Abstract
Dexmedetomidine is a selective alpha-2 adrenergic agonist with concurrent sedative and analgesic effects, and it is being increasingly used in pediatric anesthesia and intensive care. This study aimed to investigate the pharmacokinetics of intravenous dexmedetomidine in mechanically ventilated children in the intensive care unit (ICU) after neurosurgery. Pediatric patients aged 2–12 years, who were mechanically ventilated in ICU after neurosurgery, were allocated into a low-dose (n = 15) or high-dose (n = 14) group. The low-dose group received dexmedetomidine at a loading dose of 0.25 µg/kg for 10 min, followed by a maintenance dose of 0.25 µg/kg/h for 50 min, whereas the high-dose group received dexmedetomidine at a loading dose of 0.5 µg/kg for 10 min, followed by a maintenance dose of 0.5 µg/kg/h for 50 min. Serial blood samples were collected for a pharmacokinetic analysis up to 480 min after the end of the infusion. The sedative effect of dexmedetomidine was assessed using the Bispectral Index and University of Michigan Sedation Scale. Adverse reactions, electrocardiography findings, and vital signs were monitored for a safety assessment. A population pharmacokinetic analysis was performed using non-linear mixed effects modeling. Dexmedetomidine induced a moderate-to-deep degree of sedation during infusion in both groups. The pharmacokinetics of dexmedetomidine were best described by a two-compartment disposition model with first-order elimination kinetics. The parameters were standardized for a body weight of 70 kg using an allometric power model. The population estimates (95% confidence interval) per 70 kg body weight were as follows: clearance of 81.0 (72.9–90.9) L/h, central volume of distribution of 64.2 (50.6–81.0) L, intercompartment clearance of 116.4 (90.6–156.0) L/h, and peripheral volume of distribution of 167 (132–217) L. No serious adverse reactions or hemodynamic changes requiring the discontinuation of dexmedetomidine were observed. Dexmedetomidine had increased clearance and volume of distribution in mechanically ventilated children in ICU after neurosurgery, thereby indicating the need to adjust the dosage to obtain a target plasma concentration.
Highlights
Dexmedetomidine (Precedex®, Hospira, Lake Forest, IL, USA) is a selective alpha-2 adrenergic agonist with concurrent sedative and analgesic effects, only approved by the U.S Food and Drug Administration for the sedation of mechanically ventilated adults in an intensive care unit (ICU) and the procedural sedation of non-intubated adults
We developed a population PK model of intravenous dexmedetomidine in a single population of patients aged 2–12 years who were under mechanical ventilation in the ICU after neurosurgery
The population PK models are essential in determining drug dosage because they describe the behavior of a drug in a specific population and the variability expected between individuals and factors that explain this variability [14]
Summary
Dexmedetomidine (Precedex®, Hospira, Lake Forest, IL, USA) is a selective alpha-2 adrenergic agonist with concurrent sedative and analgesic effects, only approved by the U.S Food and Drug Administration for the sedation of mechanically ventilated adults in an intensive care unit (ICU) and the procedural sedation of non-intubated adults. The dosing regimen of dexmedetomidine comprises a loading dose of 1 μg/kg for 10 min, followed by a maintenance infusion of 0.2–1 μg/kg/h [1]. Dexmedetomidine is not approved for use in children. Dexmedetomidine is commonly applied in children as a premedication for anxiolysis, as a sedative for non-invasive or invasive procedures, and as an adjunct for analgesia [2]. Considering the unique properties of dexmedetomidine, such as minimal respiratory depression [3], it may be used in pediatric patients in the ICU as well as in the emergency and interventional rooms. Previous studies have used different dosages because the dosing regimen of dexmedetomidine in pediatric patients has not been established. The loading dose ranges from 0.05 to 6 μg/kg, whereas the maintenance dose ranges from 0.05 to 1.4 μg/kg/h [4,5,6,7,8,9,10,11]
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