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Circulating phthalates during critical illness in children are associated with long-term attention deficit: a study of a development and a validation cohort

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Abstract

Purpose

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.

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Acknowledgments

This work was supported by the Research Foundation-Flanders (FWO), Belgium (FWO fellowship to SV); by the Methusalem program of the Flemish government (through the University of Leuven to GVdB, METH/08/07 and to GVdB and IV, METH14/06); by an ERC Advanced Grant (AdvG-2012-321670) from the Ideas Program of the European Union 7th framework program to GVdB; and by the Institute for Science and Technology, Flanders, Belgium (through the University of Leuven to GVdB, IWT/070695/TBM).

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    Authors and Affiliations

    1. Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium

      S. Verstraete, I. Vanhorebeek, F. Güiza & G. Van den Berghe

    2. Toxicology Center, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

      A. Covaci, G. Malarvannan & P. G. Jorens

    3. Department of Critical Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium

      P. G. Jorens

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    1. S. Verstraete
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    Correspondence to G. Van den Berghe.

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    Additional information

    S. Verstraete and I. Vanhorebeek have contributed equally to this article.

    Take-home message: Critically ill children have very high circulating levels of phthalate metabolites, explained by leaching indwelling medical devices, and these high levels are independently associated with the important attention deficit observed 4 years later.

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    Verstraete, S., Vanhorebeek, I., Covaci, A. et al. Circulating phthalates during critical illness in children are associated with long-term attention deficit: a study of a development and a validation cohort. Intensive Care Med 42, 379–392 (2016). https://doi.org/10.1007/s00134-015-4159-5

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