Children with single ventricle heart disease have a greater increase in sRAGE after cardiopulmonary bypass.

INTRODUCTION: Reducing cardiopulmonary bypass (CPB) induced inflammatory injury is a potentially important strategy for children undergoing multiple operations for single ventricle palliation. We sought to characterize the soluble receptor for advanced glycation end products (sRAGE), a protein involved in acute lung injury and inflammation, in pediatric patients with congenital heart disease and hypothesized that patients undergoing single ventricle palliation would have higher levels of sRAGE following bypass than those with biventricular physiologies. METHODS: This was a prospective, observational study of children undergoing CPB. Plasma samples were obtained before and after bypass. sRAGE levels were measured and compared between those with biventricular and single ventricle heart disease using descriptive statistics and multivariate analysis for risk factors for lung injury. RESULTS: sRAGE levels were measured in 40 patients: 19 with biventricular and 21 with single ventricle heart disease. Children undergoing single ventricle palliation had a higher factor and percent increase in sRAGE levels when compared to patients with biventricular circulations (4.6 vs. 2.4, p = 0.002) and (364% vs. 181%, p = 0.014). The factor increase in sRAGE inversely correlated with the patient's preoperative oxygen saturation (Pearson correlation (r) = -0.43, p = 0.005) and was positively associated with red blood cell transfusion (coefficient = 0.011; 95% CI: 0.004, 0.017; p = 0.001). CONCLUSIONS: Children with single ventricle physiology have greater increase in sRAGE following CPB as compared to children undergoing biventricular repair. Larger studies delineating the role of sRAGE in children undergoing single ventricle palliation may be beneficial in understanding how to prevent complications in this high-risk population.

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.

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.

Shifting the Paradigm: A Quality Improvement Approach to Proactive Cardiac Arrest Reduction in the Pediatric Cardiac Intensive Care Unit.

INTRODUCTION: Children with cardiac conditions are at higher risk of in-hospital pediatric cardiopulmonary arrest (CA), resulting in significant morbidity and mortality. Despite the elevated risk, proactive cardiac arrest prevention programs in the cardiac intensive care unit (CICU) remain underdeveloped. Our team developed a multidisciplinary program centered on developing a quality improvement (QI) bundle for patients at high risk of CA. METHODS: This project occurred in a 26-bed pediatric CICU of a tertiary care children's hospital. Statistical process control methodology tracked changes in CA rates over time. The global aim was to reduce CICU mortality; the smart aim was to reduce the CA rate by 50% over 12 months. Interprofessional development and implementation of a QI bundle included visual cues to identify high-risk patients, risk mitigation strategies, a new rounding paradigm, and defined escalation algorithms. Additionally, weekly event and long-term data reviews, arrest debriefs, and weekly unit-wide dissemination of key findings supported a culture change. RESULTS: After bundle implementation, CA rates decreased by 68% compared to baseline and 45% from the historical baseline. Major complications decreased from 17.1% to 12.6% (P < 0.001) and mortality decreased from 5.7% to 5.0% (P = 0.048). These results were sustained for 30 months. CONCLUSIONS: Cardiac arrest is a modifiable, rather than inevitable, metric in the CICU. Reduction is achievable through the interprofessional implementation of bundled interventions targeting proactive CA prevention. Once incorporated into widespread efforts to engage multidisciplinary CICU stakeholders, these patient-focused interventions resulted in sustained improvement.

Serum Soluble Receptor for Advanced Glycation End Products in Infants With Bronchiolitis: Associations With Acute Severity and Recurrent Wheeze.

BACKGROUND: Although bronchiolitis contributes to substantial acute (eg, intensive care use) and chronic (eg, recurrent wheeze) morbidities in young children, the pathobiology remains uncertain. We examined the associations of serum soluble receptor for advanced glycation end products (sRAGE) with acute and chronic morbidities of bronchiolitis including recurrent wheeze. METHODS: A multicenter, multiyear, cohort study of infants hospitalized for bronchiolitis was analyzed. We measured the serum sRAGE level at hospitalization and its association with intensive care use (use of mechanical ventilation and/or admission to the intensive care unit) and development of recurrent wheeze by age 3 years. We performed causal mediation analysis to estimate indirect (mediation) and direct effects of sRAGE on recurrent wheeze. RESULTS: In 886 infants with bronchiolitis, the median age was 2.9 months. Overall, 15% underwent intensive care and 32% developed recurrent wheeze. In multivariable modeling adjusting for 11 confounders, a higher presenting sRAGE level was associated with lower risk of intensive care (odds ratio for each 1-log increment, 0.39; 95% confidence interval [CI], .16 -.91; P = .03) and significantly lower rate of recurrent wheeze (hazard ratio [HR], 0.58; 95% CI, .36 -.94; P = .03). In mediation analysis, the direct effect was significant (HR, 0.60; 95% CI, .37 -.97; P = .04), while the indirect effect was not (P = .30). CONCLUSIONS: Serum sRAGE levels were inversely associated with acute and chronic morbidities of bronchiolitis. The effect of sRAGE on development of recurrent wheeze is potentially driven through pathways other than acute severity of bronchiolitis.

High BAL sRAGE is Associated with Low Serum Eosinophils and IgE in Children with Asthma.

Asthma remains the most common chronic lung disease in childhood in the United States. The receptor for advanced glycation end products (RAGE) has been recognized as both a marker of and participant in pulmonary pathophysiology. While membrane-bound RAGE (mRAGE) perpetuates the type 2 immune response, the soluble form (sRAGE) may act as a decoy receptor for pro-inflammatory ligands. Bronchoalveolar samples from 45 pediatric patients with asthma were obtained. Patients were divided into high and low BAL sRAGE groups using median sRAGE. Descriptive statistical analysis and non-parametric testing were applied. Children in the "high" sRAGE group had a lower median serum eosinophil (0.27 [SE ± 0.04] vs. 0.57 [± 0.06] K/mcl, adjusted p = 0.003) and lower serum IgE level (194.4 [± 60.7] vs. 676.2 ± 140.5) IU/mL, adjusted p = 0.004) as compared to the "low" sRAGE group. When controlling for age and body mass index percentile, absolute eosinophil count (p = 0.03) and serum IgE (p = 0.043) remained significantly lower in the "high" sRAGE group. Children with asthma and high levels of BAL sRAGE have lower serum eosinophil and IgE levels. These findings are consistent with the hypothesis that sRAGE may act as a decoy receptor by binding ligands that normally interact with mRAGE.

Use of the pediatric intensive care unit for post-procedural monitoring in young children following microlaryngobronchoscopy: Impact on resource utilization and hospital cost.

OBJECTIVE: To assess the frequency of post-procedural complications, medical interventions, and hospital costs associated with microlaryngobronchoscopy (MLB) in children prophylactically admitted for pediatric intensive care unit (PICU) monitoring for age ≤ 2 years. METHODS: We performed a single-center, retrospective, descriptive study within a 44-bed PICU in a stand-alone, tertiary, pediatric referral center. Inclusion criteria were age ≤2 years and pre-procedural selection of prophylactic PICU monitoring after MLB between January 2010 and December 2015. Children were excluded for existing tracheostomy, if undergoing concurrent non-otolaryngeal procedures, or if intubated at the time of PICU admission. Primary outcomes were the development of major and minor procedural complications and medical rescue interventions. Secondary outcomes were hospital cost and length of stay (LOS). RESULTS: One hundred and eight subjects met inclusion criteria with a median age of 5.3 (IQR: 2.6-10.9) months. A majority (86%) underwent therapeutic instrumentation in addition to diagnostic MLB. There were no observed major complications or rescue interventions. Minor complications were noted within 5 h of monitoring and included isolated stridor (24%), desaturation <90% (10%), and nausea/emesis (8%). Minor interventions included supplemental oxygen via regular nasal cannula (39%), single-dose inhaled racemic epinephrine (19%), single-dose systemic corticosteroids (19%), or high flow nasal cannula (HFNC) therapy (4%). Save for two cases of HFNC, interventions were completed or discontinued within 5 h. Median PICU LOS was 1.1 days and median cost was $9650 (IQR: $8235- $14,861) per encounter. Estimated cost of same day observation in our post anesthesia care unit (PACU) following MLB without PICU admission is $1921 per encounter. CONCLUSIONS: In children ≤ 2 years of age prophylactically admitted for PICU observation, we did not observe severe complications or major interventions after MLB. Minor interventions and complications were noted early during post-procedural monitoring. PICU monitoring was substantially more expensive than same-day PACU observation. Young age as the sole criteria for prophylactic PICU monitoring after diagnostic or therapeutic MLB may be unjustified when comparable, cost-conscious care can be achieved in a PACU setting. Prior to pre-procedural selection of PICU monitoring, we recommend a broad contextual risk assessment including a review of comorbidities, operative plan, and intended anesthetic exposure.

Cardiopulmonary Bypass Reduces Early Thrombosis of Systemic-to-Pulmonary Artery Shunts.

BACKGROUND: Shunt thrombosis is a significant cause of morbidity and mortality after systemic-to-pulmonary artery shunt (SPS) placement. Concurrent procedures with placement of SPS may require cardiopulmonary bypass (CPB). Cardiopulmonary bypass is known to cause bleeding and platelet dysfunction in infants, which may protect from early shunt thrombosis. We hypothesized that infants undergoing SPS placement on CPB have a lower incidence of early shunt thrombosis. METHODS: Retrospective cohort study of infants undergoing SPS placement from January 2008 to December 2014 was performed. Patients with and without early shunt thrombosis and on or off CPB were compared using the Mann-Whitney U test or Fisher exact test. Multivariable regression analysis was performed to identify independent predictors of early shunt thrombosis and to assess effect of CPB independent of other factors. RESULTS: Seventy-five infants underwent SPS placement during the study period (on CPB, n = 25; off CPB, n = 50). Operative mortality was 11% (8/75). Nine (12%) patients developed early shunt thrombosis, all of whom had shunt placement off CPB. Independent risk factors for early shunt thrombosis were identified to be SPS placement off CPB ( P = .011), prematurity ( P = .034), and competitive antegrade pulmonary blood flow ( P = .038). CONCLUSION: Prematurity, competitive antegrade pulmonary blood flow, and shunt placement off CPB lead to higher risk of early shunt thrombosis. We speculate that the protection offered by use of CPB may be accounted for by the associated complex coagulopathy and platelet dysfunction associated with CPB.

Short-Term Peripheral Vasoactive Infusions in Pediatrics: Where Is the Harm?

OBJECTIVE: Pediatric shock represents a major cause of morbidity and mortality in the United States. Standardization of treatment such as volume resuscitation and vasoactive administration has resulted in improved patient outcomes. Vasoactives have been anecdotally associated with peripheral IV infiltration and extravasation. There is a paucity of evidence in pediatrics to determine the ideal route of vasoactive infusions and what, if any, risk factors and harm are associated with peripheral IV infiltration and extravasation. We aim to assess the frequency of and risk factors for peripheral IV infiltration and extravasation during peripheral IV vasoactive infusions in children admitted to the PICU. DESIGN: A retrospective, cohort study of all children admitted to a PICU from January 2012 to June 2014. SETTING: Forty-four-bed PICU at Children's National Health System. PATIENTS: All children 0-18 years old receiving a vasoactive infusion through a peripheral IV for a minimum of 1 hour. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcomes of this study were incidence of peripheral IV infiltration and extravasation and resultant tissue injury. Secondary outcomes were peripheral IV characteristics and vasoactive infusion data. One hundred two patients met inclusion criteria. Sixty-two percent (63/102) were admitted with the diagnosis of septic shock. The most commonly used vasoactive agent was dopamine. The median peak Vasoactive Infusion Score was 10 (6-14). Peripheral IV infiltration and extravasation incidence was 2% (2/102) and neither event resulted in injury requiring medical or surgical intervention. CONCLUSIONS: Vasoactive infusions through peripheral IV in children admitted to the PICU with shock were observed to have a low incidence of peripheral IV infiltration and extravasation and resultant tissue injury. Short-term delivery of vasoactives via peripheral IV catheter in a highly monitored PICU setting appears to be safe.

Doppler Ultrasonography of the Central Retinal Vessels in Children With Brain Death.

OBJECTIVE: The purpose of this observational study is to explore if bedside Doppler ultrasonography of the central retinal vessels has the potential to become an ancillary study to support the timely diagnosis of brain death in children. DESIGN: Seventeen-month prospective observational cohort. SETTING: Forty-four bed pediatric medical and surgical ICU in an academic teaching hospital. PATIENTS: All children 0-18 years old who were clinically evaluated for brain death at Children's National Health Systems were enrolled and followed until discharge or death. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients had at least one ophthalmic ultrasound within 30 minutes of each brain death examination. The central retinal artery peak systolic blood flow velocity, resistive index, pulsatility index, and Doppler waveforms were evaluated in each patient. Thirty-five ophthalmic ultrasounds were obtained on 13 patients, 3 months to 15 years old, who each had two clinical examinations consistent with brain death. The average systolic blood pressure during the ultrasound examinations was 102 mm Hg (± 28), diastolic blood pressure 65 mm Hg (± 24), mean arterial pressure 79 mm Hg (± 23), heart rate 133 beats/min (± 27), temperature 36°C (± 0.96), arterial CO2 35 mm Hg (± 9), and end-tidal CO2 23 mm Hg (± 6). For all examinations, the average peak systolic velocity of the central retinal artery was significantly decreased at 4.66 cm/s (± 3.2). Twelve of 13 patients had both resistive indexes greater than or equal to 1, average pulsatility indexes of 3.6 (± 3.5) with transcranial Doppler waveforms consistent with brain death. Waveform analysis of the 35 ultrasound examinations revealed 11% with tall systolic peaks without diastolic flow, 17% with oscillatory flow, 29% showed short systolic spikes, and 23% had no Doppler movement detected. A rippling "tardus-parvus" waveform was present in 20% of examinations. CONCLUSION: This study supports that the combination of qualitative waveform analysis and quantitative blood flow variables of the central retinal vessels may have the potential to be developed as an ancillary study for supporting the diagnosis of brain death in children.

Monitoring the harm associated with use of anticoagulants in pediatric populations through trigger-based automated adverse-event detection.

BACKGROUND: The safety profile of anticoagulants, which are being used with increasing frequency in pediatric populations, is not well studied. Automatic triggers built into electronic health record systems (EHR) have been shown to be an effective way to monitor for and identify medication errors. Anticoagulant-associated adverse events were examined through the use of an anticoagulant trigger panel. METHODS: In a retrospective, five-year (September 2007-September 2012) observational study, four automated triggers were used to detect anticoagulant-related adverse events: activated partial thromboplastin time (aPTT) > 100 seconds in patients on an unfractionated heparin (UFH) infusion, International Normalized Ratio (INR) > 4, anti-factor Xa (anti-FXa) >1.5U/mL for patients on enoxaparin, and the documented use of protamine. RESULTS: For the 1,664 triggers evaluated, 12 were associated with the aPTT trigger, only 1 of which was preventable. Receiver operator characteristic curve analysis indicated that increasing the aPTT trigger > 140 seconds would optimize sensitivity and specificity. The INR trigger identified four outpatients with adverse events. No adverse events were associated with the anti-FXa trigger. The protamine trigger identified 12 adverse events and was associated with more severe events. Minimal overlap was found with protamine and aPTT triggers. CONCLUSION: Laboratory- and medication-based triggers can be effective monitoring tools for anticoagulants. For patients receiving a UFH infusion, an aPTT cutoff value of > 140 seconds is more precise. We also found that protamine use as a trigger adds value to a trigger-based anticoagulant monitoring system. Continued improvement in the logic algorithms associated with the EHR-based trigger tool will allow expanded use of this tool in a clinical manner.

Coagulopathy and shock on admission is associated with mortality for children with traumatic injuries at combat support hospitals.

OBJECTIVE: In adults, early traumatic coagulopathy and shock are both common and independently associated with mortality. There are little data regarding both the incidence and association of early coagulopathy and shock on outcomes in pediatric patients with traumatic injuries. Our objective was to determine whether coagulopathy and shock on admission are independently associated with mortality in children with traumatic injuries. METHODS: A retrospective review of the Joint Theater Trauma Registry from U.S. combat support hospitals in Iraq and Afghanistan from 2002 to 2009 was performed. Coagulopathy was defined as an international normalized ratio of ≥1.5 and shock as a base deficit of ≥6. Laboratory values were measured on admission. Primary outcome was inhospital mortality. Univariate analyses were performed on all admission variables followed by reverse stepwise multivariate logistic regression to determine independent associations. SETTING: Combat support hospitals in Iraq and Afghanistan. PATIENTS: Patients <18 yrs of age with Injury Severity Score, international normalized ratio, base deficit, and inhospital mortality were included. Of 1998 in the cohort, 744 (37%) had a complete set of data for analysis. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The incidence of early coagulopathy and shock were 27% and 38.3% and associated with mortality of 22% and 16.8%, respectively. After multivariate logistic regression, early coagulopathy had an odds ratio of 2.2 (95% confidence interval 1.1-4.5) and early shock had an odds ratio of 3.0 (95% confidence interval 1.2-7.5) for mortality. Patients with coagulopathy and shock had an odds ratio of 3.8 (95% confidence interval 2.0-7.4) for mortality. CONCLUSIONS: In children with traumatic injuries treated at combat support hospitals, coagulopathy and shock on admission are common and independently associated with a high incidence of inhospital mortality. Future studies are needed to determine whether more rapid and accurate methods of measuring coagulopathy and shock as well as if early goal-directed treatment of these states can improve outcomes in children.