Search

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 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.

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.

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.

BackgroundUntangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of enrichment strategies and targeted therapies. In this study, our aim was to analyze the organ dysfunction-based trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify and characterize reproducible and clinically relevant sepsis phenotypes using a data-driven approach.MethodsWe collected data from patients admitted with suspected infections to 13 pediatric intensive care units (PICUs) in the U.S. between 2012-2018. We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-driven phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours of PICU admission. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance.ResultsOverall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS. Amongst patients with sepsis-associated MODS, 1,537 (10.1%) died in the hospital. We identified an organ dysfunction trajectory-based phenotype (which we termedpersistent hypoxemia 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 thepersistent hypoxemia and shockphenotype appeared to have a higher likelihood to benefit from adjuvant therapy with hydrocortisone and albumin than other patients. When compared to other high-risk clinical syndromes, thepersistent hypoxemia and shockphenotype only overlapped with 50 to 60% of patients with septic shock, those with moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tertile of organ dysfunction burden, suggesting that it represents a distinct clinical phenotype of sepsis-associated MODS with a disproportionately high risk of mortality.ConclusionsWe derived and validated thepersistent hypoxemia and shockphenotype, a trajectory-based organ dysfunction phenotype which is highly reproducible, clinically relevant, and associated with heterogeneity of treatment effect to common adjuvant therapies. Further validation is warranted. Future studies are needed to validate this phenotype, assess whether it can be predicted earlier in the course, study possible biological mechanisms underlying it, and investigate candidate therapeutic targets.

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.

Background The risks of venous thromboembolism (VTE) and bleeding in critically ill adolescents based on interventions received and anatomic site of trauma or major surgery may identify a cohort eligible for enrollment in a trial of pharmacologic prophylaxis. Methods This retrospective cohort study using the Virtual Pediatric Systems database included adolescents admitted to pediatric intensive care units after trauma or major surgery between 2013 and 2017. Mixed effects logistic regression was used to determine the adjusted risks of VTE and bleeding with central venous catheterization (CVC), mechanical ventilation (MV) and anatomic site of trauma or major surgery. The adjusted risks were used to identify the cohort eligible for enrollment. Measurements and Main Results VTE developed in 212 (0.8%) of 27,647 adolescents. The adjusted risk of VTE was > 2% with CVC and 2 or more of MV and trauma or major surgery to the brain or abdomen. Excluding those with bleeds present on admission or at high risk of bleeding, 375 (1.4%) adolescents would be eligible for enrollment. Conclusions VTE is generally uncommon in adolescents after trauma or major surgery. The small proportion of adolescents who are at high risk of VTE and at low risk of bleeding impacts the feasibility of a trial. Level of Evidence Prognostic Study Level II.

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.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).A 12-bed academic pediatric cardiac ICU.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.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.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.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 (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 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.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.

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.

Rationale: Racial disparities in pain management have been previously reported for children receiving emergency care. Objectives: To determine whether patient race or ethnicity is associated with the broader goal of pain management and sedation among pediatric patients mechanically ventilated for acute respiratory failure. Methods: Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white, n = 1,233), non-Hispanic Black (Black, n = 502), or Hispanic of any race (Hispanic, n = 536). Results: Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%). Conclusions: Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out. Clinical trial registered with clinicaltrials.gov (NCT 00814099).

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.

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 Conclusions In critically ill children with hyperglycemia requiring inotropic support and/or mechanical ventilation, early enteral nutrition was independently associated with better clinical outcomes.

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 1.5, fibrinogen level 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.

Backround: To evaluate the feasibility of a randomized controlled trial (RCT) of the fibrinolytic tissue plasminogen activator (t-PA) vs unfractionated heparin (UFH) central venous catheter (CVC) dwell therapy to reduce risk of CVC-associated deep venous thrombosis (CADVT) in critically ill children. Methods: This single center quadruple blinded pilot RCT enrolled children ≤18 years of age with CVC placed within 72 hours of admission to the pediatric intensive care unit (ICU)Weight-adjusted dose of study drug dwell (t-PA vs UFH) was installed to alternating lumen of CVC every 3 days for 10 doses, CVC removal or ICU discharge. Ultrasound with doppler was performed at study completion.Main Results: Of 426 children screened from April-Dec 2019, 86 (20%) were eligible with 20 enrolled and randomized. Primary outcome measure of enrollment rate was 23%. One child was withdrawn immediately after randomization due to development of exclusion criterion. Secondary feasibility outcome measures were proportion of children who received study drug within 24 hours of consent (100%), proportion with ultrasound (100%), and proportion completing the study (95%). Eighteen of 19 children received the first dose within 48 hours of CVC placement. All children missed some dose days because of lumen specified to be in continuous use. Median dwell time for doses received was >2 hours. There were no protocol violations. Six of 19 patients (31.6%) developed CADVT, 1 of which was occlusive. There were no catheter-associated blood stream infection or significant bleeding.Conclusion: Critically ill children requiring CVC are at high risk for CADVT. A future multicenter, blinded, RCT to determine the effectiveness of t-PA vs UFH dwell in reducing CADVT is feasible.Registered August 10, 2018 on ClinicalTrials.gov NCT03672006

We designed and developed a low-cost mechanical ventilator prototype that meets the government's minimum viable standards. We substituted alternative off-the-shelf food-grade for the medical-grade parts and improvised some components for our prototype. We cleaned the air from the oxygen tanks and compressors before going to the lung test bag. We designed a solar-powered battery system that can run electronic components for a fail-safe operation. We demonstrated how the AIC Near Cloud system can store air flow rate and air pressure data which were generated during the prototype's operation. We used Embedded Machine Learning in sensors and data processing by using flow and pressure sensors to provide accumulated data that can be utilized in training the machine learning software. The patient-ventilator asynchrony detection model was tested using data generated from the emulated ventilator waveform events that mimic the patient-ventilator asynchrony. A different compression pattern was applied to the test lung and results showed the training, validation, and model testing that yielded 98.7%, 99.1%, and 97.18 percent accuracy, respectively. Having demonstrated that the Tiny ML can be trained to detect anomalies from several data points, we realized the feasibility of detecting ventilator patient vibration anomaly, and unusual acoustic signatures, among others, for future works.

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.

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.

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.

Thrombosis within the microvasculature and medium to large vessels is a serious and common complication among critically ill individuals with 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.

OBJECTIVES: Vascular access device decision-making for pediatric patients remains a complex, highly variable process. To date, evidence-based criteria to inform these choices do not exist. The objective of the Michigan Appropriateness Guide for Intravenous Catheters in pediatrics (miniMAGIC) was to provide guidance on device selection, device characteristics, and insertion technique for clinicians, balancing and contextualizing evidence with current practice through a multidisciplinary panel of experts. METHODS: The RAND Corporation and University of California, Los Angeles Appropriateness Method was used to develop miniMAGIC, which included the following sequential phases: definition of scope and key terms, information synthesis and literature review, expert multidisciplinary panel selection and engagement, case scenario development, and appropriateness ratings by an expert panel via 2 rounds. RESULTS: The appropriateness of the selection, characteristics, and insertion technique of intravenous catheters commonly used in pediatric health care across age populations (neonates, infants, children, and adolescents), settings, diagnoses, clinical indications, insertion locations, and vessel visualization devices and techniques was defined. Core concepts including vessel preservation, insertion and postinsertion harm minimization (eg, infection, thrombosis), undisrupted treatment provision, and inclusion of patient preferences were emphasized. CONCLUSIONS: In this study, we provide evidence-based criteria for intravenous catheter selection (from umbilical catheters to totally implanted venous devices) in pediatric patients across a range of clinical indications. miniMAGIC also highlights core vascular access practices in need of collaborative research and innovation.

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.

Despite the increasing incidence of venous thromboembolism (VTE) in hospitalized children, the risks and benefits of VTE prophylaxis, particularly for those hospitalized after trauma, are unclear. The Pediatric Trauma Society and the Eastern Association for the Surgery of Trauma convened a writing group to develop a practice management guideline on VTE prophylaxis for this cohort of children using the Grading of Recommendations Assessment, Development, and Evaluation framework.A systematic review of MEDLINE using PubMed from January 1946 to July 2015 was performed. The search retrieved English-language articles on VTE prophylaxis in children 0 to 21 years old with trauma. Topics of investigation included pharmacologic and mechanical VTE prophylaxis, active radiologic surveillance for VTE, and risk factors for VTE.Forty-eight articles were identified and 14 were included in the development of the guideline. The quality of evidence was low to very low because of the observational study design and risks of bias.In children hospitalized after trauma who are at low risk of bleeding, we conditionally recommend pharmacologic prophylaxis be considered for children older than 15 years old and in younger postpubertal children with Injury Severity Score (ISS) greater than 25. For prepubertal children, even with ISS greater than 25, we conditionally recommend against routine pharmacologic prophylaxis. Second, in children hospitalized after trauma, we conditionally recommend mechanical prophylaxis be considered for children older than 15 years and in younger postpubertal children with ISS greater than 25 versus no prophylaxis or in addition to pharmacologic prophylaxis. Lastly, in children hospitalized after trauma, we conditionally recommend against active surveillance for VTE with ultrasound compared with routine daily physical examination alone for earlier detection of VTE. The limited pediatric data and paucity of high-quality evidence preclude providing more definitive recommendations and highlight the need for clinical trials of prophylaxis.Systematic review/meta-analysis, level III.

* Abbreviations: ED — : emergency department miniMAGIC — : Michigan Appropriateness Guide for Intravenous Catheters in Pediatrics NTCVAD — : nontunneled central vascular access device PED — : pediatric emergency department PICC — : peripherally inserted central catheter PIVC — : peripheral intravenous catheter VAD — : vascular access device Vascular access devices (VADs) are commonly inserted, often in a time sensitive manner, in critically ill children to provide life-sustaining therapy, including but not limited to fluid resuscitation, antibiotics, vasopressors, or parenteral nutrition, and for hemodynamic monitoring. Among children admitted to the pediatric emergency department (PED), VAD selection is limited to peripheral intravenous catheter (PIVC), intraosseous device, and nontunneled central vascular access device (NTCVAD). VAD selection is more varied in the PICU and includes peripherally inserted central catheter (PICC), midline catheter, tunneled cuffed central VAD, and totally implanted venous device in addition to those that are available in the PED. Regardless of setting of care, currently there is no evidence-based guidance for VAD selection. In general, PIVCs are the mainstay for critically ill children in the PED, and PIVC and NTCVAD are the mainstays for those in the PICU. However, given the concerns of central line–associated bloodstream … Address correspondence to Sarah B. Kandil, MD, Department of Pediatrics, Yale School of Medicine, Yale University, 333 Cedar St, New Haven, CT 06520. E-mail: sarah.kandil{at}yale.edu

Elevated surfactant protein D (SP-D) is a relatively specific indicator of lung injury and is associated with both acute and chronic lung disease in adults and respiratory distress syndrome in premature infants. The relationship between plasma SP-D and lung injury in children with acute respiratory failure is unclear.Is plasma SP-D associated with lung injury or outcome in children with acute respiratory failure?This was a prospective cohort study in children 2 weeks to 17 years of age with acute respiratory failure who participated in the BALI multi-center study. Analyses were done using SP-D levels in plasma from the first sample taken on either the day of intubation or one of the following 2 days. SP-D level was measured by enzyme-linked immunosorbent assay.Plasma samples from 350 patients were used in the analysis; 233 had pediatric ARDS (PARDS). SP-D levels varied across primary diagnoses (P .001). Elevated SP-D levels were associated with severe PARDS after adjusting for age, pediatric risk of mortality III (PRISM-III), and primary diagnosis (OR = 1.02; CI = 1.01-1.04; P = .011). Multivariable analyses also indicated that elevated SP-D levels were associated with death (OR = 1.02; CI = 1.01-1.04; P = .004), duration of mechanical ventilation (P = .012), PICU length of stay (P = .019), and highest oxygenation index (P = .040). SP-D levels also correlated with age (rElevated plasma SP-D levels are associated with severe PARDS and poor outcomes in children with acute respiratory failure. Future studies will determine whether SP-D can be used to predict the degree of lung injury or response to treatment and whether SP-D is useful in identifying PARDS endotypes.

BACKGROUND Risk assessment models (RAMs) have been developed to identify children at high risk of hospital-acquired venous thromboembolism (HA-VTE). None have been externally validated nor compared. OBJECTIVES The objective was to compare performance of these RAMs by externally validating them using the Children's Hospital-Acquired Thrombosis (CHAT) Registry, ie, a multicenter database of children with radiographic-confirmed HA-VTE and corresponding controls. PATIENTS/METHODS Risk assessment models were included if the full logistic regression equation was available and all RAM variables were collected in the CHAT Registry. A random sample of 200 cases and 200 controls was selected. The performance of the RAMs was assessed for discrimination using area under the receiver operating characteristic curves (AUROC), and calibration using plots, slopes, and intercepts, and the Hosmer-Lemeshow test. RESULTS Three RAMs were included. Each had excellent discrimination with AUROC ≥ 0.85. However, calibration was generally poor, with calibration slopes significantly different from 1 (0.71, P

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.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.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 age1 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 count350 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).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.

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.Self-administered, web-based survey with 9-point Likert scales, to qualify the clinical significance of 103 bleeding characteristics in critically ill children.Online survey.Pediatric critical care physicians and nurse practitioners.None.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.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.

To compare current analgesia and sedation management practices between critically ill children with pre-existing cognitive impairment and critically ill neurotypical children, including possible indicators of therapeutic efficacy.This study used secondary analysis of prospective data from the RESTORE clinical trial, with 2449 children admitted to the pediatric intensive care unit and receiving mechanical ventilation for acute respiratory failure. Subjects with a baseline Pediatric Cerebral Performance Category ≥3 were defined as subjects with cognitive impairment, and differences between groups were explored using regression methods accounting for pediatric intensive care unit as a cluster variable.This study identified 412 subjects (17%) with cognitive impairment. Compared with neurotypical subjects, subjects with cognitive impairment were older (median, years, 6.2 vs 1.4; P .001) with more severe pediatric acute respiratory distress syndrome (40% vs 33%; P = .009). They received significantly lower cumulative doses of opioids (median, mg/kg, 14.2 vs 16.2; P .001) and benzodiazepines (10.6 vs 14.4; P .001). Three nonverbal subjects with cognitive impairment received no analgesia or sedation. Subjects with cognitive impairment were assessed as having more study days awake and calm and fewer study days with an episode of pain. They were less likely to be assessed as having inadequate pain/sedation management or unplanned endotracheal/invasive tube removal. Subjects with cognitive impairment had more documented iatrogenic withdrawal symptoms than neurotypical subjects.Subjects with cognitive impairment in this study received less medication, but it is unclear whether they have authentically lower analgesic and/or sedative requirements or are vulnerable to inadequate assessment of discomfort because of the lack of validated assessment tools. We recommend the development of pain and sedation assessment tools specific to this patient population.

Compared with consultative US performed by the radiology department, point-of-care US performed by non-radiology physicians can accurately diagnose deep venous thrombosis in adults. In preparation for a multicenter randomized controlled trial, we determined the accuracy of point-of-care US in diagnosing central venous catheter-related thrombosis in critically ill children. Children

Objective Delayed enteral nutrition, defined as enteral nutrition started 48 hours or more after admission to the PICU, is associated with an inability to achieve full enteral nutrition and worse outcomes in critically ill children. We reviewed nutritional practices in six medical-surgical PICUs and determined risk factors associated with delayed enteral nutrition in critically ill children. Design Retrospective cross-sectional study using medical records as source of data. Setting Six medical-surgical PICUs in northeastern United States. Patients Children less than 21 years old admitted to the PICU for 72 hours or more excluding those awaiting or recovering from abdominal surgery. Measurements and main results A total of 444 children with a median age of 4.0 years were included in the study. Enteral nutrition was started at a median time of 20 hours after admission to the PICU. There was no significant difference in time to start enteral nutrition among the PICUs. Of those included, 88 children (19.8%) had delayed enteral nutrition. Risk factors associated with delayed enteral nutrition were noninvasive (odds ratio, 3.37; 95% CI, 1.69-6.72) and invasive positive-pressure ventilation (odds ratio, 2.06; 95% CI, 1.15-3.69), severity of illness (odds ratio for every 0.1 increase in pediatric index of mortality 2 score, 1.39; 95% CI, 1.14-1.71), procedures (odds ratio, 3.33; 95% CI, 1.67-6.64), and gastrointestinal disturbances (odds ratio, 2.05; 95% CI, 1.14-3.68) within 48 hours after admission to the PICU. Delayed enteral nutrition was associated with failure to reach full enteral nutrition while in the PICU (odds ratio, 4.09; 95% CI, 1.97-8.53). Nutrition consults were obtained in less than half of the cases, and none of the PICUs used tools to assure the adequacy of energy and protein nutrition. Conclusions Institutions in this study initiated enteral nutrition for a high percentage of patients by 48 hours of admission. Noninvasive positive-pressure ventilation was most strongly associated with delay enteral nutrition. A better understanding of these risk factors and assessments of nutritional requirements should be explored in future prospective studies.

BACKGROUND: As the survival of children with cardiac disease increases, chronic complications of deep venous thrombosis from cardiac catheterization, particularly post-thrombotic syndrome, may be important to monitor for and treat, if needed. We aimed to determine the prevalence of this syndrome in children who underwent cardiac catheterization.PROCEDURE: We conducted a cross-sectional study of children

Purpose of review To review the current literature on venous thromboembolism (VTE) in critically ill children. Recent findings There is an increasing concern for VTE and its complications in critically ill children. Critically ill children are at increased risk of thromboembolism because of the treatment that they are receiving and their underlying condition. A complex relationship exists between thrombosis and infection. A thrombus is a nidus for infection, while infection increases the risk of thrombosis. Pediatric-specific guidelines for the prevention and treatment of thromboembolism are lacking. Current guidelines are based on the data from adults. Novel anticoagulants are now available for use in adults. Studies are ongoing to determine their safety in children. Risk assessment tools have recently been developed to determine the risk of thromboembolism in critically ill children. Certain molecules are associated with thromboembolism in adults. Summary Pediatric critical care practitioners should be cognizant of the importance of VTE in critically ill children to allow early identification and treatment. Adequately powered clinical trials are critically needed to generate evidence that will guide the treatment and prevention of thromboembolism in critically ill children. Risk assessment tools that incorporate biomarkers may improve our ability to predict the occurrence of thromboembolism in critically ill children.

Venous thromboembolism, which includes deep venous thrombosis and pulmonary embolism, is a potentially preventable condition in children. In adults, pharmacologic prophylaxis has been shown to significantly reduce the incidence of venous thromboembolism in distinct patient cohorts. However, pediatric randomized controlled trials have failed to demonstrate the efficacy of pharmacologic prophylaxis against thrombosis associated with central venous catheters, the most important risk factor for venous thromboembolism in children. Despite the lack of supporting evidence, hospital-based initiatives are being undertaken to try to prevent venous thromboembolism in children. In this study, we sought to review the published guidelines on the prevention of venous thromboembolism in hospitalized children. We identified five guidelines, all of which were mainly targeted at adolescents and used various risk-stratification approaches. In low-risk children, ambulation was the recommended prevention strategy, while mechanical prophylaxis was recommended for children at moderate risk and pharmacologic and mechanical prophylaxis were recommended for the high-risk group. The effectiveness of these strategies has not been proven. In order to determine whether venous thromboembolism can be prevented in children, innovative clinical trial designs are needed. In the absence of these trials, guidelines can be a source of valuable information to inform our practice.

Insulin adsorbs to plastic tubing, which decreases the concentration of an insulin solution delivered from an intravenous infusion set. Dwelling insulin within tubing before starting the infusion decreases adsorption but delays treatment initiation and wastes time in infusion preparation. The lack of data on dwell time effects results in wide variability in practice. We aim to determine the effect of dwell time on insulin concentration from intravenous infusion tubing.In this in vitro study, we used insulin solutions with concentrations of 0.1 unit/mL, 1 unit/mL, and 10 units/mL. Each solution dwelled in intravenous infusion sets for 0, 15, 30, or 60 min. After the dwell, we measured insulin concentrations from the solution bags and tubing. We repeated each insulin concentration-dwell time combination five times. Comparisons were performed using analyses of variance.For each of the three insulin concentrations, the mean insulin concentrations from the tubing were not significantly different between dwell times. Duration of dwell time did not affect insulin adsorption in polypropylene intravenous infusion sets.We recommend that following a 20-mL flush, insulin infusions can be started without any dwell time. Removal of dwell times may improve clinical practice by minimizing preparation time and will allow faster initiation of insulin infusion therapy.

Background:The practice of glycemic control with intravenous insulin in critically ill patients has brought clinical focus on understanding the effects of hypoglycemia, especially in children. Very little is published on the impact of hypoglycemia in this population. We aimed to review the existing literature on hypoglycemia in critically ill neonates and children.Methods:We performed a systematic review of the literature up to August 2011 using PubMed, Ovid MEDLINE and ISI Web of Science using the search terms “hypoglycemia or hypoglyc*” and “critical care or intensive care or critical illness”. Articles were limited to “all child (0–18 years old)” and “English”.Results:A total of 513 articles were identified and 132 were included for review. Hypoglycemia is a significant concern among pediatric and neonatal intensivists. Its Definition is complicated by the use of a biochemical measure (i.e., blood glucose) for a pathophysiologic problem (i.e., neuroglycopenia). Based on associated outcomes, we suggest defining hypoglycemia as Conclusion:Studies on hypoglycemia in critically ill children have focused on spontaneous hypoglycemia. With the current practice of maintaining blood glucose within a narrow range with intravenous insulin, the risk factors and outcomes associated with insulin-induced hypoglycemia should be rigorously studied to prevent hypoglycemia and potentially improve outcomes of critically ill children.