Role of Cyclohexanone Toxicity in Mediating Congenital Cardiac Surgery Outcomes

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Congenital heart defects (CHD) are the leading cause of birth defect-associated illness and death. Neurodevelopmental delays and disabilities are the most frequent and significant consequence for CHD survivors. Efforts to reduce morbidity and improve outcomes have primarily focused on surgical techniques, cardiopulmonary bypass (CPB) strategies and pharmacologic therapies without much success. Exposure to industrial chemicals in the health care environment are increasingly being recognized as harmful, and maybe a mechanism for these poor outcomes in CHD. Cyclohexanone, is a hazardous organic industrial solvent used principally in health care as a joining compound in the fabrication of plastic medical devices. Cyclohexanone has been shown to leach from IV infusion sets and the CPB circuit and in animal studies, with significant cardiovascular effects. Therefore, our hypothesis is that cyclohexanone derived from medical plastics is associated with adverse cardiovascular and neurodevelopmental outcomes in congenital cardiac surgery. We now have significant and compelling pilot data in neonates undergoing cardiac surgery that there is a) substantial cyclohexanone exposure from IV infusions and CPB and b) with adjusted analysis, cyclohexanone levels were significantly associated with adverse post-operative cardiovascular outcomes, and worse 12 month neurodevelopmental outcomes, thus supporting our hypothesis. Our long-term goal is to develop new prevention strategies and more precise treatments to improve outcomes for neonates undergoing surgery with CPB. We will approach this hypothesis using samples and outcomes from the discovery cohort: the completed NHLBI multicenter Trial NCT01579513, entitled “Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass (MP trial)”, Eric Graham, PI (n=190, randomized to MP (methylprednisolone) therapy or placebo) and the completed external validation cohort the University of Toronto, “Clinical Assessment of Thrombosis in Children After Heart Surgery: The CATCH Study” (NCT01435473), Brian McCrindle and Cedric Manlhiot (PIs) (N=327, <5 years old) and a neonatal cardiac surgery from the University of Michigan (N=59), Mark Russell, PI. With the following Specific Aims we propose to: Aim 1) Determine if serum perioperative cyclohexanone levels are associated with perioperative morbidity, mortality, and neurodevelopmental outcomes. Aim 2) Determine cyclohexanone exposure sources and removal using zeolite molecular sieves. Finally, Aim 3) Determine cyclohexanone neural toxicity, blood brain barrier and learning/memory effects. These Aims describe a paradigm shift in the mechanism of reduced neonatal heart surgery outcomes. Innovation includes discovery of the novel role of the industrial organic solvent contaminant cyclohexanone from medical plastic fabrication on neonatal cardiac surgery clinical outcomes and methods for removal. Reduction of organic solvent exposure from medical plastics offers an immediate and actionable means to improve neonatal cardiac surgical outcomes.