Massive Transfusion in Pediatric Patients on Extracorporeal Membrane Oxygenation: A Secondary Analysis of the Massive Transfusion in Children (MATIC) Study.

Few data describe pediatric patients who receive massive transfusion for life-threatening hemorrhage (LTH) while on extracorporeal membrane oxygenation (ECMO). We present a retrospective secondary analysis of a multicenter prospective observational study to describe resource utilization and mortality in pediatric patients with LTH while on ECMO. Children who were on ECMO during an LTH were compared to children with LTH who were not on ECMO. Primary outcomes were volumes of blood products administered and 28 day mortality. Comparisons were assessed by two-sided Fisher's exact test or Wilcoxon rank sum test. A total of 449 children, including 36 on ECMO, were included. Compared to those not on ECMO, children on ECMO received a higher volume of blood products (110 [50-223] vs. 59 [28-113]) ml/kg, p = 0.002) and were more likely to receive antifibrinolytic therapy (39% vs. 10%, p < 0.001). Blood product ratios were similar. Extracorporeal membrane oxygenation patients had higher 28 day mortality (64% vs. 35%, p = 0.001), although 24 hour mortality was similar (17% vs. 23%, p = 0.5). In conclusion, children on ECMO with LTH experience high resource utilization and 28 day mortality. Studies are needed to identify children at risk for LTH and to evaluate ECMO-specific treatment strategies.

Trends in pediatric prescription-opioid overdoses in U.S. emergency departments from 2008-2020: An epidemiologic study of pediatric opioid overdose ED visits.

BACKGROUND: Opioid overdose was declared a public health emergency in the United States, but much of the focus has been on adults. Child and adolescent exposure and access to unused prescription-opioid medications is a big concern. More research is needed on the trend of pediatric (age 0-17) prescription-opioid overdose emergency department (ED) visits in the United States, particularly during the COVID-19 pandemic year. METHODS: This retrospective epidemiological study used the 2008-2020 Nationwide Emergency Department Sample to provide a national estimate of ED visits related to prescription-opioid overdose. Inclusion criteria were 0-17-year-old patients treated at the ED due to prescription-opioid overdose. Eligible visits were identified if their medical records included any administrative billing codes for prescription-opioid overdose. National estimates were broken down by age groups, sex, geographic region, primary payer, median household income by zip code, ED disposition, and hospital location/teaching status. Incidence rate per 100,000 U.S. children was calculated for age groups, sex, and geographic region. RESULTS: Overall, the prescription-opioid overdose ED visits for patients from 0-17 years old in the United States decreased by 22% from 2008 to 2019, then increased by 12% in 2020. Most patients were discharged to home following their ED visit; however, there was a 42% increase in patients admitted from 2019 to 2020. The prescription-opioid overdose rate per 100,000 U.S. children was highest in the 0 to 1 and 12 to 17 age groups, with the 12 to 17 group increasing by 27% in 2020. ED visits in the West and Midwest saw prescription-opioid visits increase by 58% and 20%, respectively, from 2019-2020. CONCLUSIONS: Prescription-opioid overdose ED visits among U.S. children and adolescents decreased over the past decade until 2019. However, there was a substantial increase in ED visits from 2019 to 2020, suggesting the potential impact due to the then-emerging COVID-19 pandemic. Findings suggest focusing on young children and adolescents to reduce further prescription-opioid overdoses in the United States.

Prevalence of Bacterial Codetection and Outcomes for Infants Intubated for Respiratory Infections.

OBJECTIVES: To determine the prevalence of respiratory bacterial codetection in children younger than 2 years intubated for acute lower respiratory tract infection (LRTI), primarily viral bronchiolitis, and identify the association of codetection with mechanical ventilation duration. DESIGN: Prospective observational study evaluating the prevalence of bacterial codetection (moderate/heavy growth of pathogenic bacterial plus moderate/many polymorphonuclear neutrophils) and the impact of codetection on invasive mechanical ventilation (IMV) duration. SETTING: PICUs in 12 high and low/middle-income countries. PATIENTS: Children younger than 2 years old requiring intubation and ICU admission for LRTI and who had a lower respiratory tract culture obtained at the time of intubation between December 1, 2019, and November 30, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 472 analyzed patients (median age 4.5 mo), 55% had a positive respiratory culture and 29% (n = 138) had codetection. 90% received early antibiotics starting at a median of 0.36 hours after respiratory culture. Median (interquartile range) IMV duration was 151 hours (88, 226), and there were 28 deaths (5.3%). Codetection was more common with younger age, a positive respiratory syncytial virus test, and an admission diagnosis of bronchiolitis; it was less common with an admission diagnosis of pneumonia, with admission to a low-/middle-income site, and in those receiving vasopressors. When adjusted for confounders, codetection was not associated with longer IMV duration (adjusted relative risk 0.854 [95% CI 0.684-1.065]). We could not exclude the possibility that codetection might be associated with a 30-hour shorter IMV duration compared with no codetection, although the CI includes the null value. CONCLUSIONS: Bacterial codetection was present in almost a third of children younger than 2 years requiring intubation and ICU admission for LRTI, but this was not associated with prolonged IMV. Further large studies are needed to evaluate if codetection is associated with shorter IMV duration.

Changes in fibrin clot properties in patients after Roux-en-Y gastric bypass surgery.

Background: Obesity is a complex condition associated with prothrombotic fibrin networks that are resistant to fibrinolysis. Altered fibrin clot properties enhance cardiovascular risk and associate with a poorer prognosis following acute ischemic events. Bariatric surgery is commonly employed to improve cardiometabolic outcomes in individuals with obesity. However, the effects of this surgical intervention on fibrin clot properties have not been comprehensively studied. Objectives: To examine fibrin clot and lysis parameters in Roux-en-Y gastric bypass (RYGB) patients before and after surgery. Methods: The fibrin clot properties of 32 individuals living with obesity before and 9 months after RYGB surgery were determined using turbidimetric analysis. Correlation and regression analyses were used to identify relationships between clot properties and anthropomorphic and clinical measures. Results: RYGB surgery resulted in a significant reduction in adiposity-associated anthropometric measures as well as improvements in glycemia and lipid profile. Clot maximum absorbance was reduced from 0.43 ± 0.11 at baseline to 0.29 ± 0.10 at 9 months postsurgery (P < .0001), while fibrin clot lysis time failed to show a difference. The change in maximum absorbance was not caused by alterations in fibrinogen levels, while plasminogen activator inhibitor-1 concentration was significantly increased after surgery from 10,560 ± 6681 pg/mL to 15,290 ± 6559 pg/mL (P = .009). Correlation and regression analyses indicated that maximum absorbance was influenced by markers of adiposity as well as glycated hemoglobin and high-sensitivity C-reactive protein concentrations. Conclusion: RYGB surgery led to a decrease in the maximum absorbance of the fibrin clot. Values of maximum absorbance were associated with measures of glycemic control and inflammation. In contrast to previous reports, fibrin clot lysis time was not affected after surgery.

Impact of pulmonary stenosis on right ventricular global longitudinal strain in repaired tetralogy of Fallot patients post transcatheter pulmonary valve replacement.

BACKGROUND: Mixed pulmonary disease with pulmonary regurgitation (PR) and stenosis (PS) in repaired tetralogy of Fallot (rTOF) can negatively impact ventricular health. Myocardial strain has been shown to be more sensitive at detecting occult ventricular dysfunction compared to right ventricular ejection fraction (RV EF). We hypothesize that rTOF patients with predominant PS will have lower RV global longitudinal strain (RV GLS) prior to and post-transcatheter pulmonary valve replacement (TPVR). METHODS: A retrospective cohort of rTOF patients who underwent cardiac magnetic resonance (CMR) and cardiac catheterization for right ventricular pressure (RVSP) measurement were analyzed at three time points: before valve implantation, at discharge and within 18 months post-TPVR. Patients were dichotomized into three groups based on RVSP: 0%-49%, 50%-74%, and >75%. RV GLS and left ventricular (LV) GLS by speckle tracking echocardiography (STE) were obtained from the apical 4-chamber using TomTec software (TOMTEC IS, Germany). RESULTS: Forty-eight patients were included. Every 14.3% increase in preimplantation RVSP above 28% was associated with an absolute magnitude 1% lower RV GLS (p = .001). Preimplantation RVSP when 75% or higher had 3.36% worse RV GLS than the lowest bin (p = .014). Overall, average RV strain magnitude was higher when preimplantation RVSP was less than 50% and had greater improvement over the three time points. Higher post implantation RVSP correlated with lower strain magnitude. CONCLUSION: Patients with significant PS (>50%) may benefit from earlier PVR and not depend solely on RV size and EF. Myocardial strain may be a more sensitive marker of function; however, larger, prospective studies are needed.

Toxin-neutralizing Abs are associated with improved T cell function following recovery from Staphylococcus aureus infection.

BACKGROUNDT cell responses are impaired in Staphylococcus aureus-infected children, highlighting a potential mechanism of immune evasion. This study tested the hypotheses that toxin-specific antibodies protect immune cells from bacterial killing and are associated with improved T cell function following infection.METHODSS. aureus-infected and healthy children (N = 33 each) were prospectively enrolled. During acute infection and convalescence, we quantified toxin-specific IgG levels by ELISA, antibody function using a cell killing assay, and functional T cell responses by ELISPOT.RESULTSThere were no differences in toxin-specific IgG levels or ability to neutralize toxin-mediated immune cell killing between healthy and acutely infected children, but antibody levels and function increased following infection. Similarly, T cell function, which was impaired during acute infection, improved following infection. However, the response to infection was highly variable; up to half of children did not have improved antibody or T cell function. Serum from children with higher α-hemolysin-specific IgG levels more strongly protected immune cells against toxin-mediated killing. Importantly, children whose serum more strongly protected against toxin-mediated killing also had stronger immune responses to infection, characterized by more elicited antibodies and greater improvement in T cell function following infection.CONCLUSIONThis study demonstrates that, despite T cell impairment during acute infection, S. aureus elicits toxin-neutralizing antibodies. Individual antibody responses and T cell recovery are variable. These findings also suggest that toxin-neutralizing antibodies protect antigen-presenting cells and T cells, thereby promoting immune recovery. Finally, failure to elicit toxin-neutralizing antibodies may identify children at risk for prolonged T cell suppression.FUNDINGNIH National Institute of Allergy and Infectious Diseases R01AI125489 and Nationwide Children's Hospital.

Myeloid-derived suppressor cells and T cell populations in children with Multisystem Inflammatory Syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) represents a hyperinflammatory state that can result in multi-organ dysfunction and death. Myeloid-derived suppressor cells (MDSC) are an immunosuppressive cell population that expands under inflammatory conditions and suppresses T cell function. We hypothesized that MDSC would be increased in children with MIS-C and that MDSC expansion would be associated with T cell lymphopenia. METHODS: We conducted a prospective, observational study. Initial blood samples were collected within 48 h of admission. Age-matched healthy controls underwent sampling once. MDSC and T cell populations were identified by flow cytometric methods. RESULTS: We enrolled 22 children with MIS-C (12 ICU, 10 ward) and 21 healthy controls (HC). Children with MIS-C demonstrated significantly higher MDSC compared to HC, and MDSC expansion persisted for >3 weeks in the ICU group. Children with MIS-C admitted to the ICU demonstrated significantly lower absolute numbers of T cells and natural killer cells. There were no significant associations between MDSC and cardiac dysfunction, duration of hospitalization, or vasoactive inotrope score. CONCLUSIONS: Our study suggests that children critically ill with MIS-C have expansion of MDSC and associated decreased T cell and NK cell populations. Our results did not demonstrate associations between MDSC and clinical outcomes. IMPACT: Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated immune response occurring several weeks after SARS-CoV-2 infection that can result in multi-organ dysfunction and death. Children severely ill with MIS-C demonstrated increased myeloid-derived suppressor cells and decreased absolute numbers of CD4+ and CD8 + T cells and NK cells compared to healthy controls. There was no significant association between MDSC numbers and clinical outcomes; including cardiac dysfunction, length of stay, or requirement of vasoactive support, in children with MIS-C.

Quality Improvement to Eliminate Disparities in Developmental Screening for Patients Needing Interpreters.

Children from households with a preferred language other than English are less likely to receive timely identification and treatment for developmental delay than children of native English speakers. In dismantling this inequity, the role of primary care pediatrics is to establish equitable systems for screening and referral. This project, conducted in a network of twelve pediatric primary care centers, focused on eliminating a small but systematic disparity in developmental screening rates between families who did and did not require interpreters (86% versus 92%). The specific aim was to increase developmental screen completion among patients needing interpreters from 86% to 92% of age-appropriate well-child visits. Methods: Data were extracted from the electronic health record (EHR) to measure the proportion of 9-, 18-, 24-, and 30-month well-child visits at which developmental screens were completed, stratified by interpreter need (n = 31,461 visits; 7500 needing interpreters). One primary care center tested small changes to standardize processes, eliminate workarounds, and leverage EHR features using the Institute for Healthcare Improvement's Model for Improvement. The QI team plotted screen completion on control charts and spread successful changes to all 12 clinics. Statistical process control evaluated the significance of changes in screening rates. Results: For patients needing interpreters, screen completion rose across all clinics from 86% to 93% when the clinics implemented the new process. Screen completion for patients not needing interpreters remained at 92%. Conclusion: A standardized process supported by the EHR improved developmental screening among patients needing interpreters, eliminating disparities.

DEMOGRAPHICS TO DEFINE PEDIATRIC BURN PATIENTS AT RISK OF ADVERSE OUTCOMES.

ABSTRACT: Background: There is currently no standard definition of a severe burn in the pediatric patient population to identify those at higher risk of infectious complications. Our aim was to correlate total burn surface area (TBSA), burn depth, and type of burn injury to nosocomial infection rates and systemic immune system responses to better define risk factors associated with adverse outcomes. Methods: A prospective observational study at a single-center, quaternary-care, American Burn Association-verified pediatric burn center was conducted from 2016 to 2021. Blood was collected within 72 h of injury from 103 pediatric patients. Whole blood was incubated with lipopolysaccharide or phytohemagglutinin stimulation reagent to measure innate and adaptive immune response, respectively. Flow cytometry was performed on whole blood samples to measure both innate and adaptive immune cells. Unstimulated plasma was also extracted, and IL-6 and IL-10 as well as soluble proteins B- and T-lymphocyte attenuator, CD27, and T-cell immunoglobulin mucin 3 were quantified. Results: There was a significant increased risk for nosocomial infection in pediatric patients with TBSA burns of ≥20%, full-thickness burn injuries ≥5%, or flame burn injuries. There was an overall decrease in both innate and adaptive immune function in patients with TBSA burns ≥20% or full-thickness burn injuries ≥5%. Both burn injury characteristics were also associated with a significant increase in unstimulated IL-6 and IL-10 and soluble immunoregulatory checkpoint proteins. We observed a significant decrease in soluble B- and T-lymphocyte attenuator for those with a flame injury, but there were no other differences between flame injury and scald/contact burns in terms of innate and adaptive immune function. Conclusion: Burns with ≥20% TBSA or ≥5% full thickness in pediatric patients are associated with systemic immune dysfunction and increased risk of nosocomial infections.

Impact of Maternal-Fetal Environment on Outcomes Following the Hybrid Procedure in the Single Ventricle Population.

Treatment of infants with hypoplastic left heart syndrome (HLHS) remains challenging, and those affected remain with significant risks for mortality and morbidity throughout their lifetimes. The maternal-fetal environment (MFE) has been shown to affect outcomes for infants with HLHS after the Norwood procedure. The hybrid procedure, comprised of both catheterization and surgical components, is a less invasive option for initial intervention compared to the Norwood procedure. It is unknown how the MFE impacts outcomes following the hybrid procedure. This is a single-center, retrospective study of infants born with HLHS who underwent hybrid palliation from January 2009 to August 2021. Predictor variables analyzed included fetal, maternal, and postnatal factors. The primary outcome was mortality prior to Stage II palliation. We studied a 144-subject cohort. There was a statistically significant difference in mortality prior to stage II palliation in infants with prematurity, small for gestational age, and aortic atresia subtype (p < 0.001, p = 0.009, and p = 0.008, respectively). There was no difference in mortality associated with maternal diabetes, hypertension, obesity, smoking or illicit drug use, or advanced maternal age. State and national area deprivation index scores were associated with increased risk of mortality in the entire cohort, such that infants born in areas with higher deprivation had a higher incidence of mortality. Several markers of an impaired MFE, including prematurity, small for gestational age, and higher deprivation index scores, are associated with mortality following hybrid palliation. Individual maternal comorbidities were not associated with higher mortality. The MFE may be a target for prenatal counseling and future interventions to improve pregnancy and neonatal outcomes in this population.

Emergency Department Visits for Heat-Related Emergency Conditions in the United States from 2008-2020.

Exposure to high temperatures is detrimental to human health. As climate change is expected to increase the frequency of extreme heat events, and raise ambient temperatures, an investigation into the trend of heat-related emergency department (ED) visits over the past decade is necessary to assess the human health impact of this growing public health crisis. ED visits were examined using the Nationwide Emergency Department Sample. Visits were included if the diagnostic field contained an ICD-9-CM or ICD-10-CM code specific to heat-related emergency conditions. Weighted counts were generated using the study design and weighting variables, to estimate the national burden of heat-related ED visits. A total of 1,078,432 weighted visits were included in this study. The annual incidence rate per 100,000 population increased by an average of 2.85% per year, ranging from 18.21 in 2009, to 32.34 in 2018. The total visit burden was greatest in the South (51.55%), with visits increasing to the greatest degree in the Midwest (8.52%). ED visit volume was greatest in July (29.79%), with visits increasing to the greatest degree in July (15.59%) and March (13.18%). An overall increase in heat-related ED visits for heat-related emergency conditions was found during the past decade across the United States, affecting patients in all regions and during all seasons.

Early detection of soluble CD27, BTLA, and TIM-3 predicts the development of nosocomial infection in pediatric burn patients.

Thermal injury induces concurrent inflammatory and immune dysfunction, which is associated with adverse clinical outcomes. However, these effects in the pediatric population are less studied and there is no standard method to identify those at risk for developing infections. Our goal was to better understand immune dysfunction and identify soluble protein markers following pediatric thermal injury. Further we wanted to determine which early inflammatory, soluble, or immune function markers are most predictive of the development of nosocomial infections (NI) after burn injury. We performed a prospective observational study at a single American Burn Association-verified Pediatric Burn Center. A total of 94 pediatric burn subjects were enrolled and twenty-three of those subjects developed a NI with a median time to diagnosis of 8 days. Whole blood samples, collected within the first 72 hours after injury, were used to compare various markers of inflammation, immune function, and soluble proteins between those who recovered without developing an infection and those who developed a NI after burn injury. Within the first three days of burn injury, innate and adaptive immune function markers (ex vivo lipopolysaccharide-induced tumor necrosis factor alpha production capacity, and ex vivo phytohemagglutinin-induced interleukin-10 production capacity, respectively) were decreased for those subjects who developed a subsequent NI. Further analysis of soluble protein targets associated with these pathways displayed significant increases in soluble CD27, BTLA, and TIM-3 for those who developed a NI. Our findings indicate that suppression of both the innate and adaptive immune function occurs concurrently within the first 72 hours following pediatric thermal injury. At the same time, subjects who developed NI have increased soluble protein biomarkers. Soluble CD27, BTLA, and TIM-3 were highly predictive of the development of subsequent infectious complications. This study identifies early soluble protein makers that are predictive of infection in pediatric burn subjects. These findings should inform future immunomodulatory therapeutic studies.