Factors associated with family decision-making after pediatric out-of-hospital cardiac arrest.

AIM: This study aims to identify demographic factors, area-based social determinants of health (SDOH), and clinical features associated with medical decision-making after pediatric out-of-hospital cardiac arrest (OHCA). METHODS: This is a retrospective, exploratory, descriptive analysis of patients < 18 years old admitted to the pediatric intensive care unit (ICU) after OHCA from 2011 to 2022 (n = 217) at an urban tertiary care, free-standing children's hospital. Outcomes of interest included: (1) whether a new advance care plan (ACP) (defined as a written advance directive including do not resuscitate and/or do not intubate) was ordered during hospitalization, and (2) whether the patient was discharged with new medical technology (defined as tracheostomy and/or feeding tube). Logistic regression models identified features associated with these outcomes. RESULTS: Of the 217 patients, 78 patients (36%) had a new ACP placed during their admission. Of the survivors, 26% (27/102) were discharged home with new medical technology. Factors associated with ACP were greater change in Pediatric Cerebral Performance Category (PCPC) score (aOR = 1.49, 95% CI [1.28-1.73], p-value < 0.001) and palliative care consultation (aOR = 2.39, 95% CI [1.16-4.89], p-value 0.018). Factors associated with new medical technology were lower change in PCPC score (aOR = 0.76, 95% C.I. [0.61-0.95], p-value = 0.015) and palliative care consultation (aOR = 7.07, 95% CI [3.01-16.60], p-value < 0.001). There were no associations between area-based SDOH and outcomes. CONCLUSIONS: Understanding factors associated with decision-making related to ACP after OHCA is critical to optimize counseling for families. Multi-institutional studies are warranted to identify whether these findings are generalizable.

Noninvasive Surrogate for Physiologic Dead Space Using the Carbon Dioxide Ventilatory Equivalent: Testing in a Single-Center Cohort, 2017-2023.

OBJECTIVES: We sought to evaluate the association between the carbon dioxide (co2) ventilatory equivalent (VEqco2 = minute ventilation/volume of co2 produced per min), a marker of dead space that does not require a blood gas measurement, and mortality risk. We compared the strength of this association to that of physiologic dead space fraction (VD/Vt = [Paco2-mixed-expired Pco2]/Paco2) as well as to other commonly used markers of dead space (i.e., the end-tidal alveolar dead space fraction [AVDSf = (Paco2-end-tidal Pco2)/Paco2], and ventilatory ratio [VR = (minute ventilation × Paco2)/(age-adjusted predicted minute ventilation × 37.5)]). DESIGN: Retrospective cohort data, 2017-2023. SETTING: Quaternary PICU. PATIENTS: One hundred thirty-one children with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All dead space markers were calculated at the same 1-minute timepoint for each patient within the first 72 hours of using invasive mechanical ventilation. The 131 children had a median (interquartile range, IQR) age of 5.8 (IQR 1.4, 12.6) years, oxygenation index (OI) of 7.5 (IQR 4.6, 14.3), VD/Vt of 0.47 (IQR 0.38, 0.61), and mortality was 17.6% (23/131). Higher VEqco2 (p = 0.003), VD/Vt (p = 0.002), and VR (p = 0.013) were all associated with greater odds of mortality in multivariable models adjusting for OI, immunosuppressive comorbidity, and overall severity of illness. We failed to identify an association between AVDSf and mortality in the multivariable modeling. Similarly, we also failed to identify an association between OI and mortality after controlling for any dead space marker in the modeling. For the 28-day ventilator-free days outcome, we failed to identify an association between VD/Vt and the dead space markers in multivariable modeling, although OI was significant. CONCLUSIONS: VEqco2 performs similarly to VD/Vt and other surrogate dead space markers, is independently associated with mortality risk, and may be a reasonable noninvasive surrogate for VD/Vt.

Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis.

Importance: Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis. Objective: To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study. Design, Setting, and Participants: This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023. Main Outcomes and Measures: Death while in the PICU. Results: Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049). Conclusions and Relevance: The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.

Determining an Optimal Oxygen Saturation Target Range Based on Neonatal Maturity: Demonstration of a Decision Tree Analytic.

The utility of decision tree machine learning in exploring the interactions among the SpO2 target range, neonatal maturity, and oxemic-risk is demonstrated. METHODS: This observational study used 3 years of paired age-SpO2-PaO2 data from a neonatal ICU. The CHAID decision tree method was used to explore the interaction of postmenstrual age (PMA) on the risk of extreme arterial oxygen levels at six different potential SpO2 target ranges (88-92%, 89-93%, 90-94%, 91-95%, 92-96% and 93-97%). Risk was calculated using a severity-weighted average of arterial oxygen outside the normal range for neonates (50-80 mmHg). RESULTS: In total, 7500 paired data points within the potential target range envelope were analyzed. The two lowest target ranges were associated with the highest risk, and the ranges of 91-95% and 92-96% were associated with the lowest risk. There were shifts in the risk associated with PMA. All the target ranges showed the lowest risk at ≥42 weeks PMA. The lowest risk for preterm infants was within a target range of 92-96% with a PMA of ≤34 weeks. CONCLUSIONS: This study demonstrates the utility of decision tree analytics. These results suggest that SpO2 target ranges that are different from typical range might reduce morbidity and mortality. Further research, including prospective randomized trials, is warranted.

Estimation of inspiratory effort using airway occlusion maneuvers in ventilated children: a secondary analysis of an ongoing randomized trial testing a lung and diaphragm protective ventilation strategy.

BACKGROUND: Monitoring respiratory effort in ventilated patients is important to balance lung and diaphragm protection. Esophageal manometry remains the gold standard for monitoring respiratory effort but is invasive and requires expertise for its measurement and interpretation. Airway pressures during occlusion maneuvers may provide an alternative, although pediatric data are limited. We sought to determine the correlation between change in esophageal pressure during tidal breathing (∆Pes) and airway pressure measured during three airway occlusion maneuvers: (1) expiratory occlusion pressure (Pocc), (2) airway occlusion pressure (P0.1), and (3) respiratory muscle pressure index (PMI) in children. We also sought to explore pediatric threshold values for these pressures to detect excessive or insufficient respiratory effort. METHODS: Secondary analysis of physiologic data from children between 1 month and 18 years of age with acute respiratory distress syndrome enrolled in an ongoing randomized clinical trial testing a lung and diaphragm protective ventilation strategy (REDvent, R01HL124666). ∆Pes, Pocc, P0.1, and PMI were measured. Repeated measure correlations were used to investigate correlation coefficients between ∆Pes and the three measures, and linear regression equations were generated to identify potential therapeutic thresholds. RESULTS: There were 653 inspiratory and 713 expiratory holds from 97 patients. Pocc had the strongest correlation with ∆Pes (r = 0.68), followed by PMI (r = 0.60) and P0.1 (r = 0.42). ∆Pes could be reliably estimated using the regression equation ∆Pes = 0.66 [Formula: see text] Pocc (R2 = 0.82), with Pocc cut-points having high specificity and moderate sensitivity to detect respective ∆Pes thresholds for high and low respiratory effort. There were minimal differences in the relationship between Pocc and ∆Pes based on age (infant, child, adolescent) or mode of ventilation (SIMV versus Pressure Support), although these differences were more apparent with P0.1 and PMI. CONCLUSIONS: Airway occlusion maneuvers may be appropriate alternatives to esophageal pressure measurement to estimate the inspiratory effort in children, and Pocc represents the most promising target. TRIAL REGISTRATION: NCT03266016; August 23, 2017.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children.

OBJECTIVES: Sepsis-associated immune suppression correlates with poor outcomes. Adult trials are evaluating immune support therapies. Limited data exist to support consideration of immunomodulation in pediatric sepsis. We tested the hypothesis that early, persistent lymphopenia predicts worse outcomes in pediatric severe sepsis. DESIGN: Observational cohort comparing children with severe sepsis and early, persistent lymphopenia (absolute lymphocyte count < 1,000 cells/µL on 2 d between study days 0-5) to children without. The composite outcome was prolonged multiple organ dysfunction syndrome (MODS, organ dysfunction beyond day 7) or PICU mortality. SETTING: Nine PICUs in the National Institutes of Health Collaborative Pediatric Critical Care Research Network between 2015 and 2017. PATIENTS: Children with severe sepsis and indwelling arterial and/or central venous catheters. INTERVENTIONS: Blood sampling and clinical data analysis. MEASUREMENTS AND MAIN RESULTS: Among 401 pediatric patients with severe sepsis, 152 (38%) had persistent lymphopenia. These patients were older, had higher illness severity, and were more likely to have underlying comorbidities including solid organ transplant or malignancy. Persistent lymphopenia was associated with the composite outcome prolonged MODS or PICU mortality (66/152, 43% vs 45/249, 18%; p < 0.01) and its components prolonged MODS (59/152 [39%] vs 43/249 [17%]), and PICU mortality (32/152, 21% vs 12/249, 5%; p < 0.01) versus children without. After adjusting for baseline factors at enrollment, the presence of persistent lymphopenia was associated with an odds ratio of 2.98 (95% CI [1.85-4.02]; p < 0.01) for the composite outcome. Lymphocyte count trajectories showed that patients with persistent lymphopenia generally did not recover lymphocyte counts during the study, had lower nadir whole blood tumor necrosis factor-α response to lipopolysaccharide stimulation, and higher maximal inflammatory markers (C-reactive protein and ferritin) during days 0-3 ( p < 0.01). CONCLUSIONS: Children with severe sepsis and persistent lymphopenia are at risk of prolonged MODS or PICU mortality. This evidence supports testing therapies for pediatric severe sepsis patients risk-stratified by early, persistent lymphopenia.

Acute Disorders of Consciousness in Pediatric Severe Sepsis and Organ Failure: Secondary Analysis of the Multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study.

OBJECTIVES: Acute disorders of consciousness (DoC) in pediatric severe sepsis are associated with increased risk of morbidity and mortality. We sought to examine the frequency of and factors associated with DoC in children with sepsis-induced organ failure. DESIGN: Secondary analysis of the multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study (PHENOMS). SETTING: Nine tertiary care PICUs in the United States. PATIENTS: Children less than 18 years old admitted to a PICU with severe sepsis and at least one organ failure during a PICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was frequency of DoC, defined as Glasgow Coma Scale (GCS) less than 12 in the absence of sedatives during an ICU stay, among children with severe sepsis and the following: single organ failure, nonphenotypeable multiple organ failure (MOF), MOF with one of the PHENOMS phenotypes (immunoparalysis-associated MOF [IPMOF], sequential liver failure-associated MOF, thrombocytopenia-associated MOF), or MOF with multiple phenotypes. A multivariable logistic regression analysis was performed to evaluate the association between clinical variables and organ failure groups with DoC. Of 401 children studied, 71 (18%) presented with DoC. Children presenting with DoC were older (median 8 vs 5 yr; p = 0.023), had increased hospital mortality (21% vs 10%; p = 0.011), and more frequently presented with both any MOF (93% vs 71%; p < 0.001) and macrophage activation syndrome (14% vs 4%; p = 0.004). Among children with any MOF, those presenting with DoC most frequently had nonphenotypeable MOF and IPMOF (52% and 34%, respectively). In the multivariable analysis, older age (odds ratio, 1.07; 95% CI, 1.01-1.12) and any MOF (3.22 [1.19-8.70]) were associated with DoC. CONCLUSIONS: One of every five children with severe sepsis and organ failure experienced acute DoC during their PICU stay. Preliminary findings suggest the need for prospective evaluation of DoC in children with sepsis and MOF.

Assessment of Brain Magnetic Resonance and Spectroscopy Imaging Findings and Outcomes After Pediatric Cardiac Arrest.

Importance: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments. Objective: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest. Design, Setting, and Participants: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023. Exposure: Brain MRI or MRS. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of <70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes. Results: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome. Conclusions and Relevance: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes.

Effort and work-of-breathing parameters strongly correlate with increased resistance in an animal model.

BACKGROUND: Effort of Breathing (EOB) calculations may be a reliable alternative to Work of Breathing (WOB) calculations in which Respiratory Inductance Plethysmography (RIP) replaces spirometry. We sought to compare EOB and WOB measurements in a nonhuman primate model of increasing extrathoracic inspiratory resistance simulating upper airway obstruction (UAO). METHODS: RIP, spirometry, and esophageal manometry were measured in spontaneously breathing, intubated Rhesus monkeys utilizing 11 calibrated resistors randomly applied for 2-min. EOB was calculated breath-by-breath as Pressure Rate Product (PRP) and Pressure Time Product (PTP). WOB was calculated from the Pressure-Volume curve based on spirometry (WOBSPIR) or RIP flow (WOBRIP). RESULTS: WOB, PRP and PTP showed similar linear increases when exposed to higher levels of resistive loads. When comparing WOBSPIR to WOBRIP, a similar strong correlation was seen for both signals as resistance increased and there were no statistically significant differences. CONCLUSION: EOB and WOB parameters utilizing esophageal manometry and RIP, independent of spirometry, showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. This allows several potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. IMPACT: EOB and WOB parameters showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. There was a strong correlation between spirometry-based WOB versus RIP-based WOB. To date, it has remained untested as to whether EOB is a reliable alternative for WOB and if RIP can replace spirometry in these measurements. Our results enable additional potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. Where spirometry is not available, there is no need to apply a facemask post extubation to a spontaneously breathing, non-intubated infant to make objective EOB measurements.

The end-tidal alveolar dead space fraction for risk stratification during the first week of invasive mechanical ventilation: an observational cohort study.

BACKGROUND: The end-tidal alveolar dead space fraction (AVDSf = [PaCO2-PETCO2]/PaCO2) is a metric used to estimate alveolar dead space. Higher AVDSf on the first day of mechanical ventilation is associated with mortality and fewer ventilator-free days. It is not clear if AVDSf is associated with length of ventilation in survivors, how AVDSf performs for risk stratification beyond the first day of ventilation, or whether AVDSf adds predictive value to oxygenation (oxygenation index [OI]) or severity of illness (Pediatric Risk of Mortality [PRISM III]) markers. METHODS: Retrospective single-center observational cohort study of children and young adults receiving invasive mechanical ventilation. In those with arterial or capillary blood gases, AVDSf was calculated at the time of every blood gas for the first week of mechanical ventilation. RESULTS: There were 2335 children and young adults (median age 5.8 years [IQR 1.2, 13.2]) enrolled with 8004 analyzed AVDSf values. Higher AVDSf was associated with mortality and longer length of ventilation in survivors throughout the first week of ventilation after controlling for OI and PRISM III. Higher OI was not associated with increased mortality until ≥ 48 h of ventilation after controlling for AVDSf and PRISM III. When using standardized variables, AVDSf effect estimates were generally higher than OI for mortality, whereas OI effect estimates were generally higher than AVDSf for the length of ventilation in survivors. An AVDSf > 0.3 was associated with a higher mortality than an AVDSf < 0.2 within each pediatric acute respiratory distress syndrome severity category. The maximum AVDSf within 12 h of intensive care unit admission demonstrated good risk stratification for mortality (AUC 0.768 [95% CI 0.732, 0.803]). AVDSf did not improve mortality risk stratification when added to PRISM III but did improve mortality risk stratification when added to the gas exchange components of PRISM III (minimum 12-h PaO2 and maximum 12-h PCO2) (p < 0.00001). CONCLUSIONS: AVDSf is associated with mortality and length of ventilation in survivors throughout the first week of invasive mechanical ventilation. Some analyses suggest AVDSf may better stratify mortality risk than OI, whereas OI may better stratify risk for prolonged ventilation in survivors than AVDSf.

Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2).

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.

Leveraging Clinical Informatics and Data Science to Improve Care and Facilitate Research in Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: The use of electronic algorithms, clinical decision support systems, and other clinical informatics interventions is increasing in critical care. Pediatric acute respiratory distress syndrome (PARDS) is a complex, dynamic condition associated with large amounts of clinical data and frequent decisions at the bedside. Novel data-driven technologies that can help screen, prompt, and support clinician decision-making could have a significant impact on patient outcomes. We sought to identify and summarize relevant evidence related to clinical informatics interventions in both PARDS and adult respiratory distress syndrome (ARDS), for the second Pediatric Acute Lung Injury Consensus Conference. DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). STUDY SELECTION: We included studies of pediatric or adult critically ill patients with or at risk of ARDS that examined automated screening tools, electronic algorithms, or clinical decision support systems. DATA EXTRACTION: Title/abstract review, full text review, and data extraction using a standardized data extraction form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-six studies were identified for full text extraction to address the Patient/Intervention/Comparator/Outcome questions, and 14 were used for the recommendations/statements. Two clinical recommendations were generated, related to the use of electronic screening tools and automated monitoring of compliance with best practice guidelines. Two research statements were generated, related to the development of multicenter data collaborations and the design of generalizable algorithms and electronic tools. One policy statement was generated, related to the provision of material and human resources by healthcare organizations to empower clinicians to develop clinical informatics interventions to improve the care of patients with PARDS. CONCLUSIONS: We present two clinical recommendations and three statements (two research one policy) for the use of electronic algorithms and clinical informatics tools for patients with PARDS based on a systematic review of the literature and expert consensus.

Operational Definitions Related to Pediatric Ventilator Liberation.

BACKGROUND: Common, operational definitions are crucial to assess interventions and outcomes related to pediatric mechanical ventilation. These definitions can reduce unnecessary variability among research and quality improvement efforts, to ensure findings are generalizable, and can be pooled to establish best practices. RESEARCH QUESTION: Can we establish operational definitions for key elements related to pediatric ventilator liberation using a combination of detailed literature review and consensus-based approaches? STUDY DESIGN AND METHODS: A panel of 26 international experts in pediatric ventilator liberation, two methodologists, and two librarians conducted systematic reviews on eight topic areas related to pediatric ventilator liberation. Through a series of virtual meetings, we established draft definitions that were voted upon using an anonymous web-based process. Definitions were revised by incorporating extracted data gathered during the systematic review and discussed in another consensus meeting. A second round of voting was conducted to confirm the final definitions. RESULTS: In eight topic areas identified by the experts, 16 preliminary definitions were established. Based on initial discussion and the first round of voting, modifications were suggested for 11 of the 16 definitions. There was significant variability in how these items were defined in the literature reviewed. The final round of voting achieved ≥ 80% agreement for all 16 definitions in the following areas: what constitutes respiratory support (invasive mechanical ventilation and noninvasive respiratory support), liberation and failed attempts to liberate from invasive mechanical ventilation, liberation from respiratory support, duration of noninvasive respiratory support, total duration of invasive mechanical ventilation, spontaneous breathing trials, extubation readiness testing, 28 ventilator-free days, and planned vs rescue use of post-extubation noninvasive respiratory support. INTERPRETATION: We propose that these consensus-based definitions for elements of pediatric ventilator liberation, informed by evidence, be used for future quality improvement initiatives and research studies to improve generalizability and facilitate comparison.

Executive Summary: International Clinical Practice Guidelines for Pediatric Ventilator Liberation, A Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Document.

Rationale: Pediatric-specific ventilator liberation guidelines are lacking despite the many studies exploring elements of extubation readiness testing. The lack of clinical practice guidelines has led to significant and unnecessary variation in methods used to assess pediatric patients' readiness for extubation. Methods: Twenty-six international experts comprised a multiprofessional panel to establish pediatrics-specific ventilator liberation clinical practice guidelines, focusing on acutely hospitalized children receiving invasive mechanical ventilation for more than 24 hours. Eleven key questions were identified and first prioritized using the Modified Convergence of Opinion on Recommendations and Evidence. A systematic review was conducted for questions that did not meet an a priori threshold of ⩾80% agreement, with Grading of Recommendations, Assessment, Development, and Evaluation methodologies applied to develop the guidelines. The panel evaluated the evidence and drafted and voted on the recommendations. Measurements and Main Results: Three questions related to systematic screening using an extubation readiness testing bundle and a spontaneous breathing trial as part of the bundle met Modified Convergence of Opinion on Recommendations criteria of ⩾80% agreement. For the remaining eight questions, five systematic reviews yielded 12 recommendations related to the methods and duration of spontaneous breathing trials, measures of respiratory muscle strength, assessment of risk of postextubation upper airway obstruction and its prevention, use of postextubation noninvasive respiratory support, and sedation. Most recommendations were conditional and based on low to very low certainty of evidence. Conclusions: This clinical practice guideline provides a conceptual framework with evidence-based recommendations for best practices related to pediatric ventilator liberation.

A 30-Minute Spontaneous Breathing Trial Misses Many Children Who Go On to Fail a 120-Minute Spontaneous Breathing Trial.

BACKGROUND: The optimal length of spontaneous breathing trials (SBTs) in children is unknown. RESEARCH QUESTIONS: What are the most common reasons for SBT failure in children, and when do they occur? Can clinical parameters at the 30-min mark of a 120-min SBT predict outcome? STUDY DESIGN AND METHODS: We performed a secondary analysis of a clinical trial in pediatric ARDS, in which 2-h SBTs are conducted daily. SBT failure is based on objective criteria, including esophageal manometry for effort of breathing, categorized as passage, early failure (≤ 30 min), or late failure (30-120 min). Spirometry was used to calculate respiratory rate (RR), tidal volume (Vt), and rapid shallow breathing index (RSBI), in addition to pulse oximetry and capnography. Predictive models evaluated parameters at 30 min against SBT outcome, using receiver operating characteristic plots and area under the curve. RESULTS: We included 100 children and 305 SBTs, with 42% of SBTs being successful, 32% failing within 30 min, and 25% failing between 30 and 120 min. Of the patients passing SBTs at 30 min, 40% went on to fail by 120 min. High respiratory effort (esophageal manometry) was present in > 80% of failed SBTs. At the 30-min mark, there were no clear thresholds for RR, Vt, RSBI, Fio2, oxygen saturation, or capnography that could reliably predict SBT outcome. Multivariable modeling identified RR (P < .001) and RSBI > 7 (P = .034) at 30 min, pre-SBT inspiratory pressure level (P = .009), and pre-SBT retractions (P = .042) as predictors for SBT failure, but this model performed poorly in an independent validation set with the receiver operating characteristic plot crossing the reference line (area under the curve, 0.67). INTERPRETATION: A 30-min SBT may be too short in children recovering from pediatric ARDS because many go on to fail between 30 and 120 min. Reassuring values of Vt, RR, and gas exchange at 30 min do not reliably predict SBT passage at 2 h, likely because they do not capture the effort of breathing. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03266016; URL: www. CLINICALTRIALS: gov.

Anticoagulation practices associated with bleeding and thrombosis in pediatric extracorporeal membrane oxygenation; a multi-center secondary analysis.

To determine associations between anticoagulation practices and bleeding and thrombosis during pediatric extracorporeal membrane oxygenation (ECMO), we performed a secondary analysis of prospectively collected data which included 481 children (<19 years), between January 2012 and September 2014. The primary outcome was bleeding or thrombotic events. Bleeding events included a blood product transfusion >80 ml/kg on any day, pulmonary hemorrhage, or intracranial bleeding, Thrombotic events included pulmonary emboli, intracranial clot, limb ischemia, cardiac clot, and arterial cannula or entire circuit change. Bleeding occurred in 42% of patients. Five percent of subjects thrombosed, of which 89% also bled. Daily bleeding odds were independently associated with day prior activated clotting time (ACT) (OR 1.03, 95% CI= 1.00, 1.05, p=0.047) and fibrinogen levels (OR 0.90, 95% CI 0.84, 0.96, p <0.001). Thrombosis odds decreased with increased day prior heparin dose (OR 0.88, 95% CI 0.81, 0.97, p=0.006). Lower ACT values and increased fibrinogen levels may be considered to decrease the odds of bleeding. Use of this single measure, however, may not be sufficient alone to guide optimal anticoagulation practice during ECMO.

Association of Blood-Based Brain Injury Biomarker Concentrations With Outcomes After Pediatric Cardiac Arrest.

Importance: Families and clinicians have limited validated tools available to assist in estimating long-term outcomes early after pediatric cardiac arrest. Blood-based brain-specific biomarkers may be helpful tools to aid in outcome assessment. Objective: To analyze the association of blood-based brain injury biomarker concentrations with outcomes 1 year after pediatric cardiac arrest. Design, Setting, and Participants: The Personalizing Outcomes After Child Cardiac Arrest multicenter prospective cohort study was conducted in pediatric intensive care units at 14 academic referral centers in the US between May 16, 2017, and August 19, 2020, with the primary investigators blinded to 1-year outcomes. The study included 120 children aged 48 hours to 17 years who were resuscitated after cardiac arrest, had pre-cardiac arrest Pediatric Cerebral Performance Category scores of 1 to 3 points, and were admitted to an intensive care unit after cardiac arrest. Exposure: Cardiac arrest. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (death or survival with a Vineland Adaptive Behavior Scales, third edition, score of <70 points) at 1 year after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCH-L1), neurofilament light (NfL), and tau concentrations were measured in blood samples from days 1 to 3 after cardiac arrest. Multivariate logistic regression and area under the receiver operating characteristic curve (AUROC) analyses were performed to examine the association of each biomarker with outcomes on days 1 to 3. Results: Among 120 children with primary outcome data available, the median (IQR) age was 1.0 (0-8.5) year; 71 children (59.2%) were male. A total of 5 children (4.2%) were Asian, 19 (15.8%) were Black, 81 (67.5%) were White, and 15 (12.5%) were of unknown race; among 110 children with data on ethnicity, 11 (10.0%) were Hispanic, and 99 (90.0%) were non-Hispanic. Overall, 70 children (58.3%) had a favorable outcome, and 50 children (41.7%) had an unfavorable outcome, including 43 deaths. On days 1 to 3 after cardiac arrest, concentrations of all 4 measured biomarkers were higher in children with an unfavorable vs a favorable outcome at 1 year. After covariate adjustment, NfL concentrations on day 1 (adjusted odds ratio [aOR], 5.91; 95% CI, 1.82-19.19), day 2 (aOR, 11.88; 95% CI, 3.82-36.92), and day 3 (aOR, 10.22; 95% CI, 3.14-33.33); UCH-L1 concentrations on day 2 (aOR, 11.27; 95% CI, 3.00-42.36) and day 3 (aOR, 7.56; 95% CI, 2.11-27.09); GFAP concentrations on day 2 (aOR, 2.31; 95% CI, 1.19-4.48) and day 3 (aOR, 2.19; 95% CI, 1.19-4.03); and tau concentrations on day 1 (aOR, 2.44; 95% CI, 1.14-5.25), day 2 (aOR, 2.28; 95% CI, 1.31-3.97), and day 3 (aOR, 2.04; 95% CI, 1.16-3.57) were associated with an unfavorable outcome. The AUROC models were significantly higher with vs without the addition of NfL on day 2 (AUROC, 0.932 [95% CI, 0.877-0.987] vs 0.871 [95% CI, 0.793-0.949]; P = .02) and day 3 (AUROC, 0.921 [95% CI, 0.857-0.986] vs 0.870 [95% CI, 0.786-0.953]; P = .03). Conclusions and Relevance: In this cohort study, blood-based brain injury biomarkers, especially NfL, were associated with an unfavorable outcome at 1 year after pediatric cardiac arrest. Additional evaluation of the accuracy of the association between biomarkers and neurodevelopmental outcomes beyond 1 year is needed.

Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Mortality Risk in Pediatric Sepsis Based on C-reactive Protein and Ferritin Levels.

OBJECTIVES: Interest in using bedside C-reactive protein (CRP) and ferritin levels to identify patients with hyperinflammatory sepsis who might benefit from anti-inflammatory therapies has piqued with the COVID-19 pandemic experience. Our first objective was to identify patterns in CRP and ferritin trajectory among critically ill pediatric sepsis patients. We then examined the association between these different groups of patients in their inflammatory cytokine responses, systemic inflammation, and mortality risks. DATA SOURCES: A prospective, observational cohort study. STUDY SELECTION: Children with sepsis and organ failure in nine pediatric intensive care units in the United States. DATA EXTRACTION: Two hundred and fifty-five children were enrolled. Five distinct clinical multi-trajectory groups were identified. Plasma CRP (mg/dL), ferritin (ng/mL), and 31 cytokine levels were measured at two timepoints during sepsis (median Day 2 and Day 5). Group-based multi-trajectory models (GBMTM) identified groups of children with distinct patterns of CRP and ferritin. DATA SYNTHESIS: Group 1 had normal CRP and ferritin levels ( n = 8; 0% mortality); Group 2 had high CRP levels that became normal, with normal ferritin levels throughout ( n = 80; 5% mortality); Group 3 had high ferritin levels alone ( n = 16; 6% mortality); Group 4 had very high CRP levels, and high ferritin levels ( n = 121; 11% mortality); and Group 5 had very high CRP and very high ferritin levels ( n = 30; 40% mortality). Cytokine responses differed across the five groups, with ferritin levels correlated with macrophage inflammatory protein 1α levels and CRP levels reflective of many cytokines. CONCLUSIONS: Bedside CRP and ferritin levels can be used together to distinguish groups of children with sepsis who have different systemic inflammation cytokine responses and mortality risks. These data suggest future potential value in personalized clinical trials with specific targets for anti-inflammatory therapies.