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.

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 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 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.

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.

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.

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.

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.

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.

Differentiating Drug-related and State-related Effects of Dexmedetomidine and Propofol on the Electroencephalogram.

BACKGROUND: Differentiating drug-related changes and state-related changes on the electroencephalogram during anesthetic-induced unconsciousness has remained a challenge. To distinguish these, we designed a rigorous experimental protocol with two drugs known to have distinct molecular mechanisms of action. We hypothesized that drug- and state-related changes can be separated. METHODS: Forty-seven healthy participants were randomized to receive dexmedetomidine (n = 23) or propofol (n = 24) as target-controlled infusions until loss of responsiveness. Then, an attempt was made to arouse the participant to regain responsiveness while keeping the drug infusion constant. Finally, the concentration was increased 1.5-fold to achieve presumable loss of consciousness. We conducted statistical comparisons between the drugs and different states of consciousness for spectral bandwidths, and observed how drug-induced electroencephalogram patterns reversed upon awakening. Cross-frequency coupling was also analyzed between slow-wave phase and alpha power. RESULTS: Eighteen (78%) and 10 (42%) subjects were arousable during the constant drug infusion in the dexmedetomidine and propofol groups, respectively (P = 0.011 between the drugs). Corresponding with deepening anesthetic level, slow-wave power increased, and a state-dependent alpha anteriorization was detected with both drugs, especially with propofol. The slow-wave and frontal alpha activities were momentarily disrupted as the subjects regained responsiveness at awakening. Negative phase-amplitude coupling before and during loss of responsiveness frontally and positive coupling during the highest drug concentration posteriorly were observed in the propofol but not in the dexmedetomidine group. CONCLUSIONS: Electroencephalogram effects of dexmedetomidine and propofol are strongly drug- and state-dependent. Changes in slow-wave and alpha activity seemed to best detect different states of consciousness.

Sedative Plasma Concentrations and Delirium Risk in Critical Illness.

BACKGROUND: The relationship between plasma concentration of sedatives and delirium is unknown. OBJECTIVE: We hypothesized that higher plasma concentrations of lorazepam are associated with increased delirium risk, whereas higher plasma concentrations of dexmedetomidine are associated with reduced delirium risk. METHODS: This prospective cohort study was embedded in a double-blind randomized clinical trial, where ventilated patients received infusions of lorazepam and dexmedetomidine. Plasma concentrations of these drugs and delirium assessments were measured at least daily. A multivariable logistic regression model accounting for repeated measures was used to analyze associations between same-day plasma concentrations of lorazepam and dexmedetomidine (exposures) and the likelihood of next-day delirium (outcome), adjusting for same-day mental status (delirium, coma, or normal) and same-day fentanyl doses. RESULTS: This critically ill cohort (n = 103) had a median age of 60 years (IQR: 48-66) with APACHE II score of 28 (interquartile range [IQR] = 24-32), where randomization resulted in assignment to lorazepam (n = 51) or dexmedetomidine (n = 52). After adjusting for same-day fentanyl dose and mental status, higher plasma concentrations of lorazepam were associated with increased probability of next-day delirium (comparing 500 vs 0 ng/mL; odds ratio [OR] = 13.2; 95% CI = 1.4-120.1; P = 0.02). Plasma concentrations of dexmedetomidine were not associated with next-day delirium (comparing 1 vs 0 ng/mL; OR = 1.1; 95% CI = 0.9-1.3; P = 0.45). CONCLUSIONS: In critically ill patients, higher lorazepam plasma concentrations were associated with delirium, whereas dexmedetomidine plasma concentrations were not. This implies that the reduced delirium risk seen in patients sedated with dexmedetomidine may be a result of avoidance of benzodiazepines, rather than a dose-dependent protective effect of dexmedetomidine.

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%.

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.

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.

Dexmedetomidine as a part of general anaesthesia for caesarean delivery in patients with pre-eclampsia: A randomised double-blinded trial.

BACKGROUND: During general anaesthesia, endotracheal intubation of patients with pre-eclampsia causes stimulation of the sympathetic nervous system and catecholamine release, which may lead to maternal and neonatal complications. OBJECTIVE: To attenuate both the stress response and the haemodynamic response to tracheal intubation in patients with pre-eclampsia. DESIGN: A randomised, double-blind, controlled study. SETTING: Single University Hospital. PATIENTS: Sixty patients aged 18 to 45 years with pre-eclampsia receiving general anaesthesia for caesarean section. INTERVENTIONS: The patients were randomly allocated to three groups. Groups D1and D2 received an infusion of dexmedetomidine 1 µg kg over the 10 min before induction of general anaesthesia, then 0.4 and 0.6 µg kg h dexmedetomidine, respectively. Group C received equivalent volumes of 0.9% saline. MAIN OUTCOME MEASURES: The primary outcome was the effect of dexmedetomidine on mean arterial blood pressure measured before induction of general anaesthesia at 1 and 5 min after intubation, and then every 5 min until 10 min after extubation. The secondary outcomes were blood glucose and serum cortisol (measured before induction of general anaesthesia, and at 1 and 5 min after intubation), postoperative visual analogue pain scores, time to first request for analgesia, the total consumption of analgesia, Ramsay sedation score, maternal and placental vein blood serum levels of dexmedetomidine and neonatal Apgar score at 1 and 5 min. RESULTS: At all assessment times, the mean arterial pressures were significantly lower in the dexmedetomidine groups than in the control group. Compared with group C, the heart rate was significantly lower in both groups D1 and D2. In group D2, the heart rate was lower than in group D1. Serum glucose and cortisol were significantly higher in the controls than in either group D1 or D2. Group D2 patients were significantly more sedated on arrival in the recovery room followed by D1. Time to first analgesia was significantly longer in groups D2 and D1 than in group C, and the visual analogue pain scores were significantly lower in groups D1 and D2 than in group C at 1, 2, 3 and 5 h. Total morphine consumption was significantly lower in groups D1 and D2 than in the control group. There was no difference in Apgar scores across the three groups despite significantly higher dexmedetomidine concentrations in group D2 (both maternal and placental vein) than in group D1. CONCLUSION: Administration of dexmedetomidine in doses 0.4 and 0.6 µg kg h was associated with haemodynamic and hormonal stability, without causing significant adverse neonatal outcome. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR201706002303170), (www.pactr.org).

Effect of dexmedetomidine on the minimum infusion rate of propofol preventing movement in dogs.

OBJECTIVE: To determine the effect of dexmedetomidine on induction dose and minimum infusion rate of propofol preventing movement (MIRNM). STUDY DESIGN: Randomized crossover, unmasked, experimental design. ANIMALS: Three male and three female healthy Beagle dogs weighing 10.2 ± 2.8 kg. METHODS: Dogs were studied on three occasions at weekly intervals. Premedications were 0.9% saline (treatment P) or dexmedetomidine (1 µg kg-1, treatment PLD; 2 µg kg-1, treatment PHD) intravenously. Anesthesia was induced with propofol (2 mg kg-1 and then 1 mg kg-1 every 15 seconds) until intubation. Anesthesia was maintained for 90 minutes in P with propofol (0.5 mg kg-1 minute-1) and saline, in PLD with propofol (0.35 mg kg-1 minute-1) and dexmedetomidine (1 µg kg-1 hour-1), and in PHD with propofol (0.3 mg kg-1 minute-1) and dexmedetomidine (2 µg kg-1 hour-1). The stimulus (50 V, 50 Hz, 10 ms) was applied to the antebrachium, and propofol infusion was increased or decreased by 0.025 mg kg-1 minute-1 based on a positive or negative response, respectively. Data were analyzed using a mixed-model anova and presented as mean ± standard error. RESULTS: Propofol induction doses were 8.68 ± 0.57 (P), 6.13 ± 0.67 (PLD) and 4.78 ± 0.39 (PHD) mg kg-1 and differed among treatments (p < 0.05). Propofol MIRNM values were 0.68 ± 0.13, 0.49 ± 0.16 and 0.26 ± 0.05 mg kg-1 minute-1 for P, PLD and PHD, respectively. Propofol MIRNM decreased 59% in PHD (p < 0.05). Plasma propofol concentrations were 14.04 ± 2.30 (P), 11.30 ± 4.30 (PLD) and 7.96 ± 0.72 (PHD) µg mL-1 and dexmedetomidine concentrations were 0.68 ± 0.12 (PLD) and 0.89 ± 0.08 (PHD) ng mL-1 at MIRNM determination. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine (1 and 2 µg kg-1) decreased propofol induction dose. Dexmedetomidine (2 µg kg-1 hour-1) resulted in a significant decrease in propofol MIRNM.

Pharmacokinetics and sedative effects of dexmedetomidine in dairy calves.

AIMS: To evaluate the pharmacokinetics of dexmedetomidine (DEX) administered I/V at a dose of 5 µg/kg bodyweight in dairy calves and to compare the sedative effects of anaesthetic protocols involving DEX and xylazine. METHODS: Nine dairy calves, aged 17-20 days, were treated with 5 µg/kg I/V dexmedetomidine. For pharmacokinetic evaluation, blood samples were collected over 12 hours and serum samples were analysed by high performance liquid chromatography-mass spectrometry. Another nine dairy calves, aged 16-20 days, were treated with 0.2 mg/kg I/V xylazine. After both treatments, heart rate, respiratory rate and rectal temperature were measured for 20 minutes. Sedation quality and recovery times were also assessed. RESULTS: The kinetics of DEX was best described by a two-compartment model. The distribution and elimination half-lives were 8.7 (SD 5.0) and 83.5 (SD 67.5) minutes, respectively. Mean maximum concentration and body clearance were 12.5 (SD 8.6) ng/mL and 27.9 (SD 13.1) mL/minute/kg, respectively; the mean volume of distribution at steady state was 2,170.8 (SD 1,657.5) mL/kg. A decrease in heart rate was observed after treatments with both DEX and xylazine. No differences in heart or respiration rate, or rectal temperature were observed between the two treatment groups. The onset of sedation occurred after 2.7 (SD 0.67) minutes for calves treated with DEX and 2.8 (SD 0.78) minutes for calves treated with xylazine, and was characterised by a similar degree of deep sedation and ease of handling of the calves. All recoveries were eventless, and no adverse reactions were noted. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine treatment resulted in a reliable and long lasting sedation in calves, a transient decrease in heart rate and no modification in respiratory rate or rectal temperature. The results were comparable to xylazine, the most popular alpha-2-agonist among bovine practitioners. The use of DEX in dairy calves for rapid procedures such as dehorning or castration could be suggested.

Dexmedetomidine Pharmacology in Neonates and Infants After Open Heart Surgery.

BACKGROUND: Dexmedetomidine is a highly selective α2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day-1 month) and 36 evaluable infants (age, 1 month-24 months) after open heart surgery. METHODS: Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 µg/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 µg/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 µg/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 µg/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. RESULTS: Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated a plasma drug clearance of 657 × (weight/70) mL/min, intercompartmental clearance of 6780 × (weight/70) mL/min, central volume of distribution of 88 × (weight/70) L and peripheral volume of distribution of 112 × (weight/70) L for a typical subject with age >1 month with a cardiopulmonary bypass time of 60 minutes and without right-to-left intracardiac shunt. Dexmedetomidine pharmacokinetics may be influenced by age during the neonatal period, weight, total bypass time, and presence of intracardiac shunt. CONCLUSIONS: Dexmedetomidine clearance is significantly diminished in full-term newborns and increases rapidly in the first few weeks of life. The dependence of clearance on age during the first few weeks of life reflects the relative immaturity of metabolic processes during the newborn period. Continuous infusions of up to 0.3 µg/kg/h in neonates and 0.75 µg/kg/h in infants were well tolerated after open heart surgery.