Faculty Bibliography

BACKGROUND:Previous latent class analysis of adults with acute respiratory distress syndrome (ARDS) identified two phenotypes, distinguished by the degree of inflammation. We aimed to identify phenotypes in children with ARDS in whom developmental differences might be important, using a latent class analysis approach similar to that used in adults. METHODS:This study was a secondary analysis of data aggregated from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial and the Genetic Variation and Biomarkers in Children with Acute Lung Injury (BALI) ancillary study. We used latent class analysis, which included demographic, clinical, and plasma biomarker variables, to identify paediatric ARDS (PARDS) phenotypes within a cohort of children included in the RESTORE and BALI studies. The association of phenotypes with clinically relevant outcomes and the performance of paediatric data in adult ARDS classification algorithms were also assessed. FINDINGS:304 children with PARDS were included in this secondary analysis. Using latent class analysis, a two-class model was a better fit for the cohort than a one-class model (p<0·001). Latent class analysis identified two classes: class 1 (181 [60%] of 304 patients with PARDS) and class 2 (123 [40%] of 304 patients with PARDS), referred to as phenotype 1 and 2 hereafter. Phenotype 2 was characterised by higher concentrations of inflammatory biomarkers, a higher incidence of vasopressor use, and more frequent diagnosis of sepsis, consistent with the adult hyperinflammatory phenotype. All levels of severity of PARDS were observed across both phenotypes. Children with the hyperinflammatory phenotype (phenotype 2) had worse clinical outcomes than those with the hypoinflammatory phenotype (phenotype 1), with a longer duration of mechanical ventilation (median 10·0 days [IQR 6·3-21·0] for phenotype 2 vs 6·6 days [4·1-10·8] for phenotype 1, p<0·0001), and higher incidence of mortality (17 [13·8%] of 123 patients vs four [2·2%] of 181 patients, p=0·0001). When using adult phenotype classification algorithms in children, the soluble tumour necrosis factor receptor-1 (sTNFr1), vasopressor use, and interleukin (IL)-6 variables gave an area under the curve (AUC) of 0·956, and the sTNFr1, vasopressor use, and IL-8 variables gave an AUC of 0·954, compared with the gold standard of latent class analysis. INTERPRETATION:Latent class analysis identified two phenotypes in children with ARDS with characteristics similar to those in adults, including worse outcomes among patients with the hyperinflammatory phenotype. PARDS phenotypes should be considered in design and analysis of future clinical trials in children. FUNDING:US National Institutes of Health.

OBJECTIVES:Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. DESIGN:Retrospective study. SETTING:Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. PATIENTS:Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. CONCLUSIONS:In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

OBJECTIVES:To describe the association between left heart decompression on veno-arterial extracorporeal membrane oxygenation and survival in patients with myocarditis and dilated cardiomyopathy. The secondary outcome is to study association of left heart decompression with survival in children with myocarditis compared with those with dilated cardiomyopathy. DESIGN:Retrospective study of a multicenter registry database. SETTING:Data reported to Extracorporeal Life Support Organization from international extracorporeal membrane oxygenation centers. PATIENTS:Patients less than or equal to 18 years old with a diagnosis of myocarditis or dilated cardiomyopathy receiving extracorporeal membrane oxygenation. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:A total of 1,438 pediatric extracorporeal membrane oxygenation runs were identified. Thirty-seven percent of the patients had myocarditis (n = 532), whereas the rest had dilated cardiomyopathy. Survival to hospital discharge was 63%. Median extracorporeal membrane oxygenation duration was 148 hours with interquartile range (84-248 hr). Nineteen percent of patients (n = 274) had left heart decompression. Multivariable analysis revealed using left heart decompression (adjusted odds ratio, 1.42; 95% CI, 1.06-1.89; p = 0.02), e-cardiopulmonary resuscitation (adjusted odds ratio, 0.63; 95% CI, 0.51-0.79; p < 0.001), higher pH (adjusted odds ratio, 3.69; 95% CI, 1.80-7.53; p < 0.001), and diagnosis of myocarditis (adjusted odds ratio, 1.69; 95% CI, 1.35-2.08; p < 0.001) were associated with greater odds of survival. In the multivariable analysis for patients with dilated cardiomyopathy, left heart decompression failed to reveal a significant association with survival (20% among survivors vs 17% among nonsurvivors, 95% CI, -2.2% to 8.0%). Meanwhile in patients with myocarditis, the multivariable analysis failed to exclude the possibility that left heart decompression was associated with up to a three-fold greater odds of survival (adjusted odds ratio, 1.77; 95% CI, 0.99-.15). CONCLUSIONS:Retrospective review of the Extracorporeal Life Support Organization registry revealed an association between left heart decompression and greater odds of survival in children with myocarditis and dilated cardiomyopathy on extracorporeal membrane oxygenation. When comparing patients with dilated cardiomyopathy against those with myocarditis, we could not exclude a three-fold greater odds of survival associated with the use of left heart decompression. This finding warrants further prospective evaluation.

OBJECTIVES/OBJECTIVE:To describe the incidence of and risk factors for acute kidney injury (AKI) in children with acute respiratory distress syndrome (ARDS) and study the effect of AKI on patient outcomes. DESIGN/METHODS:A single-center retrospective study. SETTING/METHODS:A tertiary care children's hospital. PATIENTS/METHODS:All patients less than 18 years of age who received invasive mechanical ventilation (MV) and developed ARDS between July 2010 and July 2013 were included. Acute kidney injury was defined using p-RIFLE (risk, injury, failure, loss, and end-stage renal disease) criteria. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:= .03). Only PEEP and P/F ratios were significantly associated with AKI in the unadjusted logistic regression model. Patients with AKI had a significantly longer duration of hospital stay, although there was no significant difference in the intensive care unit stay, duration of MV, and mortality. Recovery of AKI occurred in 68% of the patients. A multivariable model including PEEP, P/F ratio, weight, need for inotropes, and need for diuretics had a better receiver operating characteristic (ROC) curve with an AUC of 0.75 compared to the ROC curves for PEEP only and P/F ratio only for the prediction of AKI. CONCLUSIONS:Patients with ARDS have high rates of AKI, and its presence is associated with increased morbidity and mortality.

BACKGROUND:The use of electronic clinical decision support (CDS) systems for pediatric critical care trials is rare. We sought to describe in detail the use of a CDS tool (Children's Hospital Euglycemia for Kids Spreadsheet [CHECKS]), for the management of hyperglycemia during the 32 multicenter Heart And Lung Failure-Pediatric Insulin Titration trial. RESEARCH QUESTION:In critically ill pediatric patients who were treated with CHECKS, how was user compliance associated with outcomes; and what patient and clinician factors might account for the observed differences in CHECKS compliance? STUDY DESIGN AND METHODS:During an observational retrospective study of compliance with a CDS tool used during a prospective randomized controlled trial, we compared patients with high and low CHECKS compliance. We investigated the association between compliance and blood glucose metrics. We describe CHECKS and use a computer interface analysis framework (the user, function, representation, and task analysis framework) to categorize user interactions. We discuss implications for future randomized controlled trials. RESULTS:Over a 4.5-year period, 658 of 698 children were treated with the CHECKS protocol for ≥24 hours with a median of 119 recommendations per patient. Compliance per patient was high (median, 99.5%), with only 30 patients having low compliance (<90%). Patients with low compliance were from 16 of 32 sites, younger (P = .02), and less likely to be on inotropic support (P = .04). They were more likely to be have been assigned randomly to the lower blood glucose target (80% vs 48%; P < .001) and to have spent a shorter time (53% vs 75%; P < .001) at the blood glucose target. Overrides (classified by the user, function, representation, and task analysis framework), were largely (89%) due to the user with patient factors contributing 29% of the time. INTERPRETATION:The use of CHECKS for the Heart And Lung Failure-Pediatric Insulin Titration trial resulted in a highly reproducible and explicit method for the management of hyperglycemia in critically ill children across varied environments. CDS systems represent an important mechanism for conducting explicit complex pediatric critical care trials. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01565941, registered March 29 2012; https://clinicaltrials.gov/ct2/show/NCT01565941?term=HALF-PINT&draw=2&rank=1.

BACKGROUND:Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction. METHODS:This was a prospective observational study of 432 patients aged 2 weeks-17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses. RESULTS:sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n = 432, adjusted HR = 1.003, p = 0.02) and worse OI in the first 5 days after intubation (n = 252, Estimate = 0.02, p < 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003, p < 0.0001; and slope, Estimate = 0.01, p = 0.0009, n = 386). CONCLUSIONS:Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies. TRIAL REGISTRATION:https://clinicaltrials.gov/ct2/show/NCT00814099 . In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.

This study describes the use of bivalirudin in children on extracorporeal membrane oxygenation (ECMO). Pediatric patients receiving bivalirudin were compared to patients receiving heparin as the anticoagulant on ECMO. Data was collected for children under 18 years of age supported by ECMO from January 2016 to December 2019. Data collected included demographics, diagnosis, ECMO indication, type, and duration, indication for bivalirudin use, dose range, activated partial thromboplastin time (aPTT) levels, minor and major bleeding, hemolysis, and mortality. Forty pediatric patients received ECMO; eight received bivalirudin primarily for anticoagulation. The median age was 4 months (IQR 0.5, 92) in the heparin cohort, 0.6 months (IQR 0.0, 80.0) in the primary bivalirudin cohort. The indication for ECMO was respiratory in 5 patients (18%) in the heparin group versus 6 (75%) in the primary bivalirudin group, cardiac in 18 (67%) in heparin versus 1 (12.5%) in primary bivalirudin, and extracorporeal-cardiopulmonary resuscitation (E-CPR) in 4 (15%) in heparin versus 1 (12.5%) in primary bivalirudin. Bivalirudin was the initial anticoagulant for eight patients (66.6%) while three (25%) were switched due to concern for heparin-induced thrombocytopenia (HIT) and one (8%) for heparin resistance. The median time to achieve therapeutic aPTT was 14.5 hours compared to 12 hours in the heparin group. Sixty-five percent of aPTT values in the bivalirudin and 44% of values in the heparin group were in the therapeutic range in the first 7 days. Patients with primary bivalirudin use had significantly lower dose requirement at 12 (p = 0.003), 36 (p = 0.007), and 48 (p = 0.0002) hours compared to patients with secondary use of bivalirudin. One patient (12.5%) had major bleeding, and two patients (25%) required circuit change in the primary bivalirudin cohort. Bivalirudin may provide stable and successful anticoagulation in children. Further large, multicenter studies are needed to confirm these findings.

OBJECTIVE:There is paucity of data about prevalence of pediatric acute respiratory distress syndrome (PARDS) in children with pulmonary contusion (PC). We intend to evaluate PC in children with chest trauma and the association between PC and PARDS. DESIGN/METHODS:Retrospective review of Institutional Trauma Registry for patients with trauma. SETTING/METHODS:Level 1 trauma center. PATIENTS/METHODS:Age 18 years and younger with a diagnosis of PC. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:< .0001) compared to those who did not require IMV. Lower GCS score was independently associated with both PARDS and need for IMV. CONCLUSIONS:Pediatric ARDS in children with PC is independently associated with lower GCS score, and its presence significantly increased morbidity and mortality. Further larger studies are needed to explore association of lower GCS and higher injury score in children with PARDS and PC.