A Master Protocol Template for Pediatric ARDS Studies.

BACKGROUND: Pediatric ARDS is associated with significant morbidity and mortality. High-quality data from clinical trials in children are limited due to numerous barriers to their design and execution. Here we describe the collaborative development of a master protocol as a tool to address some of these barriers and support the conduct of pediatric ARDS studies. METHODS: Using PubMed, we performed a literature search of randomized controlled trials (RCTs) in pediatric ARDS to characterize the current state and evaluate potential benefit of harmonized master protocols. We used a multi-stakeholder, collaborative, and team science-oriented process to develop a master protocol template with links to common data elements (CDEs) for pediatric ARDS trials. RESULTS: We identified 11 RCTs that enrolled between 14-200 total subjects per trial. Interventions included mechanical ventilation, prone positioning, corticosteroids, and surfactant. Studies displayed significant heterogeneity in ARDS definition, design, inclusion and exclusion criteria, and reported outcomes. Mortality was reported in 91% of trials and ventilator-free days in 73%. The trial heterogeneity made pooled analysis unfeasible. These findings underscore the need for a method to facilitate combined analysis of future trials through standardization of trial elements. As a potential solution, we developed a master protocol, iteratively revised with input from a multidisciplinary panel of experts and organized into 3 categories: instructions and general information, templated language, and a series of text options of common pediatric ARDS trial scenarios. Finally, we linked master protocol sections to relevant CDEs previously defined for pediatric ARDS and captured in a series of electronic case report forms. CONCLUSIONS: The majority of pediatric ARDS trials identified were small and heterogeneous in study design and outcome reporting. Using a master protocol template for pediatric ARDS trials with CDEs would support combining and comparing pediatric ARDS trial findings and increase the knowledge base.

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.

Acute kidney injury in hospitalized children with proteinuria: A multicenter retrospective analysis.

BACKGROUND AND OBJECTIVE: Acute kidney injury (AKI) is a common complication in hospitalized pediatric patients. Previous studies focused on adults found that proteinuria detected during an admission urinalysis is fit to serve as an indicator for AKI and associated clinical outcomes. The objective of this study is to evaluate if proteinuria on the first day of hospital services in hospitalized children is associated with AKI, need for renal replacement therapy, shock and/or antibiotic use, critical care services, and all-cause mortality at 30 days, hypothesizing that it is associated with these outcomes. METHODS: This is a retrospective cohort study using TriNetX electronic health record data of patients 2 to 18 years of age who underwent urinalysis laboratory testing on hospital admission, had three subsequent days of hospital or critical care services billing codes and creatinine laboratory values, and no pre-existing renal-related complex chronic condition. This study evaluated for the frequency, odds, and severity of AKI as defined by Kidney Disease: Improving Global Outcomes modified criteria and assessed for associated clinical outcomes. RESULTS: This study included 971 pediatric subjects [435 (44.7%) with proteinuria]. Proteinuria on the first day of hospital services was associated with an increased odds for higher severity AKI on any day of hospitalization (odds ratio [OR] 2.41, CI 1.8-3.23, p<0.001), need for renal replacement therapy (OR 4.58, CI 1.69-12.4, p = 0.001), shock and/or antibiotic use (OR 1.34, CI 1.03-1.75, p = 0.033), and all-cause mortality at 30 days post-admission (OR 10.0, CI 1.25-80.5, p = 0.013). CONCLUSION: Children with proteinuria on the first day of hospital care services may have an increased odds of higher severity AKI, need for renal replacement therapy, shock and/or antibiotic use, and all-cause mortality at 30 days post-admission, with no significant association found for critical care services, mechanical intubation, or inotrope or vasopressor use.

A comprehensive review and shiny application on the matching-adjusted indirect comparison.

Population-adjusted indirect comparison (PAIC) is an increasingly used technique for estimating the comparative effectiveness of different treatments for the health technology assessments when head-to-head trials are unavailable. Three commonly used PAIC methods include matching-adjusted indirect comparison (MAIC), simulated treatment comparison (STC), and multilevel network meta-regression (ML-NMR). MAIC enables researchers to achieve balanced covariate distribution across two independent trials when individual participant data are only available in one trial. In this article, we provide a comprehensive review of the MAIC methods, including their theoretical derivation, implicit assumptions, and connection to calibration estimation in survey sampling. We discuss the nuances between anchored and unanchored MAIC, as well as their required assumptions. Furthermore, we implement various MAIC methods in a user-friendly R Shiny application Shiny-MAIC. To our knowledge, it is the first Shiny application that implements various MAIC methods. The Shiny-MAIC application offers choice between anchored or unanchored MAIC, choice among different types of covariates and outcomes, and two variance estimators including bootstrap and robust standard errors. An example with simulated data is provided to demonstrate the utility of the Shiny-MAIC application, enabling a user-friendly approach conducting MAIC for healthcare decision-making. The Shiny-MAIC is freely available through the link: https://ziren.shinyapps.io/Shiny_MAIC/.

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.

Immunocompromised-Associated Pediatric Acute Respiratory Distress Syndrome: Experience From the 2016/2017 Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Prospective Cohort Study.

OBJECTIVES: To characterize immunocompromised-associated pediatric acute respiratory distress syndrome (I-PARDS) and contrast it to PARDS. DESIGN: This is a secondary analysis of the 2016-2017 PARDS incidence and epidemiology (PARDIE) study, a prospective observational, cross-sectional study of children with PARDS. SETTING: Dataset of 145 PICUs across 27 countries. PATIENTS: During 10 nonconsecutive weeks (from May 2016 to June 2017), data about immunocompromising conditions (ICCs, defined as malignancy, congenital/acquired immunodeficiency, posttransplantation, or diseases requiring immunosuppression) were collected. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 708 subjects, 105 (14.8%) had ICC. Before the development of I-PARDS, those with ICC were more likely to be hospitalized (70% vs. 35%, p < 0.001), have more at-risk for PARDS ( p = 0.046), and spent more hours at-risk (20 [interquartile range, IQR: 8-46] vs. 11 [IQR: 4-33], [ p = 0.002]). Noninvasive ventilation (NIV) use was more common in those with ICC ( p < 0.001). Of those diagnosed with PARDS on NIV ( n = 161), children with ICC were more likely to be subsequently intubated ( n = 28/40 [70%] vs n = 53/121 [44%], p = 0.004). Severe PARDS was more common (32% vs 23%, p < 0.001) in I-PARDS. Oxygenation indices were higher at diagnosis and had less improvement over the first 3 days of PARDS ( p < 0.001). Children with I-PARDS had greater nonpulmonary organ dysfunction. Adjusting for Pediatric Risk of Mortality IV and oxygenation index, children with I-PARDS had a higher severity of illness-adjusted PICU mortality (adjusted hazard ratio: 3.0 [95% CI, 1.9-4.7] p < 0.001) and were less likely to be extubated alive within 28 days (subdistribution hazard ratio: 0.47 [95% CI, 0.31-0.71] p < 0.001). CONCLUSIONS: I-PARDS is a unique subtype of PARDS associated with hospitalization before diagnosis and increased: time at-risk for PARDS, NIV use, hypoxia, nonpulmonary organ dysfunction, and mortality. The opportunity for early detection and intervention seems to exist. Dedicated study in these patients is imperative to determine if targeted interventions will benefit these unique patients with the ultimate goal of improving outcomes.

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.

A Multicenter Retrospective Database Evaluation of Pediatric Patients Diagnosed With Tinea Capitis.

PURPOSE: Tinea capitis is a common pediatric superficial dermatophyte infection associated with lower socioeconomic status, overcrowded environments, and poor hygiene internationally. Nevertheless, to the authors' knowledge, no studies in the United States have reported an association between tinea capitis diagnoses and diagnostic codes for social determinants of health (SDOH). The objectives of the present study were to analyze the diagnostic and treatment approach and frequency of SDOH diagnostic codes in order to assess the presence of racial disparities in the treatment of pediatric patients aged 0 to 18 years diagnosed with tinea capitis. METHODS: This study comprised a retrospective analysis using the TriNetX electronic health record database of de-identified pediatric tinea capitis data in ambulatory and emergency settings. The data evaluated demographics, SDOH diagnostic codes, medication codes, and procedure codes. RESULTS: Analysis of 19,677 patients (17,471 [88.8%] ambulatory and 2206 [11.2%] emergency encounters) demonstrated that a low frequency of patients had a confirmatory test for tinea capitis (ie, potassium hydroxide prep or fungal culture; 5.5%), prescription for dual therapy (25.2%), or SDOH diagnostic codes (5.5%). Patients with races classified as Black (odds ratio = 0.48, 95% confidence interval = 0.41-0.57, p < 0.001) and "other" (odds ratio = 0.52, 95% confidence interval = 0.33-0.81, p = 0.004) had a lower likelihood of having an ambulatory encounter, but a higher likelihood of receiving dual therapy. CONCLUSIONS: This study found that diagnostic testing, dual therapy, and SDOH diagnostic codes were underutilized for pediatric patients diagnosed with tinea capitis. In addition, patients of races classified as Black and "other" were more likely to be diagnosed in emergency encounters, but had a higher likelihood of receiving dual therapy regardless of encounter type. Further research is needed to determine how to improve the management of tinea capitis and better understand its relationship with SDOH.

Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.

Background: Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection. Methods: We measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05). Results: Comparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week. Conclusion: Thus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.

The Modified Clinical Progression Scale for Pediatric Patients: Evaluation as a Severity Metric and Outcome Measure in Severe Acute Viral Respiratory Illness.

OBJECTIVES: To develop, evaluate, and explore the use of a pediatric ordinal score as a potential clinical trial outcome metric in children hospitalized with acute hypoxic respiratory failure caused by viral respiratory infections. DESIGN: We modified the World Health Organization Clinical Progression Scale for pediatric patients (CPS-Ped) and assigned CPS-Ped at admission, days 2-4, 7, and 14. We identified predictors of clinical improvement (day 14 CPS-Ped ≤ 2 or a three-point decrease) using competing risks regression and compared clinical improvement to hospital length of stay (LOS) and ventilator-free days. We estimated sample sizes (80% power) to detect a 15% clinical improvement. SETTING: North American pediatric hospitals. PATIENTS: Three cohorts of pediatric patients with acute hypoxic respiratory failure receiving intensive care: two influenza (pediatric intensive care influenza [PICFLU], n = 263, 31 sites; PICFLU vaccine effectiveness [PICFLU-VE], n = 143, 17 sites) and one COVID-19 ( n = 237, 47 sites). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Invasive mechanical ventilation rates were 71.4%, 32.9%, and 37.1% for PICFLU, PICFLU-VE, and COVID-19 with less than 5% mortality for all three cohorts. Maximum CPS-Ped (0 = home at respiratory baseline to 8 = death) was positively associated with hospital LOS ( p < 0.001, all cohorts). Across the three cohorts, many patients' CPS-Ped worsened after admission (39%, 18%, and 49%), with some patients progressing to invasive mechanical ventilation or death (19%, 11%, and 17%). Despite this, greater than 76% of patients across cohorts clinically improved by day 14. Estimated sample sizes per group using CPS-Ped to detect a percentage increase in clinical improvement were feasible (influenza 15%, n = 142; 10%, n = 225; COVID-19, 15% n = 208) compared with mortality ( n > 21,000, all), and ventilator-free days (influenza 15%, n = 167). CONCLUSIONS: The CPS-Ped can be used to describe the time course of illness and threshold for clinical improvement in hospitalized children and adolescents with acute respiratory failure from viral infections. This outcome measure could feasibly be used in clinical trials to evaluate in-hospital recovery.

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.

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.

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.

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.

Multicenter retrospective database evaluation of Takotsubo syndrome in subjects undergoing catheter ablation for atrial fibrillation.

Background: Intracardiac catheter ablation for atrial fibrillation with pulmonary vein isolation may result in Takotsubo syndrome (TS), but the frequency, predisposing factors (age, sex, mental health disorders), and outcomes are currently unknown. This study sought to assess the frequency, predisposing factors, and outcomes of subjects who underwent intracardiac catheter ablation for atrial fibrillation with pulmonary vein isolation and were diagnosed with TS. Methods: This was a retrospective observational cohort study utilizing TriNetX® electronic health record (EHR) data. We included subjects aged older than 18 years who underwent intracardiac catheter ablation for atrial fibrillation with pulmonary vein isolation. The study population was divided into two groups (no TS diagnostic code presence and TS diagnostic code presence). We analyzed the distributions of age, sex, race, diagnostic codes, common terminology procedures (CPT), and vasoactive medication codes and examined mortality rate within 30 days. Results: We included 69,116 subjects. Of these, 27 (0.04%) had a TS diagnostic code, the cohort was comprised mostly of females [17 (63.0%)], and 1 (3.7%) death within 30 days was reported. There were no significant differences in age and frequency of mental health disorders between those patients in TS and non-TS cohorts. Adjusting for age, sex, race, ethnicity, patient regionality, and mental health disorder diagnostic code, those patients who developed TS had a significantly higher odds of dying in 30 days after catheter ablation compared to those without TS (OR = 15.97, 95% CI: 2.10-121.55, p = .007). Conclusions: Approximately 0.04% of subjects who underwent intracardiac catheter ablation of atrial fibrillation by pulmonary vein isolation had a subsequent diagnostic code of TS. Further study is needed to determine whether there are predisposing factors associated with the development of TS in subjects who undergo catheter ablation of atrial fibrillation by pulmonary vein isolation.

Retrospective Analysis of Sugammadex Use in Adolescent Females on Progestin-Containing Contraceptives.

STUDY OBJECTIVE: Sugammadex, a novel neuromuscular blockade reversal agent, functions as a steroid binder postulated to decrease hormone exposure used within progestin-containing contraceptive medications. Thus, alternative non-medication contraceptive methods are recommended to prevent unplanned pregnancies. The study aims were to evaluate sugammadex use in adolescent females prescribed a progestin-containing contraceptive and positive pregnancy screening frequency. We hypothesized that sugammadex use is infrequent in this population and no pregnancy screens would be positive. METHODS: This is a retrospective observational cohort study utilizing the TriNetX electronic health record database of female subjects aged 12-21 years reported to be prescribed sugammadex. The data collected were analyzed for demographic characteristics, International Classification of Diseases 9th and 10th edition diagnostics, medication, procedural codes, progestin-containing medication timing, and timing of pregnancy screening. RESULTS: We included 18,686 subjects (contraceptive group, 2017 [10.8%], and no contraceptive group, 16,669 [89.2%]). Both groups had similar frequencies of pregnancy screening (contraceptive group, 54 [2.7%], vs no contraceptive group, 366 [2.2%]). Of the contraceptive group, 1 (0.05%) subject, 17 years of age, was confirmed to have a positive pregnancy screen 35 days after surgery. CONCLUSION: We found that sugammadex may be administered to adolescent females prescribed progestin-containing contraceptives, but positive pregnancy screens are rare. Effective counseling, use of nonhormonal contraceptives 7 days after sugammadex administration, and the theoretical reproductive risks of this agent may have contributed to these findings. Continued counseling after sugammadex use in the adolescent population is recommended to avoid the occurrence of unplanned pregnancies.

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.