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Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients.

ABSTRACT: Dexmedetomidine (DEX) is a fairly new alfa2-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit. This study was performed in the group of 17 males and 10 females patients with a median age of 59.5 years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weight, patients' health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 L/h for the distribution clearance. Those values are consistent with literature findings. We were unable to show any significant relationship between collected covariates and dexmedetomidine PK. This study does not provide sufficient evidence to support the individualization of dexmedetomidine dosing based on age, sex, body weight, SOFA, and infusion duration.

SUBMITTER: Smuszkiewicz P

PROVIDER: S-EPMC5845053 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients.

Smuszkiewicz Piotr P Wiczling Paweł P Ber Justyna J Warzybok Justyna J Małkiewicz Tomasz T Matysiak Jan J Klupczyńska Agnieszka A Trojanowska Iwona I Kokot Zenon Z Grześkowiak Edmund E Krzyzanski Wojciech W Bienert Agnieszka A

Journal of pharmacokinetics and pharmacodynamics 20171230 2

Dexmedetomidine (DEX) is a fairly new alfa<sub>2</sub>-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to ...[more]

PMID: 29290034

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Project description:IntroductionDelirium is very common in patients admitted to intensive care unit (ICU), and may worsen survival in these patients. Several meta-analyses have evaluated the antidelirium effects of dexmedetomidine in ICU patients, but their findings were inconsistent. Recently, several large multicentre randomised clinical trials (RCTs) were published, but they have not yet to be included in any meta-analysis. We will conduct a meta-analysis adding these data to evaluate the effects of dexmedetomidine on delirium and mortality in ICU patients, aiming to terminate controversy and provide robust evidence for guiding clinical practice.Methods and analysisThe Cochrane Central Register of Controlled Trials, PubMed, Embase, ISI Web of Science will be searched from inception to 31 December 2018 for relevant RCTs. Two reviewers will independently screen the identified citations. After quality appraisal and data extraction of included studies, we will conduct meta-analyses for outcomes of interest, including delirium, mortality, length of ICU/hospital stay, time to extubation, ICU costs and adverse effects. The statistical heterogeneity among studies will be assessed by the χ2 test and quantified by the I2 statistics. We will undertake subgroup analyses to explore heterogeneity and sensitivity analyses to evaluate whether the results are robust. Potential publication bias will be assessed by funnel plot and Egger's test. At last, the quality of evidence of the main outcomes will be rated using the Grading of Recommendations Assessment, Development and Evaluation system.Ethics and disseminationThe present study is a meta-analysis based on published studies, thus ethical approval is not needed. Our review will elucidate whether dexmedetomidine could decrease the incidence of delirium and improve survival in ICU patients. Our findings may help clinicians to choose optimal sedative agents for ICU patients. The results of this meta-analysis will be submitted to a peer reviewed journal for publication.Prospero registration numberCRD42018095358.

Project description:Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 ?g/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-? of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 ?g/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.ClinicalTrials.gov: NCT00747721.

Dataset Information

Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients.

Publications

Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients.

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