Delirium is a frequent, serious, and preventable complication in critically ill children. Inflammation has been implicated as a mechanism for the development of delirium. Platelet transfusions may potentiate the body’s pro-inflammatory responses. We hypothesized that receipt of platelets would be associated with delirium development in a pediatric intensive care unit (PICU). We performed a single-center retrospective cohort analysis including children admitted to the PICU between 2014 and 2018 who were transfused platelets within the first 14 days of admission. Data obtained included severity of illness, level of respiratory support, exposure to medications and blood products, as well as daily cognitive status. To account for time-dependent confounding, a marginal structural model (MSM) was constructed to delineate the relationship between platelet transfusion and next-day delirium. MSM demonstrated a 75% increase in the development of next-day delirium after transfusion of platelets (aOR 1.75, 95% CI 1.03–2.97). For every 1 cc/kg of platelet transfused, odds of next-day delirium increased by 9% (odds ratio 1.09, 95% CI 1.03–1.51). We reported an independent association between platelet transfusion and next-day delirium/coma after accounting for time-dependent confounders, with a dose–response effect. Minimizing platelet transfusions as much as clinically feasible may decrease delirium risk in critically ill children.

No abstract

ImportanceDiagnostic genetic testing can lead to changes in management in the pediatric intensive care unit. Genetic risk in children with critical illness but nondiagnostic exome sequencing (ES) has not been explored.ObjectiveTo assess the association between loss-of-function (LOF) variants and pediatric critical illness.Design, Setting, and ParticipantsThis genetic association study examined ES first screened for causative variants among 267 children at the Morgan Stanley Children’s Hospital of NewYork-Presbyterian, of whom 22 were otherwise healthy with viral respiratory failure; 18 deceased children with bronchiolitis from the Office of the Chief Medical Examiner of New York City, of whom 14 were previously healthy; and 9990 controls from the Institute for Genomic Medicine at Columbia University Irving Medical Center. The ES data were generated between January 1, 2015, and December 31, 2020, and analyzed between January 1, 2017, and September 2, 2022.ExposureCritical illness.Main Outcomes and MeasuresOdds ratios and P values for genes and gene-sets enriched for rare LOF variants and the loss-of-function observed/expected upper bound fraction (LOEUF) score at which cases have a significant enrichment.ResultsThis study included 285 children with critical illness (median [range] age, 4.1 [0-18.9] years; 148 [52%] male) and 9990 controls. A total of 228 children (80%) did not receive a genetic diagnosis. After quality control (QC), 231 children harbored excess rare LOF variants in genes with a LOEUF score of 0.680 or less (intolerant genes) (P = 1.0 × 10−5). After QC, 176 children without a diagnosis harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 1.8; 95% CI, 1.3-2.5). After QC, 25 children with viral respiratory failure harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 2.8; 95% CI, 1.1-6.6). A total of 114 undiagnosed children were enriched for de novo LOF variants in genes without a known disease association (observed, 14; expected, 6.8; enrichment, 2.05).Conclusions and RelevanceIn this genetic association study, excess LOF variants were observed among critically ill children despite nondiagnostic ES. Variants lay in genes without a known disease association, suggesting future investigation may connect phenotypes to causative genes.

Rapid genetic sequencing is an established and important clinical tool for management of pediatric critical illness. The burden of risk variants in children with critical illness but a non–diagnostic exome has not been explored. This was a retrospective case–control analysis of research whole exome sequencing data that first underwent a diagnostic pipeline to assess the association of rare loss–of–function variants with critical illness in children with diagnostic and non-diagnostic whole exome sequencing including those with virally mediated respiratory failure. Using a gene–based collapsing approach, the odds of a child with critical illness carrying rare loss–of–function variants were compared to controls. A subset of children with virally mediated respiratory failure was also compared to controls. Cases were drawn from the general pediatric ward and pediatric intensive care unit (PICU) at Morgan Stanley Childrens Hospital of NewYork–Presbyterian (MSCH) – Columbia University Irving Medical Center (CUIMC) and from the Office of the Chief Medical Examiner (OCME) of New York City. Of the 285 enrolled patients, 228 did not receive a diagnosis from WES. After quality control filtering and geographic ancestry matching, an analysis of 232 children with critical illness compared to 5,322 healthy and unrelated controls determined cases to harbor more predicted loss–of–function (pLOFs) in genes with a LOEUF score ≤ 0.680 (p–value = 1.0 x 10–5). After quality control and geographic ancestry matching, a subset of 176 children without a genetic diagnosis compared to 5,180 controls harbored pLOFs in genes without a disease association (OR 1.7, CI [1.2 – 2.3], FDR adjusted p–value = 4.4 x 10–3) but not in genes with a disease association (OR 1.2, CI [0.8 – 1.7], FDR adjusted p–value = 0.40). This enrichment primarily existed among ultra–rare variants not found in public data sets. Among a subset of 25 previously healthy children with virally mediated respiratory failure compared to 2,973 controls after quality control and geographic ancestry matching, cases harbored more variants than controls in genes without a disease association at the same LOEUF threshold ≤ 0.680 (OR 2.8, CI [1.2 – 7.2], FDR adjusted p–value = 0.026) but not in genes with a disease association (OR 0.7, CI [0.2 – 2.2], FDR adjusted p–value = 0.84). Finally, children with critical illness for whom whole exome sequencing data from both biological parents were available, we found an enrichment of de novo pLOF variants in genes without a disease association among 114 children without a genetic diagnosis (unadjusted p–value < 0.05) but not among 46 children with a genetic diagnosis. Children with critical illness and non–diagnostic whole exome sequencing may still carry risk variants for their clinical presentation in genes not previously associated with disease.