title: Circulating phthalates during critical illness in children are associated with long-term attention deficit: a study of a development and a validation cohort.
abstract: OBJECTIVE
  Environmental phthalate exposure has been associated with attention deficit disorders in children. We hypothesized that in children treated in the pediatric intensive care unit (PICU), circulating phthalates leaching from indwelling medical devices contribute to their long-term attention deficit.
  
  
  METHODS
  Circulating plasma concentrations of di(2-ethylhexyl)phthalate (DEHP) metabolites were quantified in 100 healthy children and 449 children who had been treated in PICU and were neurocognitively tested 4 years later. In a development patient cohort (N = 228), a multivariable bootstrap study identified stable thresholds of exposure to circulating DEHP metabolites above which there was an independent association with worse neurocognitive outcome. Subsequently, in a second patient cohort (N = 221), the observed independent associations were validated.
  
  
  RESULTS
  Plasma concentrations of DEHP metabolites, which were virtually undetectable [0.029 (0.027-0.031) µmol/l] in healthy children, were 4.41 (3.76-5.06) µmol/l in critically ill children upon PICU admission (P < 0.001). Plasma DEHP metabolite concentrations decreased rapidly but remained 18 times higher until PICU discharge (P < 0.001). After adjusting for baseline risk factors and duration of PICU stay, and further for PICU complications and treatments, exceeding the potentially harmful threshold for exposure to circulating DEHP metabolites was independently associated with the attention deficit (all P ≤ 0.008) and impaired motor coordination (all P ≤ 0.02). The association with the attention deficit was confirmed in the validation cohort (all P ≤ 0.01). This phthalate exposure effect explained half of the attention deficit in post-PICU patients.
  
  
  CONCLUSIONS
  Iatrogenic exposure to DEHP metabolites during intensive care was independently and robustly associated with the important attention deficit observed in children 4 years after critical illness. Clinicaltrials.gov identifier: NCT00214916.
authors.affiliation: Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Verstraete
authors.affiliation: Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Vanhorebeek
authors.affiliation: Toxicology Center, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Covaci
authors.affiliation: Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Güiza
authors.affiliation: Toxicology Center, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Malarvannan
authors.affiliation: Toxicology Center, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.|Department of Critical Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium.
authors.forename: P G
authors.initials: PG
authors.lastname: Jorens
authors.affiliation: Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. greet.vandenberghe@med.kuleuven.be.
authors.forename: G
authors.initials: G
authors.lastname: Van den Berghe
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000139:chemically induced*; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015278:Intensive Care Units, Pediatric; D008297:Male; D010795:Phthalic Acids / Q000097:blood* / Q000633:toxicity*; D019736:Prostheses and Implants; D012307:Risk Factors
chemical_list: D010795:Phthalic Acids; C032279:phthalic acid
keywords: Attention; Critical illness; Neurocognitive development; PICU; Phthalate; Plasticizers; Sepsis