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.

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 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.

Reductions in invasive device use and care costs after institution of a daily safety checklist in a pediatric critical care unit.

BACKGROUND: In the critical care unit, complexity of care can contribute to both medical errors and increased costs, particularly when clinicians are forced to rely on memory. Checklists can be used to improve safety and reduce cost. A number of omission-related adverse events in 2010 prompted the development of a checklist to reduce the possibility of similar future events. METHODS: The PICU Safety Checklist was implemented in the pediatric ICU (PICU) at Children's Hospitals and Clinics of Minnesota. During a 21-month period, the checklist was used to prompt the care team to address quality and safety items during rounds. The initial checklist was paper, with two subsequent versions being incorporated into the electronic medical record (EMR). RESULTS: The daily safety checklist was successfully implemented in the PICU. Work-flow improvements based on regular multidisciplinary feedback led to more consistent use of the checklist. Improvements on all quality and safety metrics were identified, including invasive device use, medication costs, antibiotic and laboratory test use, and compliance with standards of care. Staff satisfaction rates were > 80% for safety, communication, and collaboration. CONCLUSION: By using a daily safety checklist in the pediatric critical care unit, we improved quality and safety, as well as the collaborative culture among all clinicians. Incorporating the checklist into the EMR improved compliance and accountability, ensuring its application to all patients. Clinicians now often individually address many checklist items outside the formal rounding process, indicating that the checklist content has become part of their usual practice. A successful implementation showing tangible clinical improvements can lead to interest and adoption in other clinical areas within the institution.

Reducing catheter-associated bloodstream infections in the pediatric intensive care unit: Business case for quality improvement.

OBJECTIVE: To determine whether catheter-associated bloodstream infections were associated with increased lengths of stay in pediatric intensive care units and hospitals and increased healthcare costs in critically ill children. Previous studies have shown that hospital-acquired bloodstream infections are associated with longer stays in pediatric intensive care units, increased hospital costs, and increased hospital mortality. Catheter-associated bloodstream infections comprise the vast majority of hospital-acquired bloodstream infections. DESIGN: Retrospective, case-matched, cohort study and financial analysis. SETTING: University-affiliated children's medical center. PATIENTS: Twenty-two critically ill children with catheter-associated bloodstream infections and their matched controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the length of stay, mortality, and hospital costs in critically ill children with catheter-associated bloodstream infections and matched controls. The presence of catheter-associated bloodstream infections extended the entire hospital length of stay by 9 days (6.5 days while in the pediatric intensive care unit) and increased hospital costs by $33,039, primarily driven by the increase in length of stay days. Quality improvement efforts directed at reducing the prevalence of catheter-associated bloodstream infections during the period of study decreased total hospital days by 354, reduced total hospital costs by $1,298,271, and reduced total costs to payers by $1,415,676. CONCLUSION: The potential cost savings from reducing or eliminating catheter-associated bloodstream infections in the pediatric intensive care unit are significant. Elimination of catheter-associated bloodstream infections will directly reduce hospital costs, improve asset utilization, and most importantly, improve clinical care.