Racial/Ethnic Minority Children With Cancer Experience Higher Mortality on Admission to the ICU in the United States.

OBJECTIVE: We investigated whether differences in survival exist between children of various racial/ethnic groups with cancer admitted to the PICU. DESIGN: A retrospective multicenter analysis was conducted using Virtual Pediatric Systems data from reporting centers. Demographic information, Pediatric Risk for Mortality III score, and outcome variables were analyzed using mixed-effects logistic regression modeling to assess for differences in mortality. SETTING: One hundred thirty-five PICUs in the United States. PATIENTS: Pediatric patients with cancer admitted to PICUs in the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study details the analysis of 23,128 PICU admissions of 12,232 unique oncology patients representing 3% of all PICU admissions with 1,610 deaths (7.0% case fatality). African American (8.5%) and Hispanic children (8.1%) had significantly higher mortality (p < 0.05) compared with Caucasian children (6.3%). Regional analysis showed Hispanic patients to have higher mortality in the West in the United States, whereas African American patients in the South in the United States had higher mortality. A pulmonary disease diagnosis in Hispanics increased odds of mortality (odds ratio, 1.39; 95% CI, 1.13-1.70), whereas a diagnosis of shock/sepsis increased risk for mortality in African Americans (odds ratio, 1.56; 95% CI, 1.11-2.20) compared with Caucasians. There were no differences between races/ethnic groups in the rates of limitations of care. After controlling for Pediatric Risk of Mortality III, PICU length of stay, stem cell transplant status, readmissions, cancer type (solid, brain, hematologic), mechanical ventilation days, and sex, Hispanic (odds ratio, 1.24; 95% CI, 1.05-1.47) and African Americans (odds ratio, 1.37; 95% CI, 1.14-1.66) had significantly higher odds of mortality compared with Caucasians. CONCLUSIONS: The results show that after controlling for severity and cancer type, a child's race, ethnicity, and region of presentation influence mortality in the PICU. This suggests that additional investigation is warranted along with a need to rethink our approach to the evaluation and treatment of critically ill African American and Hispanic children with cancer.

Linguistic isolation correlates with length of stay and mortality for pediatric oncology patients in California.

OBJECTIVE: To evaluate social drivers of health and how they impact pediatric oncology patients' clinical outcomes during pediatric intensive care unit (PICU) admission via correlation with patient ZIP codes. METHODS: Demographic, clinical, and outcome variables from Virtual Pediatric Systems®, LLC for oncology patients (2009-2021) in California PICUs (excluding postoperative) using 3-digit ZIP Codes with social drivers of health variables linguistic isolation, poverty, race/ethnicity, and education abstracted from American Community Survey data for 3-digit ZIP Codes using the Environmental Protection Agency's EJScreen tool. Outcomes of length of stay (LOS), mortality, acuity scores, were compared with social variables. RESULTS: Positive correlation between mortality and minority racial groups (Hispanic/Latino) across ZIP Codes (correlation coefficients of 0.45 (95% CI: 0.22-0.64, p < 0.001) in 2017, 0.50 (95% CI: 0.27-0.68, p < 0.001) in 2018, 0.33 (95% CI: 0.07-0.54, p = 0.013) in 2020, and 0.32 (95% CI: 0.06-0.53, p = 0.018) in 2021). Median PICU length of stay significantly correlated with linguistic isolation (coefficient of 0.42 (95% CI: 0.18-0.61, p = 0.001) in 2021 versus -0.41 (95% CI: -0.61 to -0.16, p = 0.002) in 2019), which included PRISMIII (n = 7417). Mixed effects logistic regression model for other constant variables (PRISMIII, cancer type, race/ethnicity, year), random effect of patient, linguistic isolation (percentage as a continuous value) was significantly associated (95% CI: 1.01-1.06; p = 0.02) with mortality; (OR = 1.03). CONCLUSIONS: Linguistic isolation was correlated with LOS and mortality, however variable year to year.

Etiology of hospital mortality in children living in low- and middle-income countries: a systematic review and meta-analysis.

In 2019, 80% of the 7.4 million global child deaths occurred in low- and middle-income countries (LMICs). Global and regional estimates of cause of hospital death and admission in LMIC children are needed to guide global and local priority setting and resource allocation but are currently lacking. The study objective was to estimate global and regional prevalence for common causes of pediatric hospital mortality and admission in LMICs. We performed a systematic review and meta-analysis to identify LMIC observational studies published January 1, 2005-February 26, 2021. Eligible studies included: a general pediatric admission population, a cause of admission or death, and total admissions. We excluded studies with data before 2,000 or without a full text. Two authors independently screened and extracted data. We performed methodological assessment using domains adapted from the Quality in Prognosis Studies tool. Data were pooled using random-effects models where possible. We reported prevalence as a proportion of cause of death or admission per 1,000 admissions with 95% confidence intervals (95% CI). Our search identified 29,637 texts. After duplicate removal and screening, we analyzed 253 studies representing 21.8 million pediatric hospitalizations in 59 LMICs. All-cause pediatric hospital mortality was 4.1% [95% CI 3.4%-4.7%]. The most common causes of mortality (deaths/1,000 admissions) were infectious [12 (95% CI 9-14)]; respiratory [9 (95% CI 5-13)]; and gastrointestinal [9 (95% CI 6-11)]. Common causes of admission (cases/1,000 admissions) were respiratory [255 (95% CI 231-280)]; infectious [214 (95% CI 193-234)]; and gastrointestinal [166 (95% CI 143-190)]. We observed regional variation in estimates. Pediatric hospital mortality remains high in LMICs. Global child health efforts must include measures to reduce hospital mortality including basic emergency and critical care services tailored to the local disease burden. Resources are urgently needed to promote equity in child health research, support researchers, and collect high-quality data in LMICs to further guide priority setting and resource allocation.

Daily Nutritional Intake of Pediatric Patients (N = 64) on Extracorporeal Membrane Oxygenation from 2018 to 2022: A Single-Center Report.

Nutrition in pediatric populations who require life-saving extracorporeal membrane oxygenation (ECMO) remains a debate. We sought to identify if nutritional needs were met in a patient cohort. A retrospective chart review of patients (N = 64) requiring ECMO at Helen DeVos Children's Hospital between 2018 and 2022 was evaluated for demographics, daily nutritional data, laboratory values, ECMO complications, and outcome data, with primary outcome measures of percent protein and percent caloric intake. Secondary outcome measures included the intensive care unit length of stay, time on ECMO, mortality, and day 1 severity of illness scores (Pediatric Logistic Organ Dysfunction). The timeline partially overlapped with the COVID-19 pandemic. Data were collected for 467 ECMO days with a median age of 2.6 months; 57.8% of patients were male and 65.6% were with one pre-existing comorbidity. Venoarterial (VA) ECMO was utilized in 84.4% of patients; the ECMO indication was cardiac in 53.1% of patients. The 28-day mortality was 43.8%. The proportion of days in which the caloric goal was met was 0%; the proportion of days in which protein goals were met was 33.3%. Non-cardiac ECMO patients had a greater number of days where caloric goals were met (p-value = 0.04). Mortality at 28 days was not statistically significant (p-value = 0.28) for calories or protein administered. The patient cohort struggled to meet calorie and protein goals while on ECMO.

Combined Plasma and Urinary Metabolomics Uncover Metabolic Perturbations Associated with Severe Respiratory Syncytial Viral Infection and Future Development of Asthma in Infant Patients.

A large percentage of infants develop viral bronchiolitis needing medical intervention and often develop further airway disease such as asthma. To characterize metabolic perturbations in acute respiratory syncytial viral (RSV) bronchiolitis, we compared metabolomic profiles of moderate and severe RSV patients versus sedation controls. RSV patients were classified as moderate or severe based on the need for invasive mechanical ventilation. Whole blood and urine samples were collected at two time points (baseline and 72 h). Plasma and urinary metabolites were extracted in cold methanol and analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), and data from the two biofluids were combined for multivariate data analysis. Metabolite profiles were clustered according to severity, characterized by unique metabolic changes in both plasma and urine. Plasma metabolites that correlated with severity included intermediates in the sialic acid biosynthesis, while urinary metabolites included citrate as well as multiple nucleotides. Furthermore, metabolomic profiles were predictive of future development of asthma, with urinary metabolites exhibiting higher predictive power than plasma. These metabolites may offer unique insights into the pathology of RSV bronchiolitis and may be useful in identifying patients at risk for developing asthma.

Loss of Health Promoting Bacteria in the Gastrointestinal Microbiome of PICU Infants with Bronchiolitis: A Single-Center Feasibility Study.

The feasibility of gastrointestinal (GI) microbiome work in a pediatric intensive care unit (PICU) to determine the GI microbiota composition of infants as compared to control infants from the same hospital was investigated. In a single-site observational study at an urban quaternary care children's hospital in Western Michigan, subjects less than 6 months of age, admitted to the PICU with severe respiratory syncytial virus (RSV) bronchiolitis, were compared to similarly aged control subjects undergoing procedural sedation in the outpatient department. GI microbiome samples were collected at admission (n = 20) and 72 h (n = 19) or at time of sedation (n = 10). GI bacteria were analyzed by sequencing the V4 region of the 16S rRNA gene. Alpha and beta diversity were calculated. Mechanical ventilation was required for the majority (n = 14) of study patients, and antibiotics were given at baseline (n = 8) and 72 h (n = 9). Control subjects' bacterial communities contained more Porphyromonas, and Prevotella (p = 0.004) than those of PICU infants. The ratio of Prevotella to Bacteroides was greater in the control than the RSV infants (mean ± SD-1.27 ± 0.85 vs. 0.61 ± 0.75: p = 0.03). Bacterial communities of PICU infants were less diverse than those of controls with a loss of potentially protective populations.

The Burden of Critical Illness in Hospitalized Children in Low- and Middle-Income Countries: Protocol for a Systematic Review and Meta-Analysis.

Background: The majority of childhood deaths occur in low- and middle-income countries (LMICs). Many of these deaths are avoidable with basic critical care interventions. Quantifying the burden of pediatric critical illness in LMICs is essential for targeting interventions to reduce childhood mortality. Objective: To determine the burden of hospitalization and mortality associated with acute pediatric critical illness in LMICs through a systematic review and meta-analysis of the literature. Data Sources and Search Strategy: We will identify eligible studies by searching MEDLINE, EMBASE, CINAHL, and LILACS using MeSH terms and keywords. Results will be limited to infants or children (ages >28 days to 12 years) hospitalized in LMICs and publications in English, Spanish, or French. Publications with non-original data (e.g., comments, editorials, letters, notes, conference materials) will be excluded. Study Selection: We will include observational studies published since January 1, 2005, that meet all eligibility criteria and for which a full text can be located. Data Extraction: Data extraction will include information related to study characteristics, hospital characteristics, underlying population characteristics, patient population characteristics, and outcomes. Data Synthesis: We will extract and report data on study, hospital, and patient characteristics; outcomes; and risk of bias. We will report the causes of admission and mortality by region, country income level, and age. We will report or calculate the case fatality rate (CFR) for each diagnosis when data allow. Conclusions: By understanding the burden of pediatric critical illness in LMICs, we can advocate for resources and inform resource allocation and investment decisions to improve the management and outcomes of children with acute pediatric critical illness in LMICs.

Understanding Suicide in Our Community through the Lens of the Pediatric ICU: An Epidemiological Review (2011-2017) of One Midwestern City in the US.

Suicide frequency has tripled for some pediatric age groups over the last decade, of which, serious attempts result in pediatric intensive care unit (PICU) admissions. We paired clinical, aggregate geospatial, and temporal demographics to understand local community variables to determine if epidemiological patterns emerge that associate with risk for PICU admission. Data were extracted at an urban, high-volume, quaternary care facility from January 2011 to December 2017 via ICD 10 codes associated with suicide. Clinical, socioeconomic, geographical, and temporal variables were reviewed. In total, 1036 patients over the age of 9 were included, of which n = 161 were PICU admissions. Females represented higher proportions of all suicide-related hospital admissions (67.9%). Looking at race/ethnicity, PICU admissions were largely Caucasian (83.2%); Blacks and Hispanics had lower odds of PICU admissions (OR: 0.49; 0.17, respectively). PICU-admitted patients were older (16.0 vs. 15.5; p = 0.0001), with lower basal metabolic index (23.0 vs. 22.0; p = 0.0013), and presented in summer months (OR: 1.51, p = 0.044). Time-series decomposition showed seasonal peaks in June and August. Local regions outside the city limits identified higher numbers of PICU admissions. PICUs serve discrete geographical regions and are a source of information, when paired with clinical geospatial/seasonal analyses, highlighting clinical and societal risk factors associated with PICU admissions.

Pediatric Multi-Organ Dysfunction Syndrome: Analysis by an Untargeted "Shotgun" Lipidomic Approach Reveals Low-Abundance Plasma Phospholipids and Dynamic Recovery over 8-Day Period, a Single-Center Observational Study.

Lipids are molecules involved in metabolism and inflammation. This study investigates the plasma lipidome for markers of severity and nutritional status in critically ill children. Children with multi-organ dysfunction syndrome (MODS) (n = 24) are analyzed at three time-points and cross-referenced to sedation controls (n = 4) for a total of N = 28. Eight of the patients with MODS, needed veno-arterial extracorporeal membrane oxygenation (VA ECMO) support to survive. Blood plasma lipid profiles are quantified by nano-electrospray (nESI), direct infusion high resolution/accurate mass spectrometry (MS), and tandem mass spectrometry (MS/MS), and compared to nutritional profiles and pediatric logistic organ dysfunction (PELOD) scores. Our results show that PELOD scores were not significantly different between MODS and ECMO cases across time-points (p = 0.66). Lipid profiling provides stratification between sedation controls and all MODS patients for total lysophosphatidylserine (lysoPS) (p-value = 0.004), total phosphatidylserine (PS) (p-value = 0.015), and total ether-linked phosphatidylethanolamine (ether-PE) (p-value = 0.03) after adjusting for sex and age. Nutrition intake over time did not correlate with changes in lipid profiles, as measured by caloric and protein intake. Lipid measurement in the intensive care environment shows dynamic changes over an 8-day pediatric intensive care unit (PICU) course, suggesting novel metabolic indicators for defining critically ill children.

Hexosylceramides and Glycerophosphatidylcholine GPC(36:1) Increase in Multi-Organ Dysfunction Syndrome Patients with Pediatric Intensive Care Unit Admission over 8-Day Hospitalization.

Glycero- and sphingo-lipids are important in plasma membrane structure, caloric storage and signaling. An un-targeted lipidomics approach for a cohort of critically ill pediatric intensive care unit (PICU) patients undergoing multi-organ dysfunction syndrome (MODS) was compared to sedation controls. After IRB approval, patients meeting the criteria for MODS were screened, consented (n = 24), and blood samples were collected from the PICU at HDVCH, Michigan; eight patients needed veno-arterial extracorporeal membrane oxygenation (VA ECMO). Sedation controls were presenting for routine sedation (n = 4). Plasma lipid profiles were determined by nano-electrospray (nESI) direct infusion high resolution/accurate mass spectrometry (MS) and tandem mass spectrometry (MS/MS). Biostatistics analysis was performed using R v 3.6.0. Sixty-one patient samples over three time points revealed a ceramide metabolite, hexosylceramide (Hex-Cer) was high across all time points (mean 1.63-3.19%; vs. controls 0.22%). Fourteen species statistically differentiated from sedation controls (p-value ≤ 0.05); sphingomyelin (SM) [SM(d18:1/23:0), SM(d18:1/22:0), SM(d18:1/23:1), SM(d18:1/21:0), SM(d18:1/24:0)]; and glycerophosphotidylcholine (GPC) [GPC(36:01), GPC(18:00), GPC(O:34:02), GPC(18:02), GPC(38:05), GPC(O:34:03), GPC(16:00), GPC(40:05), GPC(O:36:03)]. Hex-Cer has been shown to be involved in viral infection and may be at play during acute illness. GPC(36:01) was elevated in all MODS patients at all time points and is associated with inflammation and brain injury.

The Feasibility of Studying Metabolites in PICU Multi-Organ Dysfunction Syndrome Patients over an 8-Day Course Using an Untargeted Approach.

Metabolites are generated from critical biological functions and metabolism. This pediatric study reviewed plasma metabolites in patients suffering from multi-organ dysfunction syndrome (MODS) in the pediatric intensive care unit (PICU) using an untargeted metabolomics approach. Patients meeting the criteria for MODS were screened for eligibility and consented (n = 24), and blood samples were collected at baseline, 72 h, and 8 days; control patients (n = 4) presented for routine sedation in an outpatient setting. A subset of MODS patients (n = 8) required additional support with veno-atrial extracorporeal membrane oxygenation (VA-ECMO) therapy. Metabolites from thawed blood plasma were determined from ion pairing reversed-phase liquid chromatography-mass spectrometry (LC-MS) analysis. Chromatographic peak alignment, identification, relative quantitation, and statistical and bioinformatics evaluation were performed using MAVEN and MetaboAnalyst 4.0. Metabolite analysis revealed 115 peaks per sample. From the partial least squares-discriminant analysis (PLS-DA) with variance of importance (VIP) scores above ≥2.0, 7 dynamic metabolites emerged over the three time points: tauro-chenodeoxycholic acid (TCDCA), hexose, p-hydroxybenzoate, hydroxyphenylacetic acid (HPLA), 2_3-dihydroxybenzoic acid, 2-keto-isovalerate, and deoxyribose phosphate. After Bonferroni adjustment for repeated measures, hexose and p-hydroxybenzoate were significant at one time point or more. Kendall's tau-b test was used for internal validation of creatinine. Metabolites may be benign or significant in describing a patient's pathophysiology and require operator interpretation.

Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.

Background: Polyamine levels are intricately controlled by biosynthetic, catabolic enzymes and antizymes. The complexity suggests that minute alterations in levels lead to profound abnormalities. We described the therapeutic course for a rare syndrome diagnosed by whole exome sequencing caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC), characterized by neurological deficits and alopecia. Methods: N-acetylputrescine levels with other metabolites were measured using ultra-performance liquid chromatography paired with mass spectrometry and Z-scores established against a reference cohort of 866 children. Results: From previous studies and metabolic profiles, eflornithine was identified as potentially beneficial with therapy initiated on FDA approval. Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support. Conclusions: This work highlights the strategy of repurposing drugs to treat a rare disease. Funding: No external funding was received for this work.

Preadmission Diet and Zip Code Influences the Pediatric Critical Care Clinical Course for Infants with Severe Respiratory Illness ( N = 187).

We examined preadmission diet and zip code in infants with severe respiratory illness in the pediatric critical care unit. Patients aged 0 to 5 months admitted to the Helen DeVos Children's Hospital from January 2011 to May 2017 ( N = 187), as exclusively formula, exclusively breastfed or mixed diet were included. Formula-fed infants ( n = 88; 47%) clustered to zip codes with lower median incomes (<0.005), used public insurance as their payer type ( p < 0.005), and were prescribed more ranitidine ( p < 0.05) on admission.