. Setting: Thirteen pediatric ICUs in the United States (2003-2023). Patients: Six hundred and eighty-one children with septic shock. Interventions: None. Measurements and Main Results: Cumulative percent positive fluid balance between day 1-7 (Day 1-7%PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of ≥ 2 organ dysfunctions by day 7. PERSEVERE-II biomarkers were used to assign mortality probability and categorize patients into high (n = 91), intermediate (n = 134), and low (n = 456) mortality risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis associated acute kidney injury (SA-AKI) on Day 3, and any use of CRRT, demonstrated that time-dependent variable Day 1-7%PFB was independently associated with increased hazard of complicated course in the cohort. Risk stratified analyses revealed that each 10% increase in Day 1-7%PFB was independently associated with increased hazard of complicated course among patients with high mortality risk strata (adj HR of 1.24 (95%CI: 1.08-1.42), p = 0.002), but not among those categorized as intermediate- or low- mortality risk. Conclusions: Our data demonstrate the independent influence of cumulative %PFB on the risk of complicated course. Contrary to our previous report, this risk was largely driven by patients categorized as having a high-mortality risk based on PERSEVERE-II biomarkers. Further research is necessary to determine whether this subset of patients may benefit from targeted deployment of restrictive fluid management or early initiation of de-escalation therapies upon resolution of shock.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

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.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

Background: Sepsis is associated with significant mortality, yet there are no efficacious therapies beyond antibiotics and supportive care. In adult sepsis studies, PCSK9 loss-of-function (LOF) and inhibition has shown therapeutic promise, likely through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance. In contrast, we previously demonstrated higher mortality in septic juvenile hosts with PCSK9 LOF. In addition to direct influence on serum lipoprotein levels, PCSK9 likely exerts pleiotropic effects on vascular endothelium. Both mechanisms may influence sepsis outcomes. We sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction in pediatric sepsis. Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. Single nucleotide polymorphisms of PCSK9 and LDLR genes were assessed. Serum PCSK9, lipoprotein, and endothelial marker concentrations were measured. Multivariable linear regression tested 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 assessed 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: 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of patients homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 levels did not correlate with endothelial dysfunction. PCSK9 LOF significantly influenced concentrations of Angiopoietin-1 (Angpt-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). However, upon adjusting for LDL and HDL, PCSK9 LOF remained significantly associated with low Angpt-1 alone. Causal Mediation Analysis demonstrated that the effect of PCSK9 LOF on mortality was partially 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: PCSK9 LOF independently influences serum Angpt-1 levels in pediatric septic shock. Angpt-1 likely contributes mechanistically to the effect of PCSK9 LOF on mortality in juvenile hosts. Mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of novel pediatric-specific sepsis therapies.

Mechanisms to expedite pediatric clinical trial site activation: The DOSE trial experience.

BACKGROUND: Timely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting. METHODS: The three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects. RESULTS: Twenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation. CONCLUSION: Study start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved. CLINICALTRIALS: gov #: NCT03938857.

Safety and Efficacy of Propofol- and Ketamine-Based Procedural Sedation Regimen in Pediatric Patients During Burn Repetitive Dressing Change: 10 Years Single Center Experience.

It is crucial to provide an adequate level of sedation and analgesia during burn dressing changes in the pediatric population due to the amount of pain and anxiety patients experience during the procedure. To evaluate the safety and efficacy of an intensivist-based deep sedation regimen using a combination of propofol and ketamine to provide procedural sedation to pediatric burn patients. This is a retrospective chart review of pediatric patients who underwent inpatient burn wound dressing changes from 2011 through 2021. Demographic and clinical data, including age, length of the procedure, recovery time, medication doses, and adverse events, were collected. A total of 104 patients aged between 45 and 135 months with a median total burn body surface area (TBSA) of 11.5 percent (interquartile range [IQR] 4.0, 25.0) underwent 378 procedural sedation encounters with propofol- and ketamine-based sedation. The median total dose of propofol was 7 mg/kg (IRQ 5.3, 9.2). Of these sedations, 64 (17 percent) had minor adverse events, of which 50 (13 percent) were transient hypoxemia, 12 (3 percent) were upper airway obstruction, and 2 (0.5 percent) were hypotension. There were no serious adverse events. Hypoxemia was not related to age, weight, gender, burn TBSA, or total dose of propofol. There were 35 (33.6 percent) patients who had repetitive sedation encounters with no statistically significant changes in propofol dose or adverse events with the repeated encounters. Children can be effectively sedated for repetitive inpatient burn dressing changes. Given the high-risk patient populations, this procedure should be performed under the vigilance of highly trained providers.

Simulation-based assessment of care for an infant with cardiogenic shock in the emergency department.

BACKGROUND: Congenital heart disease (CHD) is the leading cause of infant deaths associated with birth defects. Neonates with undiagnosed CHD often present to general emergency departments (GEDs) for initial resuscitation that are less prepared than paediatric centres, resulting in disparities in the quality of care. Neonates with undiagnosed CHD represent a challenge; thus, it is necessary for GEDs to be prepared for this population. AIM: To evaluate the process of resuscitative care provided to a neonate in cardiogenic shock due to CHD in the GEDs in a simulated setting and to describe the impact of teams and GED variables on the process of care. METHODS: This is a prospective simulation-based assessment of the process of care provided to a neonate with coarctation of the aorta in cardiogenic shock. Simulation sessions were conducted at participating GEDs utilizing each GED's interdisciplinary team and resources. The primary outcome was adherence to best practice, as measured by a 15-item overall composite adherence score (CAS). In addition, we stratified the overall CAS into CHD-critical items and the general resuscitation items CAS. The secondary outcome was the impact of the team's and GED's characteristics on the scores. RESULTS: This study enrolled 32 teams from 12 GEDs. Among 161 participants, 103 (63.97%) were registered nurses, 33 (20.50%) were physicians, 17 (10.56%) were respiratory therapists, and 8 (4.97%) were other medical professionals. The overall median CAS was 84, with the CHD-critical items having a median CAS of 34.5. The most underperformed tasks are checking pulses on the upper and lower extremities (44%), obtaining blood pressure in the upper and lower extremities (25%), and administering prostaglandin E1 (22%). CONCLUSIONS: Using in situ simulation in a set of GEDs, we revealed gaps in the resuscitation care of neonates with CHD in cardiogenic shock. RELEVANCE TO CLINICAL PRACTICE: These findings highlight the importance of targeted improvement programs for high-stakes illnesses in GED.