Publisher Correction: Exuberant fibroblast activity compromises lung function via ADAMTS4.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Exuberant fibroblast activity compromises lung function via ADAMTS4.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

Associations Between End-Tidal Carbon Dioxide During Pediatric Cardiopulmonary Resuscitation, Cardiopulmonary Resuscitation Quality, and Survival.

BACKGROUND: Supported by laboratory and clinical investigations of adult cardiopulmonary arrest, resuscitation guidelines recommend monitoring end-tidal carbon dioxide (ETCO2) as an indicator of cardiopulmonary resuscitation (CPR) quality, but they note that "specific values to guide therapy have not been established in children." METHODS: This prospective observational cohort study was a National Heart, Lung, and Blood Institute-funded ancillary study of children in the ICU-RESUS trial (Intensive Care Unit-Resuscitation Project; NCT02837497). Hospitalized children (≤18 years of age and ≥37 weeks postgestational age) who received chest compressions of any duration for cardiopulmonary arrest, had an endotracheal or tracheostomy tube at the start of CPR, and evaluable intra-arrest ETCO2 data were included. The primary exposure was event-level average ETCO2 during the first 10 minutes of CPR (dichotomized as ≥20 mm Hg versus <20 mm Hg on the basis of adult literature). The primary outcome was survival to hospital discharge. Secondary outcomes were sustained return of spontaneous circulation, survival to discharge with favorable neurological outcome, and new morbidity among survivors. Poisson regression measured associations between ETCO2 and outcomes as well as the association between ETCO2 and other CPR characteristics: (1) invasively measured systolic and diastolic blood pressures, and (2) CPR quality and chest compression mechanics metrics (ie, time to CPR start; chest compression rate, depth, and fraction; ventilation rate). RESULTS: Among 234 included patients, 133 (57%) had an event-level average ETCO2 ≥20 mm Hg. After controlling for a priori covariates, average ETCO2 ≥20 mm Hg was associated with a higher incidence of survival to hospital discharge (86/133 [65%] versus 48/101 [48%]; adjusted relative risk, 1.33 [95% CI, 1.04-1.69]; P=0.023) and return of spontaneous circulation (95/133 [71%] versus 59/101 [58%]; adjusted relative risk, 1.22 [95% CI, 1.00-1.49]; P=0.046) compared with lower values. ETCO2 ≥20 mm Hg was not associated with survival with favorable neurological outcome or new morbidity among survivors. Average 2 ≥20 mm Hg was associated with higher systolic and diastolic blood pressures during CPR, lower CPR ventilation rates, and briefer pre-CPR arrest durations compared with lower values. Chest compression rate, depth, and fraction did not differ between ETCO2 groups. CONCLUSIONS: In this multicenter study of children with in-hospital cardiopulmonary arrest, ETCO2 ≥20 mm Hg was associated with better outcomes and higher intra-arrest blood pressures, but not with chest compression quality metrics.

Recovery Trajectories in Children Requiring 3 or More Days of Invasive Ventilation.

OBJECTIVES: To characterize health-related quality of life (HRQL) and functional recovery trajectories and risk factors for prolonged impairments among critically ill children receiving greater than or equal to 3 days of invasive ventilation. DESIGN: Prospective cohort study. SETTING: Quaternary children's hospital PICU. PATIENTS: Children without a preexisting tracheostomy who received greater than or equal to 3 days of invasive ventilation, survived hospitalization, and completed greater than or equal to 1 postdischarge data collection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated 144 children measuring HRQL using proxy-report Pediatric Quality of Life Inventory and functional status using the Functional Status Scale (FSS) reflecting preillness baseline, PICU and hospital discharge, and 1, 3, 6, and 12 months after hospital discharge. They had a median age of 5.3 years (interquartile range, 1.1-13.0 yr), 58 (40%) were female, 45 (31%) had a complex chronic condition, and 110 (76%) had normal preillness FSS scores. Respiratory failure etiologies included lung disease ( n = 49; 34%), neurologic failure ( n = 23; 16%), and septic shock ( n = 22; 15%). At 1-month postdischarge, 68 of 122 (56%) reported worsened HRQL and 35 (29%) had a new functional impairment compared with preillness baseline. This improved at 3 months to 54 (46%) and 24 (20%), respectively, and remained stable through the remaining 9 months of follow-up. We used interaction forests to evaluate relative variable importance including pairwise interactions and found that therapy consultation within 3 days of intubation was associated with better HRQL recovery in older patients and those with better preillness physical HRQL. During the postdischarge year, 76 patients (53%) had an emergency department visit or hospitalization, and 62 (43%) newly received physical, occupational, or speech therapy. CONCLUSIONS: Impairments in HRQL and functional status as well as health resource use were common among children with acute respiratory failure. Early therapy consultation was a modifiable characteristic associated with shorter duration of worsened HRQL in older patients.

Epinephrine Dosing Intervals Are Associated With Pediatric In-Hospital Cardiac Arrest Outcomes: A Multicenter Study.

OBJECTIVES: Data to support epinephrine dosing intervals during cardiopulmonary resuscitation (CPR) are conflicting. The objective of this study was to evaluate the association between epinephrine dosing intervals and outcomes. We hypothesized that dosing intervals less than 3 minutes would be associated with improved neurologic survival compared with greater than or equal to 3 minutes. DESIGN: This study is a secondary analysis of The ICU-RESUScitation Project (NCT028374497), a multicenter trial of a quality improvement bundle of physiology-directed CPR training and post-cardiac arrest debriefing. SETTING: Eighteen PICUs and pediatric cardiac ICUs in the United States. PATIENTS: Subjects were 18 years young or younger and 37 weeks old or older corrected gestational age who had an index cardiac arrest. Patients who received less than two doses of epinephrine, received extracorporeal CPR, or had dosing intervals greater than 8 minutes were excluded. INTERVENTIONS: The primary exposure was an epinephrine dosing interval of less than 3 vs. greater than or equal to 3 minutes. MEASUREMENTS AND MAIN RESULTS: The primary outcome was survival to discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1-2 or no change from baseline. Regression models evaluated the association between dosing intervals and: 1) survival outcomes and 2) CPR duration. Among 382 patients meeting inclusion and exclusion criteria, median age was 0.9 years (interquartile range 0.3-7.6 yr) and 45% were female. After adjustment for confounders, dosing intervals less than 3 minutes were not associated with survival with favorable neurologic outcome (adjusted relative risk [aRR], 1.10; 95% CI, 0.84-1.46; p = 0.48) but were associated with improved sustained return of spontaneous circulation (ROSC) (aRR, 1.21; 95% CI, 1.07-1.37; p < 0.01) and shorter CPR duration (adjusted effect estimate, -9.5 min; 95% CI, -14.4 to -4.84 min; p < 0.01). CONCLUSIONS: In patients receiving at least two doses of epinephrine, dosing intervals less than 3 minutes were not associated with neurologic outcome but were associated with sustained ROSC and shorter CPR duration.

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

Racial and skin color mediated disparities in pulse oximetry in infants and young children.

Race-based and skin pigmentation-related inaccuracies in pulse oximetry have recently been highlighted in several large electronic health record-based retrospective cohort studies across diverse patient populations and healthcare settings. Overestimation of oxygen saturation by pulse oximeters, particularly in hypoxic states, is disparately higher in Black compared to other racial groups. Compared to adult literature, pediatric studies are relatively few and mostly reliant on birth certificates or maternal race-based classification of comparison groups. Neonates, infants, and young children are particularly susceptible to the adverse life-long consequences of hypoxia and hyperoxia. Successful neonatal resuscitation, precise monitoring of preterm and term neonates with predominantly lung pathology, screening for congenital heart defects, and critical decisions on home oxygen, ventilator support and medication therapies, are only a few examples of situations that are highly reliant on the accuracy of pulse oximetry. Undetected hypoxia, especially if systematically different in certain racial groups may delay appropriate therapies and may further perpetuate health care disparities. The role of biological factors that may differ between racial groups, particularly skin pigmentation that may contribute to biased pulse oximeter readings needs further evaluation. Developmental and maturational changes in skin physiology and pigmentation, and its interaction with the operating principles of pulse oximetry need further study. Importantly, clinicians should recognize the limitations of pulse oximetry and use additional objective measures of oxygenation (like co-oximetry measured arterial oxygen saturation) where hypoxia is a concern.

Endothelial Glycocalyx Degradation Patterns in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome: A Single Center Retrospective Observational Study.

BACKGROUND: Sepsis-associated destruction of the pulmonary microvascular endothelial glycocalyx (EGCX) creates a vulnerable endothelial surface, contributing to the development of acute respiratory distress syndrome (ARDS). Constituents of the EGCX shed into circulation, glycosaminoglycans and proteoglycans, may serve as biomarkers of endothelial dysfunction. We sought to define the patterns of plasma EGCX degradation products in children with sepsis-associated pediatric ARDS (PARDS), and test their association with clinical outcomes. METHODS: We retrospectively analyzed a prospective cohort (2018-2020) of children (≥1 month to <18 years of age) receiving invasive mechanical ventilation for acute respiratory failure for ≥72 h. Children with and without sepsis-associated PARDS were selected from the parent cohort and compared. Blood was collected at time of enrollment. Plasma glycosaminoglycan disaccharide class (heparan sulfate, chondroitin sulfate, and hyaluronan) and sulfation subtypes (heparan sulfate and chondroitin sulfate) were quantified using liquid chromatography tandem mass spectrometry. Plasma proteoglycans (syndecan-1) were measured through an immunoassay. RESULTS: Among the 39 mechanically ventilated children (29 with and 10 without sepsis-associated PARDS), sepsis-associated PARDS patients demonstrated higher levels of heparan sulfate (median 639 ng/mL [interquartile range, IQR 421-902] vs 311 [IQR 228-461]) and syndecan-1 (median 146 ng/mL [IQR 32-315] vs 8 [IQR 8-50]), both p = 0.01. Heparan sulfate subtype analysis demonstrated greater proportions of N-sulfated disaccharide levels among children with sepsis-associated PARDS (p = 0.01). Increasing N-sulfated disaccharide levels by quartile were associated with severe PARDS (n = 9/29) with the highest quartile including >60% of the severe PARDS patients (test for trend, p = 0.04). Higher total heparan sulfate and N-sulfated disaccharide levels were independently associated with fewer 28-day ventilator-free days in children with sepsis-associated PARDS (all p < 0.05). CONCLUSIONS: Children with sepsis-associated PARDS exhibited higher plasma levels of heparan sulfate disaccharides and syndecan-1, suggesting that EGCX degradation biomarkers may provide insights into endothelial dysfunction and PARDS pathobiology.

Association of an In-Hospital Desirability of Outcomes Ranking Scale With Postdischarge Health-Related Quality of Life: A Secondary Analysis of the Life After Pediatric Sepsis Evaluation.

OBJECTIVES: To develop a desirability of outcome ranking (DOOR) scale for use in children with septic shock and determine its correlation with a decrease in 3-month postadmission health-related quality of life (HRQL) or death. DESIGN: Secondary analysis of the Life After Pediatric Sepsis Evaluation prospective study. SETTING: Twelve U.S. PICUs, 2013-2017. PATIENTS: Children (1 mo-18 yr) with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied a 7-point pediatric critical care (PCC) DOOR scale: 7: death; 6: extracorporeal life support; 5: supported by life-sustaining therapies (continuous renal replacement therapy, vasoactive, or invasive ventilation); 4: hospitalized with or 3: without organ dysfunction; 2: discharged with or 1: without new morbidity to patients by assigning the highest applicable score on specific days post-PICU admission. We analyzed Spearman rank-order correlations (95% CIs) between proximal outcomes (PCC-DOOR scale on days 7, 14, and 21, ventilator-free days, cumulative 28-day Pediatric Logistic Organ Dysfunction-2 (PELOD-2) scores, and PICU-free days) and 3-month decrease in HRQL or death. HRQL was measured by Pediatric Quality of Life Inventory 4.0 or Functional Status II-R for patients with developmental delay. Patients who died were assigned the worst possible HRQL score. PCC-DOOR scores were applied to 385 patients, median age 6 years (interquartile range 2, 13) and 177 (46%) with a complex chronic condition(s). Three-month outcomes were available for 245 patients (64%) and 42 patients (17%) died. PCC-DOOR scale on days 7, 14, and 21 demonstrated fair correlation with the primary outcome (-0.42 [-0.52, -0.31], -0.47 [-0.56, -0.36], and -0.52 [-0.61, -0.42]), similar to the correlations for cumulative 28-day PELOD-2 scores (-0.51 [-0.59, -0.41]), ventilator-free days (0.43 [0.32, 0.53]), and PICU-free days (0.46 [0.35, 0.55]). CONCLUSIONS: The PCC-DOOR scale is a feasible, practical outcome for pediatric sepsis trials and demonstrates fair correlation with decrease in HRQL or death at 3 months.

Healthcare Burden and Resource Utilization After Pediatric Acute Respiratory Distress Syndrome: A Secondary Analysis of the Collaborative Pediatric Critical Care Research Network Acute Respiratory Distress Syndrome Study.

OBJECTIVES: To describe family healthcare burden and health resource utilization in pediatric survivors of acute respiratory distress syndrome (ARDS) at 3 and 9 months. DESIGN: Secondary analysis of a prospective multisite cohort study. SETTING: Eight academic PICUs in the United States (2019-2020). PATIENTS: Critically ill children with ARDS and follow-up survey data collected at 3 and/or 9 months after the event. INTERVENTIONS: None. METHODS AND MEASUREMENT: We evaluated family healthcare burden, a measure of healthcare provided by families at home, and child health resource use including medication use and emergency department (ED) and hospital readmissions during the initial 3- and 9-month post-ARDS using proxy-report. Using multivariable logistic regression, we evaluated patient characteristics associated with family healthcare burden at 3 months. MAIN RESULTS: Of 109 eligible patients, 74 (68%) and 63 patients (58%) had follow-up at 3- and 9-month post-ARDS. At 3 months, 46 families (62%) reported healthcare burden including (22%) with unmet care coordination needs. At 9 months, 33 families (52%) reported healthcare burden including 10 families (16%) with unmet care coordination needs. At month 3, 61 patients (82%) required prescription medications, 13 patients (18%) had ED visits and 16 patients (22%) required hospital readmission. At month 9, 41 patients (65%) required prescription medications, 19 patients (30%) had ED visits, and 16 (25%) required hospital readmission were reported. Medication use was associated with family healthcare burden at both 3 and 9 months. In a multivariable analysis, preillness functional status and chronic conditions were associated with healthcare burden at month 3 but illness characteristics were not. CONCLUSIONS: Pediatric ARDS survivors report high rates of healthcare burden and health resource utilization at 3- and 9-month post-ARDS. Future studies should assess the impact of improved care coordination to simplify care (e.g., medication management) and improve family burden.

Viral Detection by Reverse Transcriptase Polymerase Chain Reaction in Upper Respiratory Tract and Metagenomic RNA Sequencing in Lower Respiratory Tract in Critically Ill Children With Suspected Lower Respiratory Tract Infection.

OBJECTIVES: Viral lower respiratory tract infection (vLRTI) contributes to substantial morbidity and mortality in children. Diagnosis is typically confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in hospitalized patients; however, it is unknown whether nasopharyngeal detection accurately reflects presence of virus in the lower respiratory tract (LRT). This study evaluates agreement between viral detection from nasopharyngeal specimens by RT-PCR compared with metagenomic next-generation RNA sequencing (RNA-Seq) from tracheal aspirates (TAs). DESIGN: This is an analysis of of a seven-center prospective cohort study. SETTING: Seven PICUs within academic children's hospitals in the United States. PATIENTS: Critically ill children (from 1 mo to 18 yr) who required mechanical ventilation via endotracheal tube for greater than or equal to 72 hours. INTERVENTIONS: We evaluated agreement in viral detection between paired upper and LRT samples. Results of clinical nasopharyngeal RT-PCR were compared with TA RNA-Seq. Positive and negative predictive agreement and Cohen's Kappa were used to assess agreement. MEASUREMENTS AND MAIN RESULTS: Of 295 subjects with paired testing available, 200 (68%) and 210 (71%) had positive viral testing by RT-PCR from nasopharyngeal and RNA-Seq from TA samples, respectively; 184 (62%) were positive by both nasopharyngeal RT-PCR and TA RNA-Seq for a virus, and 69 (23%) were negative by both methods. Nasopharyngeal RT-PCR detected the most abundant virus identified by RNA-Seq in 92.4% of subjects. Among the most frequent viruses detected, respiratory syncytial virus demonstrated the highest degree of concordance (κ = 0.89; 95% CI, 0.83-0.94), whereas rhinovirus/enterovirus demonstrated lower concordance (κ = 0.55; 95% CI, 0.44-0.66). Nasopharyngeal PCR was more likely to detect multiple viruses than TA RNA-Seq (54 [18.3%] vs 24 [8.1%], p ≤ 0.001). CONCLUSIONS: Viral nucleic acid detection in the upper versus LRT reveals good overall agreement, but concordance depends on the virus. Further studies are indicated to determine the utility of LRT sampling or the use of RNA-Seq to determine LRTI etiology.

Survival With Favorable Neurologic Outcome and Quality of Cardiopulmonary Resuscitation Following In-Hospital Cardiac Arrest in Children With Cardiac Disease Compared With Noncardiac Disease.

OBJECTIVES: To assess associations between outcome and cardiopulmonary resuscitation (CPR) quality for in-hospital cardiac arrest (IHCA) in children with medical cardiac, surgical cardiac, or noncardiac disease. DESIGN: Secondary analysis of a multicenter cluster randomized trial, the ICU-RESUScitation Project (NCT02837497, 2016-2021). SETTING: Eighteen PICUs. PATIENTS: Children less than or equal to 18 years old and greater than or equal to 37 weeks postconceptual age receiving chest compressions (CC) of any duration during the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,100 children with IHCA, there were 273 medical cardiac (25%), 383 surgical cardiac (35%), and 444 noncardiac (40%) cases. Favorable neurologic outcome was defined as no more than moderate disability or no worsening from baseline Pediatric Cerebral Performance Category at discharge. The medical cardiac group had lower odds of survival with favorable neurologic outcomes compared with the noncardiac group (48% vs 55%; adjusted odds ratio [aOR] [95% CI], aOR 0.59 [95% CI, 0.39-0.87], p = 0.008) and surgical cardiac group (48% vs 58%; aOR 0.64 [95% CI, 0.45-0.9], p = 0.01). We failed to identify a difference in favorable outcomes between surgical cardiac and noncardiac groups. We also failed to identify differences in CC rate, CC fraction, ventilation rate, intra-arrest average target diastolic or systolic blood pressure between medical cardiac versus noncardiac, and surgical cardiac versus noncardiac groups. The surgical cardiac group had lower odds of achieving target CC depth compared to the noncardiac group (OR 0.15 [95% CI, 0.02-0.52], p = 0.001). We failed to identify a difference in the percentage of patients achieving target CC depth when comparing medical cardiac versus noncardiac groups. CONCLUSIONS: In pediatric IHCA, medical cardiac patients had lower odds of survival with favorable neurologic outcomes compared with noncardiac and surgical cardiac patients. We failed to find differences in CPR quality between medical cardiac and noncardiac patients, but there were lower odds of achieving target CC depth in surgical cardiac compared to noncardiac patients.

Early Cardiac Arrest Hemodynamics, End-Tidal C o2 , and Outcome in Pediatric Extracorporeal Cardiopulmonary Resuscitation: Secondary Analysis of the ICU-RESUScitation Project Dataset (2016-2021).

OBJECTIVES: Cannulation for extracorporeal membrane oxygenation during active extracorporeal cardiopulmonary resuscitation (ECPR) is a method to rescue patients refractory to standard resuscitation. We hypothesized that early arrest hemodynamics and end-tidal C o2 (ET co2 ) are associated with survival to hospital discharge with favorable neurologic outcome in pediatric ECPR patients. DESIGN: Preplanned, secondary analysis of pediatric Utstein, hemodynamic, and ventilatory data in ECPR patients collected during the 2016-2021 Improving Outcomes from Pediatric Cardiac Arrest study; the ICU-RESUScitation Project (ICU-RESUS; NCT02837497). SETTING: Eighteen ICUs participated in ICU-RESUS. PATIENTS: There were 97 ECPR patients with hemodynamic waveforms during cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall, 71 of 97 patients (73%) were younger than 1 year old, 82 of 97 (85%) had congenital heart disease, and 62 of 97 (64%) were postoperative cardiac surgical patients. Forty of 97 patients (41%) survived with favorable neurologic outcome. We failed to find differences in diastolic or systolic blood pressure, proportion achieving age-based target diastolic or systolic blood pressure, or chest compression rate during the initial 10 minutes of CPR between patients who survived with favorable neurologic outcome and those who did not. Thirty-five patients had ET co2 data; of 17 survivors with favorable neurologic outcome, four of 17 (24%) had an average ET co2 less than 10 mm Hg and two (12%) had a maximum ET co2 less than 10 mm Hg during the initial 10 minutes of resuscitation. CONCLUSIONS: We did not identify an association between early hemodynamics achieved by high-quality CPR and survival to hospital discharge with favorable neurologic outcome after pediatric ECPR. Candidates for ECPR with ET co2 less than 10 mm Hg may survive with favorable neurologic outcome.

Diastolic Blood Pressure Threshold During Pediatric Cardiopulmonary Resuscitation and Survival Outcomes: A Multicenter Validation Study.

OBJECTIVES: Arterial diastolic blood pressure (DBP) greater than 25 mm Hg in infants and greater than 30 mm Hg in children greater than 1 year old during cardiopulmonary resuscitation (CPR) was associated with survival to hospital discharge in one prospective study. We sought to validate these potential hemodynamic targets in a larger multicenter cohort. DESIGN: Prospective observational study. SETTING: Eighteen PICUs in the ICU-RESUScitation prospective trial from October 2016 to March 2020. PATIENTS: Children less than or equal to 18 years old with CPR greater than 30 seconds and invasive blood pressure (BP) monitoring during CPR. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Invasive BP waveform data and Utstein-style CPR data were collected, including prearrest patient characteristics, intra-arrest interventions, and outcomes. Primary outcome was survival to hospital discharge, and secondary outcomes were return of spontaneous circulation (ROSC) and survival to hospital discharge with favorable neurologic outcome. Multivariable Poisson regression models with robust error estimates evaluated the association of DBP greater than 25 mm Hg in infants and greater than 30 mm Hg in older children with these outcomes. Among 1,129 children with inhospital cardiac arrests, 413 had evaluable DBP data. Overall, 85.5% of the patients attained thresholds of mean DBP greater than or equal to 25 mm Hg in infants and greater than or equal to 30 mm Hg in older children. Initial return of circulation occurred in 91.5% and 25% by placement on extracorporeal membrane oxygenator. Survival to hospital discharge occurred in 58.6%, and survival with favorable neurologic outcome in 55.4% (i.e. 94.6% of survivors had favorable neurologic outcomes). Mean DBP greater than 25 mm Hg for infants and greater than 30 mm Hg for older children was significantly associated with survival to discharge (adjusted relative risk [aRR], 1.32; 1.01-1.74; p = 0.03) and ROSC (aRR, 1.49; 1.12-1.97; p = 0.002) but did not reach significance for survival to hospital discharge with favorable neurologic outcome (aRR, 1.30; 0.98-1.72; p = 0.051). CONCLUSIONS: These validation data demonstrate that achieving mean DBP during CPR greater than 25 mm Hg for infants and greater than 30 mm Hg for older children is associated with higher rates of survival to hospital discharge, providing potential targets for DBP during CPR.

Tobacco smoke exposure, the lower airways microbiome and outcomes of ventilated children.

BACKGROUND: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome. METHODS: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g. RESULTS: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality. CONCLUSION: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities. IMPACT: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children.

Identification of post-cardiac arrest blood pressure thresholds associated with outcomes in children: an ICU-Resuscitation study.

INTRODUCTION: Though early hypotension after pediatric in-hospital cardiac arrest (IHCA) is associated with inferior outcomes, ideal post-arrest blood pressure (BP) targets have not been established. We aimed to leverage prospectively collected BP data to explore the association of post-arrest BP thresholds with outcomes. We hypothesized that post-arrest systolic and diastolic BP thresholds would be higher than the currently recommended post-cardiopulmonary resuscitation BP targets and would be associated with higher rates of survival to hospital discharge. METHODS: We performed a secondary analysis of prospectively collected BP data from the first 24 h following return of circulation from index IHCA events enrolled in the ICU-RESUScitation trial (NCT02837497). The lowest documented systolic BP (SBP) and diastolic BP (DBP) were percentile-adjusted for age, height and sex. Receiver operator characteristic curves and cubic spline analyses controlling for illness category and presence of pre-arrest hypotension were generated exploring the association of lowest post-arrest SBP and DBP with survival to hospital discharge and survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category of 1-3 or no change from baseline). Optimal cutoffs for post-arrest BP thresholds were based on analysis of receiver operator characteristic curves and spline curves. Logistic regression models accounting for illness category and pre-arrest hypotension examined the associations of these thresholds with outcomes. RESULTS: Among 693 index events with 0-6 h post-arrest BP data, identified thresholds were: SBP > 10th percentile and DBP > 50th percentile for age, sex and height. Fifty-one percent (n = 352) of subjects had lowest SBP above threshold and 50% (n = 346) had lowest DBP above threshold. SBP and DBP above thresholds were each associated with survival to hospital discharge (SBP: aRR 1.21 [95% CI 1.10, 1.33]; DBP: aRR 1.23 [1.12, 1.34]) and survival to hospital discharge with favorable neurologic outcome (SBP: aRR 1.22 [1.10, 1.35]; DBP: aRR 1.27 [1.15, 1.40]) (all p < 0.001). CONCLUSIONS: Following pediatric IHCA, subjects had higher rates of survival to hospital discharge and survival to hospital discharge with favorable neurologic outcome when BP targets above a threshold of SBP > 10th percentile for age and DBP > 50th percentile for age during the first 6 h post-arrest.

The Design of Nested Adaptive Clinical Trials of Multiple Organ Dysfunction Syndrome Children in a Single Study.

OBJECTIVES: Describe the statistical design of the Personalized Immunomodulation in Sepsis-induced Multiple Organ Dysfunction Syndrome (MODS) (PRECISE) study. DESIGN: Children with sepsis-induced MODS undergo real-time immune testing followed by assignment to an immunophenotype-specific study cohort. Interventional cohorts include the granulocyte macrophage-colony stimulating factor (GM-CSF) for the Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS (GRACE)-2 trial, which uses the drug GM-CSF (or placebo) to reverse immunoparalysis; and the Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS) trial, which uses the drug anakinra (or placebo) to reverse systemic inflammation. Both trials have adaptive components and use a statistical framework in which frequent data monitoring assesses futility and efficacy, allowing potentially earlier stopping than traditional approaches. Prespecified simulation-based stopping boundaries are customized to each trial to preserve an overall one-sided type I error rate. The TRIPS trial also uses response-adaptive randomization, updating randomization allocation proportions to favor active arms that appear more efficacious based on accumulating data. SETTING: Twenty-four U.S. academic PICUs. PATIENTS: Septic children with specific immunologic derangements during ongoing dysfunction of at least two organs. INTERVENTIONS: The GRACE-2 trial compares GM-CSF and placebo in children with immunoparalysis. The TRIPS trial compares four different doses of anakinra to placebo in children with moderate to severe systemic inflammation. MEASUREMENTS AND MAIN RESULTS: Both trials assess primary efficacy using the sum of the daily pediatric logistic organ dysfunction-2 score over 28 days. Ranked summed scores, with mortality assigned the worst possible value, are compared between arms using the Wilcoxon Rank Sum test (GRACE-2) and a dose-response curve (TRIPS). We present simulation-based operating characteristics under several scenarios to demonstrate the behavior of the adaptive design. CONCLUSIONS: The adaptive design incorporates innovative statistical features that allow for multiple active arms to be compared with placebo based on a child's personal immunophenotype. The design increases power and provides optimal operating characteristics compared with traditional conservative methods.

Fluid Balance and Its Association With Mortality and Health-Related Quality of Life: A Nonprespecified Secondary Analysis of the Life After Pediatric Sepsis Evaluation.

OBJECTIVES: To evaluate the association between fluid balance (FB) and health-related quality of life (HRQL) among children at 1 month following community-acquired septic shock. DESIGN: Nonprespecified secondary analysis of the Life After Pediatric Sepsis Evaluation. FB was defined as 100 × [(cumulative PICU fluid input - cumulative PICU fluid output)/PICU admission weight]. Three subgroups were identified: low FB (< 5%), medium FB (5%-15%), and high FB (> 15%) based on cumulative FB on days 0-3 of ICU stay. HRQL was measured at ICU admission and 1 month after using Pediatric Quality of Life Inventory 4.0 Generic Core or Infant Scales or the Stein-Jessop Functional Status Scale. The primary outcome was a composite of mortality or greater than 25% decline in HRQL 1 month after admission compared with baseline. SETTING: Twelve academic PICUs in the United States. PATIENTS: Critically ill children between 1 month and 18 years, with community-acquired septic shock who survived to at least day 4. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred ninety-three patients were included of whom 66 (23%) had low FB, 127 (43%) had medium FB, and 100 (34%) had high FB. There was no difference in Pediatric Risk of Mortality Score 3 (median 11 [6, 17]), age (median 5 [1, 12]), or gender (47% female) between FB groups. After adjusting for potential confounders and comparing with medium FB, higher odds of mortality or greater than 25% HRQL decline were seen in both the low FB (odds ratio [OR] 2.79 [1.20, 6.57]) and the high FB (OR 2.16 [1.06, 4.47]), p = 0.027. Compared with medium FB, low FB (OR 4.3 [1.62, 11.84]) and high FB (OR 3.29 [1.42, 8.00]) had higher odds of greater than 25% HRQL decline. CONCLUSIONS: Over half of the children who survived septic shock had low or high FB, which was associated with a significant decline in HRQL scores. Prospective studies are needed to determine if optimization of FB can improve HRQL outcomes.

Utility of Early Magnetic Resonance Imaging to Enhance Outcome Prediction in Critically Ill Children with Severe Traumatic Brain Injury.

BACKGROUND: Many children with severe traumatic brain injury (TBI) receive magnetic resonance imaging (MRI) during hospitalization. There are insufficient data on how different patterns of injury on early MRI inform outcomes. METHODS: Children (3-17 years) admitted in 2010-2021 for severe TBI (Glasgow Coma Scale [GCS] score < 9) were identified using our site's trauma registry. We used multivariable modeling to determine whether the hemorrhagic diffuse axonal injury (DAI) grade and the number of regions with restricted diffusion (subcortical white matter, corpus callosum, deep gray matter, and brainstem) on MRI obtained within 7 days of injury were independently associated with time to follow commands and with Functional Independence Measure for Children (WeeFIM) scores at the time of discharge from inpatient rehabilitation. We controlled for the clinical variables age, preadmission cardiopulmonary resuscitation, pupil reactivity, motor GCS score, and fever (> 38 °C) in the first 12 h. RESULTS: Of 260 patients, 136 (52%) underwent MRI within 7 days of injury at a median of 3 days (interquartile range [IQR] 2-4). Patients with early MRI were a median age of 11 years (IQR 7-14), 8 (6%) patients received cardiopulmonary resuscitation, 19 (14%) patients had bilateral unreactive pupils, the median motor GCS score was 1 (IQR 1-4), and 82 (60%) patients had fever. Grade 3 DAI was present in 46 (34%) patients, and restricted diffusion was noted in the corpus callosum in 75 (55%) patients, deep gray matter in 29 (21%) patients, subcortical white matter in 23 (17%) patients, and the brainstem in 20 (15%) patients. After controlling for clinical variables, an increased number of regions with restricted diffusion, but not hemorrhagic DAI grade, was independently associated with longer time to follow commands (hazard ratio 0.68, 95% confidence interval 0.53-0.89) and worse WeeFIM scores (estimate ß - 4.67, 95% confidence interval - 8.33 to - 1.01). CONCLUSIONS: Regional restricted diffusion on early MRI is independently associated with short-term outcomes in children with severe TBI. Multicenter cohort studies are needed to validate these findings and elucidate the association of early MRI features with long-term outcomes in children with severe TBI.

Host Respiratory Transcriptome Signature Associated with Poor Outcome in Children with Influenza-Staphylococcus aureus Pneumonia.

Respiratory coinfection of influenza with Staphylococcus aureus often causes severe disease; methicillin-resistant S. aureus (MRSA) coinfection is frequently fatal. Understanding disease pathogenesis may inform therapies. We aimed to identify host and pathogen transcriptomic (messenger RNA) signatures from the respiratory compartment of pediatric patients critically ill with influenza-S. aureus coinfection (ISAC), signatures that predict worse outcomes. Messenger RNA extracted from endotracheal aspirate samples was evaluated for S. aureus and host transcriptomic biosignatures. Influenza-MRSA outcomes were worse, but of 190 S. aureus virulence-associated genes, 6 were differentially expressed between MRSA-coinfected versus methicillin-susceptible S. aureus-coinfected patients, and none discriminated outcome. Host gene expression in patients with ISAC was compared with that in patients with influenza infection alone. Patients with poor clinical outcomes (death or prolonged multiorgan dysfunction) had relatively reduced expression of interferons and down-regulation of interferon γ-induced immune cell chemoattractants CXCL10 and CXCL11. In ISAC, airway host but not pathogen gene expression profiles predicted worse clinical outcomes.