Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes.

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

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.

Diagnostic Validation of the Updated Pediatric Sepsis Biomarker Risk II for Acute Kidney Injury Prediction Model in Pediatric Septic Shock.

OBJECTIVES: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed. DESIGN: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022. SETTING: Ten PICUs in the United States. PATIENTS: Children with septic shock 1 week to 18 years old admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seventy-nine of 363 patients (22%) had D3 severe AKI, defined as Kidney Disease Improving Global Outcomes stage 2 or higher. Patients were assigned a probability of D3 severe AKI using the PERSEVERE-II AKI model. The model predicted D3 severe AKI with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.85-0.93), sensitivity of 77% (95% CI, 66-86%), specificity of 88% (95% CI, 84-92%), positive predictive value of 65% (95% CI, 54-74%), and negative predictive value of 93% (95% CI, 89-96%). These data represent an increase in post-test probability of D3 severe AKI with a positive test from 22% to 65%, and a prevalence threshold of 28%. On multivariable regression, the PERSEVERE-II AKI prediction model demonstrated greater adjusted odds ratio (aOR) for D3 severe AKI (aOR, 11.2; 95% CI, 4.9-25.3) and lesser aOR for failure of D3 renal recovery from early AKI (aOR, 0.31; 95% CI, 0.13-0.69). CONCLUSIONS: The PERSEVERE-II AKI model demonstrates consistently robust performance for prediction of new or persistent D3 severe AKI in children with septic shock. A major limitation is that actual D3 severe AKI prevalence is below the prevalence threshold for the test, and thus future work should focus on evaluating use in enriched populations.

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.

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.

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.

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.

Improving Pediatric Readiness and Clinical Care in General Emergency Departments: A Multicenter Retrospective Cohort Study.

OBJECTIVE: To evaluate the impact of a collaborative initiative between general emergency departments (EDs) and the pediatric academic medical center on the process of clinical care in a group of general EDs. STUDY DESIGN: This retrospective cohort study assessed the process of clinical care delivered to critically ill children presenting to 3 general EDs. Our previous multifaceted intervention included the following components: postsimulation debriefing, designation of a pediatric champion, customized performance reports, pediatric resources toolkit, and ongoing interactions. Five pediatric emergency care physicians conducted chart reviews and scored encounters using the Pediatric Emergency Care Research Network's Quality of Care Implicit Review Instrument, which assigns scores between 5 and 35 across 5 domains. In addition, safety metrics were collected for medication, imaging, and laboratory orders. RESULTS: A total of 179 ED encounters were reviewed, including 103 preintervention and 76 postintervention encounters, with an improvement in mean total quality score from 23.30 (SD 5.1) to 24.80 (4.0). In the domain of physician initial treatment plan and initial orders, scores increased from a mean of 4.18 (0.13) to 4.61 (0.15). In the category of safety, administration of wrong medications decreased from 28.2% to 11.8% after the intervention. CONCLUSION: A multifaceted collaborative initiative involving simulation and enhanced pediatric readiness was associated with improvement in the processes of care in general EDs. This work provides evidence that innovative collaborations between academic medical centers and general EDs may serve as an effective strategy to improve pediatric care.

Improving the Quality of Clinical Care of Children with Diabetic Ketoacidosis in General Emergency Departments Following a Collaborative Improvement Program with an Academic Medical Center.

OBJECTIVE: To evaluate the impact of a collaborative initiative between a group of general emergency departments (EDs) and an academic medical center (AMC) on the process of care provided to patients with diabetic ketoacidosis (DKA) across these EDs. STUDY DESIGN: A retrospective cohort study (January 2015 to December 2018) of all pediatric patients <18 years who presented with DKA to participating EDs and were subsequently admitted to the pediatric intensive care unit at the AMC. Our multifaceted intervention included simulation with postsimulation debriefing, targeted assessment reports, distribution of DKA best practices, pediatric DKA module, and scheduled check-in visits. The process of clinical care was measured by adherence to the pediatric DKA 9-item checklist. Adherence was scored based on the number of items performed correctly and calculated using equal weight for items and dividing by the total number of items. Patients' clinical outcomes also were collected. RESULTS: A total of 85 patients with DKA were included in the analysis; 38 patients were in the preintervention, and 47 were in the postintervention. There was a statistically significant improvement in adherence to the DKA checklist from 77.8% to 88.9%. Two of the 9 checklist items (hourly glucose check and appropriate fluid rate) showed statistically significant improvement. No significant change in patient clinical outcomes was noted. CONCLUSIONS: Our collaborative initiative resulted in significant improvements in adherence to pediatric DKA best practices across a group of general EDs. A collaborative approach between general EDs and AMCs is an effective improvement strategy for pediatric emergency care.

Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study.

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

Quality of Resuscitative Care Provided to an Infant With Abusive Head Trauma in Community Emergency Departments: An In Situ, Prospective, Simulation-Based Study.

OBJECTIVES: Abusive head trauma (AHT) is a very common and serious form of physical abuse, and a major cause of mortality and morbidity for young children. Early Recognition and supportive care of children with AHT is a common challenge in community emergency department (CEDs). We hypothesized that standardized, in situ simulation can be used to measure and compare the quality of resuscitative measures provided to children with AHT in a diverse set of CEDs. METHODS: This prospective, simulation-based study measured teams' performance across CEDs. The primary outcome was overall adherence to AHT using a 15-item performance assessment checklist based on the number of tasks performed correctly on the checklist. RESULTS: Fifty-three multiprofessional teams from 18 CEDs participated in the study. Of 270 participants, 20.7% were physicians, 65.2% registered nurses, and 14.1% were other providers. Out of all tasks, assessment of airway/breathing was the most successfully conducted task by 53/53 teams (100%). Although 43/53 teams (81%) verbalized the suspicion for AHT, only 21 (39.6%) of 53 teams used hyperosmolar agent, 4 (7.5%) of 53 teams applied cervical spine collar stabilization, and 6 (11.3%) of 53 teams raised the head of the bed. No significant difference in adherence to the checklist was found in the CEDs with an inpatient pediatric service or these with designated adult trauma centers compared with CEDs without. Community emergency departments closer to the main academic center outperformed CEDs these that are further away. CONCLUSIONS: This study used in situ simulation to describe quality of resuscitative care provided to an infant presenting with AHT across a diverse set of CEDs, revealing variability in the initial recognition and stabilizing efforts and provided and targets for improvement. Future interventions focusing on reducing these gaps could improve the performance of CED providers and lead to improved patient outcomes.

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.

Survival outcomes of in-hospital cardiac arrest in pediatric patients in the USA.

We report on in-hospital cardiac arrest outcomes in the USA. The data were obtained from the National (Nationwide) Inpatient Sample datasets for the years 2000-2017, which includes data from participating hospitals in 47 US states and the District of Columbia. We included pediatric patients (< 18 years of age) with cardiac arrest, and we excluded patients with no cardiopulmonary resuscitation during the hospitalization. Primary outcome of the study was in-hospital mortality after cardiac arrest. A multivariable logistic regression was performed to identify factors associated with survival. A total of 20,654 patients were identified, and 8226 (39.82%) patients survived to discharge. The median length of stay and cost of hospitalization were significantly higher in the survivors vs. non-survivors (LOS 18 days vs. 1 day, and cost $187,434 vs. $45,811, respectively, p < 0.001). In a multivariable model, patients admitted to teaching hospitals, elective admissions, and those admitted on weekdays had higher survival (aOR=1.19, CI: 1.06-1.33; aOR=2.65, CI: 2.37-2.97; and aOR=1.17, CI: 1.07-1.27, respectively). There was no difference in mortality between patients with extracorporeal cardiopulmonary resuscitation (E-CPR) and those with conventional cardiopulmonary resuscitation. E-CPR patients were likely to have congenital heart surgery (51.0% vs. 20.8%).Conclusion: We highlighted the survival predictors in these events, which can guide future studies aimed at improving outcomes in pediatric cardiac arrest. What is Known: • In-hospital cardiac arrest occurs in 2-6% of pediatric intensive care admissions. • Cardiac arrests had a significant impact on hospital resources and a significantly high mortality rate. What is New: • Factors associated with higher survival rates in patients with cardiac arrest: admission to teaching hospitals, elective admissions, and week-day admissions. • The use of rescue extracorporeal cardiopulmonary resuscitation in refractory cardiac arrest has increased by threefold over the last two decades.

Adjuvant lidocaine to a propofol-ketamine-based sedation regimen for bone marrow aspirates and biopsy in the pediatric population.

Pediatric patients with hematological malignancies repeatedly undergo painful bone marrow aspirates and biopsies (BMABs) in routine care. No standard sedation regimen has been established. This study evaluated the addition of injected local lidocaine to a propofol-ketamine sedation for BMAB and its effects on propofol dosing, safety, and efficacy. A retrospective analysis of children undergoing BMAB with propofol-ketamine with (PK+L) and without (PK-only) the injection of local lidocaine. Patients were matched through propensity probability scores. To measure efficacy, dosing, procedure length, and recovery time were evaluated. To assess safety, adverse and serious events were recorded. As an indirect measurement of analgesia, changes in heart rate and blood pressure were analyzed. Of the 420 encounters included, 188 matched pairs (376 patients) were analyzed. Patient demographics were comparable. The median dose of propofol was not significantly different between both groups. The incidence of adverse events was similar. There were no significant differences in the changes in heart rate and blood pressure with sedation between groups.Conclusion: This study suggests that the addition of local lidocaine injection to a propofol-ketamine sedation for BMAB pediatric patients does not affect the propofol dose, safety, or efficacy properties of the regimen. What is Known: •Although propofol is commonly used, there is no standard sedation regimen for pediatric patients undergoing bone marrow aspiration and biopsy. •Local lidocaine is used in analgesia in the adults undergoing the same procedure. What is New: •Local lidocaine adjuvant to propofol-ketamine sedation does not affect propofol dosing, the safety of efficacy properties of the regimen in the pediatric population.

PERSEVERE Biomarkers Predict Severe Acute Kidney Injury and Renal Recovery in Pediatric Septic Shock.

Rationale: Acute kidney injury (AKI), a common complication of sepsis, is associated with substantial morbidity and mortality and lacks definitive disease-modifying therapy. Early, reliable identification of at-risk patients is important for targeted implementation of renal protective measures. The updated Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) is a validated, multibiomarker prognostic enrichment strategy to estimate baseline mortality risk in pediatric septic shock.Objectives: To assess the association between PERSEVERE-II mortality probability and the development of severe, sepsis-associated AKI on Day 3 (D3 SA-AKI) in pediatric septic shock.Methods: We performed secondary analysis of a prospective observational study of children with septic shock in whom the PERSEVERE biomarkers were measured to assign a PERSEVERE-II baseline mortality risk.Measurements and Main Results: Among 379 patients, 65 (17%) developed severe D3 SA-AKI. The proportion of patients developing severe D3 SA-AKI increased directly with increasing PERSEVERE-II risk category, and increasing PERSEVERE-II mortality probability was independently associated with increased odds of severe D3 SA-AKI after adjustment for age and illness severity (odds ratio, 1.4; 95% confidence interval, 1.2-1.7; P < 0.001). Similar associations were found between increasing PERSEVERE-II mortality probability and the need for renal replacement therapy. Lower PERSEVERE-II mortality probability was independently associated with increased odds of renal recovery among patients with early AKI. A newly derived model incorporating the PERSEVERE biomarkers and Day 1 AKI status predicted severe D3 SA-AKI with an area under the received operating characteristic curve of 0.95 (95% confidence interval, 0.92-0.98).Conclusions: Among children with septic shock, the PERSEVERE biomarkers predict severe D3 SA-AKI and identify patients with early AKI who are likely to recover.

Improving Pediatric Diabetic Ketoacidosis Management in Community Emergency Departments Using a Simulation-Based Collaborative Improvement Program.

OBJECTIVES: The majority of pediatric patients with diabetic ketoacidosis (DKA) present to community emergency departments (CEDs) that are less prepared to care for acutely ill children owing to low pediatric volume and limited pediatric resources and guidelines. This has impacted the quality of care provided to pediatric patients in CEDs. We hypothesized that a simulation-based collaborative program would improve the quality of the care provided to simulated pediatric DKA patients presenting to CEDs. METHODS: This prospective interventional study measured adherence of multiprofessional teams caring for pediatric DKA patients preimplementation and postimplementation of an improvement program in simulated setting. The program consisted of (a) a postsimulation debriefing, (b) assessment reports, (c) distribution of educational materials and access to pediatric resources, and (d) ongoing communication with the academic medical center (AMC). All simulations were conducted in situ (in the CED resuscitation bay) and were facilitated by a collaborative team from the AMC. A composite adherence score was calculated using a critical action checklist. A mixed linear regression model was performed to examine the impact of CED and team-level variables on the scores. RESULTS: A total of 91 teams from 13 CEDs participated in simulated sessions. There was a 22-point improvement of overall adherence to the DKA checklist from the preintervention to the postintervention simulations. Six of 9 critical checklist actions showed statistically significant improvement. Community emergency departments with medium pediatric volume showed the most overall improvement. Teams from CEDs that are further from the AMC showed the least improvement from baseline. CONCLUSIONS: This study demonstrated a significant improvement in adherence to pediatric DKA guidelines in CEDs across the state after execution of an in situ simulation-based collaborative improvement program.

Proprotein Convertase Subtilisin/Kexin Type 9 Loss-of-Function Is Detrimental to the Juvenile Host With Septic Shock.

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

Progression of Respiratory Support Following Pediatric Extubation.

OBJECTIVES: High-flow nasal cannula and noninvasive positive pressure ventilation have become ubiquitous in contemporary PICUs. Practice patterns associated with the use of these modalities have not been well described. In this study, we aimed to describe the use of high-flow nasal cannula and noninvasive positive pressure ventilation in children after extubation and analyze the progression of usage in association with patient factors. Our secondary aim was to describe interventions used for postextubation stridor. DESIGN: Single-center retrospective cohort study. SETTING: A 36-bed quaternary medical-surgical PICU. PATIENTS: Mechanically ventilated pediatric patients admitted between April 2017 and March 2018. Exclusions were patients in the cardiac ICU, patients requiring a tracheostomy or chronic ventilatory support, and patients with limited resuscitation status. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data regarding respiratory modality use was collected for the first 72 hours after extubation. There were 427 patients included in the analysis; 51 patients (11.9%) were extubated to room air, 221 (51.8%) to nasal cannula, 132 (30.9%) to high-flow nasal cannula, and 23 (5.4%) to noninvasive positive pressure ventilation. By 72 hours, 314 patients (73.5%) were on room air, 52 (12.2%) on nasal cannula, 29 (6.8%) on high-flow nasal cannula, eight (1.9%) on noninvasive positive pressure ventilation, and 24 (5.6%) were reintubated. High-flow nasal cannula was the most used respiratory modality for postextubation stridor. Multivariate analysis demonstrated that longer duration of invasive mechanical ventilation increased the odds of initial high-flow nasal cannula and noninvasive positive pressure ventilation use, and a diagnosis of cerebral palsy increased the odds of escalating from high-flow nasal cannula to noninvasive positive pressure ventilation in the first 24 hours post extubation. CONCLUSIONS: High-flow nasal cannula is commonly used immediately after pediatric extubation and the development of postextubation stridor; however, its usage sharply declines over the following 72 hours. Larger multicenter trials are needed to identify high-risk patients for extubation failure that might benefit the most from prophylactic use of high-flow nasal cannula and noninvasive positive pressure ventilation after extubation.

Isolating red flags to enhance diagnosis (I-RED): An experimental vignette study.

OBJECTIVE: To investigate effects of a cognitive intervention based on isolation of red flags (I-RED) on diagnostic accuracy of 'do-not-miss diagnoses.' DESIGN: A 2 × 2 randomized case vignette-based experiment with manipulation of I-RED strategy between subjects and case complexity within subjects. SETTING: Two university-based residency programs. PARTICIPANTS: One-hundred and nine pediatric residents from all levels of training. INTERVENTIONS: Participants were randomly assigned to the I-RED vs. control group, and within each group, they were further randomized to the order in which they saw simple and complex cases. The I-RED strategy involved an instruction to look for a constellation of symptoms, signs, clinical data or circumstances that should heighten suspicion for a serious condition. MAIN OUTCOME MEASURES: Primary outcome was diagnostic accuracy, scored as 1 if any of the three differentials given by participants included the correct diagnosis, and 0 if not. We analyzed effects of I-RED strategy on diagnostic accuracy using logistic regression. RESULTS: I-RED strategy did not yield statistically higher diagnostic accuracy compared to controls (62 vs. 48%, respectively; odd ratio = 2.07 [95% confidence interval, 0.78-5.5], P = 0.14) although participants reported higher decision confidence compared to controls (7.00 vs. 5.77 on a scale of 1 to 10, P < 0.02) in simple but not complex cases. I-RED strategy significantly shortened time to decision (460 vs. 657 s, P < 0.001) and increased the number of red flags generated (3.04 vs. 2.09, P < 0.001). CONCLUSIONS: A cognitive strategy of prompting red flag isolation prior to differential diagnosis did not improve diagnostic accuracy of 'do-not-miss diagnoses.' Given the paucity of evidence-based solutions to reduce diagnostic error and the intervention's potential effect on confidence, findings warrant additional exploration.

Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response.

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