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Purpose: Palliative care patients often need sedation to alleviate intractable anxiety, stress, and pain. Dexmedetomidine is used for sedation of intensive care patients, but there is no prior information on its subcutaneous (SC) administration, a route that would be favored in palliative care. We compared the pharmacokinetics and cardiovascular, sympatholytic, and sedative effects of SC and intravenously (IV) administered dexmedetomidine in healthy volunteers., Methods: An open two-period, cross-over design with balanced randomization was used. Ten male subjects were randomized to receive 1 μg/kg dexmedetomidine both IV and SC. Concentrations of dexmedetomidine and catecholamines in plasma were measured. Pharmacokinetic variables were calculated with non-compartmental methods. In addition, cardiovascular and sedative drug effects were monitored., Results: Eight subjects completed both treatment periods. Peak concentrations of dexmedetomidine were observed 15 min after SC administration (median; range 15-240). The mean bioavailability of SC dexmedetomidine was 81% (AUC 0-∞ ratio × 100%, range 49-97%). The mean (SD) peak concentration of dexmedetomidine in plasma was 0.3 (0.1) ng/ml, and plasma concentrations associated with sedative effects (i.e., > 0.2 ng/ml) were maintained for 4 h after SC dosing. Plasma noradrenaline concentrations were significantly lower (P < 0.001) within 3 h after IV than after SC administration. Subjective scores for vigilance and performance were significantly lower 0-60 min after IV than SC dosing (P < 0.001 for both). The onset of the cardiovascular, sympatholytic, and sedative effects of dexmedetomidine was clearly less abrupt after SC than IV administration., Conclusions: Dexmedetomidine is relatively rapidly and efficiently absorbed after SC administration. Subcutaneous dexmedetomidine may be a feasible alternative in palliative sedation, and causes attenuated cardiovascular effects compared to IV administration. CLINICALTRIALS., Gov Identifier: NCT02724098 . EUDRA CT number 2015-004698-34 .

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., (© 2017 The Authors and Orion Corporation. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Dexmedetomidine is an α2-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN) administered dexmedetomidine in healthy subjects., Method: Single doses of 84 μg of dexmedetomidine were given once IV and once IN to six healthy men. Plasma dexmedetomidine concentrations were measured for 10 h along with plasma concentrations of norepinephrine (NE) and epinephrine (E). Blood pressure, heart rate, and CNS drug effects (three visual analog scales and bispectral index) were monitored to assess the pharmacological effects of dexmedetomidine. PK-PD modeling was performed for recently published data (Eur J Clin Pharmacol 67: 825, 2011)., Results: Pharmacokinetic profiles for both IV and IN doses of dexmedetomidine were well fitted using a two-compartment PK model. Intranasal bioavailability was 82%. Dexmedetomidine inhibited the release of NE and E to induce their decline in blood. This decrease in NE was captured with an indirect response model. The concentrations of the mediator NE served via a biophase/transduction step and nonlinear pharmacologic functions to produce reductions in blood pressure and heart rate, while a direct effect model was used for the CNS effects., Conclusion: The comprehensive panel of two biomarkers and seven response measures were well captured by the population PK/PD models. The subjects were more sensitive to the CNS (lower EC 50 values) than cardiovascular effects of dexmedetomidine.

Background: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach., Methods: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models., Results: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration., Conclusions: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

Anesthetic-induced changes in the neural activity of the brain have been recently utilized as a research model to investigate the neural mechanisms of phenomenal consciousness. However, the anesthesiologic definition of consciousness as "responsiveness to the environment" seems to sidestep the possibility that an unresponsive individual may have subjective experiences. The aim of the present study was to analyze subjective reports in sessions where sedation and the loss of responsiveness were induced by dexmedetomidine, propofol, sevoflurane or xenon in a nonsurgical experimental setting. After regaining responsiveness, participants recalled subjective experiences in almost 60% of sessions. During dexmedetomidine sessions, subjective experiences were associated with shallower "depth of sedation" as measured by an electroencephalography-derived anesthesia depth monitor. Results confirm that subjective experiences may occur during clinically defined unresponsiveness, and that studies aiming to investigate phenomenal consciousness under sedative and anesthetic effects should control the subjective state of unresponsive participants with post-recovery interviews., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The bispectral index (BIS) and the spectral entropy (state entropy, SE, and response entropy, RE) are depth-of-anaesthesia monitors derived from EEG and have been developed to measure the effects of anaesthetics on the cerebral cortex. We studied whether they can differentiate consciousness from unconsciousness during increasing doses of three different anaesthetic agents., Methods: Thirty healthy male volunteers aged 19-30 yr were recruited and divided into three 10-volunteer groups to receive either dexmedetomidine, propofol, or sevoflurane in escalating concentrations at 10 min intervals until loss of consciousness (LOC) was reached. Consciousness was tested at 5 min intervals and after drug discontinuation at 1 min intervals by requesting the subjects to open their eyes. LOC was defined as unresponsiveness to the request and pre-LOC as the last meaningful response. The first meaningful response to the request after drug discontinuation was defined as regaining of consciousness (ROC). For the statistical analysis, pre-LOC and ROC values were pooled to represent the responsive state while LOC values represented the unresponsive state. Prediction probability (P(K)) was estimated with the jack-knife method., Results: The lowest mean values for BIS, SE, and RE were recorded at LOC with all three drugs. The P(K) values were low for dexmedetomidine (BIS 0.62, SE 0.58, RE 0.59), propofol (BIS 0.73, SE 0.72, RE 0.72), and sevoflurane (BIS 0.70, SE 0.52, RE 0.62)., Conclusions: Because of wide inter-individual variability, BIS and entropy were not able to reliably differentiate consciousness from unconsciousness during and after stepwise increasing concentrations of dexmedetomidine, propofol, and sevoflurane.

Purpose: The aim of this proof-of-concept study was to characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine compared with its intravenous administration in a small number of healthy volunteers., Methods: Single doses of 84 μg of dexmedetomidine were given once intravenously and once intranasally to seven healthy men. Plasma dexmedetomidine concentrations were measured for 10 h, and pharmacokinetic variables were calculated with standard noncompartmental methods. Heart rate, blood pressure, concentrations of adrenaline and noradrenaline in plasma, and central nervous system drug effects (with the Maddox wing, Bispectral Index, and three visual analog scales) were monitored to assess the pharmacological effects of dexmedetomidine., Results: Six individuals were included in the analyses. Following intranasal administration, peak plasma concentrations of dexmedetomidine were reached in 38 (15-60) min and its absolute bioavailability was 65% (35-93%) (medians and ranges). Pharmacological effects were similar with both routes of administration, but their onset was more rapid after intravenous administration., Conclusions: Dexmedetomidine is rather rapidly and efficiently absorbed after intranasal administration. Compared with intravenous administration, intranasal administration may be a feasible alternative in patients requiring light sedation.

Background: Dexmedetomidine is a potent and selective α2-adrenoceptor agonist used for perioperative and intensive care sedation with certain beneficial qualities. However, based on preclinical observations, it might inhibit gastric emptying and gastrointestinal transit, which could result in unwanted effects in intensive care patients. This study evaluated the effects of dexmedetomidine on gastric emptying and oro-caecal transit time in healthy volunteers., Methods: Twelve healthy male subjects were given 1 µg kg(-1) of dexmedetomidine i.v. over 20 min followed by a continuous i.v. infusion of 0.7 µg kg(-1) h(-1) for 190 min. For comparison, subjects were also given 0.10 mg kg(-1) of morphine hydrochloride i.v. over 20 min and a placebo infusion in a randomized order. Gastric emptying was assessed with the paracetamol absorption test and oro-caecal transit time with the hydrogen breath test., Results: The time to maximum paracetamol concentration in plasma was significantly longer, maximum paracetamol concentration was significantly lower, the area under the plasma paracetamol concentration-time curve was significantly smaller, and oro-caecal transit time was significantly longer during dexmedetomidine infusion compared with morphine or placebo infusion., Conclusions: Dexmedetomidine markedly inhibits gastric emptying and gastrointestinal transit in healthy volunteers.

Introduction: 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., Methods: 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 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., Results: 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., Conclusions: The 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 Registration: ClinicalTrials.gov: NCT00747721.

Background: Information has been very limited on the pharmacokinetics of the selective alpha(2)-adrenoceptor agonist dexmedetomidine in children, particularly in children <2 yr of age., Methods: Eight children aged between 28 days and 23 months and eight children aged between 2 and 11 yr undergoing either elective bronchoscopy or nuclear magnetic resonance imaging were included in the study. Dexmedetomidine 1 microg kg(-1) was infused i.v. over 5 min. Blood samples for the measurement of plasma concentrations of dexmedetomidine were collected for 5 h after starting the infusion. Pharmacokinetic calculations were based on non-compartmental methods., Results: In the two groups of paediatric patients, the median (range) values for total plasma clearance of dexmedetomidine were 17.4 (14.1-27.6) and 17.3 (9.3-22.5) ml kg(-1) min(-1), for volume of distribution at steady state 3.8 (1.9-4.6) and 2.2 (1.3-2.8) litre kg(-1) (P<0.05), and for elimination half-life 139 (90-198) and 96 (69-140) min (P<0.05), respectively. The volume of distribution at steady state was negatively associated with subject age (r=-0.69, P<0.05)., Conclusions: To reach a certain plasma concentration, children younger than 2 yr of age evidently need larger initial doses of dexmedetomidine than the older children, as young children have a larger volume of distribution of the drug than older children and adults. Since the total plasma clearance of dexmedetomidine is independent of age, similar rates of infusion can be used in younger and older children to maintain a steady-state concentration of dexmedetomidine in plasma.

Background: Dexmedetomidine (DEX) has been shown to provide good perioperative haemodynamic stability with decreased intraoperative opioid requirements. It may have neural protective effects, and thus may be a suitable anaesthetic adjuvant to neurosurgical anaesthesia., Methods: Fifty-four patients scheduled for elective surgery of supratentorial brain tumour were randomized to receive in a double-blind manner a continuous DEX infusion (plasma target concentration 0.2 or 0.4 ng ml(-1)) or placebo, beginning 20 min before anaesthesia and continuing until the start of skin closure. The DEX groups received fentanyl 2 microg kg(-1) at the induction of anaesthesia and before the start of operation, the placebo group 4 microg kg(-1), respectively. Anaesthesia was maintained with nitrous oxide in oxygen and isoflurane., Results: The median times from the termination of N2O to extubation were 6 (3-27), 3 (0-20) and 4 (0-13) min in placebo, DEX-0.2 and DEX-0.4 groups, respectively (P<0.05 anova all-over effect). The median percentage of time points when systolic blood pressure was within more or less than 20% of the intraoperative mean was 72, 77 and 85, respectively (P<0.01), DEX-0.4 group differed significantly from the other groups. DEX blunted the tachycardic response to intubation (P<0.01) and the hypertensive response to extubation (P<0.01). DEX-0.4 group differed in the heart rate variability from placebo (93 vs 82%, P<0.01)., Conclusions: DEX increased perioperative haemodynamic stability in patients undergoing brain tumour surgery. Compared with fentanyl, the trachea was extubated [corrected] faster without respiratory depression.

In this case report, even a moderate dose of dexmedetomidine, a very selective alpha(2)-adrenergic agent, resulted in a rapid response to alcohol withdrawal delirium after the standard treatment. Psychiatrists should be aware of this relatively new drug that provides advantages over clonidine, heavy sedation and secondary restraints. Dexmedetomidine should be further evaluated in the treatment of specific forms of aggressive behavior and complicated withdrawal states.

The centrally acting alpha2-adrenoceptor agonists clonidine and dexmedetomidine have been used with success to provide haemodynamic stability for patients undergoing surgery. Particularly in the case of patients with overt or underlying cardiac disease the actions of alpha2-adrenoceptor agonists, which include maintenance of stable systemic blood pressure and low heart rate and a reduction in overall oxygen consumption, can be expected to reduce the risk of procedure-related cardiac events. This expectation has been corroborated in clinical trials with clonidine, dexmedetomidine and mivazerol and meta-analyses; additional large controlled trials would be instructive in establishing a robust estimate of the scale of the benefit. In addition, alpha2-adrenoceptor agonists used as premedication have been shown to substantially reduce anaesthetic requirements among surgical patients, and the use of these agents has been associated with a reduced risk of postoperative delirium, which may be expected to improve considerably the postoperative course for at-risk patients. Dexmedetomidine is the only alpha2-adrenoceptor agonist currently approved for use in the intensive care unit. A distinctive feature of dexmedetomidine in that setting is that in addition to haemodynamic stability it confers a distinctive and advantageous quality of sedation: patients are tranquil but responsive to requests from attending staff. This review examines the pharmacological principles underlying the use of alpha2-adrenoceptor agonists as adjuncts to surgery and clinical experience in that indication.

The centrally acting α2-adrenoceptor agonists clonidine and dexmedetomidine have been used with success to provide haemodynamic stability for patients undergoing surgery. Particularly in the case of patients with overt or underlying cardiac disease the actions of α2-adrenoceptor agonists, which include maintenance of stable systemic blood pressure and low heart rate and a reduction in overall oxygen consumption, can be expected to reduce the risk of procedure-related cardiac events. This expectation has been corroborated in clinical trials with clonidine, dexmedetomidine and mivazerol and meta-analyses; additional large controlled trials would be instructive in establishing a robust estimate of the scale of the benefit. In addition, α2-adrenoceptor agonists used as premedication have been shown to substantially reduce anaesthetic requirements among surgical patients, and the use of these agents has been associated with a reduced risk of postoperative delirium, which may be expected to improve considerably the postoperative course for at-risk patients. Dexmedetomidine is the only α2-adrenoceptor agonist currently approved for use in the intensive care unit. A distinctive feature of dexmedetomidine in that setting is that in addition to haemodynamic stability it confers a distinctive and advantageous quality of sedation: patients are tranquil but responsive to requests from attending staff. This review examines the pharmacological principles underlying the use of α2-adrenoceptor agonists as adjuncts to surgery and clinical experience in that indication. [ABSTRACT FROM AUTHOR]