High-Dimensional Single-Cell Mass Cytometry Demonstrates Differential Platelet Functional Phenotypes in Infants With Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) is a group of complex heart defects associated with hematologic abnormalities, including increased risk of thrombotic and bleeding events. Past studies have observed evidence of platelet hyperreactivity, while other studies showed decreased platelet activation in patients with CHD. The goal of this study was to develop a mass spectrometry approach to characterize single platelets in infants with CHD and identify potential etiology for such discrepant results. METHODS: We enrolled 19 infants with CHD along with 21 non-CHD controls at Yale New Haven Children's Heart Center. A single-cell high-dimensional mass cytometry method was developed to quantitatively interrogate platelet surface markers in whole blood. Additionally, plasma cytokine analysis was performed through a multiplexed panel of 52 vascular and inflammatory markers to assess for platelet releasates. RESULTS: We found that infants with CHD had significant differences in platelet activation and functional markers by mass cytometry compared with non-CHD controls. Based on cell surface markers, we classified the platelets into 8 subpopulations (P0 to P7). Distinct subpopulations of platelets (P1, P4, and P5) exhibiting decreased aggregatory phenotype but altered secretory phenotypes were also identified and found to be more abundant in the blood of infants with CHD. Electron microscopy identified increased proportion of hypogranular platelets in CHD. Moreover, cytokine analysis demonstrated an overall increase in plasma cytokines and biomarkers in CHD, including IL (interleukin)-6, IL-8, IL-27, RANTES, and VWF (von Willebrand factor), which are expressed in platelet granules and can be released upon activation. CONCLUSIONS: We developed a robust mass cytometry approach to identify platelet phenotypic heterogeneity. Infants with CHD had alterations in distinct subpopulations of platelets with overall reduced aggregatory phenotype and secretory dysfunction. These findings suggest that platelets in infants with CHD may be exhausted due to persistent stimulation and may explain both bleeding and thrombotic vascular complications associated with CHD.

Hospital-Acquired Venous Thromboembolism and Invasive Mechanical Ventilation: A Report From the Children's Hospital Acquired Thrombosis Consortium.

OBJECTIVES: To determine if the duration of invasive mechanical ventilation (IMV) was associated with hospital-acquired venous thromboembolism (HA-VTE) among critically ill children. DESIGN: A multicenter, matched case-control study as a secondary analysis of Children's Hospital Acquired Thrombosis (CHAT) Consortium registry. SETTING: PICUs within U.S. CHAT Consortium participating centers. PATIENTS: Children younger than 21 years old admitted to a PICU receiving IMV for greater than or equal to 1 day duration from January 2012 to March 2022 were included for study. Cases with HA-VTE were matched 1:2 to controls without HA-VTE by patient age groups: younger than 1, 1-12, and older than 12 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was IMV duration in days. Descriptive data included demographics, anthropometrics, HA-VTE characteristics (i.e., type, location, and timing), central venous catheterization data, thromboprophylaxis practices, and Braden Q mobility scores. Descriptive, comparative, and associative (multivariate conditional logistic regression for HA-VTE) statistics were employed. A total of 152 cases were matched to 304 controls. Cases with HA-VTE were diagnosed at a median of 7 days (interquartile range [IQR], 3-16 d) after IMV. The HA-VTE were limb deep venous thromboses in 130 of 152 (85.5%) and frequently central venous catheterization-related (111/152, 73%). Cases with HA-VTE experienced a longer length of stay (median, 34 d [IQR, 18-62 d] vs. 11.5 d [IQR, 6-21 d]; p < 0.001) and IMV duration (median, 7 d [IQR, 4-15 d] vs. 4 d [IQR, 1-7 d]; p < 0.001) as compared with controls. In a multivariate logistic model, greater IMV duration (adjusted odds ratio, 1.09; 95% CI, 1.01-1.17; p = 0.023) was independently associated with HA-VTE. CONCLUSIONS: Among critically ill children undergoing IMV, HA-VTE was associated with greater IMV duration. If prospectively validated, IMV duration should be included as part of prothrombotic risk stratification and future pediatric thromboprophylaxis trials.

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.

Characterizing Long COVID in Children and Adolescents.

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains. Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

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.

A retrospective cohort analysis of the Yale pediatric genomics discovery program.

The Pediatric Genomics Discovery Program (PGDP) at Yale uses next-generation sequencing (NGS) and translational research to evaluate complex patients with a wide range of phenotypes suspected to have rare genetic diseases. We conducted a retrospective cohort analysis of 356 PGDP probands evaluated between June 2015 and July 2020, querying our database for participant demographics, clinical characteristics, NGS results, and diagnostic and research findings. The three most common phenotypes among the entire studied cohort (n = 356) were immune system abnormalities (n = 105, 29%), syndromic or multisystem disease (n = 103, 29%), and cardiovascular system abnormalities (n = 62, 17%). Of 216 patients with final classifications, 77 (36%) received new diagnoses and 139 (64%) were undiagnosed; the remaining 140 patients were still actively being investigated. Monogenetic diagnoses were found in 67 (89%); the largest group had variants in known disease genes but with new contributions such as novel variants (n = 31, 40%) or expanded phenotypes (n = 14, 18%). Finally, five PGDP diagnoses (8%) were suggestive of novel gene-to-phenotype relationships. A broad range of patients can benefit from single subject studies combining NGS and functional molecular analyses. All pediatric providers should consider further genetics evaluations for patients lacking precise molecular diagnoses.

Central venous catheter-associated deep vein thrombosis in critically ill pediatric patients: risk factors, prevention, and treatment.

PURPOSE OF REVIEW: Central venous catheter (CVC) placement and ICU admission are the two most important risk factors for pediatric deep vein thrombosis. The optimal prevention and treatment strategies for CVC-associated deep vein thrombosis (CADVT) are unclear, but recently, seminal studies have been published. This review aims to summarize the recent literature on CADVT in critically ill children. RECENT FINDINGS: Recent publications focused on three themes: risk factors, prevention, and treatment of CADVT. Newly identified risk factors for CADVT relate to Virchow's triad of hemostasis, blood vessel injury, and hypercoagulability. New risk prediction models have moderately good accuracy in predicting CADVT. Though previous data on pharmacologic CADVT prophylaxis was equivocal, recent studies indicate that low-molecular-weight heparin may be effective in preventing CADVT, particularly in critically ill children. Finally, new studies suggest that direct oral anticoagulants and shorter treatment times are noninferior to traditional agents and treatment durations in the treatment of CADVT. SUMMARY: Recent research suggests new ways to accurately identify children at high risk of CADVT, effectively prevent CADVT, and optimize CADVT treatment. Future research should focus on understanding the pathobiology of CADVT formation, prevention, and treatment in critically ill children.

Prophylactic Enoxaparin Against Catheter-Associated Thrombosis in Postoperative Cardiac Children: An Interrupted Time Series Analysis.

OBJECTIVES: The effectiveness of pharmacologic prophylaxis against catheter-associated thrombosis in children is unclear. We evaluated the compliance and outcomes associated with a prophylactic enoxaparin protocol in postoperative cardiac children. DESIGN: The protocol was implemented as a quality improvement initiative and then analyzed using interrupted time series method. Data collected from November 2014 to December 2018 were divided into preprotocol (period 1), protocol implementation (period 2), and protocol revision (period 3). SETTING: A 12-bed academic pediatric cardiac ICU. PATIENTS: Children less than or equal to 18 years old with congenital heart disease admitted postoperatively with central venous catheter in situ for greater than or equal to 1 day. INTERVENTIONS: Before 2016, prophylactic enoxaparin was administered according to physician preference. In January 2016, an enoxaparin protocol was implemented with a goal anti-Xa range of 0.25-0.49 international units/mL. Protocol was revised in February 2017 to increase the starting dose by 25% for infants less than 1 year old. MEASUREMENTS AND MAIN RESULTS: We analyzed 780 hospitalizations from 636 children. Median percentage of catheter-days on prophylactic enoxaparin was 33% (interquartile range [IQR], 23-47%), 42% (IQR, 30-51%), and 38% (IQR, 35-52%) in periods 1-3, respectively. Percentage of catheter-days on enoxaparin showed immediate increase of 90% (95% CI, 17-210%) between periods 1 and 2 and sustained increase of 2% (95% CI, 0.3-4%) between periods 2 and 3. Median rates of thrombosis per 1,000 catheter-days were 5.8 (IQR, 0-9.3), 3.8 (IQR, 0-12), and 0 (IQR, 0-5.3) in periods 1-3, respectively. Rate of thrombosis showed immediate decrease of 67% (95% CI, 12-87%) between periods 1 and 2 and sustained decrease of 11% (95% CI, 2-18%) between periods 1 and 3. CONCLUSIONS: The temporal association between increase in percentage of catheter-days on enoxaparin and decrease in rate of thrombosis suggests the effectiveness of prophylactic enoxaparin.

A New Risk Assessment Model for Hospital-Acquired Venous Thromboembolism in Critically Ill Children: A Report From the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVES: To create a risk model for hospital-acquired venous thromboembolism in critically ill children upon admission to an ICU. DESIGN: Case-control study. SETTING: ICUs from eight children's hospitals throughout the United States. SUBJECTS: Critically ill children with hospital-acquired venous thromboembolism (cases) 0-21 years old and similar children without hospital-acquired venous thromboembolism (controls) from January 2012 to December 2016. Children with a recent cardiac surgery, asymptomatic venous thromboembolism, or a venous thromboembolism diagnosed before ICU admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The multi-institutional Children's Hospital-Acquired Thrombosis registry was used to identify cases and controls. Multivariable logistic regression was used to determine the association between hospital-acquired venous thromboembolism and putative risk factors present at or within 24 hours of ICU admission to develop the final model. A total of 548 hospital-acquired venous thromboembolism cases (median age, 0.8 yr; interquartile range, 0.1-10.2) and 187 controls (median age, 2.4 yr; interquartile range, 0.2-8.3) were analyzed. In the multivariable model, recent central venous catheter placement (odds ratio, 4.4; 95% CI, 2.7-7.1), immobility (odds ratio 3.6, 95% CI, 2.1-6.2), congenital heart disease (odds ratio 2.9, 95% CI, 1.7-4.7), length of hospital stay prior to ICU admission greater than or equal to 3 days (odds ratio, 2.5; 95% CI, 1.1-5.6), and history of autoimmune/inflammatory condition or current infection (odds ratio, 2.1; 95% CI, 1.2-3.4) were each independently associated with hospital-acquired venous thromboembolism. The risk model had an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.73-0.84). CONCLUSIONS: Using the multicenter Children's Hospital-Acquired Thrombosis registry, we identified five independent risk factors for hospital-acquired venous thromboembolism in critically ill children, deriving a new hospital-acquired venous thromboembolism risk assessment model. A prospective validation study is underway to define a high-risk group for risk-stratified interventional trials investigating the efficacy and safety of prophylactic anticoagulation in critically ill children.

Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial.

OBJECTIVES: We explored the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against central venous catheter-associated deep venous thrombosis in critically ill children. DESIGN: Post hoc analysis of a Bayesian phase 2b randomized clinical trial. SETTING: Seven PICUs. PATIENTS: Children less than 18 years old with newly inserted central venous catheter. INTERVENTIONS: Enoxaparin started less than 24 hours after insertion of central venous catheter and adjusted to anti-Xa level of 0.2-0.5 international units/mL versus usual care. MEASUREMENTS AND MAIN RESULTS: Of 51 children randomized, 24 were infants less than 1 year old. Risk ratios of central venous catheter-associated deep venous thrombosis with prophylaxis with enoxaparin were 0.98 (95% credible interval, 0.37-2.44) in infants and 0.24 (95% credible interval, 0.04-0.82) in older children greater than or equal to 1 year old. Infants and older children achieved anti-Xa level greater than or equal to 0.2 international units/mL at comparable times. While central venous catheter was in situ, endogenous thrombin potential, a measure of thrombin generation, was 223.21 nM.min (95% CI, 8.78-437.64 nM.min) lower in infants. Factor VIII activity, a driver of thrombin generation, was also lower in infants by 45.1% (95% CI, 15.7-74.4%). Median minimum platelet count while central venous catheter was in situ was higher in infants by 39 × 103/mm3 (interquartile range, 17-61 × 103/mm3). Central venous catheter:vein ratio was not statistically different. Prophylaxis with enoxaparin was less efficacious against central venous catheter-associated deep venous thrombosis at lower factor VIII activity and at higher platelet count. CONCLUSIONS: The relatively lesser contribution of thrombin generation on central venous catheter-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin.

Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial.

OBJECTIVES: We obtained preliminary evidence on the efficacy of early prophylaxis on the risk of central venous catheter-associated deep venous thrombosis and its effect on thrombin generation in critically ill children. DESIGN: Bayesian phase 2b randomized clinical trial. SETTING: Seven PICUs. PATIENTS: Children less than 18 years old with a newly inserted central venous catheter and at low risk of bleeding. INTERVENTION: Enoxaparin adjusted to anti-Xa level of 0.2-0.5 international units/mL started at less than 24 hours after insertion of central venous catheter (enoxaparin arm) versus usual care without placebo (usual care arm). MEASUREMENTS AND MAIN RESULTS: At the interim analysis, the proportion of central venous catheter-associated deep venous thrombosis on ultrasonography in the usual care arm, which was 54.2% of 24 children, was significantly higher than that previously reported. This resulted in misspecification of the preapproved Bayesian analysis, reversal of direction of treatment effect, and early termination of the randomized clinical trial. Nevertheless, with 30.4% of 23 children with central venous catheter-associated deep venous thrombosis on ultrasonography in the enoxaparin arm, risk ratio of central venous catheter-associated deep venous thrombosis was 0.55 (95% credible interval, 0.24-1.11). Including children without ultrasonography, clinically relevant central venous catheter-associated deep venous thrombosis developed in one of 27 children (3.7%) in the enoxaparin arm and seven of 24 (29.2%) in the usual care arm (p = 0.02). Clinically relevant bleeding developed in one child randomized to the enoxaparin arm. Response profile of endogenous thrombin potential, a measure of thrombin generation, was not statistically different between trial arms. CONCLUSIONS: These findings suggest the efficacy and safety of early prophylaxis that should be validated in a pivotal randomized clinical trial.

Development of a Risk Model for Pediatric Hospital-Acquired Thrombosis: A Report from the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVE: To identify pertinent clinical variables discernible on the day of hospital admission that can be used to assess risk for hospital-acquired venous thromboembolism (HA-VTE) in children. STUDY DESIGN: The Children's Hospital-Acquired Thrombosis Registry is a multi-institutional registry for all hospitalized participants aged 0-21 years diagnosed with a HA-VTE and non-VTE controls. A risk assessment model (RAM) for the development of HA-VTE using demographic and clinical VTE risk factors present at hospital admission was derived using weighted logistic regression and the least absolute shrinkage and selection (Lasso) procedure. The models were internally validated using 5-fold cross-validation. Discrimination and calibration were assessed using area under the receiver operating characteristic curve and Hosmer-Lemeshow goodness of fit, respectively. RESULTS: Clinical data from 728 cases with HA-VTE and 839 non-VTE controls, admitted between January 2012 and December 2016, were abstracted. Statistically significant RAM elements included age <1 year and 10-22 years, cancer, congenital heart disease, other high-risk conditions (inflammatory/autoimmune disease, blood-related disorder, protein-losing state, total parental nutrition dependence, thrombophilia/personal history of VTE), recent hospitalization, immobility, platelet count >350 K/µL, central venous catheter, recent surgery, steroids, and mechanical ventilation. The area under the receiver operating characteristic curve was 0.78 (95% CI 0.76-0.80). CONCLUSIONS: Once externally validated, this RAM will identify those who are at low-risk as well as the greatest-risk groups of hospitalized children for investigation of prophylactic strategies in future clinical trials.

How we approach thrombosis risk in children with COVID-19 infection and MIS-C.

Thrombosis within the microvasculature and medium to large vessels is a serious and common complication among critically ill individuals with coronavirus disease 2019 (COVID-19). While children are markedly less likely to develop severe disease than adults, they remain at risk for thrombosis during acute infection and with the post-acute inflammatory illness termed multisystem inflammatory syndrome in children. Significant knowledge deficits in understanding COVID-19-associated coagulopathy and thrombotic risk pose clinical challenges for pediatric providers who must incorporate expert opinion and personal experience to manage individual patients. We discuss clinical scenarios to provide framework for characterizing thrombosis risk and thromboprophylaxis in children with COVID-19.

Early Enteral Nutrition Is Associated With Improved Clinical Outcomes in Critically Ill Children: A Secondary Analysis of Nutrition Support in the Heart and Lung Failure-Pediatric Insulin Titration Trial.

OBJECTIVES: The impact of early enteral nutrition on clinical outcomes in critically ill children has not been adequately described. We hypothesized that early enteral nutrition is associated with improved clinical outcomes in critically ill children. DESIGN: Secondary analysis of the Heart and Lung Failure-Pediatric Insulin Titration randomized controlled trial. SETTING: Thirty-five PICUs. PATIENTS: Critically ill children with hyperglycemia requiring inotropic support and/or invasive mechanical ventilation who were enrolled for at least 48 hours with complete nutrition data. INTERVENTIONS: Subjects received nutrition via guidelines that emphasized enteral nutrition and were classified into early enteral nutrition (enteral nutrition within 48 hr of study randomization) and no early enteral nutrition (enteral nutrition after 48 hr of study randomization, or no enteral nutrition at any time). MEASUREMENTS AND MAIN RESULTS: Of 608 eligible subjects, 331 (54%) received early enteral nutrition. Both early enteral nutrition and no early enteral nutrition groups had similar daily caloric intake over the first 8 study days (median, 36 vs 36 kcal/kg/d; p = 0.93). After controlling for age, body mass index z scores, primary reason for ICU admission, severity of illness, and mean Vasopressor-Inotrope Score at the time of randomization, and adjusting for site, early enteral nutrition was associated with lower 90-day hospital mortality (8% vs 17%; p = 0.007), more ICU-free days (median, 20 vs 17 d; p = 0.02), more hospital-free days (median, 8 vs 0 d; p = 0.003), more ventilator-free days (median, 21 vs 19 d; p = 0.003), and less organ dysfunction (median maximum Pediatric Logistic Organ Dysfunction, 11 vs 12; p < 0.001). CONCLUSIONS: In critically ill children with hyperglycemia requiring inotropic support and/or mechanical ventilation, early enteral nutrition was independently associated with better clinical outcomes.

Bleeding Assessment Scale in Critically Ill Children (BASIC): Physician-Driven Diagnostic Criteria for Bleeding Severity.

OBJECTIVE: Although bleeding frequently occurs in critical illness, no published definition to date describes the severity of bleeding accurately in critically ill children. We sought to develop diagnostic criteria for bleeding severity in critically ill children. DESIGN: Delphi consensus process of multidisciplinary experts in bleeding/hemostasis in critically ill children, followed by prospective cohort study to test internal validity. SETTING: PICU. PATIENTS: Children at risk of bleeding in PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-four physicians worldwide (10 on a steering committee and 14 on an expert committee) from disciplines related to bleeding participated in development of a definition for clinically relevant bleeding. A provisional definition was created from 35 descriptors of bleeding. Using a modified online Delphi process and conference calls, the final definition resulted after seven rounds of voting. The Bleeding Assessment Scale in Critically Ill Children definition categorizes bleeding into severe, moderate, and minimal, using organ dysfunction, proportional changes in vital signs, anemia, and quantifiable bleeding. The criteria do not include treatments such as red cell transfusion or surgical interventions performed in response to the bleed. The definition was prospectively applied to 40 critically ill children with 46 distinct bleeding episodes. The kappa statistic between the two observers was 0.74 (95% CI, 0.57-0.91) representing substantial inter-rater reliability. CONCLUSIONS: The Bleeding Assessment Scale in Critically Ill Children definition of clinically relevant bleeding severity is the first physician-driven definition applicable for bleeding in critically ill children derived via international expert consensus. The Bleeding Assessment Scale in Critically Ill Children definition includes clear criteria for bleeding severity in critically ill children. We anticipate that it will facilitate clinical communication among pediatric intensivists pertaining to bleeding and serve in the design of future epidemiologic studies if it is validated with patient outcomes.

Criteria for Clinically Relevant Bleeding in Critically Ill Children: An International Survey.

OBJECTIVES: Bleeding, a feared complication of critical illness, is frequent in critically ill children. However, the concept of clinically relevant bleeding is ill-defined in this population. There are many established diagnostic criteria for bleeding, but only one estimates bleeding in critically ill adults, and none exist for critically ill children. Our objective was to identify the factors that influence pediatric intensivists' perception of clinically relevant bleeding. DESIGN: Self-administered, web-based survey with 9-point Likert scales, to qualify the clinical significance of 103 bleeding characteristics in critically ill children. SETTING: Online survey. SUBJECTS: Pediatric critical care physicians and nurse practitioners. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The response rate was 40%, with 225 respondents from 16 countries. Characteristics most frequently identified as clinically relevant were bleeding in critical locations (e.g., pericardium, pleural space, CNS, and lungs); requiring interventions; leading to physiologic repercussions, including organ failure; and of prolonged duration. Quantifiable bleeding greater than 5 mL/kg/hr for more than 1 hour was frequently considered clinically relevant. Respondents identified the following characteristics as clinically irrelevant: dressings required to be changed no less frequently than every 6 hours, streaks of blood in gastric tubes, streaks of blood in endotracheal tubes or blood in endotracheal tubes only during suctioning, lightly blood-tinged urine, quantifiable bleeding less than 1 mL/kg/hr, and noncoalescing petechiae. Perception of the clinical relevance of bleeding was not associated with the respondent's geographical location of clinical practice or years of experience. CONCLUSIONS: This international survey provides a better understanding of the factors that influence the pediatric intensivists' assessment of the clinical relevance of bleeding in critically ill children. It provides the foundation for the development of a validated, diagnostic definition of clinically relevant bleeding in this population.

Bleeding Scales Applicable to Critically Ill Children: A Systematic Review.

OBJECTIVES: To summarize current bleeding scales and their validation to assess applicability to bleeding in critically ill children. DATA SOURCES: We conducted electronic searches of Ovid MEDLINE, Ovid EMBASE, Cochrane Library, and Web of Science Core Collection databases from database inception to 2017. STUDY SELECTION: Included studies contained a bleeding score, bleeding measurement tool, or clinical measurement of hemorrhage. DATA EXTRACTION: We identified 2,097 unique citations; 20 full-text articles were included in the final review. DATA SYNTHESIS: Of the 18 studies that included subjects (two others were expert consensus definitions), seven (39%) were pediatric-only, seven (39%) were adult-only, and four (22%) included both adults and children. Nine (50%) occurred with inpatients (two studies in critical care units), seven (39%) involved outpatients and two (11%) included both inpatients and outpatients. Thirty-nine percent of the scales were developed for those with idiopathic thrombocytopenic purpura and only two (12%) described critically ill patients. The majority (80%) included need for treatment (either RBC transfusion or surgical intervention). The majority (65%) did not report measures of reliability or validation to clinical outcomes. CONCLUSIONS: There is a lack of validated bleeding scales to adequately assess bleeding and outcomes in critically ill children. Validated scales of bleeding are necessary and urgently needed.

Sera From Children After Cardiopulmonary Bypass Reduces Permeability of Capillary Endothelial Cell Barriers.

OBJECTIVES: Children undergoing cardiopulmonary bypass develop clinically impactful capillary leak of unclear etiology. A widely held hypothesis that exposure of circulating cells to the cardiopulmonary bypass circuit induces the release of inflammatory mediators that act to disrupt intercellular junctions of capillary endothelial cells inducing paracellular capillary leak either directly or through new gene expression. DESIGN: Cohort study. SETTING: Tertiary pediatric hospital. PATIENTS: Twenty children undergoing surgery with cardiopulmonary bypass for congenital heart disease. Serum was collected before cardiopulmonary bypass, 2 hours after cardiopulmonary bypass, and 18 hours after cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed the effects of 10% patient sera on the "function, structure, and gene expression" of cultured human dermal and pulmonary microvascular endothelial cells. Changes in barrier "function" were measured using transendothelial electrical resistance. Associations between changes in transendothelial electrical resistance and subject characteristics were analyzed using linear mixed effects model with area under the resistance curve as outcome. Changes in junctional "structure" were assessed by analyzing the organization of the endothelial cell junctional proteins claudin-5 and VE-cadherin using immunofluorescence microscopy. Changes in inflammatory "gene expression" were measured using real-time quantitative reverse transcription-polymerase chain reaction. All serum samples induced a transient, 120-minute increase in transendothelial electrical resistance followed by persistent loss of barrier function. Unexpectedly, sera collected postcardiopulmonary bypass-induced significantly less loss of barrier function in both dermal and pulmonary capillary endothelial cell compared with precardiopulmonary bypass sera. Consistent with the transendothelial electrical resistance results, claudin-5 and vascular endothelial-cadherin junctional staining showed less disruption in cultures treated with postcardiopulmonary bypass sera. Expression of genes commonly associated with inflammation was largely unaffected by patient sera. CONCLUSIONS: Contrary to the hypothesis, sera taken from children after cardiopulmonary bypass induces less capillary barrier disruption relative to sera taken from children before cardiopulmonary bypass, and none of the sera induced significant changes in expression of inflammatory genes.