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  • Clinical Research Article
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Cyclohexanone and metabolites exposure in critically Ill neonates and children

Pediatric Research (2025)Cite this article

Abstract

Background

Cyclohexanone is a volatile organic compound known to be toxic to humans and animals, used in the medical setting as a solvent sealer for intravenous (IV) fluid administration devices. We aimed to determine exposure sources as well as plasma and urine levels of cyclohexanone and metabolites in critically ill infants and children.

Methods

We prospectively enrolled children in a single center pediatric intensive care unit (ICU) (n = 66), and conducted a secondary analysis of a multicenter trial in premature neonates (n = 69). Cyclohexanone and its predominant metabolites, trans-1,2-cyclohexanediol and trans-1,4-cyclohexanediol, were measured serially in medical fluids, plasma, and urine.

Results

Cyclohexanone was detected in all IV solutions used in standard ICU care (IV fluids, medications, dialysate and red blood cell bags, n = 53 fluid samples). Cyclohexanone and metabolites were higher in urine versus plasma in both cohorts. In premature neonates, plasma and urine cyclohexanone concentrations were highest on day of randomization, while metabolite concentrations were highest on days 7–14.

Conclusions

Currently, cyclohexanone may represent an inevitable exposure to children who require intensive care inclusive of IV fluid and medication administration devices. Further studies are needed to develop replacement or mitigation strategies for cyclohexanone exposure in the vulnerable neonatal and pediatric ICU populations.

Impact

  • Direct bloodstream exposure to cyclohexanone in the hospital environment has been poorly described in the healthcare setting.

  • Cyclohexanone was present in all tested types of intravenous solutions used in standard intensive care (intravenous fluids, medications, dialysate and stored red blood cell bags).

  • In a single center pediatric intensive care unit cohort and a multicenter neonatal intensive care unit cohort, cyclohexanone and its metabolites were detected in every blood and urine sample tested.

  • In a multicenter neonatal intensive care unit cohort, plasma and urine cyclohexanone concentrations were highest on day 1 of admission and metabolite concentrations were highest on days 7–14.

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Fig. 1: Distribution of cyclohexanone concentrations in medical fluids, plasma, and urine of children admitted to a single pediatric intensive care unit.
Fig. 2: Distribution of cyclohexanone concentrations in medical fluids, stratified by fluid type and intravenous fluid bag size.

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Data availability

The datasets generated during and/or analysed during the current study are not publicly available due to grant period still ongoing but are available from the corresponding author on reasonable request.

References

  1. U.S. Environmental Protection Agency (EPA). Comptox chemicals dashboard V2.4.1. 376 https://comptox.epa.gov/dashboard/chemical/details/DTXSID6020359. Accessed on: March 10, 377.

  2. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some organic 379 solvents, resin monomers and related compounds, pigments and occupational exposures in paint 380 manufacture and painting. Lyon, France: International Agency for Research on Cancer.

  3. Jarsky, A. Elcam stopcocks: Solvent tube bonding. Elcam Medical. Revision 2, February 382 2014. https://www.yumpu.com/en/document/read/37373371/solvent-tube-bonding-elcam-383 medical. Accessed January 2, 2023.

  4. Danielson, J. W. Capillary gas chromatographic determination of cyclohexanone and 2-ethyl-1-385 hexanol leached from solution administration sets. J. Assoc. Anal. Chem. 74, 476–478 (1991).

  5. Story, D. A., Leeder, J., Cullis, P. & Bellomo, R. Biologically active contaminants of intravenous 387 saline in PVC packaging: Australasian, European, and North American samples. Anaesth. Intensive Care 33, 78–81 (2005).

    CAS  PubMed  Google Scholar 

  6. Snell, R. P. Gas chromatographic determination of cyclohexanone leached from hemodialysis 390 tubing. J. AOAC Int 76, 1127–1132 (1993).

    CAS  PubMed  Google Scholar 

  7. Ulsaker, G. A. & Korsnes, R. M. Determination of cyclohexanone in intravenous solutions stored in 392 PVC bags by gas chromatography. Analyst 102, 882–883 (1977).

    CAS  PubMed  Google Scholar 

  8. Thompson-Torgerson, C. S., Champion, H. C., Santhanam, L., Harris, Z. L. & Shoukas, A. A. Cyclohexanone contamination from extracorporeal circuits impairs cardiovascular function. Am. J. Physiol. Heart Circ. Physiol. 296, 1926 (2009).

    Google Scholar 

  9. Prazad, P., Donovan, R., Won, B. & Cortes, D. Migration of cyclohexanone and 3,3,5-397 trimethylcyclohexanone from a neonatal enteral feeding system into human milk. J. Perinatol. 41, 1074–1082 (2021).

    CAS  PubMed  Google Scholar 

  10. Colareta Ugarte, U. et al. Emission of volatile organic compounds 400 from medical equipment inside neonatal incubators. J. Perinatol. 34, 624–628 (2014).

    CAS  PubMed  Google Scholar 

  11. Mills, G. A. & Walker, V. Urinary excretion of cyclohexanediol, a metabolite of the solvent 402 cyclohexanone, by infants in a special care unit. Clin. Chem. 36, 870–874 (1990).

    CAS  PubMed  Google Scholar 

  12. Gupta, P. K., Lawrence, W. H., Turner, J. E. & Autian, J. Toxicological aspects of cyclohexanone. 404 Toxicol. Appl. Pharm. 49, 525–533 (1979).

    CAS  Google Scholar 

  13. Martis, L, Tolhurst, T, Koeferl, M T, Miller, T R & Darby, T D Disposition kinetics of 406 cyclohexanone in beagle dogs. Toxicol. Appl. Pharm. 55, 545–553 (1980).

    CAS  Google Scholar 

  14. Koeferl, M.T. et al. Influence of 408 concentration and rate of intravenous administration on the toxicity of cyclohexanone in beagle 409 dogs. Toxicol. Appl Pharm. 59, 215–229 (1981).

    CAS  Google Scholar 

  15. Mraz, J., Galova, E., Nohova, H. & Vitkova, D. Uptake, metabolism and elimination of 421 cyclohexanone in humans. Int Arch. Occup. Environ. Health 66, 203–208 (1994).

    CAS  PubMed  Google Scholar 

  16. Centers for Disease Control and Prevention, The National Institute for Occupational Safety 411 and Health. Cyclohexanone. https://www.cdc.gov/niosh/npg/npgd0163.html. Updated 2019. 412 Accessed June 4, 2020.

  17. Everett, A. D. et al. Association of neurodevelopmental outcomes with 414 environmental exposure to cyclohexanone during neonatal congenital cardiac operations: A 415 secondary analysis of a randomized clinical trial. JAMA Netw. Open 3, e204070 (2020).

    PubMed  PubMed Central  Google Scholar 

  18. Bembea, M. M. et al. Cyclohexanone exposure in children on 417 extracorporeal membrane oxygenation support. ASAIO J. 68, 419–425 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Juul, S. E. et al. A randomized trial of erythropoietin for 419 neuroprotection in preterm infants. N. Engl. J. Med. 382, 233–243 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Mráz, J., Gálová, E., Nohová, H. & Vitková, D. 1,2- and 1,4-cyclohexanediol: Major urinary 460 metabolites and biomarkers of exposure to cyclohexane, cyclohexanone, and cyclohexanol in 461 humans. Int Arch. Occup. Environ. Health 71, 560–565 (1998).

    PubMed  Google Scholar 

  21. Leteurtre, S. et al. Groupe Francophone de Réanimation et d’Urgences Pédiatriques (GFRUP). PELOD-2: an update of the PEdiatric logistic organ dysfunction score. Crit. Care Med. 41, 1761–1773 (2013).

    PubMed  Google Scholar 

  22. Diciccio, T. & Tibshirani, R. Bootstrap Confidence Intervals and Bootstrap Approximations. J. Am. Stat. Assoc. 82, 163–170 (1987).

    Google Scholar 

  23. Pazzaglia, M., Tullo, S., Voudouris, S. & Tosti, A. Contact dermatitis due to cyclohexanone: A 423 further case. Contact Dermat. 49, 313–1873 (2003).

    Google Scholar 

  24. Sanmartin, O. & de la Cuadra, J. Occupational contact dermatitis from cyclohexanone as a PVC 425 adhesive. Contact Dermat. 27, 189–190 (1992).

    CAS  Google Scholar 

  25. Mutti, A. et al. Absorption and alveolar 427 excretion of cyclohexane in workers in a shoe factory. J. Appl Toxicol. 1 220–223 (1981).

    CAS  PubMed  Google Scholar 

  26. Paciencia, I. et al. Exposure to indoor endocrine-disrupting 429 chemicals and childhood asthma and obesity. Allergy 74, 1277–1291 (2019).

    CAS  PubMed  Google Scholar 

  27. Api A.M., et al. RIFM fragrance ingredient safety assessment, cyclohexanone, CAS registry number 108-94-1. Food Chem. Toxicol. 138, 111231 (2020).

  28. Wiedmer, C. & Buettner, A. Identification and characterisation of odorants in a squishy toy using 433 gas chromatography-mass spectrometry/olfactometry after thermal extraction. Anal. Bioanal. Chem. 411, 3757–3761 (2019).

    CAS  PubMed  Google Scholar 

  29. Wiedmer, C., Velasco-Schon, C. & Buettner, A. Characterization of odorants in inflatable aquatic 436 toys and swimming learning devices-which substances are causative for the characteristic odor 437 and potentially harmful?. Anal. Bioanal. Chem. 409, 3905–3916 (2017).

    CAS  PubMed  Google Scholar 

  30. Liu, Y. et al. Nontargeted analysis and comparison strategies for volatile and semivolatile substances in toys made of different materials. Chemosphere. 342, 140170 (2023)

  31. Wiedmer, C. & Buettner, A. Quantification of organic solvents in aquatic toys and swimming 442 learning devices and evaluation of their influence on the smell properties of the corresponding 443 products. Anal. Bioanal. Chem. 410(10), 2585–2595 (2018).

    CAS  PubMed  Google Scholar 

  32. Gui, X. et al. Identification and validation of volatile organic compounds in 445 bile for differential diagnosis of perihilar cholangiocarcinoma. Clin. Chim. Acta.541, (2023).

  33. Felton, T. W. et al. Analysis of exhaled breath to identify critically ill 448 patients with ventilator-associated pneumonia. Anaesthesia 78, 712–721 (2023).

    CAS  PubMed  Google Scholar 

  34. Rogosch, T. et al. Detection of bloodstream infections and prediction 450 of bronchopulmonary dysplasia in preterm neonates with an electronic nose. J. Pediatr. 165, 622–624 (2014).

    PubMed  Google Scholar 

  35. de Meij, T. G. J. et al. Early detection of necrotizing 453 enterocolitis by fecal volatile organic compounds analysis. J. Pediatr. 167, 562–7.e1 (2015).

    PubMed  Google Scholar 

  36. Wright, H., Bannaga, A. S., Iriarte, R., Mahmoud, M. & Arasaradnam, R. P. Utility of volatile organic 455 compounds as a diagnostic tool in preterm infants. Pediatr. Res. 89, 263–268 (2021).

    PubMed  Google Scholar 

  37. Mochalski, P. et al. Blood and breath profiles 457 of volatile organic compounds in patients with end-stage renal disease. BMC Nephrol. 15, 43–43 (2014).

    PubMed  PubMed Central  Google Scholar 

  38. Perico, A., Cassinelli, C., Brugnone, F., Bavazzano, P. & Perbellini, L. Biological monitoring of 463 occupational exposure to cyclohexane by urinary 1,2- and 1,4-cyclohexanediol determination. Int. Arch. Occup. Environ. Health 72, 115–120 (1999).

    CAS  PubMed  Google Scholar 

  39. Okunishi, H., Shimoura, K., Wang, D. Q. & Kakizoe, E. Cardiotoxic interaction of metabolites from a prodrug segment cilexetil (cyclohexyloxy-carbonyloxy-ethyl) with digoxin in the canine failing heart. Pharm. Res. 46, 301–310 (2002).

    CAS  Google Scholar 

  40. El-Metwally, D. et al. Urinary metabolites of volatile organic 466 compounds of infants in the neonatal intensive care unit. Pediatr. Res. 83, 1158–1164 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Course C. et al. Volatile organic 468 compounds as disease predictors in newborn infants: A systematic review. J. Breath Res. 15, https://doi.org/10.1088/1752-7163/abe283 (2021).

Download references

Funding

Support for this work included funding from the National Heart Lung and Blood Institute under award R01HL158593 (ADE and DG) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award R01NS106292 (MMB).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Suneetha Desiraju & Maureen Gilmore

  2. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Emily Zhao

  3. Department of Environmental and Occupational Health, The George Washington University Milken Institute School of Public Health, Washington, DC, USA

    Jordan Kuiper

  4. Kennedy Krieger Institute, Baltimore, MD, USA

    Cynthia F. Salorio

  5. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    David Graham, Gregory Ellis, Lauren Jantzie & Allen D. Everett

  6. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA

    Jessie P. Buckley

  7. Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Mark W. Russell

  8. Department of Pediatrics, Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, SC, USA

    Eric M. Graham

  9. Department of Surgery, Division of Pediatric Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Danielle Gottlieb Sen

  10. Department of Pediatrics, University of Washington, Seattle, WA, USA

    Sandra E. Juul

  11. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Kamala Simkhada & Melania M. Bembea

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  1. Suneetha Desiraju
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  16. Melania M. Bembea
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Contributions

M.M.B. and A.D.E. conceived and designed the study. S.D., E.Z., C.F.S., D.G., M.G., K.S., A.D.E., and M.M.B. all contributed to the acquisition of data. J.K. provided statistical analysis. S.D., E.Z., J.K. and M.M.B. drafted the article while all authors contributed to interpretation of data and the revision and final approval of the manuscript.

Corresponding author

Correspondence to Melania M. Bembea.

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The authors declare no competing interests.

Consent statement

Written informed consent was obtained from parents or legal guardians within 48 h of pediatric intensive care unit admission for the pediatric cohort and within 24 h of birth for the PENUT cohort.

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Desiraju, S., Zhao, E., Kuiper, J. et al. Cyclohexanone and metabolites exposure in critically Ill neonates and children. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04027-8

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