Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1–34.0 months) and underwent CPB for 161 minutes (63–394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6–24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7–45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL. Accepted for publication June 27, 2018. Funding: K.O.Z. is funded by grant KL2TR001115-03 from the Duke Clinical and Translational Science Awards and K23 grant HD091398 from the National Institutes of Health (NIH). H.W. received salary support from grant K23HD0785891 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) for completion of this project. M.L. receives support from the US government for work in neonatal clinical pharmacology, clinical trials, and cohort studies including Food and Drug Administration (FDA) R01 FD005101, Prinicipal Investigator (PI) M.L.; National Heart, Lung and Blood Institute (NHLBI) R34 HL124038, PI M.L.; the NIH Office of the Director, Environmental Influences on Child Health Outcomes (ECHO) Coordinating Center U2C OD023375, PI P.B.S., Duke University School of Medicine; the NICHD Pediatric Trials Network Government Contract HHSN267200700051C, PI Daniel Benjamin Jr, Duke University School of Medicine; and as the satellite site PI for the NICHD Neonatal Research Network NICHD U10 HD040492, PI C. Michael Cotten, Duke University School of Medicine. R.G.G. receives salary support for research from the NIH training grants (5T32HD043029-13), NIH awards (HHSN 275201000003I, HHSN 272201300017I), and from the FDA (HHSF223201610082C). P.B.S. receives salary support for research from the NIH (NIH-1R21HD080606-01ª1) and the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the NICHD (HHSN275201000003I), and the FDA (1R18-FD005292-01). C.P.H. receives salary support for research from the National Center for Advancing Translational Sciences of the NIH (UL1TR001117) and the US government for his work in pediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C, PI: Daniel Benjamin Jr under the Best Pharmaceuticals for Children Act). M.C.-W. receives support for research from the NIH (1R01-HD076676-01A1), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the NICHD (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and industry for drug development in adults and children (https://ift.tt/2PAHZY8). K.M.W. receives support from the Pediatric Critical Care and Trauma Scientist Development Program (5K12HD047349) and the NICHD (1K23HD075891) for his work in pediatric clinical pharmacology. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Kanecia O. Zimmerman, MD, MPH, Department of Pediatrics, Duke University School of Medicine, Box 3850, Durham, NC 27710. Address e-mail to Kanecia.obie@dm.duke.edu. © 2018 International Anesthesia Research Society

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