Postoperative Pharmacokinetics and Sympatholytic Effects of Dexmedetomidine

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Abstract
Dexmedetomidine is a selective alpha2-adrenoceptor agonist with centrally mediated sympatholytic, sedative, and analgesic effects. This study evaluated: 1) pharmacokinetics of dexmedetomidine in plasma and cerebrospinal fluid (CSF) in surgical patients; 2) precision of a computer-controlled infusion protocol (CCIP) for dexmedetomidine during the immediate postoperative period; and 3) dexmedetomidine's sympatholytic effects during that period. Dexmedetomidine was infused postoperatively by CCIP for 60 min to eight women, targeting a plasma concentration (Cp) of 600 pg/mL. Before, during, and after infusion, blood was sampled to determine plasma concentrations of norepinephrine, epinephrine, and dexmedetomidine, and CSF was sampled to determine dexmedetomidine concentrations (C[CSF]). Heart rate and arterial blood pressure were measured continuously from 5 min before until 3 h after the end of infusion. During the infusion, Cp values generally exceeded the target value: median percent error averaged 21% and ranged from -2% to 74%; median absolute percent error averaged 23% and ranged from 4% to 74%. After infusion, C(CSF) was 4% +/- 1% of Cp. Because C(CSF) barely exceeded the assay's limit of quantitation, CSF pharmacokinetics were not determined. During the infusion, norepinephrine decreased from 2.1 +/- 0.8 to 0.7 +/- 0.3 nmol/L; epinephrine decreased from 0.7 +/- 0.5 to 0.2 +/- 0.2 nmol/L; heart rate decreased from 76 +/- 15 to 64 +/- 11 bpm; and systolic blood pressure decreased from 158 +/- 23 to 140 +/- 23 mm Hg. We conclude that infusion of dexmedetomidine by CCIP using published pharmacokinetic parameters overshoots target dexmedetomidine concentrations during the early postoperative period. Hemodynamic and catecholamine results suggest that dexmedetomidine attenuates sympathetic activity during the immediate postoperative period. We studied the pharmacokinetic and sympatholytic effects of dexmedetomidine during the immediate postoperative period and found that during this period, the published pharmacokinetic data slightly overshoot target plasma dexmedetomidine concentrations. We also found that heart rate, blood pressure, and plasma catecholamine concentrations decrease during dexmedetomidine infusion.