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Circulating phthalates during critical illness in children are associated with long-term attention deficit: a study
S Verstraete1, I Vanhorebeek1, A Covaci2
1Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
Insights
Pediatric intensive care unit (PICU) patients exposed to di(2-ethylhexyl)phthalate (DEHP) metabolites from medical devices showed long-term attention deficits. This phthalate exposure explained half of the attention deficit in children 4 years after critical illness.
Area of Science:
- Environmental Health
- Pediatric Critical Care
- Neurodevelopmental Disorders
Background:
- Environmental phthalate exposure is linked to childhood attention deficits.
- Children in the pediatric intensive care unit (PICU) are exposed to phthalates from medical devices.
- The long-term neurocognitive effects of this exposure in critically ill children are not well understood.
Purpose of the Study:
- To investigate if circulating phthalates, specifically di(2-ethylhexyl)phthalate (DEHP) metabolites, leaching from medical devices contribute to long-term attention deficits in children treated in the PICU.
- To identify exposure thresholds associated with adverse neurocognitive outcomes.
Main Methods:
- Quantified plasma concentrations of DEHP metabolites in healthy children and children treated in the PICU.
- Neurocognitive testing was performed 4 years after PICU treatment.
- Multivariable bootstrap analysis identified exposure thresholds in a development cohort and validated findings in a second cohort.
Main Results:
- Plasma DEHP metabolite concentrations were significantly higher in critically ill children upon PICU admission and remained elevated until discharge compared to healthy children.
- Exceeding harmful DEHP metabolite exposure thresholds was independently associated with attention deficit and impaired motor coordination, even after adjusting for baseline risk factors and PICU treatments.
- The association with attention deficit was confirmed in a validation cohort, with phthalate exposure explaining half of the observed attention deficit.
Conclusions:
- Iatrogenic exposure to DEHP metabolites during intensive care is independently and robustly associated with significant attention deficits in children 4 years post-critical illness.
- Findings highlight a potential environmental contributor to neurodevelopmental issues in post-PICU patients.
- Clinicaltrials.gov identifier: NCT00214916.
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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