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.

Considerations for instituting pediatric pulmonary embolism response teams: A tool kit.

The incidence of pediatric pulmonary embolism (PE) has increased by 200 % in the last decade, but at a single center, it is still infrequent. Given the unique epidemiologic features of pediatric PE, diagnosis is often delayed, and the management is empiric, based on individual physician experience or preference. Thus, there is a strong need for center-specific uniform management of pediatric PE patients. In adults, the development of pulmonary embolism response teams (PERTs) or PE critical care pathways has shortened the time to diagnosis and the initiation of definitive management. Evidence to support an improvement in PE outcomes after the development of PERTs does not exist in children. Nonetheless, we have summarized the practical practice guidelines that physicians and institutions can adopt to establish their institutional PERTs or critical pathways. We also provide strategies for resource-challenged institutions for partnering with centers with expertise in the management of pediatric PE.

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.

Antithrombin activity and central venous catheter-associated thrombosis in critically ill children at high risk of bleeding.

BACKGROUND: Normalization of antithrombin activity may prevent catheter-associated thrombosis in critically ill children at high risk of bleeding. OBJECTIVES: To characterize the temporal pattern of antithrombin activity, assess its association with catheter-associated thrombosis and clinically relevant bleeding, and evaluate its relationship with thrombin generation in these children. METHODS: In this prospective cohort study, critically ill children <18 years old at high risk of bleeding with central venous catheter were eligible. Antithrombin activity and thrombin generation were measured from platelet-poor plasma and after in vitro antithrombin supplementation. Systematic surveillance ultrasound was performed to diagnose thrombosis. Children were followed for bleeding. RESULTS: We enrolled 8 infants (median age: 0.2 years, IQR: 0.2, 0.3 years) and 72 older children (median age: 14.3 years, IQR: 9.1, 16.1 years). Mean antithrombin on the day of catheter insertion was 64 IU/dL (SD: 32 IU/dL) in infants and 83 IU/dL (SD: 35 IU/dL) in older children. Antithrombin normalized by the day of catheter removal. Thrombosis developed in 27 children, while 31 children bled. Thrombosis (regression coefficient: 0.008, 95% CI: -0.01, 0.03) and bleeding (regression coefficient: -0.0007, 95% CI: -0.02, 0.02) were not associated with antithrombin. Antithrombin was not correlated with in vivo change in endogenous thrombin potential (correlation coefficient: -0.07, 95% CI: -0.21, 0.08). In vitro supplementation reduced endogenous thrombin potential (correlation coefficient: -0.78; 95% CI: -0.95, -0.23). CONCLUSION: These findings may not support normalization of antithrombin activity to prevent catheter-associated thrombosis in critically ill children at high risk of bleeding.

Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes-an international multicentre retrospective study.

Background: Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. Methods: We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n = 383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n = 1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24 h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. Findings: LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p < 0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04-3.34) in the European cohort and 1.6 (1.2-2.2) in the U.S. cohort. Interpretation: We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Funding: Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

External validation and biomarker assessment of a high-risk, data-driven pediatric sepsis phenotype characterized by persistent hypoxemia, encephalopathy, and shock.

Objective: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. Data-driven phenotyping approaches that leverage electronic health record (EHR) data hold promise given the widespread availability of EHRs. We sought to externally validate the data-driven 'persistent hypoxemia, encephalopathy, and shock' (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk-strata. Design: We trained and validated a random forest classifier using organ dysfunction subscores in the EHR dataset used to derive the PHES phenotype. We used the classifier to assign phenotype membership in a test set consisting of prospectively enrolled pediatric septic shock patients. We compared biomarker profiles of those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk-strata. Setting: 25 pediatric intensive care units (PICU) across the U.S. Patients: EHR data from 15,246 critically ill patients sepsis-associated MODS and 1,270 pediatric septic shock patients in the test cohort of whom 615 had biomarker data. Interventions: None. Measurements and Main Results: The area under the receiver operator characteristic curve (AUROC) of the new classifier to predict PHES phenotype membership was 0.91(95%CI, 0.90-0.92) in the EHR validation set. In the test set, patients with the PHES phenotype were independently associated with both increased odds of complicated course (adjusted odds ratio [aOR] of 4.1, 95%CI: 3.2-5.4) and 28-day mortality (aOR of 4.8, 95%CI: 3.11-7.25) after controlling for age, severity of illness, and immuno-compromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and overlapped with high risk-strata based on PERSEVERE biomarkers predictive of death and persistent MODS. Conclusions: The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlap with higher risk-strata based on validated biomarker approaches.

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.

Mechanical Ventilation and Hospital-Acquired Venous Thromboembolism Among Critically Ill Children.

OBJECTIVES: To estimate the occurrence of, and evaluate associations between, hospital-acquired venous thromboembolism (HA-VTE) and invasive mechanical ventilation (MV) among children hospitalized in the PICU. METHODS: We performed a multicenter, retrospective cohort study comparing HA-VTE frequencies among subjects <18 years of age hospitalized in the PICU from January 2018 through December 2019 among 47 participating centers, via the Pediatric Health Information Systems registry. We excluded perinatal encounters, those with VTE present at admission, and those with observational status. The primary outcome was the proportion of HA-VTE events before hospital discharge, including extremity deep venous thrombosis, pulmonary embolism, and organ-specific deep venous thrombosis. The HA-VTE frequencies were compared using χ2 tests. The association between HA-VTE and MV was investigated via multivariable logistic regression, adjusting for previously described VTE risk factors. RESULTS: Of the 205 231 PICU encounters identified for study, 70 829 (34.5%) underwent MV. The occurrence of HA-VTE was 2.2% and was greater among children who received, versus did not receive, MV (4.4% versus 1.1%, P < .001). Multivariable logistic regression revealed significant association between MV and HA-VTE (odds ratio 2.51, 95% confidence interval 2.33-2.69; P < .001). CONCLUSIONS: In this multicenter, retrospective, registry-based cohort study, HA-VTE were diagnosed in 2.2% of critically-ill children, and after adjustment for central venous catheterization, MV independently increased the risk of HA-VTE 2.5-fold. These findings warrant prospective validation to inform the design of future risk-stratified clinical trials of thromboprophylaxis in critically-ill children.

Risk of venous thromboembolism in pediatric hospitalized patients undergoing noncardiac surgery: A report from the Children's Hospital-Acquired Thrombosis consortium.

Background: Surgery is a known risk factor for hospital-acquired venous thromboembolism (HA-VTE) in children. Objectives: To assess whether the odds of HA-VTE differs across six anatomic sites of noncardiac surgery and to identify risk factors for HA-VTE in these children. Methods: This was a multicenter, case-control study. Anatomic sites of surgery and risk factors for HA-VTE were collected on hospitalized pediatric patients who had undergone a single noncardiac surgery and developed HA-VTE (cases), and those who did not develop HA-VTE (controls), via the Children's Hospital-Acquired Thrombosis (CHAT) Registry. Logistic regression estimated the odds ratio (OR) and 95% confidence intervals (CIs) between six anatomic sites of surgery and 16 putative HA-VTE risk factors. Variables with a p value of 0.10 or less in unadjusted analyses were included in adjusted models for further evaluation. The final model used backward selection, with a significance level of 0.05. Results: From January 2012 to March 2020, 163 cases (median age, 5.7 years; interquartile range [IQR], 0.3-14.2) and 208 controls (median age of 7.5 years; IQR, 3.7-12.9) met our criteria. There was no statistically significant increased odds of VTE among the types of noncardiac surgery. In the final adjusted model, central venous catheter (CVC; OR, 14.69; 95% CI, 7.06-30.55), intensive care unit (ICU) stay (OR, 5.31; 95% CI, 2.53-11.16), and hospitalization in the month preceding surgery (OR, 2.75; 95% CI, 1.24-6.13) were each independently significant risk factors for HA-VTE. Conclusion: In children undergoing noncardiac surgery, placement of CVCs, admission/transfer to the ICU, or hospitalization in the month prior to surgery were positively associated with HA-VTE.

Accuracy of physical examination in detecting central venous catheter-associated thrombosis in critically ill children.

INTRODUCTION: Lack of standardized definition impedes our ability to understand the clinical significance of asymptomatic central venous catheter (CVC) associated deep venous thrombosis (CADVT). Using standardized definitions, we aimed to determine the accuracy of physical examination in detecting CADVT in critically ill children and to identify characteristics associated with this accuracy. MATERIALS AND METHODS: In a post hoc study, we analyzed 236 children <18 years old admitted to the pediatric intensive care unit, had an untunneled CVC and surveilled for CADVT using ultrasound with paired physical examination. RESULTS: Of 236 paired examinations, 79 (33.5 %) had CADVT on ultrasound, while 56 (23.7 %) had signs of inflammation or venous obstruction on physical examination or CVC dysfunction. Sensitivity was 29.2 % (95 % confidence interval, CI: 19.9 %, 38.5 %), specificity was 80.2 % (95 % CI: 73.9 %, 86.4 %) and area under the receiver operating characteristic curve (AUROC) was 0.55 (95 % CI: 0.49, 0.60). When CVC dysfunction was excluded, sensitivity was lower (11.1 %; 95 % CI: 4.6 %, 17.6 %; p = 0.002), but specificity was higher (88.7 %; 95 % CI: 83.6 %, 93.7 %, p = 0.04). AUROC was 0.50 (95 % CI: 0.46, 0.54; p = 0.17). Use of point-of-care ultrasound and CVC inserted in the internal jugular vein (vs femoral vein) had lower sensitivity. Sepsis or infection and vasoactive support had lower specificity. Center of enrollment was associated with variable sensitivity. CONCLUSIONS: Physical examination has poor accuracy in detecting CADVT in critically ill children. Despite poor accuracy, physical examination that includes assessment of CVC dysfunction, in combination with imaging, is key to understanding the clinical significance of asymptomatic CADVT.

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.

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.

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.

Symptomatic pulmonary embolus after catheter removal in children with catheter related thrombosis: A report from the CHAT Consortium.

BACKGROUND: Appropriate timing of central venous catheter (CVC) removal, in relation to start of anticoagulation, in children after the diagnosis of a CVC-related thrombosis (CRT) is not well established. OBJECTIVES: This retrospective cohort study evaluated the incidence of symptomatic pulmonary embolism (PE) after CVC removal using data from the multi-institutional Children's Hospital-Acquired Thrombosis (CHAT) Consortium Registry. PATIENTS/METHODS: The CHAT Registry consists of data from children aged 0-21 years with a hospital-acquired venous thromboembolism. Eligible subjects were those with CRT diagnosed <3 days after CVC removal. Subjects were excluded if the CRT was due to a failed CVC insertion. Subjects were divided into three groups: those with CVC removal without anticoagulation, those with CVC removal <48 h after starting anticoagulation, and those with CVC removal ≥48 h after starting anticoagulation. RESULTS: A total of 687 CRT events from 663 subjects were included. A majority of CRT events were in subjects with peripherally inserted central catheters (62.3%, n = 428). For the 611 CRT events in which the CVC was removed, there was only one case of symptomatic PE (0.16%), which occurred <48 h after initiation of anticoagulation. CONCLUSIONS: While current guidelines suggest anticoagulation before CVC removal in the setting of a CRT to prevent embolization, CVC removal is not associated with symptomatic PE regardless of duration of anticoagulation before CVC removal.

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.

Coagulation Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

CONTEXT: Previous criteria for coagulation dysfunction in critically ill children were based mainly on expert opinion. OBJECTIVE: To evaluate current evidence regarding coagulation tests associated with adverse outcomes in children to inform criteria for coagulation dysfunction during critical illness. DATA SOURCES: Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020 by using a combination of medical subject heading terms and text words to define concepts of coagulation dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION: Studies were included if critically ill children with coagulation dysfunction were evaluated, if performance characteristics of assessment and/or scoring tools to screen for coagulation dysfunction were evaluated, and if outcomes related to mortality or functional status, organ-specific outcomes, or other patient-centered outcomes were assessed. DATA EXTRACTION: Data were abstracted from each eligible study into a standard data extraction form, along with risk of bias assessment, by a task force member. RESULTS: The systematic review supports the presence of at least 2 of the following criteria reflecting coagulation dysfunction in the absence of liver dysfunction: platelet count <100 000 cells per µL, international normalized ratio >1.5, fibrinogen level <150 mg/dL, and D-dimer value above 10 times the upper limit of normal, or above the assay's upper limit of detection if this limit is below 10 times the upper limit of normal. LIMITATIONS: The proposed criteria for coagulation dysfunction are limited by the available evidence and will require future validation. CONCLUSIONS: Validation of the proposed criteria and identified scientific priorities will enhance our understanding of coagulation dysfunction in critically ill children.

Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Contemporary Organ Dysfunction Criteria: Executive Summary.

Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.

Validation of risk assessment models for venous thromboembolism and bleeding in critically ill adolescents.

OBJECTIVE: To determine the performance of risk assessment models that were developed for adults, in predicting venous thromboembolism (VTE) and bleeding in critically ill adolescents. STUDY DESIGN: We conducted a retrospective cohort study of adolescents 12 to 17 years old admitted to the pediatric intensive care unit who received cardiopulmonary support but did not have VTE on admission nor received anticoagulation. Discrimination, using areas under the receiver operating characteristic (AUROC) and precision-recall (AUPRC) curves, and calibration, using Hosmer-Lemeshow test, of the Geneva, Padua, IMPROVE VTE and IMPROVE Bleed models were calculated. RESULTS: Of 536 adolescents analyzed, 7 (1.3%) developed VTE and 13 (2.4%) bled. AUROCs of the Geneva, Padua and IMPROVE VTE models ranged from 0.46 to 0.59, with 95% confidence intervals (CI) including 0.5. AUPRCs ranged from 0.011 to 0.017, with 95% CIs including 0.013. Only IMPROVE VTE model had non-statistically significant Hosmer-Lemeshow test. IMPROVE Bleed model had AUROC and AUPRC of 0.75 and 0.062, with 95% CIs excluding 0.5 and 0.024, respectively. Hosmer-Lemeshow test was not statistically significant. CONCLUSION: Despite similarities in coagulation between adolescents and adults, risk assessment models for VTE in adults should not be used for critically ill adolescents. The model for bleeding may be useful.