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Objective Adolescent e-cigarette use has risen to epidemic levels in the US, revealing a new phenomenon of e-cigarette vaping-associated lung injury (EVALI). It is important to better characterize EVALI in critically ill adolescents as this is a vulnerable and rapidly growing demographic. Methods This was a retrospective case series of patients ≤21 years old with confirmed or probable EVALI (as defined by the Centers for Disease Control) that resulted in admission to the pediatric intensive care unit (PICU) of a large tertiary academic children's hospital between August 2019 and January 2020. Results There were six eligible patients, with a median age of 17 years. All patients reported tetrahydrocannabinol as well as nicotine e-cigarette use. Half of the patients had a preexisting diagnosis of asthma and four patients had mental health comorbidities. All patients presented with respiratory alkalosis and chest radiography showing diffuse bilateral infiltrates; two patients had pneumomediastinum, subcutaneous air and/or pneumothorax. The lowest documented ratio of oxygen saturation to inspired oxygen (SpO2:FiO2 or S/F ratio) ranged from 146 to 296. Two patients required an arterial line, with the lowest ratio of arterial oxygen to inspired oxygen (PaO2:FiO2 or P/F ratio) of 197 and 165. Two patients tested positive for rhinovirus and respiratory cultures were negative for all patients. Four patients underwent chest computed tomography imaging, which showed diffuse ground-glass opacities. Every patient required noninvasive positive pressure ventilation, with one progressing to invasive ventilation. All patients received broad-spectrum intravenous antibiotics and steroids, though there was considerable variability in dose, frequency, and duration of steroids. The hospital length of stay ranged from 5 to 16 days (median 8.3 days) with PICU length of stay ranging from 4 to 10 days (median 5.5 days). Four patients had pulmonary function testing before discharge, two of which showed decreased diffusing capacity of the lung for carbon monoxide. There were no patient deaths. Conclusions This single-center case series describes the presentation, course, and treatment of EVALI in a pediatric intensive care unit setting. Our results show nuanced differences in the presentation and management of the critically ill adolescent, and raise many questions about the long term implications on lung health, morbidity, and mortality. Importantly, these cases illustrate the critical care consequences of a public health phenomenon and should spur further research and policy to address the negative health effects of vaping.

Background Social distancing is encouraged to mitigate viral spreading during outbreaks. However, the association between distancing and patient-centered outcomes in coronavirus disease 2019 (COVID-19) has not been demonstrated. In the United States, social distancing orders are implemented at the state level with variable timing of onset. Emergency declarations and school closures were 2 early statewide interventions. Methods To determine whether later distancing interventions were associated with higher mortality, we performed a state-level analysis in 55 146 COVID-19 nonsurvivors. We tested the association between timing of emergency declarations and school closures with 28-day mortality using multivariable negative binomial regression. Day 1 for each state was set to when they recorded ≥ 10 deaths. We performed sensitivity analyses to test model assumptions. Results At time of analysis, 37 of 50 states had ≥ 10 deaths and 28 follow-up days. Both later emergency declaration (adjusted mortality rate ratio [aMRR] 1.05 per day delay; 95% confidence interval [CI], 1.00–1.09; P = .040) and later school closure (aMRR 1.05; 95% CI, 1.01–1.09; P = .008) were associated with more deaths. When assessing all 50 states and setting day 1 to the day a state recorded its first death, delays in declaring an emergency (aMRR 1.05; 95% CI, 1.01–1.09; P = .020) or closing schools (aMRR 1.06; 95% CI, 1.03–1.09; P Conclusions Later statewide emergency declarations and school closure were associated with higher Covid-19 mortality. Each day of delay increased mortality risk 5 to 6%.

OBJECTIVES Capillary refill time is a noninvasive method to assess tissue perfusion to determine shock status. Capillary refill time is defined as the time required to regain skin color after blanching pressure is applied. Although common methods to measure capillary refill time depend on clinicians' visual assessment, a new approach using a pulse oximeter waveform analysis exists, referred to as full finger reperfusion time. We aim to evaluate reproducibility and validity of the novel full finger reperfusion time measurement using clinicians' visual capillary refill time assessment as a reference standard. DESIGN Prospective observational study. SETTING PICUs and operating suites at a large academic children's hospital. PATIENTS Ninety-nine children 1-12 years old with various skin color tones. INTERVENTIONS Each child had 10 measurements, including five full finger reperfusion time and five clinician capillary refill time, alternating second and third digits. MEASUREMENTS AND MAIN RESULTS Eighteen children had prolonged capillary refill time (> 2 s) and four children with capillary refill time greater than 3 seconds. Four-hundred eighty-five data pairs were analyzed. Intraclass correlation coefficient of full finger reperfusion time within each patient was 0.76 (95% CI, 0.68-0.83), demonstrating good reproducibility. Correlation coefficient between full finger reperfusion time and clinician capillary refill time was moderate: r = 0.37 (p < 0.0001; 95% CI, 0.29-0.44) for the pairs and r = 0.52 (p < 0.0001; 95% CI, 0.36-0.65) for patient average. Bland-Altman plot showed a consistent difference between full finger reperfusion time and clinician capillary refill time (full finger reperfusion time 1.14 s longer). Weak association was found between force and full finger reperfusion time (β = -0.033 ± 0.016; 95% CI, -0.065 to -0.0016; p = 0.04), finger thickness (β = -0.20 ± 0.089; 95% CI, -0.37 to -0.19; p = 0.03), except for color tone (p = 0.31). Finger temperature was associated with full finger reperfusion time (β = -0.18 ± 0.041; 95% CI, -0.26 to -0.0999; p < 0.0001). CONCLUSIONS Full finger reperfusion time demonstrated good reproducibility. Full finger reperfusion time showed moderate correlation with clinician capillary refill time. Full finger reperfusion time was 1.14 seconds longer than capillary refill time. Future studies should focus on the clinical value of full finger reperfusion time as a monitoring device for hemodynamics in critically ill children.

Rationale: Few data exist to guide early adjunctive therapy use in pediatric acute respiratory distress syndrome (PARDS).Objectives: To describe contemporary use of adjunctive therapies for early PARDS as a framework for future investigations.Methods: This was a preplanned substudy of a prospective, international, cross-sectional observational study of children with PARDS from 100 centers over 10 study weeks.Measurements and Main Results: We investigated six adjunctive therapies for PARDS: continuous neuromuscular blockade, corticosteroids, inhaled nitric oxide (iNO), prone positioning, high-frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation. Almost half (45%) of children with PARDS received at least one therapy. Variability was noted in the median starting oxygenation index of each therapy; corticosteroids started at the lowest oxygenation index (13.0; interquartile range, 7.6-22.0) and HFOV at the highest (25.7; interquartile range, 16.7-37.3). Continuous neuromuscular blockade was the most common, used in 31%, followed by iNO (13%), corticosteroids (10%), prone positioning (10%), HFOV (9%), and extracorporeal membrane oxygenation (3%). Steroids, iNO, and HFOV were associated with comorbidities. Prone positioning and HFOV were more common in middle-income countries and less frequently used in North America. The use of multiple ancillary therapies increased over the first 3 days of PARDS, but there was not an easily identifiable pattern of combination or order of use.Conclusions: The contemporary description of prevalence, combinations of therapies, and oxygenation threshold for which the therapies are applied is important for design of future studies. Region of the world, income, and comorbidities influence adjunctive therapy use and are important variables to include in PARDS investigations.

Objectives Diaphragm atrophy is evident during invasive ventilation for pediatric acute respiratory failure, but with unknown significance. We hypothesized that diaphragm atrophy in pediatric acute respiratory failure is associated with prolonged noninvasive positive pressure ventilation following extubation. Design Prospective observational study. Setting Single-center academic PICU. Patients Invasively ventilated children with acute respiratory failure. Interventions Diaphragm ultrasound was performed within 36 hours after intubation and repeated within 48 hours preceding extubation. Rapid shallow breathing index at 15 and 30 minutes of a spontaneous breathing trial and negative inspiratory force were collected in a subset of patients concurrently with the ultrasound measurements. Measurements and main results Diaphragm thickness at end-expiration was measured to assess for diaphragm atrophy during mechanical ventilation. Percentage change in diaphragm thickness at end-expiration was defined as baseline diaphragm thickness at end-expiration minus final, preextubation diaphragm thickness at end-expiration divided by baseline diaphragm thickness at end-expiration. The primary outcome measure was duration of noninvasive positive pressure ventilation following extubation with prolonged use defined as noninvasive positive pressure ventilation use for greater than 24 hours postextubation. Among 56 children, 47 (median age, 15.5 mo; interquartile range, 6-53 mo) had diaphragm thickness at end-expiration measured within 48 hours prior to extubation. Fourteen (30%) had prolonged noninvasive positive pressure ventilation use with median duration 110 hours (interquartile range, 52-130 hr). The median percentage change of diaphragm thickness at end-expiration from baseline among those with and without prolonged noninvasive positive pressure ventilation use was -20% (interquartile range, -32% to -10%) versus -7% (interquartile range, -21% to 0%) (p = 0.04). Conclusions Diaphragm atrophy is associated with prolonged postextubation noninvasive positive pressure ventilation in children with acute respiratory failure. Serial bedside diaphragm ultrasound may identify children at risk for prolonged noninvasive positive pressure ventilation use after extubation.

Objectives Acute respiratory failure is a common reason for admission to PICUs. Short- and long-term effects on pulmonary health in previously healthy children after acute respiratory failure requiring mechanical ventilation are unknown. The aim was to determine if clinical course or characteristics of mechanical ventilation predict persistent respiratory morbidity at follow-up. Design Prospective cohort study with follow-up questionnaires at 6 and 12 months. Setting Ten U.S. PICUs. Patients Two-hundred fifty-five children were included in analysis after exclusion for underlying chronic disease or incomplete data. One-hundred fifty-eight and 130 children had follow-up data at 6 and 12 months, respectively. Interventions None. Measurements and main results Pulmonary dysfunction at discharge a priori defined as one of: mechanical ventilation, supplemental oxygen, bronchodilators or steroids at 28 days or discharge. Persistent respiratory morbidity a priori defined as a respiratory PedsQL, a pediatric quality of life measure, greater than or equal to 5 or asthma diagnosis, bronchodilator or inhaled steroids, or unscheduled clinical evaluation for respiratory symptoms. Multivariate backward stepwise regression using Akaike information criterion minimization determined independent predictors of these outcomes. Pulmonary dysfunction at discharge was present in 34% of patients. Positive bacterial respiratory culture predicted pulmonary dysfunction at discharge (odds ratio, 4.38; 95% CI, 1.66-11.56). At 6- and 12-month follow-up 42% and 44% of responders, respectively, had persistent respiratory morbidity. Pulmonary dysfunction at discharge was associated with persistent respiratory morbidity at 6 months, and persistent respiratory morbidity at 6 months was strongly predictive of 12-month persistent respiratory morbidity (odds ratio, 18.58; 95% CI, 6.68-52.67). Positive bacterial respiratory culture remained predictive of persistent respiratory morbidity in patients at both follow-up points. Conclusions Persistent respiratory morbidity develops in up to potentially 44% of previously healthy children less than or equal to 24 months old at follow-up after acute respiratory failure requiring mechanical ventilation. This is the first study, to our knowledge, to suggest a prevalence of persistent respiratory morbidity and the association between positive bacterial respiratory culture and pulmonary morbidity in a population of only previously healthy children with acute respiratory failure.

Supplemental Digital Content is available in the text., Objectives: Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome. Design: Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children’s Hospital of Philadelphia. Setting: The derivation cohort represented 100 centers worldwide; the validation cohort was from Children’s Hospital of Philadelphia. Patients: There were 624 and 640 subjects in the derivation and validation cohorts, respectively. Interventions: None. Measurements and Main Results: The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and Pao2/Fio2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts. Conclusions: We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

OBJECTIVES To characterize neurofilament light levels in children who achieved return of spontaneous circulation following cardiac arrest compared with healthy controls and determine an association between neurofilament light levels and clinical outcomes. DESIGN Retrospective cohort study. SETTING Academic quaternary PICU. PATIENTS Children with banked plasma samples from an acute respiratory distress syndrome biomarker study who achieved return of spontaneous circulation after a cardiac arrest and healthy controls. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Neurofilament light levels were determined with a highly sensitive single molecule array digital immunoassay. Patients were categorized into survivors and nonsurvivors and into favorable (Pediatric Cerebral Performance Category score of 1-2 or unchanged from baseline) or unfavorable (Pediatric Cerebral Performance Category score of 3-6 or Pediatric Cerebral Performance Category score change ≥1 from baseline). Associations between neurofilament light level and outcomes were determined using Wilcoxon rank-sum test. We enrolled 32 patients with cardiac arrest and 18 healthy controls. Demographics, severity of illness, and baseline Pediatric Cerebral Performance Category scores were similar between survivors and nonsurvivors. Healthy controls had lower median neurofilament light levels than patients after cardiac arrest (5.5 [interquartile range 5.0-8.2] vs 31.0 [12.0-338.6]; p < 0.001). Neurofilament light levels were higher in nonsurvivors than survivors (78.5 [26.2-509.1] vs 12.4 [10.3-28.2]; p = 0.012) and higher in survivors than healthy controls (p = 0.009). The four patients who survived with a favorable outcome had neurofilament light levels that were not different from patients with unfavorable outcomes (21.9 [8.5--35.7] vs 37.2 [15.4-419.1]; p = 0.60) although two of the four patients who survived with favorable outcomes had progressive encephalopathies with both baseline and postcardiac arrest Pediatric Cerebral Performance Category scores of 4. CONCLUSIONS Neurofilament light is a blood biomarker of hypoxic-ischemic brain injury and may help predict survival and neurologic outcome after pediatric cardiac arrest. Further study in a larger, dedicated cardiac arrest cohort with serial longitudinal measurements is warranted.

Objectives The trajectory and importance of right ventricular systolic function and pulmonary hypertension during the course of pediatric acute respiratory distress syndrome are unknown. We hypothesized that new or persistent right ventricular systolic dysfunction and pulmonary hypertension would be associated with worse patient outcomes. Design Retrospective, single-center cohort study. Setting Tertiary care, university-affiliated PICU. Patients Children who had at least two echocardiograms less than 8 days following pediatric acute respiratory distress syndrome diagnosis. Interventions None. Measurements and main results Between July 1, 2012, and April 30, 2018, 74 children met inclusion criteria. The first echocardiogram was performed a median of 0.61 days (interquartile range, 0.36-0.94 d) and the second echocardiogram was performed a median of 2.57 days (interquartile range, 1.67-3.63 d) after pediatric acute respiratory distress syndrome diagnosis. Univariate analyses showed that new or persistent right ventricular systolic dysfunction as defined by global longitudinal strain or free wall strain was associated with a greater number of ICU days in survivors (global longitudinal strain p = 0.04, free wall strain p = 0.04), lower ventilator-free days at 28 days (global longitudinal strain p = 0.03, free wall strain p = 0.01), and higher rate of PICU death (global longitudinal strain p = 0.046, free wall strain p = 0.01). Mixed-effects multivariate modeling showed that right ventricular global longitudinal strain and right ventricular fractional area change stayed relatively constant over the course of the first 8 days in nonsurvivors and that there was a linear improvement in global longitudinal strain (p = 0.037) and fractional area change (p = 0.05) in survivors. Worsening right ventricular dysfunction at the time of repeat echocardiogram as defined by global longitudinal strain and free wall strain were independently associated with decreased probability of extubation (subdistribution hazard ratio, 0.30 [0.14-0.67]; p = 0.003 and subdistribution hazard ratio, 0.47 [0.23-0.98]; p = 0.043, respectively). In univariate and multivariate analyses, pulmonary hypertension had no significant associations with outcomes in his cohort. Conclusions New or persistent right ventricular systolic dysfunction over the first week following pediatric acute respiratory distress syndrome onset is associated with worse patient outcomes, including decreased probability of extubation and higher PICU mortality.

OBJECTIVES: Interventional trials aimed at pediatric acute respiratory distress syndrome prevention require accurate identification of high-risk patients. In this study, we aimed to characterize the frequency and outcomes of children meeting "at risk for pediatric acute respiratory distress syndrome" criteria as defined by the Pediatric Acute Lung Injury Consensus Conference.DESIGN: Planned substudy of the prospective multicenter, international Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study conducted during 10 nonconsecutive weeks (May 2016-June 2017).SETTING: Thirty-seven international PICUs.PATIENTS: Three-hundred ten critically ill children meeting Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency of children at risk for pediatric acute respiratory distress syndrome and rate of subsequent pediatric acute respiratory distress syndrome diagnosis and used multivariable logistic regression to identify factors associated with subsequent pediatric acute respiratory distress syndrome. Frequency of at risk for pediatric acute respiratory distress syndrome was 3.8% (95% CI, 3.4-5.2%) among the 8,122 critically ill children who were screened and 5.8% (95% CI, 5.2-6.4%) among the 5,334 screened children on positive pressure ventilation or high-flow oxygen. Among the 310 at-risk children, median age was 2.1 years (interquartile range, 0.5-7.3 yr). Sixty-six children (21.3%) were subsequently diagnosed with pediatric acute respiratory distress syndrome, a median of 22.6 hours (interquartile range, 9.8-41.0 hr) later. Subsequent pediatric acute respiratory distress syndrome was associated with increased mortality (21.2% vs 3.3%; p < 0.001) and longer durations of invasive ventilation and PICU care. Subsequent pediatric acute respiratory distress syndrome rate did not differ by respiratory support modality at the time of meeting at risk criteria but was independently associated with lower initial saturation:FIO2 ratio, progressive tachycardia, and early diuretic administration.CONCLUSIONS: The Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria identify critically ill children at high risk of pediatric acute respiratory distress syndrome and poor outcomes. Interventional trials aimed at pediatric acute respiratory distress syndrome prevention should target patients early in their illness course and include patients on high-flow oxygen and positive pressure ventilation.

Ventilator-free days (VFDs) are a commonly reported composite outcome measure in acute respiratory distress syndrome trials. VFDs combine survival and duration of ventilation in a manner that summarizes the “net effect” of an intervention on these two outcomes. However, this combining of outcome measures makes VFDs difficult to understand and analyze, which contributes to imprecise interpretations. We discuss the strengths and limitations of VFDs and other “failure-free day” composites, and we provide a framework for when and how to use these outcome measures. We also provide a comprehensive discussion of the different analytic methods for analyzing and interpreting VFDs, including Student’s t tests and rank-sum tests, as well as competing risk regressions treating extubation as the primary outcome and death as the competing risk. Using simulations, we illustrate how the statistical test with optimal power depends on the relative contributions of mortality and ventilator duration on the composite effect size. Finally, we recommend a simple analysis and reporting framework using the competing risk approach, which provides clear information on the effect size of an intervention, a statistical test and measure of confidence with the ability to adjust for baseline factors and allow interim monitoring for trials. We emphasize that any approach to analyzing a composite outcome, including other “failure-free day” constructs, should also be accompanied by an examination of the components.

Background There is on-going controversy regarding the potential for increased respiratory effort to generate patient self-inflicted lung injury (P-SILI) in spontaneously breathing patients with COVID-19 acute hypoxaemic respiratory failure. However, direct clinical evidence linking increased inspiratory effort to lung injury is scarce. We adapted a computational simulator of cardiopulmonary pathophysiology to quantify the mechanical forces that could lead to P-SILI at different levels of respiratory effort. In accordance with recent data, the simulator parameters were manually adjusted to generate a population of 10 patients that recapitulate clinical features exhibited by certain COVID-19 patients, i.e., severe hypoxaemia combined with relatively well-preserved lung mechanics, being treated with supplemental oxygen. Results Simulations were conducted at tidal volumes (VT) and respiratory rates (RR) of 7 ml/kg and 14 breaths/min (representing normal respiratory effort) and at VT/RR of 7/20, 7/30, 10/14, 10/20 and 10/30 ml/kg / breaths/min. While oxygenation improved with higher respiratory efforts, significant increases in multiple indicators of the potential for lung injury were observed at all higher VT/RR combinations tested. Pleural pressure swing increased from 12.0 ± 0.3 cmH2O at baseline to 33.8 ± 0.4 cmH2O at VT/RR of 7 ml/kg/30 breaths/min and to 46.2 ± 0.5 cmH2O at 10 ml/kg/30 breaths/min. Transpulmonary pressure swing increased from 4.7 ± 0.1 cmH2O at baseline to 17.9 ± 0.3 cmH2O at VT/RR of 7 ml/kg/30 breaths/min and to 24.2 ± 0.3 cmH2O at 10 ml/kg/30 breaths/min. Total lung strain increased from 0.29 ± 0.006 at baseline to 0.65 ± 0.016 at 10 ml/kg/30 breaths/min. Mechanical power increased from 1.6 ± 0.1 J/min at baseline to 12.9 ± 0.2 J/min at VT/RR of 7 ml/kg/30 breaths/min, and to 24.9 ± 0.3 J/min at 10 ml/kg/30 breaths/min. Driving pressure increased from 7.7 ± 0.2 cmH2O at baseline to 19.6 ± 0.2 cmH2O at VT/RR of 7 ml/kg/30 breaths/min, and to 26.9 ± 0.3 cmH2O at 10 ml/kg/30 breaths/min. Conclusions Our results suggest that the forces generated by increased inspiratory effort commonly seen in COVID-19 acute hypoxaemic respiratory failure are comparable with those that have been associated with ventilator-induced lung injury during mechanical ventilation. Respiratory efforts in these patients should be carefully monitored and controlled to minimise the risk of lung injury.

Objectives Fluid overload is associated with worse outcomes in adult and pediatric acute respiratory distress syndrome. However, the time-course of fluid overload and its relationship to outcome has not been described. We aimed to determine the relationship between the timing of fluid overload and outcomes over the first 7 days after acute respiratory distress syndrome onset in children. Design Retrospective cohort study. Setting Single tertiary care PICU. Patients Intubated children with acute respiratory distress syndrome between 2011 and 2019. Interventions None. Measurements and main results Daily and cumulative total fluid intake, total output, urine output, and fluid balance were collected for each 24-hour period from days 1 to 7 after acute respiratory distress syndrome onset. We tested the association between daily cumulative fluid metrics with PICU mortality and probability of extubation by 28 days using multivariable logistic and competing risk regression, respectively. In a subset of children, plasma was collected on day 1 and day 3 of acute respiratory distress syndrome and angiopoietin-2 quantified. Of 723 children with acute respiratory distress syndrome, 132 died (18%). In unadjusted analysis, nonsurvivors had higher cumulative fluid balance starting on day 3. In multivariable analysis, a positive cumulative fluid balance on days 5 through 7 was associated with increased mortality. Higher cumulative fluid balance on days 4 to 7 was associated with lower probability of extubation. Elevated angiopoietin-2 on day 1 predicted early (within 3 d) fluid overload greater than or equal to 10%, and elevated angiopoietin-2 on day 3 predicted late (between days 4 and 7) fluid overload. Conclusions Fluid overload after day 4 of acute respiratory distress syndrome, but not before, was associated with worse outcomes. Higher angiopoietin-2 predicted subsequent fluid overload. Our results suggest that future interventions aimed at managing fluid overload may have differential efficacy depending on when in the time-course of acute respiratory distress syndrome they are initiated.

BackgroundThere is on-going controversy regarding the potential for increased respiratory effort to generate patient self-inflicted lung injury (P-SILI) in spontaneously breathing patients with COVID-19 acute hypoxaemic respiratory failure. However, direct clinical evidence linking increased inspiratory effort to lung injury is scarce. We adapted a computational simulator of cardiopulmonary pathophysiology to quantify the mechanical forces that could lead to P-SILI at different levels of respiratory effort. In accordance with recent data, the simulator parameters were manually adjusted to generate a population of 10 patients that recapitulate clinical features exhibited by certain COVID-19 patients, i.e. severe hypoxaemia combined with relatively well-preserved lung mechanics, being treated with supplemental oxygen.ResultsSimulations were conducted at tidal volumes (VT) and respiratory rates (RR) of 7 ml/kg and 14 breaths/min (representing normal respiratory effort) and at VT/RR of 7/20, 7/30, 10/14, 10/20 and 10/30 ml/kg / breaths/min. While oxygenation improved with higher respiratory efforts, significant increases in multiple indicators of the potential for lung injury were observed at all higher VT/RR combinations tested. Pleural pressure swing increased from 12.0±0.3 cmH2O at baseline to 33.8±0.4 cmH2O at VT/RR of 7 ml/kg/30 breaths/min and to 46.2±0.5 cmH2O at 10 ml/kg/30 breaths/min. Transpulmonary pressure swing increased from 4.7±0.1 cmH2O at baseline to 17.9±0.3 cmH2O at VT/RR of 7 ml/kg/30 breaths/min and to 24.2±0.3 cmH2O at 10 ml/kg/30 breaths/min. Total lung strain increased from 0.29±0.006 at baseline to 0.65±0.016 at 10 ml/kg/30 breaths/min. Mechanical power increased from 1.6±0.1 J/min at baseline to 12.9±0.2 J/min at VT/RR of 7 ml/kg/30 breaths/min, and to 24.9±0.3 J/min at 10 ml/kg/30 breaths/min. Driving pressure increased from 7.7±0.2 cmH2O at baseline to 19.6±0.2 at VT/RR of 7 ml/kg/30 breaths/min, and to 26.9±0.3 cmH2O at 10 ml/kg/30 breaths/min.ConclusionsOur results suggest that the forces generated by increased inspiratory effort commonly seen in COVID-19 acute hypoxaemic respiratory failure are comparable with those that have been associated with ventilator-induced lung injury during mechanical ventilation. Respiratory efforts in these patients should be carefully monitored and controlled to minimise the risk of lung injury.

OBJECTIVES: Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown. DESIGN: We performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome. SETTING: Large academic tertiary-care PICU. PATIENTS: Intubated children meeting Berlin criteria for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome. CONCLUSIONS: Plasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.

Initially described in adults, acute respiratory distress syndrome (ARDS) is well recognized in pediatrics. Pediatric ARDS (PARDS) possesses a distinct epidemiology from adult ARDS, including a lower mortality. The recent adoption of a pediatric-specific definition will assist with future studies of the pathophysiology, mechanism, treatment, and epidemiology of PARDS. As we await such studies, much of our understanding of pediatric ARDS pathogenesis and treatment is extrapolated from adult ARDS. No specific targeted treatments have been shown to be beneficial in adult ARDS or PARDS, and supportive care with lung-protective ventilation and fluid restriction remains the mainstay of treatment. Here, we review what is currently understood about PARDS and offer recommendations for initial treatment strategies.

The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3- to 4-year recurring cycle of topics. These topics will be presented at the 2020 International Conference. Below is the pediatric pulmonary medicine core, including pediatric hypoxemic respiratory failure; modalities in noninvasive management of chronic respiratory failure in childhood; surgical and nonsurgical management of congenital lung malformations; an update on smoke inhalation lung injury; an update on vaporizers, e-cigarettes, and other electronic delivery systems; pulmonary complications of sarcoidosis; pulmonary complications of congenital heart disease; and updates on the management of congenital diaphragmatic hernia.

Supplemental Digital Content is available in the text., Objectives: To identify and compare serum and lower respiratory tract fluid biomarkers of lung injury using well-characterized mouse models of lung injury. To explore the relationship between these preclinical biomarkers and clinical outcomes in a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. Design: Prospective, observational cohort study. Setting: A basic science laboratory and the PICU of a tertiary-care children’s hospital. Patients: PICU patients intubated for respiratory failure from a suspected respiratory infection. Interventions: Prospective enrollment and collection of lower respiratory tract fluid samples. Measurements and Main Results: C57BL6/J mice were intranasally inoculated with escalating doses of influenza A virus or toll-like receptor agonists to simulate varying degrees of lung injury. Serum and bronchoalveolar lavage fluid were measured for the presence of cytokines using commercially available multiplex cytokine assays. Elevated levels of C-C motif chemokine ligand 7 at the peak of inflammation in both bronchoalveolar lavage fluid and serum correlated with lethality, with the bronchoalveolar lavage fluid ratio of C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 providing the best prediction in the mouse models. These preclinical biomarkers were examined in the plasma and lower respiratory tract fluid of a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. The primary clinical outcome measure was ventilator-free days, with secondary outcomes of pediatric acute respiratory distress syndrome severity and mortality. Elevation in peak lower respiratory tract fluid C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratios demonstrated a significant negative correlation with ventilator-free days (r = –0.805; p < 0.02). Conclusions: This study provides evidence that lung immune profiling via lower respiratory tract fluid cytokine analysis is feasible and may provide insight into clinical outcomes. Further validation of markers, including the C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratio in this limited study, in a larger cohort of patients is necessary.

Background Acute respiratory distress syndrome (ARDS) is heterogeneous and may be amenable to sub-phenotyping to improve enrichment for trials. We aimed to identify subtypes of pediatric ARDS based on whole blood transcriptomics. Methods This was a prospective observational study of children with ARDS at the Children’s Hospital of Philadelphia (CHOP) between January 2018 and June 2019. We collected blood within 24 h of ARDS onset, generated expression profiles, and performed k-means clustering to identify sub-phenotypes. We tested the association between sub-phenotypes and PICU mortality and ventilator-free days at 28 days using multivariable logistic and competing risk regression, respectively. Results We enrolled 106 subjects, of whom 96 had usable samples. We identified three sub-phenotypes, dubbed CHOP ARDS Transcriptomic Subtypes (CATS) 1, 2, and 3. CATS-1 subjects (n = 31) demonstrated persistent hypoxemia, had ten subjects (32%) with immunocompromising conditions, and 32% mortality. CATS-2 subjects (n = 29) had more immunocompromising diagnoses (48%), rapidly resolving hypoxemia, and 24% mortality. CATS-3 subjects (n = 36) had the fewest comorbidities and also had rapidly resolving hypoxemia and 8% mortality. The CATS-3 subtype was associated with lower mortality (OR 0.18, 95% CI 0.04–0.86) and higher probability of extubation (subdistribution HR 2.39, 95% CI 1.32–4.32), relative to CATS-1 after adjustment for confounders. Conclusions We identified three sub-phenotypes of pediatric ARDS using whole blood transcriptomics. The sub-phenotypes had divergent clinical characteristics and prognoses. Further studies should validate these findings and investigate mechanisms underlying differences between sub-phenotypes.

In an era of tremendous medical advancements, it is important to characterise and address inequities in the provision of health care and in outcomes. There is a large body of evidence describing such disparities by race or ethnicity and socioeconomic position in critically ill adults; however, this important issue has received less attention in children and adolescents (aged ≤21 years). This Review presents a summary of the available evidence on disparities in outcomes in paediatric critical illness in the USA as a result of racism and socioeconomic privilege. The majority of evidence of racial and socioeconomic disparities in paediatric critical care originates from the USA and is retrospective, with only one prospective intervention-based study. Although there is mixed evidence of disparities by race or ethnicity and socioeconomic position in general paediatric intensive care unit admissions and outcomes in the USA, there are striking trends within some disease processes. Notably, there is evidence of disparities in management and outcomes for out-of-hospital cardiac arrest, asthma, severe trauma, sepsis, and oncology, and in families' perceptions of care. Furthermore, there is clear evidence that critical care research is limited by under-enrolment of participants from minority race or ethnicity groups. We advocate for rigorous research standards and increases in the recruitment and enrolment of a diverse range of participants in paediatric critical care research to better understand the disparities observed, including the effects of racism and poverty. A clearer understanding of when, where, and how such disparities affect patients will better enable the development of effective strategies to inform practice, interventions, and policy.

Rationale: Clinicians commonly use short-term physiologic markers to assess the benefit of ventilator adjustments. Improved arterial oxygen tension/pressure (Pa(O(2)))/fraction of inspired oxygen (Fi(O(2))) after ventilator adjustment in acute respiratory distress syndrome is associated with lower mortality. However, as driving pressure (ΔP) reflects lung stress and strain, changes in ΔP may more accurately reflect benefits or harms of ventilator adjustments compared with changes in oxygenation. Objectives: We aimed to compare the association between mortality and the changes in Pa(O(2))/Fi(O(2)) and ΔP following protocolized ventilator changes. Methods: We assessed associations between mortality and changes in Pa(O(2))/Fi(O(2)) (ΔPa(O(2))/Fi(O(2))) and ΔP (ΔΔP) after postrandomization positive end-expiratory pressure (PEEP) and tidal volume adjustment in reanalyses of the ALVEOLI (Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury) and ExPress (Expiratory Pressure) trials. We included subjects with available pre- and postintervention Pa(O(2))/Fi(O(2)) and ΔP (372 in ALVEOLI and 596 in ExPress). In each separate trial cohort, we performed multivariable Cox regression testing the association between ΔPa(O(2))/Fi(O(2)) and ΔΔP with mortality. Results: In ALVEOLI, when analyzed as separate variables, ΔPa(O(2))/Fi(O(2)) was associated with mortality only in subjects in whom PEEP increased, whereas ΔΔP was associated with mortality irrespective of direction of PEEP change. When modeled together, improved ΔPa(O(2))/Fi(O(2)) was not associated with mortality, whereas ΔΔP remained associated with mortality (adjusted hazard ratio [aHR], 1.50 per 5 cm H(2)O increase; 95% confidence interval [95% CI], 1.21–1.85). When modeled together in ExPress, ΔΔP (aHR, 1.42; 95% CI, 1.14–1.78) was more strongly associated with mortality than ΔPa(O(2))/Fi(O(2)) (aHR, 0.95 per 25 mm Hg increase; 95% CI, 0.90–1.00). Conclusions: Reduced ΔP following protocolized ventilator changes was more strongly and consistently associated with lower mortality than was increased Pa(O(2))/Fi(O(2)), making ΔΔP more informative about benefit from ventilator adjustments. Our results reinforce the primacy of ΔP, rather than oxygenation, as the key variable associated with outcome.

Since first described, acute respiratory distress syndrome (ARDS) has been understood to be an inflammatory disease with a dysregulated hyperinflammatory response. While fewer investigations have studied these phenomena in pediatric ARDS (PARDS), similar pathways are believed to be involved. Significant attention has been paid to the innate immune system, particularly neutrophils and neutrophil-related signaling, more recent studies have provided additional nuance regarding the role of upstream damage-associated molecular patterns (DAMPs) and subsequent neutrophil-mediated inflammation, lung permeability, and alveolar epithelial damage. For example, neutrophil extracellular traps (NETs) and inflammasome signaling have been identified as critical mediators existing at the junction of DAMPs and downstream inflammation. We demonstrate how the conclusions obtained from pre-clinical studies of lung injury are highly dependent upon the model chosen, and how this can lead us astray when developing therapies. More recently the adaptive immune system, specifically select T cell subpopulations, have also been implicated in ARDS. This raises the possibility of antigen-specific immunomodulation as a potential therapeutic avenue in ARDS. Finally, we briefly review randomized controlled trials attempting to manipulate the immune dysregulation in ARDS, including pleiotropic immunomodulators like corticosteroids and interferon-β, and what these studies can teach us about the design of novel therapeutics and the design of future trials.

Supplemental Digital Content is available in the text., Objectives: Patients with coronavirus disease 2019 acute respiratory distress syndrome appear to present with at least two distinct phenotypes: severe hypoxemia with relatively well-preserved lung compliance and lung gas volumes (type 1) and a more conventional acute respiratory distress syndrome phenotype, displaying the typical characteristics of the “baby lung” (type 2). We aimed to test plausible hypotheses regarding the pathophysiologic mechanisms underlying coronavirus disease 2019 acute respiratory distress syndrome and to evaluate the resulting implications for ventilatory management. Design: We adapted a high-fidelity computational simulator, previously validated in several studies of acute respiratory distress syndrome, to: 1) develop quantitative insights into the key pathophysiologic differences between the coronavirus disease 2019 acute respiratory distress syndrome and the conventional acute respiratory distress syndrome and 2) assess the impact of different positive end-expiratory pressure, Fio2, and tidal volume settings. Setting: Interdisciplinary Collaboration in Systems Medicine Research Network. Subjects: The simulator was calibrated to represent coronavirus disease 2019 acute respiratory distress syndrome patients with both normal and elevated body mass indices undergoing invasive mechanical ventilation. Interventions: None. Measurements and Main Results: An acute respiratory distress syndrome model implementing disruption of hypoxic pulmonary vasoconstriction and vasodilation leading to hyperperfusion of collapsed lung regions failed to replicate clinical data on type 1 coronavirus disease 2019 acute respiratory distress syndrome patients. Adding mechanisms to reflect disruption of alveolar gas-exchange due to the effects of pneumonitis and heightened vascular resistance due to the emergence of microthrombi produced levels of ventilation perfusion mismatch and hypoxemia consistent with data from type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, while preserving close-to-normal lung compliance and gas volumes. Atypical responses to positive end-expiratory pressure increments between 5 and 15 cm H2O were observed for this type 1 coronavirus disease 2019 acute respiratory distress syndrome model across a range of measures: increasing positive end-expiratory pressure resulted in reduced lung compliance and no improvement in oxygenation, whereas mechanical power, driving pressure, and plateau pressure all increased. Fio2 settings based on acute respiratory distress syndrome network protocols at different positive end-expiratory pressure levels were insufficient to achieve adequate oxygenation. Incrementing tidal volumes from 5 to 10 mL/kg produced similar increases in multiple indicators of ventilator-induced lung injury in the type 1 coronavirus disease 2019 acute respiratory distress syndrome model to those seen in a conventional acute respiratory distress syndrome model. Conclusions: Our model suggests that use of standard positive end-expiratory pressure/Fio2 tables, higher positive end-expiratory pressure strategies, and higher tidal volumes may all be potentially deleterious in type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, and that a highly personalized approach to treatment is advisable.

Summary Background Disparities in outcomes of adult sepsis are well described by insurance status and race and ethnicity. There is a paucity of data looking at disparities in sepsis outcomes in children. We aimed to determine whether hospital outcomes in childhood severe sepsis were influenced by race or ethnicity and insurance status, a proxy for socioeconomic position. Methods This population-based, retrospective cohort study used data from the 2016 database release from the Healthcare Cost and Utilization Project Kids’ Inpatient Database (KID). The 2016 KID included 3 117 413 discharges, accounting for 80% of national paediatric discharges from 4200 US hospitals across 47 states. Using multilevel logistic regression, clustered by hospital, we tested the association between race or ethnicity and insurance status and hospital mortality, adjusting for individual-level and hospital-level characteristics, in children with severe sepsis. The secondary outcome of length of hospital stay was examined through multilevel time to event (hospital discharge) regression, with death as a competing risk. Findings 12 297 children (aged 0–21 years) with severe sepsis with or without shock were admitted to 1253 hospitals in the 2016 KID dataset. 1265 (10·3%) of 12 297 patients did not have race or ethnicity data recorded, 15 (0·1%) were missing data on insurance, and 1324 (10·8%) were transferred out of hospital, resulting in a final cohort of 9816 children. Black children had higher odds of death than did White children (adjusted odds ratio [OR] 1·19, 95 % CI 1·02–1·38; p=0·028), driven by higher Black mortality in the south (1·30, 1·04–1·62; p=0·019) and west (1·58, 1·05–2·38; p=0·027) of the USA. We found evidence of longer hospital stays for Hispanic children (adjusted hazard ratio 0·94, 95% CI 0·88–1·00; p=0·049) and Black children (0·88, 0·82–0·94; p=0·0002), particularly Black neonates (0·53, 95% CI 0·36–0·77; p=0·0011). We observed no difference in survival between publicly and privately insured children; however, other insurance status (self-pay, no charge, and other) was associated with increased mortality (adjusted OR 1·30, 95% CI 1·04–1·61; p=0·021). Interpretation In this large, representative analysis of paediatric severe sepsis in the USA, we found evidence of outcome disparities by race or ethnicity and insurance status. Our findings suggest that there might be differential sepsis recognition, approaches to treatment, access to health-care services, and provider bias that contribute to poorer sepsis outcomes for racial and ethnic minority patients and those of lower socioeconomic position. Studies are warranted to investigate the mechanisms of poorer sepsis outcomes in Black and Hispanic children. Funding None.

ObjectivesPatients with COVID-19 Acute Respiratory Distress Syndrome (CARDS) appear to present with at least two distinct phenotypes: severe hypoxemia with relatively well-preserved lung compliance and lung gas volumes (Type 1) and a more conventional ARDS phenotype displaying the typical characteristics of the ‘baby lung’ (Type 2). We aimed to test plausible hypotheses regarding the pathophysiological mechanisms underlying CARDS, and to evaluate the resulting implications for ventilatory management.DesignWe adapted a high-fidelity computational simulator, previously validated in several studies of ARDS, to (a) develop quantitative insights into the key pathophysiologic differences between CARDS and conventional ARDS, and (b) assess the impact of different PEEP, FiO2 and tidal volume settings.SettingInterdisciplinary Collaboration in Systems Medicine Research Network.SubjectsThe simulator was calibrated to represent CARDS patients with both normal and elevated body mass indices undergoing invasive mechanical ventilation.Measurements and Main ResultsAn ARDS model implementing disruption of hypoxic pulmonary vasoconstriction and vasodilation leading to hyperperfusion of collapsed lung regions failed to replicate clinical data on Type 1 CARDS patients. Adding mechanisms to reflect disruption of alveolar gas-exchange due to the effects of pneumonitis, and heightened vascular resistance due to the emergence of microthrombi, produced levels of V/Q mismatch and hypoxemia consistent with data from Type 1 CARDS patients, while preserving close to normal lung compliance and gas volumes. Atypical responses to PEEP increments between 5 and 15 cmH2O were observed for this Type 1 CARDS model across a range of measures: increasing PEEP resulted in reduced lung compliance and no improvement in oxygenation, while Mechanical Power, Driving Pressure and Plateau Pressure all increased. FiO2 settings based on ARDSnet protocols at different PEEP levels were insufficient to achieve adequate oxygenation. Incrementing tidal volumes from 5 to 10 ml/kg produced similar increases in multiple indicators of ventilator induced lung injury in the Type 1 CARDS model to those seen in a conventional ARDS model.ConclusionsOur model suggests that use of standard PEEP/ FiO2 tables, higher PEEP strategies, and higher tidal volumes, may all be potentially deleterious in Type 1 CARDS patients, and that a highly personalized approach to treatment is advisable.

Objectives Mechanical power and driving pressure have been proposed as indicators, and possibly drivers, of ventilator-induced lung injury. We tested the utility of these different measures as targets to derive maximally protective ventilator settings. Design A high-fidelity computational simulator was matched to individual patient data and used to identify strategies that minimize driving pressure, mechanical power, and a modified mechanical power that removes the direct linear, positive dependence between mechanical power and positive end-expiratory pressure. Setting Interdisciplinary Collaboration in Systems Medicine Research Network. Subjects Data were collected from a prospective observational cohort of pediatric acute respiratory distress syndrome from the Children's Hospital of Philadelphia (n = 77) and from the low tidal volume arm of the Acute Respiratory Distress Syndrome Network tidal volume trial (n = 100). Interventions Global optimization algorithms evaluated more than 26.7 million changes to ventilator settings (approximately 150,000 per patient) to identify strategies that minimize driving pressure, mechanical power, or modified mechanical power. Measurements and main results Large average reductions in driving pressure (pediatric: 23%, adult: 23%), mechanical power (pediatric: 44%, adult: 66%), and modified mechanical power (pediatric: 61%, adult: 67%) were achievable in both cohorts when oxygenation and ventilation were allowed to vary within prespecified ranges. Reductions in driving pressure (pediatric: 12%, adult: 2%), mechanical power (pediatric: 24%, adult: 46%), and modified mechanical power (pediatric: 44%, adult: 46%) were achievable even when no deterioration in gas exchange was allowed. Minimization of mechanical power and modified mechanical power was achieved by increasing tidal volume and decreasing respiratory rate. In the pediatric cohort, minimum driving pressure was achieved by reducing tidal volume and increasing respiratory rate and positive end-expiratory pressure. The Acute Respiratory Distress Syndrome Network dataset had limited scope for further reducing tidal volume, but driving pressure was still significantly reduced by increasing positive end-expiratory pressure. Conclusions Our analysis identified different strategies that minimized driving pressure or mechanical power consistently across pediatric and adult datasets. Minimizing standard and alternative formulations of mechanical power led to significant increases in tidal volume. Targeting driving pressure for minimization resulted in ventilator settings that also reduced mechanical power and modified mechanical power, but not vice versa.

The importance of preoperative cardiac function in pediatric lung transplantation is unknown. We hypothesized that worse preoperative right ventricular (RV) systolic and worse left ventricular (LV) diastolic function would be associated with a higher risk of primary graft dysfunction grade 3 (PGD 3) between 48 and 72 hours. We performed a single center, retrospective pilot study of children (

The hallmarks of pediatric acute respiratory failure (ARF) are dysregulated inflammation and surfactant dysfunction. The objective is to study association of surfactant protein (SP) genes&rsquo, single nucleotide polymorphisms (SNPs) with ARF and its morbidity: pulmonary dysfunction at discharge (PDAD), employing a single-, two-, and three-SNP interaction model. We enrolled 468 newborn controls and 248 children aged &le, 24 months with ARF, 86 developed PDAD. Using quantitative genetic principles, we tested the association of SP genes SNPs with ARF and PDAD. We observed a dominant effect of rs4715 of the SFTPC on ARF risk. In a three-SNP model, we found (a) 34 significant interactions among SNPs of SFTPA1, SFTPA2, and SFTPC associated with ARF (p = 0.000000002&ndash, 0.05), 15 and 19 of those interactions were associated with increased and decreased risk for ARF, respectively, (b) intergenic SNP&ndash, SNP interactions of both hydrophobic and hydrophilic SP genes associated with PDAD (p = 0.00002&ndash, 0.03). The majority of intra- and intergenic interactions associated with ARF involve the SFTPA2 SNPs, whereas most of the intra- and intergenic interactions associated with PDAD are of SFTPA1 SNPs. We also observed a dominant effect of haplotypes GG of SFTPA1 associated with increased and AA of SFTPC associated with decreased ARF risk (p = 0.02). To the best of our knowledge, this is the first study showing an association of complex interactions of SP genes with ARF and PDAD. Our data indicate that SP genes polymorphisms may contribute to ARF pathogenesis and subsequent PDAD and/or may serve as markers for disease susceptibility in healthy children.

OBJECTIVES: Systemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome. DESIGN: Observational cohort. SETTING: Academic PICU. PATIENTS: Patients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3–6 days (time 2) and 7–14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoi-etin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course. CONCLUSIONS: Children with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

Investigations of acute respiratory distress syndrome in adults suggest hypoxemia is an uncommon cause of death. However, the epidemiology of death in pediatric acute respiratory distress syndrome is not well characterized. We aimed to describe the cause, mode, and timing of death in pediatric acute respiratory distress syndrome nonsurvivors. We hypothesized that most deaths would be due to nonpulmonary factors, rather than hypoxemia.Retrospective, decedent-only analysis.Two large, academic PICUs.Nonsurvivors with pediatric acute respiratory distress syndrome.None.Of 798 subjects with pediatric acute respiratory distress syndrome, there were 153 nonsurvivors (19% mortality). Median time to death was 6 days (interquartile range, 3-13 d) after pediatric acute respiratory distress syndrome onset. Patients dying less than 7 days after pediatric acute respiratory distress syndrome onset had greater illness severity and worse oxygenation. Patients dying less than 7 days were more likely to die of a neurologic cause, including brain death. Patients dying greater than or equal to 7 days after pediatric acute respiratory distress syndrome onset were more commonly immunocompromised. Multisystem organ failure predominated in deaths greater than or equal to 7 days. Withdrawal of therapy was the most common mode of death at all timepoints, accounting for 66% of all deaths. Organ dysfunction was common at time of death, irrespective of cause of death. Refractory hypoxemia accounted for only a minority of pediatric acute respiratory distress syndrome deaths (20%).In pediatric acute respiratory distress syndrome, early deaths were due primarily to neurologic failure, whereas later deaths were more commonly due to multisystem organ failure. Deaths from neurologic causes accounted for a substantial portion of nonsurvivors. Refractory hypoxemia accounted for only a minority of deaths. Our study highlights limitations associated with using death as an endpoint in therapeutic pediatric acute respiratory distress syndrome trials.

Objectives:To investigate the association between inhaled nitric oxide treatment and ICU mortality and 28-day ventilator-free days in pediatric acute respiratory distress syndrome.Design:Retrospective cohort study. A propensity score for inhaled nitric oxide treatment was developed and used in the a

Acute respiratory distress syndrome (ARDS) is heterogeneous in etiology, which may affect outcomes. Stratification into biologically-defined subtypes may reduce heterogeneity. However, it is unknown whether pediatric ARDS has clinically relevant subtypes. We aimed to determine whether clinical characteristics and predictors of mortality differed between direct and indirect ARDS, and separately between infectious and non-infectious ARDS. This was a single center, prospective cohort study of 544 children with ARDS (Berlin) between July 2011 and June 2017, stratified into direct versus indirect ARDS, and separately into infectious versus non-infectious ARDS. Multiple logistic regression was used to test for predictors of mortality in the entire cohort, and separately within subtypes. Effect modification by subtype was assessed using interaction tests. Direct ARDS had lower severity of illness (p

Rationale: The ARDS Network (ARDSNet) used a positive end-expiratory pressure (PEEP)/FiO2 model in many studies. In general, pediatric intensivists use less PEEP and higher FiO2 than this model.Obj...

Objectives Diaphragm atrophy is associated with delayed weaning from mechanical ventilation and increased mortality in critically ill adults. We sought to test for the presence of diaphragm atrophy in children with acute respiratory failure. Design Prospective, observational study. Setting Single-center tertiary noncardiac PICU in a children's hospital. Patients Invasively ventilated children with acute respiratory failure. Measurements and main results Diaphragm thickness at end-expiration and end-inspiration were serially measured by ultrasound in 56 patients (median age, 17 mo; interquartile range, 5.5-52), first within 36 hours of intubation and last preceding extubation. The median duration of mechanical ventilation was 140 hours (interquartile range, 83-201). At initial measurement, thickness at end-expiration was 2.0 mm (interquartile range, 1.8-2.5) and thickness at end-inspiration was 2.5 mm (interquartile range, 2-2.8). The change in thickness at end-expiration during mechanical ventilation between first and last measurement was -13.8% (interquartile range, -27.4% to 0%), with a -3.4% daily atrophy rate (interquartile range, -5.6 to 0%). Thickening fraction = ([thickness at end-inspiration - thickness at end-expiration]/thickness at end-inspiration) throughout the course of mechanical ventilation was linearly correlated with spontaneous breathing fraction (beta coefficient, 9.4; 95% CI, 4.2-14.7; p = 0.001). For children with a period of spontaneous breathing fraction less than 0.5 during mechanical ventilation, those with exposure to a continuous neuromuscular blockade infusion (n = 15) had a significantly larger decrease in thickness at end-expiration compared with children with low spontaneous breathing fraction who were not exposed to a neuromuscular blockade infusion (n = 18) (-16.4%, [interquartile range, -28.4% to -7.0%] vs -7.3%; [interquartile range, -10.9% to -0%]; p = 0.036). Conclusions Diaphragm atrophy is present in children on mechanical ventilation for acute respiratory failure. Diaphragm contractility, measured as thickening fraction, is strongly correlated with spontaneous breathing fraction. The combination of exposure to neuromuscular blockade infusion with low overall spontaneous breathing fraction is associated with a greater degree of atrophy.

OBJECTIVES Our objective was to determine survival and variables associated with poor outcomes for patients requiring high frequency oscillatory ventilator (HFOV) support. We tested the ability of markers of oxygenation to predict outcome, specifically, the oxygenation index (OI), both prior to and after initiation of HFOV. We also aimed to examine the effect of immunocompromised condition (IC), and specifically stem cell transplant (SCT), on outcome. DESIGN A retrospective, observational study was performed at two pediatric intensive care units (ICU) and included patients treated with HFOV over a 5 year time period. Oxygenation index and PF ratios were calculated for all patients prior to and at 24 h of HFOV support. RESULTS Of the 134 patients meeting inclusion criteria, mortality was 42% with a higher rate of mortality (P

The original Pediatric Sepsis Biomarker Risk Model and revised (Pediatric Sepsis Biomarker Risk Model-II) biomarker-based risk prediction models have demonstrated utility for estimating baseline 28-day mortality risk in pediatric sepsis. Given the paucity of prediction tools in pediatric acute respiratory distress syndrome, and given the overlapping pathophysiology between sepsis and acute respiratory distress syndrome, we tested the utility of Pediatric Sepsis Biomarker Risk Model and Pediatric Sepsis Biomarker Risk Model-II for mortality prediction in a cohort of pediatric acute respiratory distress syndrome, with an a priori plan to revise the model if these existing models performed poorly.Prospective observational cohort study.University affiliated PICU.Mechanically ventilated children with acute respiratory distress syndrome.Blood collection within 24 hours of acute respiratory distress syndrome onset and biomarker measurements.In 152 children with acute respiratory distress syndrome, Pediatric Sepsis Biomarker Risk Model performed poorly and Pediatric Sepsis Biomarker Risk Model-II performed modestly (areas under receiver operating characteristic curve of 0.61 and 0.76, respectively). Therefore, we randomly selected 80% of the cohort (n = 122) to rederive a risk prediction model for pediatric acute respiratory distress syndrome. We used classification and regression tree methodology, considering the Pediatric Sepsis Biomarker Risk Model biomarkers in addition to variables relevant to acute respiratory distress syndrome. The final model was comprised of three biomarkers and age, and more accurately estimated baseline mortality risk (area under receiver operating characteristic curve 0.85, p0.001 and p = 0.053 compared with Pediatric Sepsis Biomarker Risk Model and Pediatric Sepsis Biomarker Risk Model-II, respectively). The model was tested in the remaining 20% of subjects (n = 30) and demonstrated similar test characteristics.A validated, biomarker-based risk stratification tool designed for pediatric sepsis was adapted for use in pediatric acute respiratory distress syndrome. The newly derived Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model demonstrates good test characteristics internally and requires external validation in a larger cohort. Tools such as Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model have the potential to provide improved risk stratification and prognostic enrichment for future trials in pediatric acute respiratory distress syndrome.

Background Nordihydroguaiaretic acid (NDGA) is a plant extract that has been shown to act as a free radical scavenger and pluripotent inhibitor of pro-inflammatory cytokines, two major cellular processes involved in the pathophysiology of sepsis. We investigated whether NDGA would improve markers of organ injury as well as survival in a rodent model of sepsis. Methods Abdominal sepsis was induced by cecal ligation and double puncture (CLP) in male Sprague-Dawley rats. NDGA was administered either at the time of injury (pre-) or 6 hours later (post-treatment). A sham surgery group and a vehicle only group were also followed as controls. Blood and lung tissue were collected 24 h after CLP. Lung tissue was used for histopathologic analysis and to measure pulmonary edema. Arterial oxygenation was measured directly to generate PaO2/FiO2, and markers of renal injury (blood urea nitrogen), liver injury (alanine aminotransferase), and tissue hypoxia (lactate) were measured. In a separate set of animals consisting of the same treatment groups, animals were followed for up to 36 hours for survival. Results NDGA pre-treatment resulted in improved oxygenation, less lung edema, lower lactate, lower BUN, and reduced histologic lung injury. NDGA post-treatment resulted in less lung edema, lower lactate, lower BUN, and less histologic lung injury, but did not significantly change oxygenation. None of the NDGA treatment groups statistically affected ALT or creatinine. NDGA pre-treatment showed improved survival compared with control CLP animals at 36 hours, while post-treatment did not. Conclusions NDGA represents a novel pleiotropic anti-inflammatory agent with potential clinical utility for modulation of organ injury secondary to sepsis.

PURPOSE: Acute respiratory distress syndrome (ARDS) is heterogeneous in etiology, which may affect outcomes. Stratification into biologically-defined subtypes may reduce heterogeneity. However, it is unknown whether pediatric ARDS has clinically relevant subtypes. We aimed to determine whether clinical characteristics and predictors of mortality differed between direct and indirect ARDS, and separately between infectious and non-infectious ARDS. METHODS: Single center, prospective cohort study of 544 children with ARDS (Berlin) between July 2011 and June 2017, stratified into direct versus indirect ARDS, and separately into infectious versus non-infectious ARDS. Multiple logistic regression was used to test for predictors of mortality in the entire cohort, and separately within subtypes. Effect modification by subtype was assessed using interaction tests. RESULTS: Direct ARDS had lower severity of illness (p < 0.001) but worse oxygenation (p < 0.001), relative to indirect. Predictors of mortality were similar for direct and indirect ARDS. When comparing infectious and non-infectious ARDS, infectious ARDS had lower severity of illness (p < 0.001), worse oxygenation (p = 0.014), and lower mortality (p = 0.013). In multivariable analysis, immunocompromised status demonstrated effect modification between infectious and non-infectious ARDS (p = 0.005 for interaction), with no association with mortality in non-infectious ARDS. CONCLUSIONS: In children, direct and indirect ARDS have distinct clinical characteristics, but similar outcomes and similar predictors of mortality. In contrast, infectious and non-infectious ARDS demonstrate heterogeneity of clinical characteristics, mortality, and predictors of mortality, with traditional predictors of ARDS mortality only applicable to infectious ARDS.

Pediatric acute respiratory distress syndrome (PARDS) has a distinct epidemiological and outcome profile, relative to adult ARDS. Nonpulmonary processes, including multisystem organ failure, immunocompromising comorbidities, and acute neurologic failure, substantially impact short-term mortality, rendering this a problematic endpoint for interventional studies, either alone or as part of a composite, such as ventilator-free days (VFDs). Indeed, VFD itself contains hidden biases, making its use as an endpoint similarly difficult. However, endpoints other than short-term mortality and VFD are profoundly understudied in PARDS. Given the neuropsychiatric and functional impairment in adult survivors of ARDS, characterization of these morbidities in children with PARDS is of paramount importance. This chapter summarizes the existing pediatric literature and, using adult ARDS as a framework, suggests alternative clinically relevant outcomes deserving of further investigation. The goal is to identify important outcomes, both short- and long-term, to inform future interventional trials in PARDS.

Infectious pneumonia is the most common cause of acute respiratory distress syndrome, with viruses frequently implicated as causative. However, the significance of viruses in pediatric acute respiratory distress syndrome is unknown. We aimed to characterize the epidemiology of viral pneumonia in pediatric acute respiratory distress syndrome and compare characteristics and outcomes between pneumonia subjects with and without viruses. Secondarily, we examined the association between specific viruses and outcomes.We performed a secondary analysis of a prospectively enrolled pediatric acute respiratory distress syndrome cohort. Subjects with pneumonia acute respiratory distress syndrome underwent testing of respiratory secretions for viruses and culture for bacteria and fungi and were stratified according to presence or absence of a virus.Tertiary care children's hospital.Children with acute respiratory distress syndrome.None.Of 544 children with acute respiratory distress syndrome, 282 (52%) had pneumonia as their inciting etiology, of whom 212 were virus-positive. In 141 of 282 (50%) pneumonia acute respiratory distress syndrome cases, a virus was the sole pathogen identified. Virus-positive pneumonia had fewer organ failures but worse oxygenation, relative to virus-negative pneumonia, with no differences in antibiotic use, ventilator duration, or mortality. Subjects with respiratory syncytial virus-associated acute respiratory distress syndrome had lower mortality (0%), and subjects with influenza-associated acute respiratory distress syndrome had shorter ventilator duration, relative to other viral acute respiratory distress syndrome. Nonadeno herpesviruses, tested for exclusively in immunocompromised subjects, had greater than 80% mortality.Pneumonia was the most common cause of pediatric acute respiratory distress syndrome, and viruses were commonly isolated as the sole pathogen. Respiratory syncytial virus and influenza were associated with better outcomes relative to other viral etiologies. Viral pneumonias in immunocompromised subjects, particularly nonadeno herpesviruses, drove the mortality rate for pneumonia acute respiratory distress syndrome. Specific viral etiologies are associated with differential outcomes in pediatric acute respiratory distress syndrome and should be accounted for in future studies.

The impact of tidal volume on outcomes in mechanically ventilated children with pediatric acute respiratory distress syndrome remains unclear. To date, observational investigations have failed to calculate tidal volume based on standardized corrections of weight. We investigated the impact of tidal volume on mortality and probability of extubation in pediatric acute respiratory distress syndrome using ideal body weight-adjusted tidal volume.Retrospective analysis of an ongoing prospective cohort of pediatric acute respiratory distress syndrome patients. Tidal volume was calculated based on actual body weight and two different formulations of ideal body weight.PICU at a large, tertiary care children's hospital.Pediatric acute respiratory distress syndrome patients on conventional ventilation with a documented height or length.None.There were 483 patients with a measured height or length at pediatric acute respiratory distress syndrome onset included in the final analysis, with 73 nonsurvivors (15%). At 24 hours, there remained 400 patients on conventional ventilation. When calculating tidal volume based on ideal body weight by either method, volumes were larger both at onset and at 24 hours compared with tidal volume based on actual body weight (all p0.001), and the proportion of patients being ventilated with tidal volumes greater than 10 mL/kg based on ideal body weight was larger both at onset (12.4% and 15.5%) and 24 hours (10.3% and 11.5%) compared with actual body weight at onset (3.5%) and 24 hours (4.0%) (all p0.001). Tidal volume, based on both actual body weight and ideal body weight, was not associated with either increased mortality or decreased probability of extubation after adjusting for oxygenation index in the whole cohort, whereas associations between higher tidal volume and poor outcomes were seen in subgroup analyses in overweight children and in severe pediatric acute respiratory distress syndrome.Our retrospective analysis of a cohort of pediatric acute respiratory distress syndrome patients did not find a consistent association between tidal volume adjusted for ideal body weight and outcomes, although an association may exist in certain subgroups. Although it remains to be shown in a prospective trial whether high volumes or pressures are injurious in pediatric acute respiratory distress syndrome, tidal volume is likely an imprecise parameter for titrating lung-protective ventilation.

Objectives Subclassification based on clinical or biologic commonalities (endotypes) is one approach to reduce heterogeneity in acute hypoxemic respiratory failure. In adults, biomarker-defined endotypes of respiratory failure have been described, with differential outcome profiles and response to therapy. To date, no studies have tested whether endotypes exist in pediatric acute hypoxemic respiratory failure, although messenger RNA expression-based endotypes have been described in pediatric sepsis. The aim of the present study was to test whether endotypes identified in pediatric sepsis are applicable to pediatric acute hypoxemic respiratory failure. Design Secondary analysis of a previously reported microarray-based study of pediatric sepsis. Setting Multiple PICUs in the United States. Patients Sixty-seven children with acute hypoxemic respiratory failure caused by sepsis. Interventions None. Measurements and main results Of the larger septic shock cohort, 67 met eligibility for acute hypoxemic respiratory failure. Twenty-three subjects were assigned to endotype A, and 44 to endotype B. Subjects assigned to endotype A had over four-fold greater unadjusted 28-day mortality, and nearly three-fold greater rates of complicated course. The association with mortality (odds ratio, 8.0; 95% CI, 1.6-41.0) and complicated course (odds ratio, 4.2; 95% CI, 1.2-14.9) persisted after adjustment for age, severity of illness, and PaO2/FIO2. Conclusions Applying a previously reported endotyping strategy in children with septic shock identified endotypes of pediatric acute hypoxemic respiratory failure secondary to sepsis, with differential risk for poor outcomes. To our knowledge, this is the first demonstration of endotypes in pediatric respiratory failure. Our results support an investigation into using transcriptomics to identify messenger RNA-based endotypes in a dedicated, well-defined acute hypoxemic respiratory failure cohort.