Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

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.

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.

Critical congenital heart disease beyond HLHS and TGA: neonatal brain injury and early neurodevelopment.

BACKGROUND: Characterization of brain injury and neurodevelopmental (ND) outcomes in critical congenital heart disease (cCHD) has primarily focused on hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA). This study reports brain injury and ND outcomes among patients with heterogeneous cCHD diagnoses beyond HLHS and TGA. METHODS: This prospective cohort study included infants with HLHS, TGA, or heterogenous "Other cCHD" including left- or right-sided obstructive lesions, anomalous pulmonary venous return, and truncus arteriosus. Brain injury on perioperative brain MRI and ND outcomes on the Bayley-II at 30 months were compared. RESULTS: A total of 218 participants were included (HLHS = 60; TGA = 118; "Other cCHD" = 40, including 8 with genetic syndromes). Pre-operative (n = 209) and post-operative (n = 189) MRI showed similarly high brain injury rates across groups, regardless of cardiopulmonary bypass exposure. At 30 months, participants with "Other cCHD" had lower cognitive scores (p = 0.035) compared to those with HLHS and TGA, though worse ND outcome in this group was driven by those with genetic disorders. CONCLUSIONS: Frequency of brain injury and neurodevelopmental delay among patients with "Other cCHD" is similar to those with HLHS or TGA. Patients with all cCHD lesions are at risk for impaired outcomes; developmental and genetic screening is indicated. IMPACT: This study adds to literature on risk of brain injury in patients with critical congenital heart disease (cCHD) diagnoses other than hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), a heterogenous cohort of patients that has often been excluded from imaging studies. Children with cCHD beyond HLHS and TGA have similarly high rates of acquired brain injury. The high rate of neurodevelopmental impairment in this heterogenous group of cCHD diagnoses beyond HLHS and TGA is primarily driven by patients with comorbid genetic syndromes such as 22q11.2 deletion syndrome.

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.

Fetal circulatory physiology and brain development in complex congenital heart disease: A multi-modal imaging study.

OBJECTIVE: Fetuses with complex congenital heart disease have altered physiology, contributing to abnormal neurodevelopment. The effects of altered physiology on brain development have not been well studied. We used multi-modal imaging to study fetal circulatory physiology and brain development in hypoplastic left heart syndrome (HLHS) and d-transposition of the great arteries (TGA). METHODS: This prospective, cross-sectional study investigated individuals with fetal congenital heart disease and controls undergoing fetal echocardiography and fetal brain MRI. MRI measured total brain volume and cerebral oxygenation by the MRI quantification method T2*. Indexed cardiac outputs (CCOi) and vascular impedances were calculated by fetal echocardiography. Descriptive statistics assessed MRI and echocardiogram measurement relationships by physiology. RESULTS: Sixty-six participants enrolled (control = 20; HLHS = 25; TGA = 21), mean gestational age 33.8 weeks (95% CI: 33.3-34.2). Total brain volume and T2* were significantly lower in fetuses with cardiac disease. CCOi was lower in HLHS, correlating with total brain volume - for every 10% CCOi increase, volume increased 8 mm3 (95% CI: 1.78-14.1; p = 0.012). Echocardiography parameters and cerebral oxygenation showed no correlation. TGA showed no CCOi or aortic output correlation with MRI measures. CONCLUSIONS: In HLHS, lower cardiac output is deleterious to brain development. Our findings provide insight into the role of fetal cardiovascular physiology in brain health.

Transfusion-Associated Delirium in Children: No Difference Between Short Storage Versus Standard Issue RBCs.

OBJECTIVES: Primary objective is to determine if transfusion of short storage RBCs compared with standard issue RBCs reduced risk of delirium/coma in critically ill children. Secondary objective is to assess if RBC transfusion was independently associated with delirium/coma. DESIGN: This study was performed in two stages. First, we compared patients receiving either short storage or standard RBCs in a multi-institutional prospective randomized controlled trial. Then, we compared all transfused patients in the randomized controlled trial with a single-center cohort of nontransfused patients matched for confounders of delirium/coma. SETTING: Twenty academic PICUs who participated in the Age of Transfused Blood in Critically Ill Children trial. PATIENTS: Children 3 days to 16 years old who were transfused RBCs within the first 7 days of admission. INTERVENTIONS: Subjects were randomized to either short storage RBC study arm (defined as RBCs stored for up to seven days) or standard issue RBC study arm. In addition, subjects were screened for delirium prior to transfusion and every 12 hours after transfusion for up to 3 days. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was development of delirium/coma within 3 days of initial transfusion. Additional outcome measures were dose-response relationship between volume of RBCs transfused and delirium/coma, and comparison of delirium/coma rates between transfused patients and individually matched nontransfused patients. We included 146 subjects in the stage I analysis; 69 were randomized to short storage RBCs and 77 to standard issue. There was no significant difference in delirium/coma development between study arms (79.5% vs 70.1%; p = 0.184). In the stage II analysis, adjusted odds for delirium in the transfused cohort was more than eight-fold higher than in the nontransfused matched cohort, even after controlling for hemoglobin (adjusted odds ratio, 8.9; CI, 2.8-28.4; p < 0.001). CONCLUSIONS: RBC transfusions (and not anemia) are independently associated with increased odds of subsequent delirium/coma. However, storage age of RBCs does not affect delirium risk.

Association of Pathogen Type With Outcomes of Children Encountering Community-Acquired Pediatric Septic Shock.

OBJECTIVES: To determine the association of pathogen type with mortality, functional status, and health-related quality of life (HRQL) among children at hospital discharge/1 month following hospitalization for septic shock. DESIGN: Secondary database analysis of a prospective, descriptive cohort investigation. SETTING: Twelve academic PICUs in the United States. PATIENTS: Critically ill children, 1 month to 18 years old, enrolled from 2013 to 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Association of clinical outcomes with pathogen type was assessed for all patients and separately for surviving patients enrolled in the primary Life After Pediatric Sepsis Evaluation (LAPSE) investigation. For this secondary analysis, we predicted that age would be associated with pathogen type and outcomes, and accordingly, it was incorporated as a confounding variable in primary analyses. Among 389 children enrolled with septic shock, at 1 month/hospital discharge, we observed no statistically significant differences in relation to pathogen types for the composite outcome mortality or substantial new functional morbidity: no causative organism identified (27% [28/103]), pure viral infections (26% [24/91]), pure bacterial/fungal infections (25% [31/125]), and bacterial/fungal+viral coinfections (33% [23/70]). Similarly, we observed no statistically significant differences in relation to pathogen types for the composite outcome, mortality, or persistent serious deterioration of HRQL: no causative organism identified (43% [44/103]), pure viral infections (33% [30/91]), pure bacterial/fungal infections (46% [57/125]), and bacterial/fungal+viral coinfections (43% [30/70]). However, we did identify statistically significant associations between pathogen type and the outcome ventilator-free days ( p = 0.0083) and PICU-free days (0.0238). CONCLUSIONS: This secondary analysis of the LAPSE database identified no statistically significant association of pathogen type with composite mortality and morbidity outcomes. However, pathogen type may be associated with PICU resources employed to treat sepsis organ dysfunction. Ultimately, pediatric septic shock was frequently associated with adverse patient-centered, clinically meaningful outcomes regardless of infectious disease pathogen type.

Assessment of Patient Health-Related Quality of Life and Functional Outcomes in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: To describe health-related quality of life (HRQL) and functional outcomes in pediatric acute respiratory distress syndrome (ARDS) and to determine risk factors associated with poor outcome defined as death or severe reduction in HRQL at 28 days or ICU discharge. DESIGN: Prospective multisite cohort-outcome study conducted between 2019 and 2020. SETTING: Eight academic PICUs in the United States. PATIENTS: Children with ARDS based on standard criteria. INTERVENTIONS: Patient characteristics and illness severity were collected during PICU admission. Parent proxy-report measurements were obtained at baseline, day 28/ICU discharge, month 3, and month 9, utilizing Pediatric Quality of Life Inventory and Functional Status Scale (FSS). A composite outcome evaluated using univariate and multivariate analysis was death or severe reduction in HRQL (>25% reduction in the Pediatric Quality of Life Inventory at day 28/ICU discharge. MEASUREMENTS AND MAIN RESULTS: This study enrolled 122 patients with a median age of 3 years (interquartile range, 1-12 yr). Common etiologies of ARDS included pneumonia ( n = 63; 52%) and sepsis ( n = 27; 22%). At day 28/ICU discharge, half (50/95; 53%) of surviving patients with follow-up data reported a greater than 10% decrease in HRQL from baseline, and approximately one-third of participants ( n = 19/61; 31%) reported a greater than 10% decrease in HRQL at 9 months. Trends in FSS were similar. Of 104 patients with data, 47 patients (45%) died or reported a severe decrease of greater than 25% in HRQL at day 28/ICU discharge. Older age was associated with an increased risk of death or severe reduction in HRQL (odds ratio, 1.08; CI, 1.01-1.16). CONCLUSIONS: Children with ARDS are at risk for deterioration in HRQL and FSS that persists up to 9 months after ARDS. Almost half of children with ARDS experience a poor outcome including death or severe reduction in HRQL at day 28/ICU discharge.

Characterization of Inhaled Nitric Oxide Use for Cardiac Indications in Pediatric Patients.

OBJECTIVES: Characterize the use of inhaled nitric oxide (iNO) for pediatric cardiac patients and assess the relationship between patient characteristics before iNO initiation and outcomes following cardiac surgery. DESIGN: Observational cohort study. SETTING: PICU and cardiac ICUs in seven Collaborative Pediatric Critical Care Research Network hospitals. PATIENTS: Consecutive patients, less than 18 years old, mechanically ventilated before or within 24 hours of iNO initiation. iNO was started for a cardiac indication and excluded newborns with congenital diaphragmatic hernia, meconium aspiration syndrome, and persistent pulmonary hypertension, or when iNO started at an outside institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four-hundred seven patients with iNO initiation based on cardiac dysfunction. Cardiac dysfunction patients were administered iNO for a median of 4 days (2-7 d). There was significant morbidity with 51 of 407 (13%) requiring extracorporeal membrane oxygenation and 27 of 407 (7%) requiring renal replacement therapy after iNO initiation, and a 28-day mortality of 46 of 407 (11%). Of the 366 (90%) survivors, 64 of 366 patients (17%) had new morbidity as assessed by Functional Status Scale. Among the postoperative cardiac surgical group (n = 301), 37 of 301 (12%) had a superior cavopulmonary connection and nine of 301 (3%) had a Fontan procedure. Based on echocardiographic variables prior to iNO (n = 160) in the postoperative surgical group, right ventricle dysfunction was associated with 28-day and hospital mortalities (both, p < 0.001) and ventilator-free days (p = 0.003); tricuspid valve regurgitation was only associated with ventilator-free days (p < 0.001), whereas pulmonary hypertension was not associated with mortality or ventilator-free days. CONCLUSIONS: Pediatric patients in whom iNO was initiated for a cardiac indication had a high mortality rate and significant morbidity. Right ventricular dysfunction, but not the presence of pulmonary hypertension on echocardiogram, was associated with ventilator-free days and mortality.

Sodium Bicarbonate Use During Pediatric Cardiopulmonary Resuscitation: A Secondary Analysis of the ICU-RESUScitation Project Trial.

OBJECTIVES: To evaluate associations between sodium bicarbonate use and outcomes during pediatric in-hospital cardiac arrest (p-IHCA). DESIGN: Prespecified secondary analysis of a prospective, multicenter cluster randomized interventional trial. SETTING: Eighteen participating ICUs of the ICU-RESUScitation Project (NCT02837497). PATIENTS: Children less than or equal to 18 years old and greater than or equal to 37 weeks post conceptual age who received chest compressions of any duration from October 2016 to March 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Child and event characteristics, prearrest laboratory values (2-6 hr prior to p-IHCA), pre- and intraarrest hemodynamics, and outcomes were collected. In a propensity score weighted cohort, the relationships between sodium bicarbonate use and outcomes were assessed. The primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC) and survival to hospital discharge with favorable neurologic outcome. Of 1,100 index cardiopulmonary resuscitation events, median age was 0.63 years (interquartile range, 0.19-3.81 yr); 528 (48.0%) received sodium bicarbonate; 773 (70.3%) achieved ROSC; 642 (58.4%) survived to hospital discharge; and 596 (54.2%) survived to hospital discharge with favorable neurologic outcome. Among the weighted cohort, sodium bicarbonate use was associated with lower survival to hospital discharge rate (adjusted odds ratio [aOR], 0.7; 95% CI, 0.54-0.92; p = 0.01) and lower survival to hospital discharge with favorable neurologic outcome rate (aOR, 0.69; 95% CI, 0.53-0.91; p = 0.007). Sodium bicarbonate use was not associated with ROSC (aOR, 0.91; 95% CI, 0.62-1.34; p = 0.621). CONCLUSIONS: In this propensity weighted multicenter cohort study of p-IHCA, sodium bicarbonate use was common and associated with lower rates of survival to hospital discharge.

The Temporal Association of the COVID-19 Pandemic and Pediatric Cardiopulmonary Resuscitation Quality and Outcomes.

OBJECTIVES: The COVID-19 pandemic resulted in adaptations to pediatric resuscitation systems of care. The objective of this study was to determine the temporal association between the pandemic and pediatric in-hospital cardiac arrest (IHCA) process of care metrics, cardiopulmonary resuscitation (cardiopulmonary resuscitation) quality, and patient outcomes. DESIGN: Multicenter retrospective analysis of a dataset comprising observations of IHCA outcomes pre pandemic (March 1, 2019 to February 29, 2020) versus pandemic (March 1, 2020 to February 28, 2021). SETTING: Data source was the ICU-RESUScitation Project ("ICU-RESUS;" NCT028374497), a prospective, multicenter, cluster randomized interventional trial. PATIENTS: Children (≤ 18 yr) who received cardiopulmonary resuscitation while admitted to the ICU and were enrolled in ICU-RESUS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 429 IHCAs meeting inclusion criteria, occurrence during the pandemic period was associated with higher frequency of hypotension as the immediate cause of arrest. Cardiac arrest physiology, cardiopulmonary resuscitation quality metrics, and postarrest physiologic and quality of care metrics were similar between the two periods. Survival with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline) occurred in 102 of 195 subjects (52%) during the pandemic compared with 140 of 234 (60%) pre pandemic ( p = 0.12). Among survivors, occurrence of IHCA during the pandemic period was associated with a greater increase in Functional Status Scale (FSS) (i.e., worsening) from baseline (1 [0-3] vs 0 [0-2]; p = 0.01). After adjustment for confounders, IHCA survival during the pandemic period was associated with a greater increase in FSS from baseline (+1.19 [95% CI, 0.35-2.04] FSS points; p = 0.006) and higher odds of a new FSS-defined morbidity (adjusted odds ratio, 1.88 [95% CI, 1.03-3.46]; p = 0.04). CONCLUSIONS: Using the ICU-RESUS dataset, we found that relative to the year prior, pediatric IHCA during the first year of the COVID-19 pandemic was associated with greater worsening of functional status and higher odds of new functional morbidity among survivors.

The Effect of Size and Asymmetry at Birth on Brain Injury and Neurodevelopmental Outcomes in Congenital Heart Disease.

Poor and asymmetric fetal growth have been associated with neonatal brain injury (BI) and worse neurodevelopmental outcomes (NDO) in the growth-restricted population due to placental insufficiency. We tested the hypothesis that postnatal markers of fetal growth (birthweight (BW), head circumference (HC), and head to body symmetry) are associated with preoperative white matter injury (WMI) and NDO in infants with single ventricle physiology (SVP) and d-transposition of great arteries (TGA). 173 term newborns (106 TGA; 67 SVP) at two sites had pre-operative brain MRI to assess for WMI and measures of microstructural brain development. NDO was assessed at 30 months with the Bayley Scale of Infant Development-II (n = 69). We tested the association between growth parameters at birth with the primary outcome of WMI on the pre-operative brain MRI. Secondary outcomes included measures of NDO. Newborns with TGA were more likely to have growth asymmetry with smaller heads relative to weight while SVP newborns were symmetrically small. There was no association between BW, HC or asymmetry and WMI on preoperative brain MRI or with measures of microstructural brain development. Similarly, growth parameters at birth were not associated with NDO at 30 months. In a multivariable model only cardiac lesion and site were associated with NDO. Unlike other high-risk infant populations, postnatal markers of fetal growth including head to body asymmetry that is common in TGA is not associated with brain injury or NDO. Lesion type appears to play a more important role in NDO in CHD.

Effect of Physiologic Point-of-Care Cardiopulmonary Resuscitation Training on Survival With Favorable Neurologic Outcome in Cardiac Arrest in Pediatric ICUs: A Randomized Clinical Trial.

Importance: Approximately 40% of children who experience an in-hospital cardiac arrest survive to hospital discharge. Achieving threshold intra-arrest diastolic blood pressure (BP) targets during cardiopulmonary resuscitation (CPR) and systolic BP targets after the return of circulation may be associated with improved outcomes. Objective: To evaluate the effectiveness of a bundled intervention comprising physiologically focused CPR training at the point of care and structured clinical event debriefings. Design, Setting, and Participants: A parallel, hybrid stepped-wedge, cluster randomized trial (Improving Outcomes from Pediatric Cardiac Arrest-the ICU-Resuscitation Project [ICU-RESUS]) involving 18 pediatric intensive care units (ICUs) from 10 clinical sites in the US. In this hybrid trial, 2 clinical sites were randomized to remain in the intervention group and 2 in the control group for the duration of the study, and 6 were randomized to transition from the control condition to the intervention in a stepped-wedge fashion. The index (first) CPR events of 1129 pediatric ICU patients were included between October 1, 2016, and March 31, 2021, and were followed up to hospital discharge (final follow-up was April 30, 2021). Intervention: During the intervention period (n = 526 patients), a 2-part ICU resuscitation quality improvement bundle was implemented, consisting of CPR training at the point of care on a manikin (48 trainings/unit per month) and structured physiologically focused debriefings of cardiac arrest events (1 debriefing/unit per month). The control period (n = 548 patients) consisted of usual pediatric ICU management of cardiac arrest. Main Outcomes and Measures: The primary outcome was survival to hospital discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1 to 3 or no change from baseline (score range, 1 [normal] to 6 [brain death or death]). The secondary outcome was survival to hospital discharge. Results: Among 1389 cardiac arrests experienced by 1276 patients, 1129 index CPR events (median patient age, 0.6 [IQR, 0.2-3.8] years; 499 girls [44%]) were included and 1074 were analyzed in the primary analysis. There was no significant difference in the primary outcome of survival to hospital discharge with favorable neurologic outcomes in the intervention group (53.8%) vs control (52.4%); risk difference (RD), 3.2% (95% CI, -4.6% to 11.4%); adjusted OR, 1.08 (95% CI, 0.76 to 1.53). There was also no significant difference in survival to hospital discharge in the intervention group (58.0%) vs control group (56.8%); RD, 1.6% (95% CI, -6.2% to 9.7%); adjusted OR, 1.03 (95% CI, 0.73 to 1.47). Conclusions and Relevance: In this randomized clinical trial conducted in 18 pediatric intensive care units, a bundled intervention of cardiopulmonary resuscitation training at the point of care and physiologically focused structured debriefing, compared with usual care, did not significantly improve patient survival to hospital discharge with favorable neurologic outcome among pediatric patients who experienced cardiac arrest in the ICU. Trial Registration: ClinicalTrials.gov Identifier: NCT02837497.

Temporal airway microbiome changes related to ventilator-associated pneumonia in children.

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of Streptococcus, Lactobacillales and Prevotella were lower for VAP subjects versus non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included Prevotella species (19%), Pseudomonas aeruginosa (14%) and Streptococcus mitis/pneumoniae (10%). Mycoplasma and Ureaplasma were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.

Incentive delivery timing and follow-up survey completion in a prospective cohort study of injured children: a randomized experiment comparing prepaid and postpaid incentives.

BACKGROUND: Retaining participants over time is a frequent challenge in research studies evaluating long-term health outcomes. This study's objective was to compare the impact of prepaid and postpaid incentives on response to a six-month follow-up survey. METHODS: We conducted an experiment to compare response between participants randomized to receive either prepaid or postpaid cash card incentives within a multisite study of children under 15 years in age who were hospitalized for a serious, severe, or critical injury. Participants were parents or guardians of enrolled children. The primary outcome was survey response. We also examined whether demographic characteristics were associated with response and if incentive timing influenced the relationship between demographic characteristics and response. We evaluated whether incentive timing was associated with the number of calls needed for contact. RESULTS: The study enrolled 427 children, and parents of 420 children were included in this analysis. Follow-up survey response did not differ according to the assigned treatment arm, with the percentage of parents responding to the survey being 68.1% for the prepaid incentive and 66.7% with the postpaid incentive. Likelihood of response varied by demographics. Spanish-speaking parents and parents with lower income and lower educational attainment were less likely to respond. Parents of Hispanic/Latino children and children with Medicaid insurance were also less likely to respond. We found no relationship between the assigned incentive treatment and the demographics of respondents compared to non-respondents. CONCLUSIONS: Prepaid and postpaid incentives can obtain similar participation in longitudinal pediatric critical care outcomes research. Incentives alone do not ensure retention of all demographic subgroups. Strategies for improving representation of hard-to-reach populations are needed to address health disparities and ensure the generalizability of studies using these results.