Accuracy and Interpretation of Transcutaneous Carbon Dioxide Monitoring in Critically Ill Children.

OBJECTIVES: Transcutaneous carbon dioxide (Tcco2) monitoring can noninvasively assess ventilation by estimating carbon dioxide (CO2) levels in the blood. We aimed to evaluate the accuracy of Tcco2 monitoring in critically ill children by comparing it to the partial pressure of arterial carbon dioxide (Paco2). In addition, we sought to determine the variation between Tcco2 and Paco2 acceptable to clinicians to modify patient care and to determine which patient-level factors may affect the accuracy of Tcco2 measurements. DESIGN: Retrospective observational cohort study. SETTING: Single, quaternary care PICU from July 1, 2012, to August 1, 2020. PATIENTS: Included participants were admitted to the PICU and received noninvasive ventilation support (i.e., continuous or bilevel positive airway pressure), conventional mechanical ventilation, or high-frequency oscillatory or percussive ventilation with Tcco2 measurements obtained within 15 minutes of Paco2 measurement. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three thousand four hundred seven paired arterial blood gas and Tcco2 measurements were obtained from 264 patients. Bland-Altman analysis revealed a bias of -4.4 mm Hg (95% CI, -27 to 18.3 mm Hg) for Tcco2 levels against Paco2 levels on the first measurement pair for each patient, which fell within the acceptable range of ±5 mm Hg stated by surveyed clinicians, albeit with wide limits of agreement. The sensitivity and specificity of Tcco2 to diagnose hypercarbia were 93% and 71%, respectively. Vasoactive-Infusion Score (VIS), age, and self-identified Black/African American race confounded the relationship between Tcco2 with Paco2 but percent fluid overload, weight-for-age, probe location, and severity of illness were not significantly associated with Tcco2 accuracy. CONCLUSIONS: Tcco2 monitoring may be a useful adjunct to monitor ventilation in children with respiratory failure, but providers must be aware of the limitations to its accuracy.

Performance of Tools and Measures to Predict Fluid Responsiveness in Pediatric Shock and Critical Illness: A Systematic Review and Meta-Analysis.

OBJECTIVES: In this systematic review and meta-analysis we asked: Do predictors of fluid responsiveness in children perform comparably: 1) in the PICU as in non-PICU settings? 2) in shock states compared with nonshock states? Additionally, 3) is there an association between preload responsiveness and clinical response? DATA SOURCES: Ovid Medline, PubMed, and Embase databases were searched from inception through May 2022. STUDY SELECTION: Included studies reported physiological response to IV fluid administration in humans less than 18 years. Only studies reporting an area under the receiver operating characteristic curve (AUROC) were included for descriptive analysis. Only studies for which a se could be estimated were included for meta-analysis. DATA EXTRACTION: Title, abstract, full text screening, and extraction were completed by two authors (S.B.W., J.M.W.). Variables extracted included predictors ("tools") and outcome measures ("reference tests") of fluid responsiveness, demographic, and clinical variables. DATA SYNTHESIS: We identified 62 articles containing 204 AUROCs for 55 tools, primarily describing mechanically ventilated children in an operating room or PICU. Meta-analysis across all tools showed poor predictive performance (AUROC, 0.66; 95% CI, 0.63-0.69), although individual performance varied greatly (range, 0.49-0.87). After controlling for PICU setting and shock state, PICU setting was associated with decreased predictive performance (coefficient, -0.56; p = 0.0007), while shock state was associated with increased performance (0.54; p = 0.0006). Effect of PICU setting and shock state on each tool was not statistically significant but analysis was limited by sample size. The association between preload responsiveness and clinical response was rarely studied but results did not suggest an association. Ultrasound measurements were prone to inherent test review and incorporation biases. CONCLUSIONS: We suggest three opportunities for further research in fluid responsiveness in children: 1) assessing predictive performance of tools during resuscitation in shock states; 2) separating predictive tool from reference test when using ultrasound techniques; and 3) targeting decreasing time in a shock state, rather than just increase in preload.

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.

The Pediatric Data Science and Analytics Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators Network: Use of Supervised Machine Learning Applications in Pediatric Critical Care Medicine Research.

OBJECTIVE: Perform a scoping review of supervised machine learning in pediatric critical care to identify published applications, methodologies, and implementation frequency to inform best practices for the development, validation, and reporting of predictive models in pediatric critical care. DESIGN: Scoping review and expert opinion. SETTING: We queried CINAHL Plus with Full Text (EBSCO), Cochrane Library (Wiley), Embase (Elsevier), Ovid Medline, and PubMed for articles published between 2000 and 2022 related to machine learning concepts and pediatric critical illness. Articles were excluded if the majority of patients were adults or neonates, if unsupervised machine learning was the primary methodology, or if information related to the development, validation, and/or implementation of the model was not reported. Article selection and data extraction were performed using dual review in the Covidence tool, with discrepancies resolved by consensus. SUBJECTS: Articles reporting on the development, validation, or implementation of supervised machine learning models in the field of pediatric critical care medicine. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 5075 identified studies, 141 articles were included. Studies were primarily (57%) performed at a single site. The majority took place in the United States (70%). Most were retrospective observational cohort studies. More than three-quarters of the articles were published between 2018 and 2022. The most common algorithms included logistic regression and random forest. Predicted events were most commonly death, transfer to ICU, and sepsis. Only 14% of articles reported external validation, and only a single model was implemented at publication. Reporting of validation methods, performance assessments, and implementation varied widely. Follow-up with authors suggests that implementation remains uncommon after model publication. CONCLUSIONS: Publication of supervised machine learning models to address clinical challenges in pediatric critical care medicine has increased dramatically in the last 5 years. While these approaches have the potential to benefit children with critical illness, the literature demonstrates incomplete reporting, absence of external validation, and infrequent clinical implementation.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

Artificial intelligence-based clinical decision support in pediatrics.

Machine learning models may be integrated into clinical decision support (CDS) systems to identify children at risk of specific diagnoses or clinical deterioration to provide evidence-based recommendations. This use of artificial intelligence models in clinical decision support (AI-CDS) may have several advantages over traditional "rule-based" CDS models in pediatric care through increased model accuracy, with fewer false alerts and missed patients. AI-CDS tools must be appropriately developed, provide insight into the rationale behind decisions, be seamlessly integrated into care pathways, be intuitive to use, answer clinically relevant questions, respect the content expertise of the healthcare provider, and be scientifically sound. While numerous machine learning models have been reported in pediatric care, their integration into AI-CDS remains incompletely realized to date. Important challenges in the application of AI models in pediatric care include the relatively lower rates of clinically significant outcomes compared to adults, and the lack of sufficiently large datasets available necessary for the development of machine learning models. In this review article, we summarize key concepts related to AI-CDS, its current application to pediatric care, and its potential benefits and risks. IMPACT: The performance of clinical decision support may be enhanced by the utilization of machine learning-based algorithms to improve the predictive performance of underlying models. Artificial intelligence-based clinical decision support (AI-CDS) uses models that are experientially improved through training and are particularly well suited toward high-dimensional data. The application of AI-CDS toward pediatric care remains limited currently but represents an important area of future research.

Novel approaches to capturing and using continuous cardiorespiratory physiological data in hospitalized children.

Continuous cardiorespiratory physiological monitoring is a cornerstone of care in hospitalized children. The data generated by monitoring devices coupled with machine learning could transform the way we provide care. This scoping review summarizes existing evidence on novel approaches to continuous cardiorespiratory monitoring in hospitalized children. We aimed to identify opportunities for the development of monitoring technology and the use of machine learning to analyze continuous physiological data to improve the outcomes of hospitalized children. We included original research articles published on or after January 1, 2001, involving novel approaches to collect and use continuous cardiorespiratory physiological data in hospitalized children. OVID Medline, PubMed, and Embase databases were searched. We screened 2909 articles and performed full-text extraction of 105 articles. We identified 58 articles describing novel devices or approaches, which were generally small and single-center. In addition, we identified 47 articles that described the use of continuous physiological data in prediction models, but only 7 integrated multidimensional data (e.g., demographics, laboratory results). We identified three areas for development: (1) further validation of promising novel devices; (2) more studies of models integrating multidimensional data with continuous cardiorespiratory data; and (3) further dissemination, implementation, and validation of prediction models using continuous cardiorespiratory data. IMPACT: We performed a comprehensive scoping review of novel approaches to capture and use continuous cardiorespiratory physiological data for monitoring, diagnosis, providing care, and predicting events in hospitalized infants and children, from novel devices to machine learning-based prediction models. We identified three key areas for future development: (1) further validation of promising novel devices; (2) more studies of models integrating multidimensional data with continuous cardiorespiratory data; and (3) further dissemination, implementation, and validation of prediction models using cardiorespiratory data.

Heart rate variability is associated with encephalopathy and outcomes in pediatric acute liver failure.

BACKGROUND: More than half of children with pediatric acute liver failure (PALF) experience hepatic encephalopathy (HE), which is related to poor outcomes; however, HE is difficult to diagnose in children. The objective of this study was to evaluate if heart rate variability (HRV), a continuous measure of autonomic nervous system function, was related to the presence and severity of HE as well as clinical outcomes in children with PALF. METHODS: We conducted a retrospective observational cohort study of 38 critically ill children with PALF to examine the association between HRV and HE severity and clinical outcome. HRV was estimated using the integer HRV (HRVi). Categorical variables were compared using the Fisher Exact test and continuous variables were compared using Kruskal-Wallis tests. Associations between grades of HE and minimum and median HRVi were evaluated with Pearson's correlation, with p values <0.05 considered significant. RESULTS: A more negative median and minimum HRVi, indicating poorer autonomic nervous system function, was significantly associated with abnormal EEG findings, presence of HE, and poor outcomes (death or listing for transplant). CONCLUSIONS: Heart rate variability may hold promise to predict outcomes in children with PALF, but these findings should be replicated in a larger sample. IMPACT: The findings of our study suggest that heart rate variability is associated with clinical outcomes in children with acute liver failure, a cohort for which prognostics are challenging, especially in young children and infants. Use of heart rate variability in the clinical setting may facilitate earlier detection of children with pediatric acute liver failure (PALF) at high risk for severe hepatic encephalopathy and poor outcomes. Identification of children with PALF at high risk of decompensation may assist clinicians in making decisions about liver transplantation, an important, but resource-limited, treatment of PALF.

Fluid balance in pediatric postoperative liver transplant recipients.

BACKGROUND: Positive fluid balance (FB) is associated with poor outcomes in critically ill children but has not been studied in pediatric liver transplant (LT) recipients. Our goal is to investigate the relationship between postoperative FB and outcomes in pediatric LT recipients. METHODS: We performed a retrospective cohort study of first-time pediatric LT recipients at a quaternary care children's hospital. Patients were stratified into three groups based on their FB in the first 72 h postoperatively: <10%, 10-20%, and > 20%. Outcomes were pediatric intensive care unit (PICU) and hospital length of stay, ventilator-free days (VFD) at 28 days, day 3 severe acute kidney injury, and postoperative complications. Multivariate analyses were adjusted for age, preoperative admission status, and Pediatric Risk of Mortality (PRISM)-III score. RESULTS: We included 129 patients with median PRISM-III score of 9 (interquartile range, IQR 7-15) and calculated Pediatric End-stage Liver Disease score of 15 (IQR 2-23). A total of 37 patients (28.7%) had 10-20% FB, and 26 (20.2%) had >20% FB. Greater than 20% FB was associated with an increased likelihood of an additional PICU day (adjusted incident rate ratio [aIRR] 1.62, 95% CI: 1.18-2.24), an additional hospital day (aIRR 1.39, 95% CI: 1.10-1.77), and lower likelihood of a VFD at 28 days (aIRR 0.85, 95% CI: 0.74-0.97). There were no differences between groups in the likelihood of postoperative complications. CONCLUSIONS: In pediatric LT recipients, >20% FB at 72 h postoperatively is associated with increased morbidities, independent of age and severity of illness. Additional studies are needed to explore the impact of fluid management strategies on outcomes.

Leveraging Clinical Informatics and Data Science to Improve Care and Facilitate Research in Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: The use of electronic algorithms, clinical decision support systems, and other clinical informatics interventions is increasing in critical care. Pediatric acute respiratory distress syndrome (PARDS) is a complex, dynamic condition associated with large amounts of clinical data and frequent decisions at the bedside. Novel data-driven technologies that can help screen, prompt, and support clinician decision-making could have a significant impact on patient outcomes. We sought to identify and summarize relevant evidence related to clinical informatics interventions in both PARDS and adult respiratory distress syndrome (ARDS), for the second Pediatric Acute Lung Injury Consensus Conference. DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). STUDY SELECTION: We included studies of pediatric or adult critically ill patients with or at risk of ARDS that examined automated screening tools, electronic algorithms, or clinical decision support systems. DATA EXTRACTION: Title/abstract review, full text review, and data extraction using a standardized data extraction form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-six studies were identified for full text extraction to address the Patient/Intervention/Comparator/Outcome questions, and 14 were used for the recommendations/statements. Two clinical recommendations were generated, related to the use of electronic screening tools and automated monitoring of compliance with best practice guidelines. Two research statements were generated, related to the development of multicenter data collaborations and the design of generalizable algorithms and electronic tools. One policy statement was generated, related to the provision of material and human resources by healthcare organizations to empower clinicians to develop clinical informatics interventions to improve the care of patients with PARDS. CONCLUSIONS: We present two clinical recommendations and three statements (two research one policy) for the use of electronic algorithms and clinical informatics tools for patients with PARDS based on a systematic review of the literature and expert consensus.

Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock.

OBJECTIVES: Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies. DESIGN: Multicenter observational cohort study. SETTING: Thirteen PICUs in the United States. PATIENTS: Patients admitted with suspected infections to the PICU between 2012 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS. CONCLUSIONS: We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.

Reporting of Social Determinants of Health in Pediatric Sepsis Studies.

OBJECTIVE: Standardized, consistent reporting of social determinants of health (SDOH) in studies on children with sepsis would allow for: 1) understanding the association of SDOH with illness severity and outcomes, 2) comparing populations and extrapolating study results, and 3) identification of potentially modifiable socioeconomic factors for policy makers. We, therefore, sought to determine how frequently data on SDOH were reported, which factors were collected and how these factors were defined in studies of sepsis in children. DATA SOURCES AND SELECTION: We reviewed 106 articles (published between 2005 and 2020) utilized in a recent systematic review on physiologic criteria for pediatric sepsis. DATA EXTRACTION: Data were extracted by two reviewers on variables that fell within the World Health Organization's SDOH categories. DATA SYNTHESIS: SDOH were not the primary outcome in any of the included studies. Seventeen percent of articles (18/106) did not report on any SDOH, and a further 36.8% (39/106) only reported on gender/sex. Of the remaining 46.2% of articles, the most reported SDOH categories were preadmission nutritional status (35.8%, 38/106) and race/ethnicity (18.9%, 20/106). However, no two studies used the same definition of the variables reported within each of these categories. Six studies reported on socioeconomic status (3.8%, 6/106), including two from upper-middle-income and four from lower middle-income countries. Only three studies reported on parental education levels (2.8%, 3/106). No study reported on parental job security or structural conflict. CONCLUSIONS: We found overall low reporting of SDOH and marked variability in categorizations and definitions of SDOH variables. Consistent and standardized reporting of SDOH in pediatric sepsis studies is needed to understand the role these factors play in the development and severity of sepsis, to compare and extrapolate study results between settings and to implement policies aimed at improving socioeconomic conditions related to sepsis.

Operationalizing Appropriate Sepsis Definitions in Children Worldwide: Considerations for the Pediatric Sepsis Definition Taskforce.

Sepsis is a leading cause of global mortality in children, yet definitions for pediatric sepsis are outdated and lack global applicability and validity. In adults, the Sepsis-3 Definition Taskforce queried databases from high-income countries to develop and validate the criteria. The merit of this definition has been widely acknowledged; however, important considerations about less-resourced and more diverse settings pose challenges to its use globally. To improve applicability and relevance globally, the Pediatric Sepsis Definition Taskforce sought to develop a conceptual framework and rationale of the critical aspects and context-specific factors that must be considered for the optimal operationalization of future pediatric sepsis definitions. It is important to address challenges in developing a set of pediatric sepsis criteria which capture manifestations of illnesses with vastly different etiologies and underlying mechanisms. Ideal criteria need to be unambiguous, and capable of adapting to the different contexts in which children with suspected infections are present around the globe. Additionally, criteria need to facilitate early recognition and timely escalation of treatment to prevent progression and limit life-threatening organ dysfunction. To address these challenges, locally adaptable solutions are required, which permit individualized care based on available resources and the pretest probability of sepsis. This should facilitate affordable diagnostics which support risk stratification and prediction of likely treatment responses, and solutions for locally relevant outcome measures. For this purpose, global collaborative databases need to be established, using minimum variable datasets from routinely collected data. In summary, a "Think globally, act locally" approach is required.

Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2).

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.

Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

A specialized multi-disciplinary care program for children with sepsis and multiple organ dysfunction-associated immune dysregulation.

The complex physiology and medical requirements of children with sepsis and multiple organ dysfunction syndrome (MODS) challenge traditional care coordination models. While the involvement of multiple clinical subspecialty services is often necessary to support different care processes and individual organ system dysfunctions, it can also delay the diagnostic process, monitoring, and treatment. The logistics of coordinating with many specialty providers for critically ill patients are challenging and time consuming, and often can result in fragmented communication. To address these and other related issues, we developed a new multi-disciplinary consult service focused on streamlining diagnostics, management, and communication for patients with sepsis and MODS-associated immune dysregulation. The service, called the Program in Inflammation, Immunity, and the Microbiome (PrIIMe), is now a hospital-wide clinical consult service at our institution caring for a broad group of patients with immune dysregulation, particularly focusing on patients with sepsis and MODS. In this paper, we summarize the development, structure, and function of the program, as well as the initial impact. This information may be helpful to clinicians and healthcare leaders who are developing multi-disciplinary consult services for children with complex care needs, especially those with sepsis and MODS-associated immune dysregulation. IMPACT: The care of children with sepsis and multiple organ dysfunction-associated immune dysregulation requires rapid and flexible involvement of multiple clinical subspecialists that is difficult to achieve without fragmented care and delayed decision making. In this narrative review we describe the development, structure, and function of a multi-disciplinary consult service at a children's hospital dedicated to helping coordinate management and provide continuity of care for patients with sepsis and multiple organ dysfunction-associated immune dysregulation. This information may be helpful to clinicians and healthcare leaders who are developing multi-disciplinary consult services for children with complex care needs, especially those with sepsis and MODS-associated immune dysregulation.

Non-resuscitation fluid in excess of hydration requirements is associated with higher mortality in critically ill children.

BACKGROUND: Large volumes of non-resuscitation fluids are often administered to critically ill children. We hypothesize that excess maintenance fluid is a significant contributor to non-resuscitation fluid and that non-resuscitation fluid administered beyond hydration requirements is associated with worse clinical outcomes in critically ill children. METHODS: We evaluated all patients admitted to two large urban pediatric intensive care units (PICU) between January 2010-August 2016 and January 2010-August 2018, respectively, who survived and remained in the hospital for at least 3 days following PICU admission. The primary outcome was in-hospital mortality. Association of excess fluid with outcomes was adjusted for confounders (age, Pediatric Risk of Mortality III score, study site, day 3 acute kidney injury, PICU era, resuscitation volume, and volume output) using multivariable regression. RESULTS: We evaluated 14,483 patients; 52% received non-resuscitation fluid in excess of hydration requirements. Non-resuscitation fluid in excess of hydration requirements was associated with higher in-hospital mortality after adjustment for confounders (adjusted odds ratio 1.01 per 10 mL/kg in excess fluid, 95% confidence interval: 1.002-1.02). CONCLUSIONS: Non-resuscitation fluid in excess of hydration requirements is associated with increased mortality in critically ill children. Excess maintenance fluid is a modifiable contributor to this fluid volume. Strategies to reduce excess maintenance fluids warrant further study. IMPACT: Critically ill children frequently receive non-resuscitation fluid in excess of their estimated hydration requirements. Non-resuscitation fluid volume in excess of estimated hydration requirements is associated with higher morbidity and mortality in critically ill children. Critically ill children receive a large volume burden from maintenance fluid. Maintenance fluid represents a modifiable contributor of non-resuscitation fluid in excess of hydration requirements. Strategies focused on limitation of maintenance fluid warrant further study.

Vitamin therapy in sepsis.

Vitamins are essential micronutrients with key roles in many biological pathways relevant to sepsis. Some of these relevant biological mechanisms include antioxidant and anti-inflammatory effects, protein and hormone synthesis, energy generation, and regulation of gene transcription. Moreover, relative vitamin deficiencies in plasma are common during sepsis and vitamin therapy has been associated with improved outcomes in some adult and pediatric studies. High-dose intravenous vitamin C has been the vitamin therapy most extensively studied in adult patients with sepsis and septic shock. This includes three randomized control trials (RCTs) as monotherapy with a total of 219 patients showing significant reduction in organ dysfunction and lower mortality when compared to placebo, and five RCTs as a combination therapy with thiamine and hydrocortisone with a total of 1134 patients showing no difference in clinical outcomes. Likewise, the evidence for the role of other vitamins in sepsis remains mixed. In this narrative review, we present the preclinical, clinical, and safety evidence of the most studied vitamins in sepsis, including vitamin C, thiamine (i.e., vitamin B1), and vitamin D. We also present the relevant evidence of the other vitamins that have been studied in sepsis and critical illness in both children and adults, including vitamins A, B2, B6, B12, and E. IMPACT: Vitamins are key effectors in many biological processes relevant to sepsis. We present the preclinical, clinical, and safety evidence of the most studied vitamins in pediatric sepsis. Designing response-adaptive platform trials may help fill in knowledge gaps regarding vitamin use for critical illness and association with clinical outcomes.

Acute kidney injury and kidney recovery after cardiopulmonary bypass in children.

BACKGROUND: Acute kidney injury (AKI) that improves in the pediatric intensive care unit (PICU) is associated with better outcomes compared to AKI that persists, but no study has investigated whether this also occurs in children undergoing cardiopulmonary bypass (CPB). METHODS: A retrospective study of children ≤18 years who underwent CPB in three children's hospitals was conducted. Patients were classified into groups by kidney recovery after AKI according to Acute Disease Quality Initiative (ADQI) guidelines. Adjusted regression models evaluated associations between kidney recovery group and hospital outcomes. RESULTS: Among 3620 children, AKI developed in 701 (19.4%): 610 transient AKI, 47 persistent AKI, and 44 acute kidney disease (AKD). Mortality increased with severity of kidney recovery group: 4.5% in the never developed AKI group, 8.9% in the transient AKI group, 25.5% in the persistent AKI group, and 31.8% in the AKD group (p <0.0001). In adjusted analysis, transient AKI (HR 1.4, CI 1.02, 2), persistent AKI (HR 22.4, CI 10.2, 49.2), and AKD (HR 3.7, CI 1.7, 7.9) had a greater hazard of mortality when compared to the never developed AKI group. Patients with transient AKI had a longer length of PICU stay than those with never developed AKI (HR 5.1, CI 2.9, 7.3). CONCLUSIONS: Patterns of kidney recovery after AKI were associated with worse PICU outcomes in children after CPB compared to those who did not develop AKI, even after rapid AKI recovery. Identification of factors that increase risk for these AKI patterns is necessary for prevention of AKI during CPB in children. A higher resolution version of the Graphical abstract is available as Supplementary information.