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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., Competing Interests: Dr. Stanski’s institution received funding from the National Institute of General Medical Sciences (NIGMS); she disclosed that they hold a provisional patent for the Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (AKI) Prediction Model. Drs. Stanski, Cvijanovich, Fitzgerald, Thomas, Weiss, Atreya, Lautz, and Kaplan received support for article research from the National Institutes of Health. Dr. Cvijanovich’s institution received funding from the Cincinnati Children’s Hospital Medical Center, the Nationwide Children’s Hospital, the Boston Children’s Hospital, and the Collaborative Pediatric Critical Care Research Network. Dr. Fitzgerald received funding from the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK119463, P50DK114786) and the Commonwealth of Pennsylvania Department of Health Cure Grant. Dr. Jain received funding from AltaThera Pharmaceuticals. Dr. Lautz received funding from the NIGMS (K08GM148957-01, R21GM150093-01, and L40GM134527-03). Dr. Atreya’s institution received funding from the Cincinnati Children’s Research Foundation; he disclosed that they hold a provisional patent for the integrated PERSEVERE and endothelial biomarker risk model to predict sepsis-associted acute kidney injury (PERSEVEREnce SA-AKI model); and he received funding through the Procter K to R Scholar program awarded by the Cincinnati Children’s Research Foundation and the NIGMS (R21GM151703 and R21GM15009). Dr. Weiss received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD102396, R01HD101528) and the U.S. Centers for Disease Control and Prevention (75D30123C17693). Dr. Zingarelli’s institution received funding from the NIGMS (R01 GM115973, R21 GM151734, 1R21GM150093, and R01GM145698); she received funding from the National Heart, Lung, and Blood Institute (R01 HL141229); and she disclosed that they are editor of the Shock journal. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

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., (© 2024. The Author(s).)

Background: Multiple organ dysfunction syndrome (MODS) disproportionately drives morbidity and mortality among critically ill patients. However, we lack a comprehensive understanding of its pathobiology. Identification of genes associated with a persistent MODS trajectory may shed light on underlying biology and allow for accurate prediction of those at-risk., Methods: Secondary analyses of publicly available gene-expression datasets. Supervised machine learning (ML) was used to identify a parsimonious set of genes associated with a persistent MODS trajectory in a training set of pediatric septic shock. We optimized model parameters and tested risk-prediction capabilities in independent validation and test datasets, respectively. We compared model performance relative to an established gene-set predictive of sepsis mortality., Findings: Patients with a persistent MODS trajectory had 568 differentially expressed genes and characterized by a dysregulated innate immune response. Supervised ML identified 111 genes associated with the outcome of interest on repeated cross-validation, with an AUROC of 0.87 (95% CI: 0.85-0.88) in the training set. The optimized model, limited to 20 genes, achieved AUROCs ranging from 0.74 to 0.79 in the validation and test sets to predict those with persistent MODS, regardless of host age and cause of organ dysfunction. Our classifier demonstrated reproducibility in identifying those with persistent MODS in comparison with a published gene-set predictive of sepsis mortality., Interpretation: We demonstrate the utility of supervised ML driven identification of the genes associated with persistent MODS. Pending validation in enriched cohorts with a high burden of organ dysfunction, such an approach may inform targeted delivery of interventions among at-risk patients., Funding: H.R.W.'s NIHR35GM126943 award supported the work detailed in this manuscript. Upon his death, the award was transferred to M.N.A. M.R.A., N.S.P, and R.K were supported by NIHR21GM151703. R.K. was supported by R01GM139967., Competing Interests: Declaration of interests Conflict of interest: M.R.A, S.B, R.K, and Cincinnati Children's Hospital Medical Center hold a provisional patent for the work detailed in this manuscript. M.W.H received funding through the NIH, received royalties and honoraria, served on DSMB, and received study drug for clinical trials, all unrelated to the current manuscript. N.S.P has stocks in Celldom, Saccharo and Allyx, and has received grants from NIH. The remaining authors have no conflict of interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 × 10 3 /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., (© 2023. The Author(s).)

Background: Single-center studies have identified risk factors for peri-intubation cardiac arrest in the emergency department (ED). The study objective was to generate validity evidence from a more diverse, multicenter cohort of patients., Methods: We completed a retrospective cohort study of 1200 paediatric patients who underwent tracheal intubation in eight academic paediatric EDs (150 per ED). The exposure variables were 6 previously studied high-risk criteria for peri-intubation arrest: (1) persistent hypoxemia despite supplemental oxygen, (2) persistent hypotension, (3) concern for cardiac dysfunction, (4) post-return of spontaneous circulation (ROSC), (5) severe metabolic acidosis (pH < 7.1), and (6) status asthmaticus. The primary outcome was peri-intubation cardiac arrest. Secondary outcomes included extracorporeal membrane oxygenation (ECMO) cannulation and in-hospital mortality. We compared all outcomes between patients that met one or more versus no high-risk criteria, using generalized linear mixed models., Results: Of the 1,200 paediatric patients, 332 (27.7%) met at least one of 6 high-risk criteria. Of these, 29 (8.7%) suffered peri-intubation arrest compared to zero arrests in patients meeting none of the criteria. On adjusted analysis, meeting at least one high-risk criterion was associated with all 3 outcomes - peri-intubation arrest (AOR 75.7, 95% CI 9.7-592.6), ECMO (AOR 7.1, 95% CI 2.3-22.3) and mortality (AOR 3.4, 95% 1.9-6.2). Four of 6 criteria were independently associated with peri-intubation arrest: persistent hypoxemia despite supplemental oxygen, persistent hypotension, concern for cardiac dysfunction, and post-ROSC., Conclusions: In a multicenter study, we confirmed that meeting at least one high-risk criterion was associated with paediatric peri-intubation cardiac arrest and patient mortality., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Preston Dean reports financial support was provided by American Academy of Pediatrics’., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Sepsis-associated myocardial dysfunction is common in pediatric septic shock and negatively impacts outcomes. Early estimation of sepsis-associated myocardial dysfunction risk has the potential to inform clinical care and improve clinical trial design. The Pediatric Sepsis Biomarker Risk Model II is validated as a biomarker-based enrichment algorithm to discriminate children with septic shock with high baseline mortality probability. The objectives were to determine if Pediatric Sepsis Biomarker Risk Model biomarkers are associated with risk for sepsis-associated myocardial dysfunction in pediatric septic shock and to develop a biomarker-based model to reliably estimate sepsis-associated myocardial dysfunction risk., Design: Secondary analysis of prospective cohort study., Setting: Single-center, quaternary-care PICU., Patients: Children less than 18 years old admitted to the PICU from 2003 to 2018 who had Pediatric Sepsis Biomarker Risk Model biomarkers measured for determination of Pediatric Sepsis Biomarker Risk Model II mortality probability and an echocardiogram performed within 48 hours of septic shock identification., Interventions: None., Measurements and Main Results: Pediatric Sepsis Biomarker Risk Model II mortality probability was calculated from serum biomarker concentrations and admission platelet count. Echocardiograms were reread by a single cardiologist blinded to Pediatric Sepsis Biomarker Risk Model II data, and sepsis-associated myocardial dysfunction was defined as left ventricular ejection fraction less than 45% for primary analyses. Multivariable logistic regression analyzed the association of Pediatric Sepsis Biomarker Risk Model II mortality probability with sepsis-associated myocardial dysfunction. Classification and regression tree methodology was employed to derive a Pediatric Sepsis Biomarker Risk Model biomarker-based model for sepsis-associated myocardial dysfunction. Thirty-two of 181 children with septic shock demonstrated sepsis-associated myocardial dysfunction. Pediatric Sepsis Biomarker Risk Model II mortality probability was independently associated with sepsis-associated myocardial dysfunction (odds ratio, 1.45; 95% CI, 1.17-1.81; p = 0.001). Modeling with Pediatric Sepsis Biomarker Risk Model biomarkers estimated sepsis-associated myocardial dysfunction risk with an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.85-0.95). Upon 10-fold cross-validation, the derived model had a summary area under the receiver operating characteristic curve of 0.74. Model characteristics were similar when sepsis-associated myocardial dysfunction was defined by both low left ventricular ejection fraction and abnormal global longitudinal strain., Conclusions: A newly derived Pediatric Sepsis Biomarker Risk Model biomarker-based model reliably estimates risk of sepsis-associated myocardial dysfunction in pediatric septic shock, but independent prospective validation is needed., Competing Interests: Dr. Lautz’s institution received funding from the National Institutes of Health (NIH) K12 HD028827. Drs. Lautz and Wong received support for article research from the NIH. Dr. Wong’s institution received funding from the NIH R35 GM126943, and he disclosed that he and Cincinnati Children’s Hospital Medical Center hold U.S. patents for the Pediatric Sepsis Biomarker Risk Model biomarkers used in this study. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objective: Cerebral mitochondrial dysfunction is a key mediator of neurologic injury following cardiac arrest (CA) and is regulated by the balance of fusion and fission (mitochondrial dynamics). Under stress, fission can decrease mitochondrial mass and signal apoptosis, while fusion promotes oxidative phosphorylation efficiency. This study evaluates mitochondrial dynamics and content in brain tissue 24 h after CA between two cardiopulmonary resuscitation (CPR) strategies., Interventions: Piglets (1 month), previously randomized to three groups: (1) Std-CPR (n = 5); (2) HD-CPR (n = 5; goal systolic blood pressure 90 mmHg, goal coronary perfusion pressure 20 mmHg); (3) Shams (n = 7). Std-CPR and HD-CPR groups underwent 7 min of asphyxia, 10 min of CPR, and standardized post-resuscitation care. Primary outcomes: (1) cerebral cortical mitochondrial protein expression for fusion (OPA1, OPA1 long to short chain ratio, MFN2) and fission (DRP1, FIS1), and (2) mitochondrial mass by citrate synthase activity. Secondary outcomes: (1) intra-arrest haemodynamics and (2) cerebral performance category (CPC) at 24 h., Results: HD-CPR subjects had higher total OPA1 expression compared to Std-CPR (1.52; IQR 1.02-1.69 vs 0.67; IQR 0.54-0.88, p = 0.001) and higher OPA1 long to short chain ratio than both Std-CPR (0.63; IQR 0.46-0.92 vs 0.26; IQR 0.26-0.31, p = 0.016) and shams. Citrate synthase activity was lower in Std-CPR than sham (11.0; IQR 10.15-12.29 vs 13.4; IQR 12.28-15.66, p = 0.047), but preserved in HD-CPR. HD-CPR subjects had improved intra-arrest haemodynamics and CPC scores at 24 h compared to Std-CPR., Conclusions: Following asphyxia-associated CA, HD-CPR exhibits increased pro-mitochondrial fusion protein expression, preservation of mitochondrial mass, improved haemodynamics and superior neurologic scoring compared to Std-CPR., Institutional Protocol Number: IAC 16-001023., (© 2021 The Authors.)

Background: The risk factors for peri-intubation cardiac arrest in critically ill children are incompletely understood. The study objective was to derive physiologic risk factors for deterioration during tracheal intubation in a pediatric emergency department (PED)., Methods: This was a retrospective cohort study of patients undergoing emergency tracheal intubation in a PED. Using the published literature and expert opinion, a multidisciplinary team developed high-risk criteria for peri-intubation arrest: 1) hypotension, 2) concern for cardiac dysfunction, 3) persistent hypoxemia, 4) severe metabolic acidosis (pH < 7.1), 5) post-return of spontaneous circulation (ROSC), and 6) status asthmaticus. We completed a structured review of the electronic health record for a historical cohort of patients intubated in the PED. The primary outcome was peri-intubation arrest. Secondary outcomes included tracheal intubation success rate, extracorporeal membrane oxygenation (ECMO) activation, and in-hospital mortality. We compared outcomes between patients meeting one or more versus no high-risk criteria., Results: Peri-intubation cardiac arrest occurred in 5.6% of patients who met at least one high-risk criterion compared to 0% in patients meeting none (5.6% difference, 95% confidence interval [CI] = 1.0 to 18.1, p = 0.028). Patients meeting at least one criterion had higher rates of any postintubation cardiac arrest in the PED (11.1% vs. 0%, 11.1% difference, 95% CI = 4.1 to 25.3, p = 0.0007), in-hospital mortality (25% vs. 2.3%, 22.7% difference, 95% CI = 11.0 to 38.9, p < 0.0001), ECMO activation (8.3% vs. 0%, 8.3% difference, 95% CI = 2.5 to 21.8, p = 0.004), and lower likelihood of first-pass intubation success (47.2% vs. 66.1%, -18.9% difference, 95% CI = -35.5 to -1.5, p = 0.038), respectively., Conclusions: We have developed criteria that successfully identify physiologically difficult airways in the PED. Children with hypotension, persistent hypoxemia, concern for cardiac dysfunction, severe metabolic acidosis, status asthmaticus or who are post-ROSC are at higher risk for peri-intubation cardiac arrest and in-hospital mortality. Further multicenter investigation is needed to validate our findings., (© 2020 by the Society for Academic Emergency Medicine.)

Patients with physiologic disorders, such as hypoxemia or hypotension, are at high risk of peri-intubation cardiac arrest. Standardization improves emergency tracheal intubation safety, but no published reports describe initiatives to reduce the risk of cardiac arrest. This initiative aims to improve the care of children at risk of peri-intubation cardiac arrest in a pediatric emergency department (PED). We specifically aimed to increase the number of patients between those with peri-intubation cardiac arrest by 50%, from a baseline of 11-16, over 12-months., Methods: Our multidisciplinary team outlined a theory of improvement and designed interventions aimed at key drivers. The primary intervention was creating a PICU-ED Team (PET) and a checklist to guide the assessment and mitigation of risk for peri-intubation arrest and rapid consultation of the pediatric intensivists. The PET was iteratively refined, and we collected data by a video review of tracheal intubations., Results: Fifty-one patients with risk factors for peri-intubation arrest underwent tracheal -intubation in the PED from January 2016 to March 2020: 14 with PET activation since PET go-live in April 2019. None of the 14 PET patients had a peri-intubation cardiac arrest. Ninety-three percent (13/14) of PET patients were intubated in the PED, and 78% (10/13) of these patients had the first intubation attempt completed by PED physicians (balancing measures)., Conclusion: We successfully developed the PET to mitigate the risk of peri-intubation cardiac arrest without significantly reducing key procedural opportunities for the PED. Initial data are promising, but further refinement is needed., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Circulatory dysfunction has been associated with mortality in children with septic shock. However, the mortality risk attributable to myocardial dysfunction per se has not been established, and the association between myocardial dysfunction and mortality is confounded by illness severity. The objective was to determine if sepsis-associated myocardial dysfunction defined by low left ventricular ejection fraction or global longitudinal strain is associated with mortality in pediatric septic shock after adjusting for baseline mortality probability., Design: Retrospective, observational study., Setting: Single-center, quaternary-care PICU., Patients: Children less than 18 years old admitted to the PICU from 2003 to 2018 who had an echocardiogram performed within 48 hours of septic shock identification and Pediatric Sepsis Biomarker Risk Model II data available., Interventions: None., Measurements and Main Results: All echocardiograms were reread by a cardiologist blinded to patient data for left ventricular ejection fraction and global longitudinal strain. Low left ventricular ejection fraction was defined as less than 45%, and low global longitudinal strain was defined as greater than z score of -2 for body surface area. Multivariable logistic regression separately analyzed the associations of low left ventricular ejection fraction and low global longitudinal strain with mortality, adjusting for Pediatric Sepsis Biomarker Risk Model II mortality risk. A post hoc logistic regression analyzed the association of left ventricular ejection fraction as a continuous variable with mortality, where linearity was maintained for left ventricular ejection fraction less than 65%. Eighteen percent of 181 children had low left ventricular ejection fraction. After adjusting for baseline mortality risk, low left ventricular ejection fraction remained independently associated with mortality (odds ratio, 4.4 [1.0-19.8]; p = 0.0497). Likewise, left ventricular ejection fraction was associated with mortality (odds ratio, 0.96 [0.93-0.99]; p = 0.037) on multivariable analysis for left ventricular ejection fraction less than 65%. Thirty-six percent of 169 children had low global longitudinal strain, and low global longitudinal strain was also independently associated with mortality (odds ratio, 4.6 [1.2-18.0]; p = 0.027)., Conclusions: Sepsis-associated myocardial dysfunction, whether defined by low left ventricular ejection fraction or low global longitudinal strain, is an independent risk factor for mortality in pediatric septic shock after accounting for the confounding effects of septic shock severity., Competing Interests: Dr. Wong and Cincinnati Children’s Hospital Medical Center hold U.S. patents for the Pediatric Sepsis Biomarker Risk Model biomarkers used in this study. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Myocardial dysfunction is common in septic shock and post-cardiac arrest but manifests differently in pediatric and adult patients. By conventional echocardiographic parameters, biventricular systolic dysfunction is more prevalent in children with septic shock, though strain imaging reveals that myocardial injury may be more common in adults than previously thought. In contrast, diastolic dysfunction in general and post-arrest myocardial systolic dysfunction appear to be more widespread in the adult population. A growing body of evidence suggests that mitochondrial dysfunction mediates myocardial depression in critical illness; alterations in mitochondrial electron transport system function, bioenergetic production, oxidative and nitrosative stress, uncoupling, mitochondrial permeability transition, fusion, fission, biogenesis, and autophagy all may play key pathophysiologic roles. In this review we summarize the epidemiologic and clinical phenotypes of myocardial dysfunction in septic shock and post-cardiac arrest and the multifaceted manifestations of mitochondrial injury in these disease processes. Since neonatal and pediatric-specific data for mitochondrial dysfunction remain sparse, conclusive age-dependent differences are not clear; instead, we highlight what evidence exists and identify gaps in knowledge to guide future research. Finally, since focal ischemic injury (with or without reperfusion) leading to myocardial infarction is predominantly an atherosclerotic disease of the elderly, this review focuses specifically on septic shock and global ischemia-reperfusion injury occurring after resuscitation from cardiac arrest.

Objectives: Less than half of the thousands of children who suffer in-hospital cardiac arrests annually survive, and neurologic injury is common among survivors. Hemodynamic-directed cardiopulmonary resuscitation improves short-term survival, but its impact on longer term survival and mitochondrial respiration-a potential neurotherapeutic target-remains unknown. The primary objectives of this study were to compare rates of 24-hour survival with favorable neurologic outcome after cardiac arrest treated with hemodynamic-directed cardiopulmonary resuscitation versus standard depth-guided cardiopulmonary resuscitation and to compare brain and heart mitochondrial respiration between groups 24 hours after resuscitation., Design: Randomized preclinical large animal trial., Setting: A large animal resuscitation laboratory at a large academic children's hospital., Subjects: Twenty-eight 4-week-old female piglets (8-11 kg)., Interventions: Twenty-two swine underwent 7 minutes of asphyxia followed by ventricular fibrillation and randomized treatment with either hemodynamic-directed cardiopulmonary resuscitation (n = 10; compression depth titrated to aortic systolic pressure of 90 mm Hg, vasopressors titrated to coronary perfusion pressure ≥ 20 mm Hg) or depth-guided cardiopulmonary resuscitation (n = 12; depth 1/3 chest diameter, epinephrine every 4 min). Six animals (sham group) underwent anesthesia and instrumentation without cardiac arrest. The primary outcomes were favorable neurologic outcome (swine Cerebral Performance Category ≤ 2) and mitochondrial maximal oxidative phosphorylation utilizing substrate for complex I and complex II (OXPHOSCI+CII) in the cerebral cortex and hippocampus., Measurements and Main Results: Favorable neurologic outcome was more likely with hemodynamic-directed cardiopulmonary resuscitation (7/10) than depth-guided cardiopulmonary resuscitation (1/12; p = 0.006). Hemodynamic-directed cardiopulmonary resuscitation resulted in higher intra-arrest coronary perfusion pressure, aortic pressures, and brain tissue oxygenation. Hemodynamic-directed cardiopulmonary resuscitation resulted in higher OXPHOSCI+CII (pmol oxygen/s × mg/citrate synthase) in the cortex (6.00 ± 0.28 vs 3.88 ± 0.43; p < 0.05) and hippocampus (6.26 ± 0.67 vs 3.55 ± 0.65; p < 0.05) and higher complex I respiration (pmol oxygen/s × mg) in the right (20.62 ± 1.06 vs 15.88 ± 0.81; p < 0.05) and left ventricles (20.14 ± 1.40 vs 14.17 ± 1.53; p < 0.05)., Conclusions: In a model of asphyxia-associated pediatric cardiac arrest, hemodynamic-directed cardiopulmonary resuscitation increases rates of 24-hour survival with favorable neurologic outcome, intra-arrest hemodynamics, and cerebral and myocardial mitochondrial respiration.

We retrospectively studied the effect of introducing procalcitonin into clinical practice on antibiotic use within a large academic pediatric intensive care unit. In the absence of a standardized algorithm, availability of the procalcitonin assay did not reduce the frequency of antibiotic initiations or the continuation of antibiotics for greater than 72 hours.

Rationale: Many in-hospital cardiac arrests are precipitated by hypotension, often associated with systemic inflammation. These patients are less likely to be successfully resuscitated, and novel approaches to their treatment are needed., Objectives: To determine if the addition of inhaled nitric oxide (iNO) to hemodynamic-directed cardiopulmonary resuscitation (HD-CPR) would improve short-term survival from cardiac arrest associated with shock and systemic inflammation., Methods: In 3-month-old swine (n = 21), LPS was intravenously infused, inducing systemic hypotension. Ventricular fibrillation was induced, and animals were randomized to blinded treatment with either: 1) HD-CPR with iNO, or 2) HD-CPR without iNO. During HD-CPR, chest compression depth was titrated to peak aortic compression pressure of 100 mm Hg, and vasopressor administration was titrated to coronary perfusion pressure greater than or equal to 20 mm Hg. Defibrillation attempts began after 10 minutes of resuscitation. The primary outcome was 45-minute survival., Measurements and Main Results: The iNO group had higher rates of 45-minute survival (10 of 10 vs. 3 of 11; P = 0.001). During cardiopulmonary resuscitation, the iNO group had lower pulmonary artery relaxation pressure (mean ± SEM, 10.9 ± 2.4 vs. 18.4 ± 2.4 mm Hg; P = 0.03), higher coronary perfusion pressure (21.1 ± 1.5 vs. 16.9 ± 1.0 mm Hg; P = 0.005), and higher aortic relaxation pressure (36.6 ± 1.6 vs. 30.4 ± 1.1 mm Hg; P < 0.001) despite shallower chest compressions (5.88 ± 0.25 vs. 6.46 ± 0.40 cm; P = 0.02) and fewer vasopressor doses in the first 10 minutes (median, 4 [interquartile range, 3-4] vs. 5 [interquartile range, 5-6], P = 0.03)., Conclusions: The addition of iNO to HD-CPR in LPS-induced shock-associated cardiac arrest improved short-term survival and intraarrest hemodynamics.

Objectives: Miscommunication has been implicated as a leading cause of medical errors, and standardized handover programs have been associated with improved patient outcomes. However, the role of structured handovers in pediatric emergencies remains unclear. We sought to determine if training with an airway, breathing, circulation, situation, background, assessment, recommendation handover tool could improve the transmission of essential patient information during multidisciplinary simulations of critically ill children., Methods: We conducted a prospective, randomized, intervention study with first-year pediatric residents at a quaternary academic children's hospital. Baseline and second handovers were recorded for residents in the intervention group ( n = 12) and residents in the control group ( n = 8) during multidisciplinary simulations throughout the academic year. The intervention group received handover education after baseline handover observation and a cognitive aid before second handover observation. Audio-recorded handovers were scored by using a Delphi-developed assessment tool by a blinded rater., Results: There was no difference in baseline handover scores between groups ( P = .69), but second handover scores were significantly higher in the intervention group (median 12.5 [interquartile range 12-13] versus median 7.5 [interquartile range 6-8] in the control group; P < .01). Trained residents were more likely to include a reason for the call ( P < .01), focused history ( P = .02), and summative assessment ( P = .03). Neither timing of the second observation in the academic year nor duration between first and second observation were associated with the second handover scores (both P > .5)., Conclusions: Structured handover training and provision of a cognitive aid may improve the inclusion of essential patient information in the handover of simulated critically ill children., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Objectives: To determine whether peak blood procalcitonin (PCT) measured within 48 hours of pediatric intensive care unit (PICU) admission can differentiate severe bacterial infections from sterile inflammation and viral infection and identify potential subgroups of PICU patients for whom PCT may not have clinical utility., Study Design: This was a retrospective, observational study of 646 critically ill children who had PCT measured within 48 hours of admission to an urban, academic PICU. Patients were stratified into 6 categories by infection status. We compared test characteristics for peak PCT, C-reactive protein (CRP), white blood cell count (WBC), absolute neutrophil count (ANC), and % immature neutrophils. The area under the receiver operating characteristic curve was determined for each biomarker to discriminate bacterial infection., Results: The area under the receiver operating characteristic curve was similar for PCT (0.73, 95% CI 0.69, 0.77) and CRP (0.75, 95% CI 0.71, 0.79; P = .36), but both outperformed WBC, ANC, and % immature neutrophils (P < .01 for all pairwise comparisons). The combination of PCT and CRP was no better than either PCT or CRP alone. Diagnostic patterns prone to false-positive and false-negative PCT values were identified., Conclusions: Peak blood PCT measured close to PICU admission was not superior to CRP in differentiating severe bacterial infection from viral illness and sterile inflammation; both PCT and CRP outperformed WBC, ANC, and % immature neutrophils. PCT appeared especially prone to inaccuracies in detecting localized bacterial central nervous system infections or bacterial coinfection in acute viral illness causing respiratory failure., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A 6-year-old girl presented with a history of leg pain and cramping that progressively worsened over a 2- to 3-week period of time. Her examination was notable for normal vital signs, limited range of motion of her left hip, and a limp. Inflammatory markers were slightly elevated, but the serum electrolytes, calcium, and magnesium, complete blood cell count and differential, and creatine kinase level were normal. She was hospitalized for further diagnostic evaluation and was noted to have abnormal muscle movements classified as myokymia (continuous involuntary quivering, rippling, or undulating movement of muscles). Electromyography confirmed the myokymia but did not reveal evidence of a myopathy or neuropathy, prompting additional evaluation for a systemic etiology., (Copyright © 2015 by the American Academy of Pediatrics.)

A 33-month-old girl presented with 3 days of fever and 1 day of multiple paroxysmal episodes of screaming with apparent unresponsiveness, flexed lower extremities, clenched hands, and upward eye deviation. These events lasted seconds to a minute at a time and occurred only during sleep. She slept peacefully between episodes and was easily awakened. She had a history of mild speech delay and mild intermittent asthma but was otherwise healthy. She was tired-appearing and fussy on examination with dry mucous membranes, but her examination was otherwise normal. A complete blood count with differential and serum levels of sodium, potassium, chloride, and calcium were normal, but her bicarbonate level was 12 mmol/L. Her fingerstick glucose level was 69 mg/dL. Urine dipstick was notable for large ketones, and a urine drug screen was normal. Cerebrospinal fluid examination yielded 2 white blood cells and 1040 red blood cells/mm(3) with normal chemistries. A computed tomography (CT) scan of her head was unremarkable, and an abdominal ultrasound demonstrated no evidence of intussusception. Over the course of her hospitalization, these paroxysmal episodes persisted, and she subsequently developed mutism, right-sided weakness, and difficulty swallowing liquids. Here we present her case, diagnostic evaluation, and ultimate diagnosis., (Copyright © 2015 by the American Academy of Pediatrics.)