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Background: Optimal respiratory support in early COVID-19 pneumonia is controversial and remains unclear. Using computational modelling, we examined whether lung injury might be exacerbated in early COVID-19 by assessing the impact of conventional oxygen therapy (COT), high-flow nasal oxygen therapy (HFNOT), continuous positive airway pressure (CPAP), and noninvasive ventilation (NIV). Methods: Using an established multi-compartmental cardiopulmonary simulator, we first modelled COT at a fixed FiO2 (0.6) with elevated respiratory effort for 30 min in 120 spontaneously breathing patients, before initiating HFNOT, CPAP, or NIV. Respiratory effort was then reduced progressively over 30-min intervals. Oxygenation, respiratory effort, and lung stress/strain were quantified. Lung-protective mechanical ventilation was also simulated in the same cohort. Results: HFNOT, CPAP, and NIV improved oxygenation compared with conventional therapy, but also initially increased total lung stress and strain. Improved oxygenation with CPAP reduced respiratory effort but lung stress/strain remained elevated for CPAP >5 cm H2O. With reduced respiratory effort, HFNOT maintained better oxygenation and reduced total lung stress, with no increase in total lung strain. Compared with 10 cm H2O PEEP, 4 cm H2O PEEP in NIV reduced total lung stress, but high total lung strain persisted even with less respiratory effort. Lung-protective mechanical ventilation improved oxygenation while minimising lung injury. Conclusions: The failure of noninvasive ventilatory support to reduce respiratory effort may exacerbate pulmonary injury in patients with early COVID-19 pneumonia. HFNOT reduces lung strain and achieves similar oxygenation to CPAP/NIV. Invasive mechanical ventilation may be less injurious than noninvasive support in patients with high respiratory effort.

OBJECTIVES Emergency transfers (ETs), deterioration events with late recognition requiring ICU interventions within 1 hour of transfer, are associated with adverse outcomes. We leveraged electronic health record (EHR) data to assess the association between ETs and outcomes. We also evaluated the association between intervention timing (urgency) and outcomes. METHODS We conducted a propensity-score-matched study of hospitalized children requiring ICU transfer between 2015 and 2019 at a single institution. The primary exposure was ET, automatically classified using Epic Clarity Data stored in our enterprise data warehouse endotracheal tube in lines/drains/airway flowsheet, vasopressor in medication administration record, and/or ≥60 ml/kg intravenous fluids in intake/output flowsheets recorded within 1 hour of transfer. Urgent intervention was defined as interventions within 12 hours of transfer. RESULTS Of 2037 index transfers, 129 (6.3%) met ET criteria. In the propensity-score-matched cohort (127 ET, 374 matched controls), ET was associated with higher in-hospital mortality (13% vs 6.1%; odds ratio, 2.47; 95% confidence interval [95% CI], 1.24–4.9, P = .01), longer ICU length of stay (subdistribution hazard ratio of ICU discharge 0.74; 95% CI, 0.61–0.91, P < .01), and longer posttransfer length of stay (SHR of hospital discharge 0.71; 95% CI, 0.56–0.90, P < .01). Increased intervention urgency was associated with increased mortality risk: 4.1% no intervention, 6.4% urgent intervention, and 10% emergent intervention. CONCLUSIONS An EHR measure of deterioration with late recognition is associated with increased mortality and length of stay. Mortality risk increased with intervention urgency. Leveraging EHR automation facilitates generalizability, multicenter collaboratives, and metric consistency.

Both sepsis and acute respiratory distress syndrome (ARDS) rely on imprecise clinical definitions leading to heterogeneity, which has contributed to negative trials. Because circulating protein/DNA complexes have been implicated in sepsis and ARDS, we aimed to develop a proteomic signature of DNA-bound proteins to discriminate between children with sepsis with and without ARDS. We performed a prospective case-control study in 12 children with sepsis with ARDS matched to 12 children with sepsis without ARDS on age, severity of illness score, and source of infection. We performed co-immunoprecipitation and downstream proteomics in plasma collected ≤ 24 h of intensive care unit admission. Expression profiles were generated, and a random forest classifier was used on differentially expressed proteins to develop a signature which discriminated ARDS. The classifier was tested in six independent blinded samples. Neutrophil and nucleosome proteins were over-represented in ARDS, including two S100A proteins, superoxide dismutase (SOD), and three histones. Random forest produced a 10-protein signature that accurately discriminated between children with sepsis with and without ARDS. This classifier perfectly assigned six independent blinded samples as having ARDS or not. We validated higher expression of the most informative discriminating protein, galectin-3-binding protein, in children with ARDS. Our methodology has applicability to isolation of DNA-bound proteins from plasma. Our results support the premise of a molecular definition of ARDS, and give preliminary insight into why some children with sepsis, but not others, develop ARDS.

Nucleic acid sensing is an essential function of the immune system critical for detecting infection and sterile injury. Red blood cells (RBCs) express the DNA-sensing receptor TLR9 and detect excess CpG-DNA during pathologic states, triggering rapid clearance and immune activation. These findings suggest that RBCs modulate immune responses, yet whether RBCs detect microbial DNA during infection is unknown. We show that RBCs acquire microbial DNA during sepsis. In vitro, RBCs bind microbial DNA and enhance DNA delivery to macrophages. Erythroid-specific deletion of TLR9 attenuated cytokine production and increased splenic bacterial dissemination during polymicrobial sepsis. Congruently, RBC-bound bacterial DNA is elevated in septic patients when compared with healthy subjects, and 16S rRNA gene sequencing of RBC-bound DNA revealed distinct microbial communities that associated are associated with host inflammatory cytokines. These findings identify RBCs as immunomodulatory cells that mediate host inflammatory responses through microbial DNA delivery during sepsis.

OBJECTIVE: Given the complex interrelatedness of fluid overload (FO), creatinine, acute kidney injury (AKI), and clinical outcomes, the association of AKI with poor outcomes in critically ill children may be underestimated due to definitions used. We aimed to disentangle these temporal relationships in a large cohort of children with acute respiratory distress syndrome (ARDS). DESIGN: Retrospective cohort study. SETTING: Quaternary care pediatric intensive care unit (PICU). PATIENTS: 720 intubated children with ARDS between 2011 and 2019. INTERVENTIONS: None. MEASUREMENTS: Daily fluid balance, urine output (UOP), and creatinine for days 1-7 of ARDS were retrospectively abstracted. A subset of patients had angiopoietin 2 (ANGPT2) quantified on days 1, 3, and 7. Patients were classified as AKI by KDIGO Stage 2/3 then grouped by timing of AKI onset (Early if days 1-3 of ARDS, Late if days 4-7 of ARDS, Persistent if both) for comparison of PICU mortality and ventilator free days (VFDs). A final category of “Cryptic AKI” was used to identify subjects who met KDIGO Stage 2/3 criteria only when creatinine was adjusted for FO. Outcomes compared between those who had Cryptic AKI identified by FO-adjusted creatinine versus those who had No AKI. MAIN RESULTS: Conventionally-defined AKI occurred in 26% of patients (Early 10%, Late 3%, Persistent 13%). AKI was associated with higher mortality and fewer VFDs, with no differences according to timing of onset. The Cryptic AKI group (6% of those labeled No AKI) had higher mortality and fewer VFDs than patients who did not meet AKI with FO-adjusted creatinine. FO, FO-adjusted creatinine, and ANGPT2 increased one day prior to meeting AKI criteria in the Late AKI group. CONCLUSIONS: AKI was associated with higher mortality and fewer VFDs in pediatric ARDS irrespective of timing. FO-adjusted creatinine captures a group of patients with Cryptic AKI with outcomes approaching those who meet AKI by traditional criteria. Increases in FO, FO-adjusted creatinine, and ANGPT2 occur prior to meeting conventional AKI criteria.

Acute respiratory distress syndrome guidelines suggest limiting plateau pressures to 28-30 cm H2O. Plateau pressure is most accurately measured in square-flow modes, such as volume control. In children, decelerating-flow modes, such as pressure-regulated volume control and pressure control, are more common. Consequently, plateau pressures are rarely obtained, and pressure limits are instead provided for peak inspiratory pressure. The degree to which peak inspiratory pressure in decelerating-flow overestimates plateau pressure is unknown. Therefore, we assessed the correlation and accuracy of peak inspiratory pressure in decelerating-flow ventilation for approximating plateau pressure during square-flow ventilation.Prospective, observational study.Tertiary, academic PICU.Fifty-two intubated children with acute respiratory distress syndrome enrolled between January 2020 and May 2021.Measurement of peak inspiratory pressure in decelerating-flow ventilation and plateau pressure after transition to square-flow ventilation.Peak inspiratory pressure in decelerating-flow was highly correlated (r2 = 0.99; p0.001) with plateau pressure in square-flow. Peak inspiratory pressure was 1.0 ± 0.6 cm H2O higher than plateau pressure, with 96% of values within 2 cm H2O. The single outlier had coexistent asthma and inspiratory flows that did not reach zero.Peak inspiratory pressure measured during decelerating-flow ventilation may be an adequate surrogate of plateau pressure in pediatric acute respiratory distress syndrome when inspiratory flow approaches zero. Practitioners should be aware that peak inspiratory pressures in decelerating-flow may not be substantially higher than plateau pressures.

OBJECTIVE: Heterogeneity has hampered sepsis trials, and sub-phenotyping may assist with enrichment strategies. However, biomarker-based strategies are difficult to operationalize. Four sub-phenotypes defined by distinct temperature trajectories in the first 72 hours have been reported in adult sepsis. Given the distinct epidemiology of pediatric sepsis, the existence and relevance of temperature trajectory-defined sub-phenotypes in children is unknown. We aimed to classify septic children into de novo sub-phenotypes derived from temperature trajectories in the first 72 hours, and compare cytokine, immune function, and immunometabolic markers across subgroups. METHODS: This was a secondary analysis of a prospective cohort of 191 critically ill septic children recruited from a single academic pediatric intensive care unit. We performed group-based trajectory modeling using temperatures over the first 72 hours of sepsis to identify latent profiles. We then used mixed effects regression to determine if temperature trajectory-defined sub-phenotypes were associated with cytokine levels, immune function, and mitochondrial respiration. RESULTS: We identified four temperature trajectory-defined sub-phenotypes: hypothermic, normothermic, hyperthermic fast-resolvers, and hyperthermic slow-resolvers. Hypothermic patients were less often previously healthy and exhibited lower levels of pro- and anti-inflammatory cytokines and chemokines. Hospital mortality did not differ between hypothermic children (17%) and other sub-phenotypes (3 to 11%; p = 0.26). CONCLUSIONS: Critically ill septic children can be categorized into temperature trajectory-defined sub-phenotypes that parallel adult sepsis. Hypothermic children exhibit a blunted cytokine and chemokine profile. Group-based trajectory modeling has utility for identifying subtypes of clinical syndromes by incorporating readily available longitudinal data, rather than relying on inputs from a single timepoint.

OBJECTIVES The goal of this study was to determine the incidence, prognostic performance, and generalizability of the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) organ dysfunction criteria using electronic health record (EHR) data. Additionally, we sought to compare the performance of the PODIUM criteria with the organ dysfunction criteria proposed by the 2005 International Pediatric Sepsis Consensus Conference (IPSCC). METHODS Retrospective observational cohort study of critically ill children at 2 medical centers in the United States between 2010 and 2018. We assessed prevalence of organ dysfunction based on the PODIUM and IPSCC criteria for each 24-hour period from admission to 28 days. We studied the prognostic performance of the criteria to discriminate in-hospital mortality. RESULTS Overall, 22 427 PICU admissions met inclusion criteria, and in-hospital mortality was 2.3%. The cumulative incidence of each PODIUM organ dysfunction ranged from 15% to 30%, with an in-hospital mortality of 6% to 10% for most organ systems. The number of concurrent PODIUM organ dysfunctions demonstrated good-to-excellent discrimination for in-hospital mortality (area under the curve 0.87–0.93 for day 1 through 28) and compared favorably to the IPSCC criteria (area under the curve 0.84–0.92, P < .001 to P = .06). CONCLUSIONS We present the first evaluation of the PODIUM organ dysfunction criteria in 2 EHR databases. The use of the PODIUM organ dysfunction criteria appears promising for epidemiologic and clinical research studies using EHR data. More studies are needed to evaluate the PODIUM criteria that are not routinely collected in structured format in EHR databases.

While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking.A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1-365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021.Advanced age (HR 2.77, 95%CI 2.53-3.04, p 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03-4.17, p 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55-5.00, p 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14-1.39, p 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37-0.46, p 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17-1.54, p 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20-1.58, p 0.0001), male sex (HR 1.67, 95%CI 1.45-1.93, p 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80-13.91, p 0.0001), and hypertension (HR 1.22, 95%CI 1.10-1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32-1.67) and 365 days (RR 1.54, 95%CI 1.21-1.96) compared to COVID-19 patients with no AKI.COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery.Authors are supported by various funders, with full details stated in the acknowledgement section.

Excess mortality risk imparted by acute respiratory failure in children is unknown. We determined excess mortality risk associated with mechanically ventilated acute respiratory failure in pediatric sepsis. Novel ICD10-based algorithms were derived and validated to identify a surrogate for acute respiratory distress syndrome to calculate excess mortality risk. Algorithm-identified ARDS was identified with specificity of 96.7% (CI 93.0 − 98.9) and sensitivity of 70.5% (CI 44.0 – 89.7). Excess risk of mortality for ARDS was 24.4% (CI 22.9 – 26.2). Development of ARDS requiring mechanical ventilation imparts modest excess risk of mortality in septic children.

Transgender and non-binary young people experience discrimination that has been linked to suicidal ideation and self-harm, but few studies have examined this association systematically. We aimed to study the association between gender dysphoria-related diagnostic coding and hospital admission for suicidality or self-harm in a large representative pediatric inpatient database from the USA.Using the 2016 and 2019 Kids' Inpatient Database (KID), we identified transgender and non-binary young people (aged 6-20 years) with International Classification of Diseases (ICD)-10 codes related to gender dysphoria. We identified suicidal ideation using explicit suicidality ICD-10 codes, and self-harm using 355 self-harm ICD-10 codes. Prevalence of suicidality (primary outcome), self-harm, and the combination of suicidality and self-harm (secondary outcomes) was compared between young people with and without gender dysphoria-related codes. Univariable and multivariable regression was used to test for an association between gender dysphoria and suicidality, self-harm, or suicidality and self-harm combined.1 090 544 individuals were included from KID 2016 and 1 026 752 from KID 2019. Gender dysphoria-related diagnoses were prevalent in 161 per 100 000 hospital admissions in KID 2016 and 475 per 100 000 hospital admissions in KID 2019. In KID 2016 and KID 2019, among individuals who were White, privately insured, or from higher median income ZIP code areas, proportionately more had gender dysphoria-related codes. Prevalence of suicidality was greater in individuals with gender dysphoria-related codes than in individuals without gender dysphoria-related codes in KID 2016 (635 [36%] of 1755 individuals with gender dysphoria-related codes vs 55 351 [5%] of 1 088 789 individuals without gender dysphoria-related codes; unadjusted prevalence ratio [PR] 7·19 [95% CI 6·75-7·66]) and KID 2019 (2680 [55%] of 4872 individuals with gender dysphoria-related codes vs 38 831 [4%] of 1 021 880 individuals without gender dysphoria-related codes; unadjusted PR 5·45 [5·30-5·60]). This association persisted in multivariable modelling adjusting for confounders in KID 2016 (adjusted PR 5·02 [95% CI 4·67-5·41]) and KID 2019 (4·14 [4·02-4·28]). Increased unadjusted and adjusted PRs for individuals with gender dysphoria-related codes, relative to those without, were also evident for self-harm and when combining suicidality and self-harm in both the 2016 and 2019 datasets.In a large representative national sample, transgender and non-binary young people with gender dysphoria-related diagnoses were frequently admitted to hospital for suicidality or self-harm. The lower rates of gender-dysphoria-related codes among young people who were non-White, publicly insured, and from low-income households suggest that underlying inequities might shape the identification and management of gender dysphoria. Structural and health-care provider-level interventions are needed to reduce discrimination and expand gender-affirming competencies to prevent adverse outcomes for hospitalised transgender and non-binary young people with gender dysphoria.National Institutes of Health.

Primary Hypothesis: We hypothesized that higher alveolar dead space fraction (AVDSf) at PARDS onset would be associated with right ventricular (RV) systolic dysfunction within the first 24 hours of PARDS. Study Design and Methods: We performed a retrospective single-center cohort study of PARDS patients with clinically obtained echocardiograms within 24 hours. Primary exposure was AVDSf at PARDS onset. Primary outcome was RV systolic dysfunction as defined by RV global longitudinal strain (GLS) (> - 18%). Secondary outcomes included pulmonary hypertension (PH) and RV systolic dysfunction as defined by other echocardiogram parameters, and measures of oxygenation. Unadjusted and adjusted logistic and linear regression were used to investigate AVDSf associations with outcomes. Results: Seventy-six patients were included: median age 6.2 years, 50% female, and 66% with moderate or severe PARDS. Median AVDSf was 0.2 (IQR 0.1-0.3), 32% had RV dysfunction, and 24% had PH. Unadjusted and adjusted logistic regression showed no association between AVDSf and RV systolic dysfunction or PH by any echocardiographic measure. Unadjusted and adjusted linear regression demonstrated the association of AVDSf with both oxygenation index and PaO /FiO . AVDSf did not discriminate RV dysfunction (AUROC for RV GLS was 0.51, 95% CI 0.36-0.66). Conclusion: AVDSf at PARDS onset was not associated with RV systolic dysfunction or PH within 24 hours but was associated with metrics of hypoxemia and may be more reflective of pulmonary causes of ventilation-perfusion mismatch. Future investigations should focus on clarifying the clinical utility of AVDSf in relation to existing metrics throughout the course of PARDS.

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.