Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics.

BACKGROUND: Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. METHODS: The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. RESULTS: A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml-1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. CONCLUSIONS: This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml-1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines.

Effects of intravenous lidocaine, dexmedetomidine, and their combination on IL-1, IL-6 and TNF-α in patients undergoing laparoscopic hysterectomy: a prospective, randomized controlled trial.

BACKGROUND: Surgical-related inflammatory responses have negative effects on postoperative recovery. Intravenous (IV) lidocaine and dexmedetomidine inhibits the inflammatory response. We investigated whether the co-administration of lidocaine and dexmedetomidine could further alleviate inflammatory responses compared with lidocaine or dexmedetomidine alone during laparoscopic hysterectomy. METHODS: A total of 160 patients were randomly allocated into four groups following laparoscopic hysterectomy: the control group (group C) received normal saline, the lidocaine group (group L) received lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D) received dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion), and the lidocaine plus dexmedetomidine group (group LD) received a combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion) and dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion). The levels of plasma interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at different time points were the primary outcomes. Secondary outcomes included hemodynamic variables, postoperative visual analogue scale (VAS) scores, time to first flatus, and incidence of nausea and vomiting after surgery. RESULTS: The levels of plasma IL-1, IL-6, and TNF-α were lower in groups D and LD than in group C and were lowest in group LD at the end of the procedure and 2 h after the operation (P < 0.05). The VAS scores were decreased in groups D and LD compared with group C (P < 0.05). The heart rate (HR) was decreased at the end of the procedure and 2 h after the operation in groups D and LD compared to groups C and L (P < 0.001). The mean blood pressure (MBP) was lower at 2 h after the operation in groups L, D, and LD than in group C (P < 0.001). There was a lower incidence of postoperative nausea and vomiting (PONV) in group LD than in group C (P < 0.05). CONCLUSIONS: The combination of lidocaine and dexmedetomidine significantly alleviated the inflammatory responses, decreased postoperative pain, and led to fewer PONV in patients undergoing laparoscopic hysterectomy. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03276533 ), registered on August 23, 2017.

Pharmacokinetics and Pharmacodynamics of 3 Doses of Oral-Mucosal Dexmedetomidine Gel for Sedative Premedication in Women Undergoing Modified Radical Mastectomy for Breast Cancer.

BACKGROUND: Buccal dexmedetomidine (DEX) produces adequate preoperative sedation and anxiolysis when used as a premedication. Formulating the drug as a gel decreases oral losses and improves the absorption of buccal DEX. We compared pharmacokinetic and pharmacodynamic properties of 3 doses of buccal DEX gel formulated in our pharmaceutical laboratory for sedative premedication in women undergoing modified radical mastectomy for breast cancer. METHODS: Thirty-six patients enrolled in 3 groups (n = 12) to receive buccal DEX gel 30 minutes before surgery at 0.5 µg/kg (DEX 0.5 group), 0.75 µg/kg (DEX 0.75 group), or 1 µg/kg (DEX 1 group). Assessments included plasma concentrations of DEX, and pharmacokinetic variables calculated with noncompartmental methods, sedative, hemodynamic and analgesic effects, and adverse effects. RESULTS: The median time to reach peak serum concentration of DEX (Tmax) was significantly shorter in patients who received 1 µg/kg (60 minutes) compared with those who received 0.5 µg/kg (120 minutes; P = .003) and 0.75 µg/kg (120 minutes; P = .004). The median (first quartile-third quartile) peak concentration of DEX (maximum plasma concentration [Cmax]) in plasma was 0.35 ng/mL (0.31-0.49), 0.37 ng/mL (0.34-0.40), and 0.54 ng/mL (0.45-0.61) in DEX 0.5, DEX 0.75, and DEX 1 groups (P = .082). The 3 doses did not produce preoperative sedation. The 1 µg/kg buccal DEX gel produced early postoperative sedation and lower intraoperative and postoperative heart rate values. Postoperative analgesia was evident in the 3 doses in a dose-dependent manner with no adverse effects. CONCLUSIONS: Provided that it is administered 60-120 minutes before surgery, sublingual administration of DEX formulated as an oral-mucosal gel may provide a safe and practical means of sedative premedication in adults.

Effects of Dexmedetomidine on the Pharmacokinetics of Dezocine, Midazolam and Its Metabolite 1-Hydroxymidazolam in Beagles by UPLC-MS/MS.

OBJECTIVE: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. MATERIALS AND METHODS: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 µg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 µg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. RESULTS: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. CONCLUSION: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug-drug interaction should be paid attention to when the drugs were used in combination.

Development and validation of a chiral LC-MS method for the enantiomeric resolution of (+) and (-)-medetomidine in equine plasma by using polysaccharide-based chiral stationary phases.

The detection and separation of medetomidine enantiomers from the complex biological matrices poses a great analytical challenge, especially in the field of forensic toxicology and pharmacology. Couple of researchers reported resolution of medetomidine using protein-based chiral columns, but the reported method is quiet challenging and tedious to be employed for routine analysis. This research paper reported a method that enables the enantio-separation of medetomidine by using polysaccharide cellulose chiral column. The use of chiralcel OJ-3R column was found to have the highest potential for successful chiral resolution. Ammonium hydrogen carbonate was the ideal buffer salt for chiral liquid chromatography (LC) with electrospray ionization (ESI)+ mass spectrometry (MS) detection for the successful separation and detection of racemic compound. The method was linear over the range of 0 to 20 ng/mL in equine plasma and the inter-day precisions of levomedetomidine, dexmedetomidine were 1.36% and 1.89%, respectively. The accuracy of levomedetomidine was in the range of 99.25% to 101.57% and that for dexmedetomidine was 99.17% to 100.99%. The limits of quantification for both isomers were 0.2 ng/mL. Recovery and matrix effect on the analytes were also evaluated. Under the optimized conditions, the validated method can be adapted for the identification and resolution of the medetomidine enantiomers in different matrices used for drug testing and analysis.

Pharmacokinetics of Dexmedetomidine in Infants and Children After Orthotopic Liver Transplantation.

BACKGROUND: Dexmedetomidine (DEX) is a sedative and analgesic medication that is frequently used postoperatively in children after liver transplantation. Hepatic dysfunction, including alterations in drug clearance, is common immediately after liver transplantation. However, the pharmacokinetics (PK) of DEX in this population is unknown. The objective of this study was to determine the PK profile of DEX in children after liver transplantation. METHODS: This was a single-center, open-label PK study of DEX administered as an intravenous loading dose of 0.5 µg/kg followed by a continuous infusion of 0.5 µg/kg/h. Twenty subjects, 1 month to 18 years of age, who were admitted to the pediatric intensive care unit after liver transplantation were enrolled. Whole blood was collected and analyzed for DEX concentration using a dried blood spot method. Nonlinear mixed-effects modeling was used to characterize the population PK of DEX. RESULTS: DEX PK was best described by a 2-compartment model with first-order elimination. A typical child after liver transplantation with an international normalized ratio (INR) of 1.8 was found to have a whole blood DEX clearance of 52 L/h (95% confidence interval [CI], 31-73 L/h). In addition, intercompartmental clearance was 246 L/h (95% CI, 139-391 L/h), central volume of distribution was 186 L/70 kg (95% CI, 140-301 L/70 kg), and peripheral volume of distribution was 203 L (95% CI, 123-338 L). Interindividual variability ranged from 11% to 111% for all parameters. Clearance was not found to be associated with weight but was found to be inversely proportional to INR. An increase in INR to 3.2 resulted in a 50% decrease in DEX clearance. Weight was linearly correlated with central volume of distribution. All other covariates, including age, ischemic time, total bilirubin, and alanine aminotransferase, were not found to be significant predictors of DEX disposition. CONCLUSIONS: Children who received DEX after liver transplantation have large variability in clearance, which was not found to be associated with weight but is influenced by underlying liver function, as reflected by INR. In this population, titration of DEX dosing to clinical effect may be important because weight-based dosing is poorly associated with blood concentrations. More attention to quality of DEX sedation may be warranted when INR values are changing.

Intranasal dexmedetomidine in healthy beagles: An echocardiographic and pharmacokinetic/pharmacodynamic study.

The aim of this study was to compare the sedative and cardiovascular effects of dexmedetomidine (DEX) administrated via intranasal (IN) and intramuscular (IM) routes. This masked, randomised, crossover study used six male beagle dogs, receiving 0.02 mg/kg dexmedetomidine either IN (DEX-IN) or IM (DEX-IM), and an equal volume of saline by the alternative route. Dexmedetomidine plasma concentration was measured before (TB) and at time points (T) 2, 5, 10, 15, 30, 45, 60, 90 and 120 min after drug administration (T0). Physiological variables, sedation scores and sedation times were recorded until recovery. Echocardiography was performed at TB and between T20-T40. Repeated data over time were analysed using a Scheirer-Ray-Hare test. Other data were compared using a Wilcoxon or Student's t test. Times from T0 to sternal position and from lateral to sternal position were longer for DEX-IN than DEX-IM (P = 0.018 and P = 0.009, respectively). Time from sternal to standing position was shorter for DEX-IN than DEX-IM (P = 0.03). Dexmedetomidine plasma concentrations were significantly lower for DEX-IN than DEX-IM from T10 to T120. Heart rate was significantly lower for DEX-IM than DEX-IN from T5 to T20. Echocardiography showed a decrease in systolic function and calculated cardiac output in DEX-IM as compared to baseline. The DEX concentration-sedation curve for DEX-IN as compared to DEX-IM was leftward shifted, whereas the IN and IM DEX concentration-variation-in-heart-rate curves overlapped. Although reaching lower plasma concentrations, IN dexmedetomidine produced similar sedation to IM dexmedetomidine without affecting cardiovascular function.

Pharmacodynamic Interaction of Remifentanil and Dexmedetomidine on Depth of Sedation and Tolerance of Laryngoscopy.

BACKGROUND: Dexmedetomidine is a sedative with modest analgesic efficacy, whereas remifentanil is an opioid analgesic with modest sedative potency. Synergy is often observed when sedative-hypnotics are combined with opioid analgesics in anesthetic practice. A three-phase crossover trial was conducted to study the pharmacodynamic interaction between remifentanil and dexmedetomidine. METHODS: After institutional review board approval, 30 age- and sex- stratified healthy volunteers were studied. The subjects received consecutive stepwise increasing target-controlled infusions of dexmedetomidine, remifentanil, and remifentanil with a fixed dexmedetomidine background concentration. Drug effects were measured using binary (yes or no) endpoints: no response to calling the subject by name, tolerance of shaking the patient while shouting the name ("shake and shout"), tolerance of deep trapezius squeeze, and tolerance of laryngoscopy. The drug effect was measured using the electroencephalogram-derived "Patient State Index." Pharmacokinetic-pharmacodynamic modeling related the administered dexmedetomidine and remifentanil concentration to these observed effects. RESULTS: The binary endpoints were correlated with dexmedetomidine concentrations, with increasing concentrations required for increasing stimulus intensity. Estimated model parameters for the dexmedetomidine EC50 were 2.1 [90% CI, 1.6 to 2.8], 9.2 [6.8 to 13], 24 [16 to 35], and 35 [23 to 56] ng/ml, respectively. Age was inversely correlated with dexmedetomidine EC50 for all four stimuli. Adding remifentanil did not increase the probability of tolerance of any of the stimuli. The cerebral drug effect as measured by the Patient State Index was best described by the Hierarchical interaction model with an estimated dexmedetomidine EC50 of 0.49 [0.20 to 0.99] ng/ml and remifentanil EC50 of 1.6 [0.87 to 2.7] ng/ml. CONCLUSIONS: Low dexmedetomidine concentrations (EC50 of 0.49 ng/ml) are required to induce sedation as measured by the Patient State Index. Sensitivity to dexmedetomidine increases with age. Despite falling asleep, the majority of subjects remained arousable by calling the subject's name, "shake and shout," or a trapezius squeeze, even when reaching supraclinical concentrations. Adding remifentanil does not alter the likelihood of response to graded stimuli.

Plasma concentrations at two dexmedetomidine constant rate infusions in isoflurane anaesthetized horses: a clinical study.

OBJECTIVE: To determine dexmedetomidine plasma concentrations at two infusion rates in isoflurane anaesthetized horses and compare cardiovascular effects and anaesthetic recovery between treatments. STUDY DESIGN: Prospective, randomized, masked clinical study. ANIMALS: Healthy, adult, client-owned, non-food producing horses presented for castration. METHODS: Premedication consisted of acepromazine, romifidine and morphine, and anaesthesia was induced with ketamine and midazolam. The horses were randomized to receive dexmedetomidine 0.5 µg kg-1 hour-1 (treatment DL, n = 7) or 1.75 µg kg-1 hour-1 (treatment DH, n = 7) for 90 minutes of isoflurane anaesthesia at an end-tidal concentration of 1.2%. Venous plasma concentrations were determined with liquid chromatography-electrospray-ionization-tandem mass spectrometry. Jugular venous and arterial blood was sampled for blood gas analysis at the start and end of the infusion. Changes in cardiovascular variables from the start to the end of the infusion, and recovery parameters were statistically compared between treatments. RESULTS: Fourteen male horses, 2-6 years old, 325-536 kg were included. Mean ± standard deviation dexmedetomidine plasma concentrations at 30, 60 and 90 minutes with treatment DL were 0.22 ± 0.05, 0.29 ± 0.07 and 0.33 ± 0.08 ng mL-1, and with treatment DH were 0.65 ± 0.11, 0.89 ± 0.10 and 1.01 ± 0.10 ng mL-1. The 95% confidence interval for change minute-1 in dexmedetomidine plasma concentrations between 75 and 90 minutes was 0-1% for both treatments. With treatment DH, the heart rate decreased significantly more from the beginning to the end of the infusion compared to DL (p = 0.043). No other significant differences were found between treatments in cardiovascular or recovery parameters. CONCLUSIONS AND CLINICAL RELEVANCE: Infusion of dexmedetomidine in isoflurane anaesthetized horses resulted in plasma concentrations with low variation at both infusion rates, approaching stable levels after 75 minutes of infusion. No differences of clinical importance were found when comparing cardiovascular variables and quality of recovery between treatments.

Cardiopulmonary effects of dexmedetomidine, with and without vatinoxan, in isoflurane-anesthetized cats.

OBJECTIVE: To characterize the cardiopulmonary effects of dexmedetomidine, with or without vatinoxan, in isoflurane-anesthetized cats. STUDY DESIGN: Randomized, crossover experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were instrumented during anesthesia with isoflurane in oxygen. Isoflurane end-tidal concentration was set to 1.25 minimum alveolar concentration (MAC). Dexmedetomidine was administered using a target-controlled infusion system to achieve and maintain 10 target plasma concentrations ranging from 0 to 40 ng mL-1. Furthermore, vatinoxan or an equivalent volume of saline was administered using a target-controlled infusion system to achieve and maintain a target plasma concentration of 4 µg mL-1. Isoflurane concentration was adjusted after each change in dexmedetomidine concentration to maintain a concentration equivalent to 1.25 MAC. Heart rate (HR), arterial blood pressure, central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary artery occlusion pressure (PAOP), body temperature, cardiac output, arterial and mixed-venous blood gas and pH and drug concentrations were measured. Additional variables were calculated from the measurements. RESULTS: Dexmedetomidine alone resulted in decreased HR, cardiac index, stroke index and oxygen delivery, and increased systolic, mean (MAP) and diastolic arterial pressure, CVP, PAP, PAOP, systemic vascular resistance index, rate-pressure product, left ventricular stroke work index and oxygen extraction ratio. Vatinoxan resulted in severe hypotension at target plasma dexmedetomidine concentrations <10 ng mL-1. Vatinoxan attenuated the cardiovascular effects of dexmedetomidine at the 10 and 20 ng mL-1 targets, but MAP could be maintained above 60 mmHg only when isoflurane concentration was <1.25 MAC. Less improvement in cardiovascular function was seen with vatinoxan at the 40 ng mL-1 target plasma dexmedetomidine concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan, at the plasma concentration maintained in this study, attenuated the cardiovascular effects of dexmedetomidine in isoflurane-anesthetized cats. However, its administration resulted in hypotension, which may limit its clinical usefulness.

Quantitative ultra-high-performance liquid chromatography-tandem mass spectrometry for determination of dexmedetomidine in pediatric plasma samples: Correlation with genetic polymorphisms.

Dexmedetomidine is an important sedative agent administered as premedication to achieve procedural sedation in children. To describe the correlation between the genetic state and the concentration of dexmedetomidine, it is necessary to develop a specific, time-saving and economical method for detection of dexmedetomidine in plasma samples. In this work, an ultra-high-performance liquid chromatography (UHPLC)-tandem mass spectrometry method has been established and validated for detection of dexmedetomidine in plasma from pediatric population. After a simple liquid-liquid extraction with an organic solution, the analytes were separated on an ACQUITY BEH C18 column (2.1 mm × 50 mm, 1.7 µm particle size) by gradient elution with the mobile phase of acetonitrile and 1‰ aqueous formic acid (flow rate 0.3 mL min-1 ). Mass spectrometry measurements were performed under the positive selected reaction monitoring and the mass transitions monitored were m/z 201.3 → 95.1, 204.2 → 98.0 for dexmedetomidine and deuterated medetomidine (internal standard), respectively. Validation of the method based on China Food and Drug Administration guidelines showed acceptable selectivity. The UHPLC method employed a stable isotope-labeled internal standard, showed good specificity and was successfully used to detect dexmedetomidine in plasma samples from 260 pediatric patients. A subsequent application of this method to a pharmacogenetic study was also described. Importantly, this is the first study to report the correlation between CYP2A6 rs835309 activity and concentration of dexmedetomidine.

Neurocognitive performance under combined regimens of ketamine-dexmedetomidine and ketamine-fentanyl in healthy adults: A randomised trial.

Analgesic doses of ketamine affects neurocognition; however, deficits under co-administration regimens are unknown. This study evaluated the effects of ketamine, alone and in combination with dexmedetomidine or fentanyl on neurocognition. Using a randomised, within-subjects gender stratified design, 39 participants (mean age = 28.4, SD ±â€¯5.8) received a ketamine bolus of 0.3 mg/kg followed by 0.15 mg/kg/h infusion of ketamine (3 h duration). At 1.5 h post-ketamine infusion commencement, participants received either: i) 0.7 µg/kg/h infusion of dexmedetomidine (n = 19) (KET/DEX) or (ii) three 25 µg fentanyl injections over 1.5 h (n = 20) (KET/FENT). Reaction and Movement time (RTI, Simple and 5Choice), Visuospatial Working Memory (SWM) and Verbal Recognition Memory (VRM) were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Whole blood drug concentrations were determined during ketamine-only infusion, at co-administration (KET/DEX or KET/FENT) and at 2-h post-treatment. Ketamine-only administration impaired psychomotor response speed (Simple and 5Choice) and impaired memory (all p < .001), however did not alter executive function abilities. Independent of sedation, co-administration of dexmedetomidine produced synergistic performance and memory deficits which persisted at post-treatment (KET/DEX) (all p < .001), and were comparatively greater than for KET/FENT (all p < .05). Ketamine, norketamine and dexmedetomidine concentrations were modestly associated with reduced psychomotor speed and accuracy (all p < .05), and an inverse relationship was found between blood concentrations of ketamine, norketamine and dexmedetomidine and performance on memory tasks. Co-administration of ketamine with dexmedetomidine but not with fentanyl exerts synergistic effects on psychomotor performance and memory without executive dysfunction. Assessment of these effects in clinical groups is warranted.

Determination of blood dexmedetomidine in dried blood spots by LC-MS/MS to screen therapeutic levels in paediatric patients.

Dexmedetomidine is an imidazole derivative, with high affinity for α2 adrenergic receptors, used for sedation, analgesia and adjuvant anaesthesia. In this study, an analytical method for the quantification of dexmedetomidine in dried blood spots was developed, validated and applied. The drug was extracted from dried blood spot by liquid extraction; the separation was carried out by ultra high-resolution liquid chromatography in reverse phase coupled to tandem mass spectrometry method. An X Select cyano 5 µm HSS column (2.1 X 150 mm, Waters) and a mobile phase composed of 0.1% formic acid: acetonitrile [50:50 v/v], were used. The test was linear over the concentration range of 50 to 2000 pg/mL. The coefficients of variation for the intra and interday trials were less than 15%. The drug was stable under the conditions tested. The method was successfully applied for the quantification of 6 patients, aged 0 to 2 years, with classification ASA I, who underwent ambulatory surgeries, receiving a dose of 1 µg/Kg dexmedetomidine IV. The drug concentrations in the different sampling times were in the range of 76 to 868 pg/mL.

An improved ultra-high-performance liquid chromatography-tandem mass spectrometric method for the quantitation of dexmedetomidine in small volume of pediatric plasma.

Dexmedetomidine (Dex), a highly selective α2 -adrenergic agonist, is used primarily for the sedation and anxiolysis of adults and children in the intensive care setting. A sensitive and selective assay for Dex in pediatric plasma was developed by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with d4-Dex as an internal standard. Dex was extracted from 0.1 mL of plasma by micro-elution solid-phase extraction. Separation was achieved with a Waters XBridge C18 column with a flow rate of 0.3 mL/min using a mobile phase comprising 5 mm ammonium acetate buffer with 0.03% formic acid in water and methanol-acetonitrile (50:50, v/v). The intra-day precision (coefficient of variation) and accuracy for quality control samples ranged from 1.32 to 8.91% and from 92.8 to 108%, respectively. The inter-day precision and accuracy ranged from 2.13 to 8.45% and from 97.0 to 104%, respectively. The analytical method showed excellent sensitivity using a small sample volume (0.1 mL) with a lower limit of quantitation of 5 pg/mL. This method is robust and has been successfully employed in a pharmacokinetic study of Dex in neonates and infants postoperative from cardiac surgery.

The pharmacokinetics of dexmedetomidine in patients with obstructive jaundice: A clinical trial.

OBJECTIVES: Dexmedetomidine, a highly selective central α2-agonist, undergoes mainly biotransformation in the liver. The pharmacokinetics of dexmedetomidine were significantly affected by hepatic insufficiency. The clearance of dexmedetomidine in patients with severe hepatic failure decreased by 50% compared with controls. We tested the hypothesis that the pharmacokinetics of dexmedetomidine would be affected by obstructive jaundice. The prospective registration number of clinical trial is ChiCTR-IPR-15007572. METHODS: 18 patients with obstructive jaundice and 12 non-jaundiced patient controls received dexmedetomidine, 1 µg/kg, over 10 min. Arterial blood samples were drawn before, during, and up to 5 h after the infusion. Plasma dexmedetomidine concentrations were determined by 1290 infinity high performance liquid chromatography coupled with 6470 tandem mass spectrometry. The relevant pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 7.0. RESULTS: Plasma clearance of dexmedetomidine was decreased by 33.3% in the obstructive jaundice group as compared with the control group (0.0068±0.0017 vs. 0.0102±0.0033 L/kg/min; P = 0.002). Volume of distribution was decreased by 29.2% in the obstructive jaundice group as compared with the control group (1.43±0.58 vs. 2.02±0.84 L/kg; P = 0.041). CONCLUSIONS: This study demonstrates that the clearance and distribution volume of dexmedetomidine were decreased in patients with obstructive jaundice. It may be advisable to adjust the dose of dexmedetomidine in those patients.

Electroencephalographic Arousal Patterns Under Dexmedetomidine Sedation.

BACKGROUND: The depth of dexmedetomidine-induced sedation is difficult to assess without arousing the patient. We evaluated frontal electroencephalogram (EEG) as an objective measure of dexmedetomidine-induced sedation. Our aims were to characterize the response patterns of EEG during a wide range of dexmedetomidine-induced sedation and to determine which spectral power best correlated with assessed levels of dexmedetomidine-induced sedation. METHODS: Sedline EEG sensor was positioned on the forehead of 16 volunteers. Frontal EEG data were collected at 250 Hz using the Sedline monitor. A computer-controlled infusion pump was used to infuse dexmedetomidine to four 15-minute target plasma concentrations of 0.3, 0.6, 1.2, and 2.4 ng/mL. Arterial blood samples for dexmedetomidine plasma concentration and sedation (self-reported numerical rating scale) and arousal were measured at baseline and at the end of each infusion step. The EEG signal was used to estimate spectral power in sequential 4-second data segments with 75% overlap for 3 power bands: delta = 0.5-1.5 Hz, alpha = 9-14 Hz, beta = 15-24 Hz. We quantified the relationships among the plasma concentrations of dexmedetomidine, level of sedation, and various EEG parameters. RESULTS: EEG data at the end of the dexmedetomidine infusion steps show progressive loss of high frequencies (beta) and increase in alpha and delta powers, with increasing dexmedetomidine concentrations. Beta prearousal spectral power was best in predicting dexmedetomidine-induced level of sedation (R = -0.60, 95% CI, -0.43 to -0.75). The respective values for delta and alpha powers were R = 0.28 (95% CI, 0.03-0.45) and R = 0.16 (95% CI, -0.09 to 0.38). When the beta power has dropped below -16 dB or the delta power is above 15 dB, the subjects show moderate to deep levels of sedation. When awakening the subject, there is a reduction in power in the delta and alpha bands at the 0.6, 1.2, and 2.4 ng/mL dexmedetomidine target levels (P < .001 for all). In beta band, there is a rapid awakening-induced increase in power (P < .001) followed by a slow return toward baseline values. After arousing the subjects, the EEG powers returned toward baseline values significantly slower than our clinical observation of the subjects' wakefulness would have suggested. CONCLUSIONS: Using a wide range of dexmedetomidine doses, we found that frontal EEG beta power of less than -16 dB and/or a delta power of over 15 dB was associated with a state of moderate to deep sedation and that poststimulus return of EEG powers toward baseline values took significantly longer than expected from observation of the arousal response. It is unclear whether these observations are robust enough for clinical applicability.

Spoken words are processed during dexmedetomidine-induced unresponsiveness.

BACKGROUND: Studying the effects of anaesthetic drugs on the processing of semantic stimuli could yield insights into how brain functions change in the transition from wakefulness to unresponsiveness. Here, we explored the N400 event-related potential during dexmedetomidine- and propofol-induced unresponsiveness. METHODS: Forty-seven healthy subjects were randomised to receive either dexmedetomidine (n=23) or propofol (n=24) in this open-label parallel-group study. Loss of responsiveness was achieved by stepwise increments of pseudo-steady-state plasma concentrations, and presumed loss of consciousness was induced using 1.5 times the concentration required for loss of responsiveness. Pre-recorded spoken sentences ending either with an expected (congruous) or an unexpected (incongruous) word were presented during unresponsiveness. The resulting electroencephalogram data were analysed for the presence of the N400 component, and for the N400 effect defined as the difference between the N400 components elicited by congruous and incongruous stimuli, in the time window 300-600 ms post-stimulus. Recognition of the presented stimuli was tested after recovery of responsiveness. RESULTS: The N400 effect was not observed during dexmedetomidine- or propofol-induced unresponsiveness. The N400 component, however, persisted during dexmedetomidine administration. The N400 component elicited by congruous stimuli during unresponsiveness in the dexmedetomidine group resembled the large component evoked by incongruous stimuli at the awake baseline. After recovery, no recognition of the stimuli heard during unresponsiveness occurred. CONCLUSIONS: Dexmedetomidine and propofol disrupt the discrimination of congruous and incongruous spoken sentences, and recognition memory at loss of responsiveness. However, the processing of words is partially preserved during dexmedetomidine-induced unresponsiveness. CLINICAL TRIAL REGISTRATION: NCT01889004.

Impact of dexmedetomidine on hemodynamics in rabbits.

PURPOSE: To evaluate the effects of single intravenous administration of Dexmedetomidine (DEX) on hemodynamics in rabbits. METHODS: A total of 32 New Zealand white rabbits were randomly divided into the control group (Group C), Group D1 (2.75 µg/kg), Group D2 (5.5 µg/kg), and Group D3 (8.25 µg/kg) to compare systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), central venous pressure (CVP), left ventricular systolic pressure (LVSP), left ventricular end-stage diastolic pressure (LVEDP), left ventricular developmental pressure (LVDP), +dp/dtmax, -dp/dtmax, and t-dp/dtmax at different time points. RESULTS: The levels of SBP, DBP, HR, LVSP, and LVEDP in Group D1, D2, and D3 were lower than that of Group C from T1 to T5 (P<0.05), but there was no significant difference at T6 and T7 (P>0.05). Compared with T0, the levels of SBP, DBP, HR, LVSP, LVEDP, and left arterial pressure (LAP) from T1 to T7 were decreased (P<0.05), but there was no significant difference in the other indexes (P>0.05). CONCLUSION: Dexmedetomidine can decrease blood pressure and heart rate in rabbits in a dose-dependent manner, but there is no effect on the myocardial systolic and diastolic function.

Subcutaneously administered dexmedetomidine is efficiently absorbed and is associated with attenuated cardiovascular effects in healthy volunteers.

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% (AUC0-∞ 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 .

Does intranasal dexmedetomidine provide adequate plasma concentrations for sedation in children: a pharmacokinetic study.

BACKGROUND: Atomised intranasal dexmedetomidine administration is an attractive option when sedation is required for paediatric diagnostic procedures, as vascular access is not required. The risk of haemodynamic instability caused by dexmedetomidine necessitates better understanding of its pharmacokinetics in young children. To date, intranasal dexmedetomidine pharmacokinetics has only been studied in adults. METHODS: Eighteen paediatric patients received dexmedetomidine 1 or 2 µg kg-1 intranasally or 1 µg kg-1 i.v. Plasma concentrations were determined by liquid chromatography/mass spectrometry. Non-compartmental analysis provided estimates of Cmax and Tmax. Volume of distribution, clearance, and bioavailability were estimated by simultaneous population PK analysis of data after intranasal and i.v. administration. Dexmedetomidine plasma concentration-time profiles were evaluated by simulation for intranasal and i.v. administration. RESULTS: An average peak plasma concentration of 199 pg ml-1 was achieved 46 min after 1 µg kg-1 dosing and 355 pg ml-1 was achieved 47 min after 2 µg kg-1 dosing. A two-compartment pharmacokinetic model, with allometrically scaled parameters, adequately described the data. Typical bioavailability was 83.8% (95% confidence interval 69.5-98.1%). CONCLUSION: Mean arterial plasma concentrations of dexmedetomidine in infants and toddlers approached 100 pg ml-1, the low end reported for sedative efficacy, within 20 min of an atomised intranasal administration of 1 µg kg-1. Doubling the dose to 2 µg kg-1 reached this plasma concentration within 10 min and achieved almost twice the peak concentration. Peak plasma concentrations with both doses were reached within 47 min of intranasal administration, with an overall bioavailability of 84%.