Delirium and Mortality in Critically Ill Children: Epidemiology and Outcomes of Pediatric Delirium.

OBJECTIVES: Delirium occurs frequently in adults and is an independent predictor of mortality. However, the epidemiology and outcomes of pediatric delirium are not well-characterized. The primary objectives of this study were to describe the frequency of delirium in critically ill children, its duration, associated risk factors, and effect on in-hospital outcomes, including mortality. Secondary objectives included determination of delirium subtype, and effect of delirium on duration of mechanical ventilation, and length of hospital stay. DESIGN: Prospective, longitudinal cohort study. SETTING: Urban academic tertiary care PICU. PATIENTS: All consecutive admissions from September 2014 through August 2015. INTERVENTIONS: Children were screened for delirium twice daily throughout their ICU stay. MEASUREMENTS AND MAIN RESULTS: Of 1,547 consecutive patients, delirium was diagnosed in 267 (17%) and lasted a median of 2 days (interquartile range, 1-5). Seventy-eight percent of children with delirium developed it within the first 3 PICU days. Most cases of delirium were of the hypoactive (46%) and mixed (45%) subtypes; only 8% of delirium episodes were characterized as hyperactive delirium. In multivariable analysis, independent predictors of delirium included age less than or equal to 2 years old, developmental delay, severity of illness, prior coma, mechanical ventilation, and receipt of benzodiazepines and anticholinergics. PICU length of stay was increased in children with delirium (adjusted relative length of stay, 2.3; CI = 2.1-2.5; p < 0.001), as was duration of mechanical ventilation (median, 4 vs 1 d; p < 0.001). Delirium was a strong and independent predictor of mortality (adjusted odds ratio, 4.39; CI = 1.96-9.99; p < 0.001). CONCLUSIONS: Delirium occurs frequently in critically ill children and is independently associated with mortality. Some in-hospital risk factors for delirium development are modifiable. Interventional studies are needed to determine best practices to limit delirium exposure in at-risk children.

Cost Associated With Pediatric Delirium in the ICU.

OBJECTIVE: To determine the costs associated with delirium in critically ill children. DESIGN: Prospective observational study. SETTING: An urban, academic, tertiary-care PICU in New York city. PATIENTS: Four-hundred and sixty-four consecutive PICU admissions between September 2, 2014, and December 12, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All children were assessed for delirium daily throughout their PICU stay. Hospital costs were analyzed using cost-to-charge ratios, in 2014 dollars. Median total PICU costs were higher in patients with delirium than in patients who were never delirious ($18,832 vs $4,803; p < 0.0001). Costs increased incrementally with number of days spent delirious (median cost of $9,173 for 1 d with delirium, $19,682 for 2-3 d with delirium, and $75,833 for > 3 d with delirium; p < 0.0001); this remained highly significant even after adjusting for PICU length of stay (p < 0.0001). After controlling for age, gender, severity of illness, and PICU length of stay, delirium was associated with an 85% increase in PICU costs (p < 0.0001). CONCLUSIONS: Pediatric delirium is associated with a major increase in PICU costs. Further research directed at prevention and treatment of pediatric delirium is essential to improve outcomes in this population and could lead to substantial healthcare savings.

Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components.

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of the copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, the molecular mechanisms by which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes in animal models are highly dependent on transgene dosage. Thus, issues of whether the ALS-like phenotypes of these models stem from overexpression of mutant alleles or from aspects of the SOD1 mutation itself are not easily deconvolved. To address concerns about levels of mutant SOD1 in disease pathogenesis, we have genetically engineered four human ALS-causing SOD1 point mutations (G37R, H48R, H71Y, and G85R) into the endogenous locus of Drosophila SOD1 (dsod) via ends-out homologous recombination and analyzed the resulting molecular, biochemical, and behavioral phenotypes. Contrary to previous transgenic models, we have recapitulated ALS-like phenotypes without overexpression of the mutant protein. Drosophila carrying homozygous mutations rendering SOD1 protein enzymatically inactive (G85R, H48R, and H71Y) exhibited neurodegeneration, locomotor deficits, and shortened life span. The mutation retaining enzymatic activity (G37R) was phenotypically indistinguishable from controls. While the observed mutant dsod phenotypes were recessive, a gain-of-function component was uncovered through dosage studies and comparisons with age-matched dsod null animals, which failed to show severe locomotor defects or nerve degeneration. We conclude that the Drosophila knock-in model captures important aspects of human SOD1-based ALS and provides a powerful and useful tool for further genetic studies.

Validity of the Richmond Agitation-Sedation Scale (RASS) in critically ill children.

BACKGROUND: The Richmond Agitation-Sedation Scale (RASS) is a single tool that is intuitive, is easy to use, and includes both agitation and sedation. The RASS has never been formally validated for pediatric populations. The objective of this study was to assess inter-rater agreement and criterion validity of the RASS in critically ill children. METHODS: To evaluate validity, the RASS score was compared to both a visual analog scale (VAS) scored by the patient's nurse, and the University of Michigan Sedation Scale (UMSS), performed by a researcher. The nurse completed the VAS by drawing a single line on a 10-cm scale anchored by "unresponsive" and "combative." The UMSS was used to validate the sedation portion of the RASS only, as it does not include grades of agitation. For inter-rater agreement, one researcher and the patient's nurse simultaneously but independently scored the RASS. RESULTS: One hundred patient encounters were obtained from 50 unique patients, ages 2 months to 21 years. Of these, 27 assessments were on children who were mechanically ventilated and 73 were on children who were spontaneously breathing. In validity testing, the RASS was highly correlated with the nurse's VAS (Spearman correlation coefficient 0.810, p < .0001) and with the UMSS (weighted kappa 0.902, p < .0001). Inter-rater agreement between nurse- and researcher-assessed RASS was excellent, with weighted kappa of 0.825 (p < .0001). CONCLUSIONS: The RASS is a valid responsiveness tool for use in critically ill children. It allows for accurate assessment of awareness in mechanically ventilated and spontaneously breathing patients, and may improve our ability to titrate sedatives and assess for delirium in pediatrics.