Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children

Journal Article · 31 March 2024 · Clinical and Translational Science

DOI: https://doi.org/10.1111/cts.13780 · OSTI ID:2471308

Chakravartula, Shilpa ^[1]; Thrasher, Bradlee ^[1]; Mann, John ^[1]; Chaturbedi, Anik ^[1]; Han, Xiaomei ^[1]; Dahan, Albert  ^[2]; Florian, Jeffry ^[1]; Strauss, David ^[1]; Li, Zhihua ^[1]

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1. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Office of Translational Sciences Center for Drug Evaluation and Research
2. Leiden Univ. (Netherlands). Medical Center

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO₂tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

• Research Organization: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
• Sponsoring Organization: USDOE Office of Science (SC); USFDA
• Grant/Contract Number: SC0014664
• OSTI ID: 2471308
• Journal Information: Clinical and Translational Science, Journal Name: Clinical and Translational Science Journal Issue: 4 Vol. 17; ISSN 1752-8054
• Publisher: WileyCopyright Statement
• Country of Publication: United States
• Language: English