Chris Garratt

Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients

IntroductionOnly 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.MethodsThirteen 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 μg/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.ResultsThe 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.ConclusionsThe results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.Trial RegistrationClinicalTrials.gov: NCT00747721

Effects of dexmedetomidine and propofol on patient-ventilator interaction in difficult-to-wean, mechanically ventilated patients: a prospective, open-label, randomised, multicentre study

BackgroundDexmedetomidine can be used for sedation of mechanically ventilated patients and has minor respiratory effects. The aim of this study was to compare the incidence of patient-ventilator dyssynchronies during sedation with dexmedetomidine or propofol.MethodsWe conducted a multicentre, prospective, open-label, randomised clinical trial, comparing dexmedetomidine with standard propofol sedation at three intensive care units of university hospitals in Italy. Twenty difficult-to-wean patients for whom the first weaning trial had failed and who were on pressure support ventilation were randomised to receive sedation with either dexmedetomidine or propofol at a similar level of sedation (Richmond Agitation-Sedation Scale [RASS] score +1 to −2). The asynchrony index (AI) was calculated using tracings of airflow, airway pressure and electrical activity of the diaphragm sampled at 0, 0.5, 1, 2, 6, 12, 18 and 24 h.ResultsThe mean AI was lower with dexmedetomidine than with propofol from 2 h onwards, although the two groups significantly differed only at 12 h (2.68 % vs 9.10 %, p < 0.05). No further difference was observed at 18 and 24 h.ConclusionsWhen sedation with propofol and dexmedetomidine was compared at similar RASS scores of patients in whom first weaning trial had failed, the AI was lower with dexmedetomidine than with propofol, and this difference was statistically significant at 12 h. These results suggest that sedation with dexmedetomidine may offer some advantages in terms of patient-ventilator synchrony.

A multinational, drug utilization study to investigate the use of dexmedetomidine (Dexdor®) in clinical practice in the EU

Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off‐label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine‐treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.

Methodological Considerations for the Implementation of A European Mandated Retrospective Drug Utilisation Study (Dus) to Investigate the Use of Dexmedetomidine (Dexdor®) in Clinical Practice

A chart review DUS of patients treated with dexmedetomidine was conducted in 16 hospitals across Austria, Finland, Germany and Poland. Patients were identified either prospectively or retrospectively, with anonymised data abstraction performed retrospectively post-administration. Chart data on patient demographics, indication, dexmedetomidine administration, concomitant medications and therapeutic effectiveness were collected via an electronic data collection tool.

A multinational, drug utilisation study to investigate the use of dexmedetomidine (DEXDOR®) in clinical practice in the EU

Dexmedetomidine (Dex) is a sedative drug approved as dexdor® (Orion Pharma, Finland) for ICU sedation in adults in the European Union in 2011. This observational, retrospective drug utilisation study was requested by the Committee for Human Medicinal Products for Human Use of the European Medicines Agency to investigate Dex use in clinical practice.