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.

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.

Practice variation in the immediate postoperative care of pediatric liver transplant patients: Framework for a national consensus.

Advancements in critical care management have led to improvement in pediatric LT outcomes. However, there are no specific guidelines for many aspects of immediate post-LT care. This survey examines practice variations in the immediate postoperative care of pediatric LT patients at a large number of active US centers. This study is a cross-sectional survey of medical directors at PALISI-affiliated PICU in the United States. Centers performing pediatric LT were analyzed. Study measures included PICU practices regarding staffing, composition of the multidisciplinary team, early post-LT graft and patient monitoring, and anticoagulation. Of the thirty-five responding centers, twenty-five had a LT program which accounted for one-half of all US pediatric LTs. For analysis, centers were categorized by volume: high (7), medium (11), and low (7). The majority of PICU teams included an intensivist (80%) and hepatologist (84%). High-volume centers were less likely to have 24-hour in-house attending coverage (29%, compared to 64% (medium) and 100% (low)). High-volume centers were most likely to have pre-printed orders, but least likely to have written PICU management protocols. Most centers utilize routine daily liver ultrasound. Routine prophylactic anticoagulation, and the agent of choice, was variable. There is marked inconsistency in post-LT practice across PALISI centers in regards to team composition and immediate post-LT management. A national US consensus for post-LT PICU practices would facilitate outcomes research and would establish a platform for multicenter studies.

Disparities in Adherence to Pediatric Diabetic Ketoacidosis Management Guidelines Across a Spectrum of Emergency Departments in the State of Indiana: An Observational In Situ Simulation-Based Study.

BACKGROUND: Diabetic ketoacidosis (DKA) is a common presentation to an emergency department (ED), with the majority presenting to community EDs. Adherence to clinical guidelines in these EDs can reduce morbidity and mortality. Few methods to describe practice gaps for DKA management have been reported. OBJECTIVES: We hypothesized that high-fidelity in situ simulation can be used to measure and compare the quality of the care provided to pediatric patients with DKA presenting to community EDs in the state of Indiana. METHODS: This observational study examined multiprofessional teams caring for a simulated pediatric patient who presented with DKA to community EDs. The primary outcome was overall adherence to pediatric DKA guidelines as measured by a validated performance checklist. A composite adherence score (CAS) was calculated using the sum of 9 checklist performance parameters. Multivariable logistic regression was used to examine the impact of ED volume and characteristics on the scores. RESULTS: A 49 multiprofessional teams from 13 sites were enrolled. Of the 252 participants, 26 (10.3%) were physicians, 143 (56.7%) registered nurses, 25 (9.9%) respiratory therapists, and 58 (23.0%) were other. The overall CAS for all sites was 55.6% (25th, 75th interquartile range, 44.4%, 66.7%). Excessive intravenous fluid boluses were given by 53.1%, whereas 30.6% and 26.5% incorrectly administered insulin and sodium bicarbonate boluses, respectively. Only 10.2% used an appropriate intravenous fluid rate, and 57.1% performed an hourly glucose. No significant difference in the CAS was found due to pediatric ED volume or presence of an inpatient pediatric service. CONCLUSIONS: Using validated in situ simulation; we revealed high variability in adherence to the pediatric DKA management guidelines at a wide range of community EDs. A statewide education initiative focused on decreasing variation and improving adherence to pediatric DKA guidelines is necessary for patient safety.

An Interprofessional Quality Improvement Initiative to Standardize Pediatric Extubation Readiness Assessment.

OBJECTIVES: Establishing protocols to wean mechanical ventilation and assess readiness for extubation, with the goal of minimizing morbidity associated with extubation failure and prolonged mechanical ventilation, have become increasingly important in contemporary PICUs. The aim of this quality improvement initiative is to establish a respiratory therapist-led daily spontaneous breathing trial protocol to standardize extubation readiness assessment and documentation in our PICU. DESIGN: A quality improvement project. SETTING: Single center, tertiary care Children's Hospital PICU. PATIENTS: All intubated patients admitted to PICU requiring conventional mechanical ventilation between February 2013 and January 2016. INTERVENTIONS: A working group of pediatric intensivists, respiratory therapists, nurses, and information technology specialists established the protocol, standardized documentation via the electronic medical record, and planned education. Daily spontaneous breathing trial protocol implementation began in February 2015. All patients on mechanical ventilation were screened daily at approximately 4 AM by a respiratory therapist to determine daily spontaneous breathing trial eligibility. If all screening criteria were met, patients were placed on continuous positive airway pressure of 5 cm H2O with pressure support of 8 cm H2O for up to 2 hours. If tolerated, patients would be extubated to supplemental oxygen delivered via nasal cannula in the morning, after intensivist approval. Daily audits were done to assess screening compliance and accuracy of documentation. MEASUREMENTS AND MAIN RESULTS: We analyzed data from 398 mechanically ventilated patients during daily spontaneous breathing trial period (February 2015-January 2016), compared with 833 patients from the pre-daily spontaneous breathing trial period (February 2013-January 2015). During the daily spontaneous breathing trial period, daily screening occurred in 92% of patients. Extubation failure decreased from 7.8% in the pre-daily spontaneous breathing trial period to 4.5% in daily spontaneous breathing trial period. The use of high-flow nasal cannula slightly increased during the project, while there was no change in duration of mechanical ventilation or the use of noninvasive ventilation. CONCLUSIONS: An interprofessionally developed respiratory therapist-led extubation readiness protocol can be successfully implemented in a busy tertiary care PICU without adverse events.