Association of Neurodevelopmental Outcomes With Environmental Exposure to Cyclohexanone During Neonatal Congenital Cardiac Operations: A Secondary Analysis of a Randomized Clinical Trial

Allen D Everett, Jessie P Buckley, Greg Ellis, Jun Yang, David Graham, Megan Griffiths, Melania Bembea, Eric M Graham, Allen D Everett, Jessie P Buckley, Greg Ellis, Jun Yang, David Graham, Megan Griffiths, Melania Bembea, Eric M Graham

Abstract

Importance: Cyclohexanone is an industrial solvent used as a coupling agent in medical plastics. Perioperative exposure to cyclohexanone could play a role in lower scores on measures of neurodevelopmental outcomes after neonatal cardiac operations.

Objective: To examine the presence and association of serum cyclohexanone level with neonatal cardiac operations and neurodevelopmental outcomes.

Design, setting, and participants: This ad hoc secondary analysis used data from the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass randomized clinical trial. The cohort included neonates younger than 31 days and with at least 37 weeks postgestational age at surgical treatment who were enrolled at a single center between June 1, 2012, and October 31, 2016, and who had completed a neurodevelopmental assessment at age 12 months. Data were analyzed from July 8 to August 20, 2019.

Exposures: Serum cyclohexanone and its metabolites were measured preoperatively (prior to skin incision), postoperatively (immediately after the surgical procedure was completed), and 12 hours postoperatively. Cyclohexanone and the molar sum of its metabolites were examined at each point and as a geometric mean of all 3 points.

Main outcomes and measures: Neurodevelopment was assessed at age 12 months with the Bayley Scales of Infant and Toddler Development III, assessing cognitive, language, and motor function composite scores standardized to a population mean (SD) of 100 (15). Linear regression models were used to determine covariate-adjusted differences in 12-month cognitive, language, and motor composite scores per interquartile range increase in cyclohexanone level or summed metabolite molar concentrations.

Results: Among 85 included neonates, mean (SD) age at surgical treatment was 9.7 (5.3) days, 49 (58%) were boys, and 54 (64%) underwent corrective repair. Mean (SD) Bayley Scales of Infant and Toddler Development III composite scores were 108.2 (12.2) for cognitive function, 104.7 (11.0) for language function, and 94.7 (15.7) for motor function. Median (interquartile range) cyclohexanone levels increased approximately 3-fold from immediately prior to surgical treatment to immediately after surgical treatment (572 [389-974] vs 1744 [1469-2291] μg/L; P = .001). In adjusted analyses, higher geometric mean cyclohexanone levels were associated with significantly lower composite scores for cognitive (-4.23; 95% CI, -7.39 to -1.06; P = .01) and language (-3.65; 95% CI, -6.41 to -0.88; P = .01) function. The difference in composite scores for motor function among infants with higher geometric mean cyclohexanone levels was not statistically significant(-3.93, 95% CI: -8.19 to 0.33, P = .07).

Conclusions and relevance: The findings of this secondary analysis of a randomized clinical trial suggest that infants who underwent neonatal cardiac surgical treatment with cardiopulmonary bypass had substantial cyclohexanone levels, which were associated with adverse neurodevelopmental function at age 12 months.

Trial registration: ClinicalTrials.gov identifier: NCT01579513.

Conflict of interest statement

Conflict of Interest Disclosures: Dr E. Graham reported receiving personal fees from Bayer outside the submitted work. No other disclosures were reported.

Figures

Figure.. Parent Study Flow Chart
Figure.. Parent Study Flow Chart
ECMO indicates extracorporeal membrane oxygenation.

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