Population Pharmacokinetics of Dexmedetomidine in Neonates with Hypoxic-Ischemic Encephalopathy Undergoing Therapeutic Hypothermia: Insights from a Prospective Real-World Study

Objectives: Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) require sedation to manage stress and shivering. Dexmedetomidine, an alpha-2 adrenergic agonist, provides sedation and analgesia without respiratory or gastrointestinal compromise. However, its use is limited by bradycardia, which may necessitate discontinuation and subsequent re-initiation of opioid rescue. Optimal dosing to balance effective sedation and minimize bradycardia during TH remains undefined. Therefore, this study aimed to (i) develop a population pharmacokinetic model to characterize dexmedetomidine in neonates with HIE undergoing TH, and (ii) evaluate intrinsic and extrinsic factors affecting pharmacokinetic parameters during hypothermia, comparing these findings with existing data from normothermic neonatal populations. Methods: A prospective pharmacokinetic study, currently conducted, at the University of Maryland Medical Center, in neonates with HIE undergoing TH who received intravenous infusion of dexmedetomidine for sedation as part of routine clinical care. Dexmedetomidine plasma concentrations were quantified from residual blood samples using liquid chromatography-tandem mass spectrometry. Given the sparse sampling design (an average of two samples per patient), previously published rich-sampling data from McAdams et al.[ 1] in a comparable neonatal population informed the structural pharmacokinetic model development. Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling in Pumas software (version 2.6.1) with JuliaPro (version 1.10.5). The final model was evaluated through standard goodness of fit diagnostic plots. Results: A total of eleven neonates (5 males, 6 females) receiving dexmedetomidine during therapeutic hypothermia for HIE were included in the analysis. The cohort had a mean birthweight of 3.44 ± 0.85 kg and a mean gestational age of 38.5 ± 1.6 weeks. Across all subjects, 23 plasma samples were collected, with measured dexmedetomidine concentrations ranging from 16 to 2,220 pg/mL at infusion rates of 0.2–1.0 μg/kg/h; each neonate contributed an average of two samples. A one-compartment model with a combined residual error structure adequately captured the pharmacokinetic data. Clearance (CL) and volume of distribution (Vc) were scaled allometrically by body weight, and no additional covariates were identified. The population mean CL and Vc were 24.2 L/h/70 kg (95% CI: 10.8–41.6), and 341.4 L/70 kg, respectively, consistent with previously reported estimates in both hypothermic (CL: 18.41 L/h/70 kg) and normothermic neonates (CL: 13.3–29.7 L/h/70kg)[ 2– 4]. Substantial between-subject variability in clearance (93%) was observed. Conclusions: This preliminary popPK model characterizes dexmedetomidine in neonates undergoing TH for HIE, suggesting minimal impact of hypothermia on PK parameters. However, the high inter-subject variability underscores the importance of individualized dosing. Additional PK data will be collected and coupled with pharmacodynamic assessments to optimize dosing strategies to achieve effective sedation with minimal adverse effects in this vulnerable population.