Determination of the ED95 of a single bolus dose of dexmedetomidine for adequate sedation in obese or nonobese children and adolescents.

BACKGROUND: With the increasing prevalence of children who are overweight and with obesity, anaesthesiologists must determine the optimal dosing of medications given the altered pharmacokinetics and pharmacodynamics in this population. We therefore determined the single dose of dexmedetomidine that provided sufficient sedation in 95% (ED95) of children with and without obesity as measured by a minimum Ramsay sedation score (RSS) of 4. METHODS: Forty children with obesity (BMI >95th percentile for age and gender) and 40 children with normal weight (BMI 25th-84th percentile), aged 3-17 yr, ASA physical status 1-2, undergoing elective surgery, were recruited. The biased coin design was used to determine the target dose. Positive responses were defined as achievement of adequate sedation (RSS ≥4). The initial dose for both groups was dexmedetomidine 0.3 µg kg-1 i.v. infusion for 10 min. An increment or decrement of 0.1 µg kg-1 was used depending on the responses. Isotonic regression and bootstrapping methods were used to determine the ED95 and 95% confidence intervals (CIs), respectively. RESULTS: The ED95 of dexmedetomidine for adequate sedation in children with obesity was 0.75 µg kg-1 with 95% CI of 0.638-0.780 µg kg-1, overlapping the CI of the ED95 estimate of 0.74 µg kg-1 (95% CI: 0.598-0.779 µg kg-1) for their normal-weight peers. CONCLUSIONS: The ED95 values of dexmedetomidine administered over 10 min were 0.75 and 0.74 µg kg-1 in paediatric subjects with and without obesity, respectively, based on total body weight. CLINICAL TRIAL REGISTRATION: ChiCTR1800014266.

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.

Determination of dexmedetomidine using high performance liquid chromatography coupled with tandem mass spectrometric (HPLC-MS/MS) assay combined with microdialysis technique: Application to a pharmacokinetic study.

Dexmedetomidine, as a safe sedative, mainly exerts on the central nervous system particularly in the locus coeruleus producing arousable sedation with potential analgesic and anxiolytic effects. The quantification and pharmacokinetic investigation of dexmedetomidine in the central nervous system have been described rarely. In order to estimate the unbound dexmedetomidine concentrations in brain extracellular fluid and blood simultaneously, we employed microdialysis technique as a sampling method and primarily established a rapid, sensitive and selective high-performance liquid chromatography coupled with tandem mass spectrometry method (HPLC-MS/MS). Dexmedetomidine and the internal standard (dexmedetomidine-d4) were extracted in liquid-liquid extraction procedure with ethyl acetate from 10 µL of alkalinized microdialysate sample. After evaporation under nitrogen at room temperature, the analytes were reconstituted in acetonitrile and transferred to be detected. HPLC was performed on an Agilent Poroshell 120 Hilic column (4.6 × 100 mm, 2.7 µm) with isocratic elution at a flow rate of 0.3 mL/min by 0.1% formic acid/acetonitrile (60:40, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction monitoring (MRM) mode using the respective [M+H]+ ions m/z 201.2 to m/z 95.1 for DEX and m/z 205.2 to m/z 99.1 for IS (DEX-d4). The concentration-response relationship was of good linearity over a concentration range of 1.00-1000.00 ng/mL with the correlation coefficient above 0.999. The lower limit of quantification was 1.00 ng/mL with a relative standard deviation of less than 20%. The intra- and inter-day accuracy were within ±5.00% and precision was <7.23%. The recoveries of dexmedetomidine in microdialysates were 76.61-93.38%. The validated HPLC-MS/MS method has been successfully applied to study the pharmacokinetics of dexmedetomidine in rats after a caudal vein administration.

Pharmacokinetics and clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia.

This study determined the pharmacokinetics and compared the clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia. Six healthy horses aged 8.5 ± 3 years and weighing 462 ± 50 kg were anesthetized with isoflurane for 2 hr under standard conditions on two occasions one-week apart. In recovery, horses received 200 µg/kg xylazine or 0.875 µg/kg dexmedetomidine intravenously and were allowed to recover without assistance. These doses were selected because they have been used for postanesthetic sedation in clinical and research studies. Serial venous blood samples were collected for quantification of xylazine and dexmedetomidine, and the pharmacokinetic parameters were calculated. Two individuals blinded to treatment identity evaluated recovery quality with a visual analog scale. Times to stand were recorded. Results (mean ± SD) were compared using paired t tests or Wilcoxon signed-ranked test with p < .05 considered significant. Elimination half-lives (62.7 ± 21.8 and 30.1 ± 8 min for xylazine and dexmedetomidine, respectively) and steady-state volumes of distribution (215 ± 123 and 744 ± 403 ml/kg) were significantly different between xylazine and dexmedetomidine, whereas clearances (21.1 ± 17.3 and 48.6 ± 28.1 ml/minute/kg), times to stand (47 ± 24 and 53 ± 12 min) and recovery quality (51 ± 24 and 61 ± 22 mm VAS) were not significantly different. When used for postanesthetic sedation following isoflurane anesthesia in healthy horses, dexmedetomidine displays faster plasma kinetics but is not associated with faster recoveries compared to xylazine.

Dexmedetomidine protects PC12 cells from oxidative damage through regulation of miR-199a/HIF-1α.

Background: Although dexmedetomidine (Dex) has a significant neuroprotective effect in various nerve-damage models, the exact mechanism of which Dex protects cells from oxidative damage is not fully clear. This article recommended the protective effect of Dex on oxidative damage in PC12 cells.Methods: The PC12 cells were incubated by hydrogen peroxide (H2O2) for 24 h and pre-treated by Dex for 30 min. Cell viability, apoptosis, HIF-1α expression and ROS level were detected by CCK-8, apoptosis assay, Western blot and ROS assay, respectively. The miR-199a expression was tested by qRT-PCR. Targeting relationship between miR-199a and HIF-1α was performed by dual luciferase activity assay. The activation of PI3K/AKT/mTOR and Wnt/ß-catenin pathways was tested by western blot.Results: Dex attenuated H2O2-induced oxidative damage, including the decline of cell viability, the raise of apoptosis and the generation of ROS in PC12 cells by down-regulating miR-199a expression. Moreover, Dex up-regulated HIF-1α expression via decreasing miR-199a level in PC12 cells and miR-199a targeted the 3'-UTR of HIF-1α. In addition, Dex activated PI3K/AKT/mTOR and Wnt/ß-catenin pathways by declining miR-199a level.Conclusions: This article illustrated the protective effect of Dex on oxidative damage in PC12 cells. Furthermore, Dex prevented PC12 cells from oxidative injury through the regulation of miR-199a/HIF-1α.

Pharmacokinetics and Sedative Effects of Intranasal Dexmedetomidine in Ambulatory Pediatric Patients.

BACKGROUND: Our aim was to characterize the pharmacokinetics and sedative effects of intranasally (IN) administered dexmedetomidine used as an adjuvant in pediatric patients scheduled for magnetic resonance imaging (MRI) requiring sedation. METHODS: This was an open-label, single-period study without randomization. Pediatric patients from 5 months to 11 years of age scheduled for MRI and receiving IN dexmedetomidine for premedication as part of their care were included in this clinical trial. Single doses of 2-3 µg·kg of dexmedetomidine were applied IN approximately 1 hour before MRI. Five or 6 venous blood samples were collected over 4 hours for dexmedetomidine concentration analysis. Sedation was monitored with Comfort-B scores, and vital signs were recorded. Pharmacokinetic variables were calculated with noncompartmental methods and compared between 3 age groups (between 1 and 24 months, from 24 months to 6 years, and over 6-11 years). RESULTS: We evaluated 187 consecutive patients for suitability, of which 132 were excluded. Remaining 55 patients were recruited, of which 5 were excluded before the analysis. Data from 50 patients were analyzed. The average (standard deviation [SD]) dose-corrected peak plasma concentration (Cmax) was 0.011 liter (0.0051), and the median (interquartile range [IQR]) time to reach peak concentration (tmax) was 37 minutes (30-45 minutes). There was negative correlation with Cmax versus age (r = -0.58; 95% confidence interval [CI], -0.74 to -0.37; P < .001), but not with tmax (r = -0.14; 95% CI, 0.14-0.39; P = .35). Dose-corrected areas under the concentration-time curve were negatively correlated with age (r = -0.53; 95% CI, 0.70 to -0.29; P < .001). Median (IQR) maximal reduction in Comfort-B sedation scores was 8 (6-9), which was achieved 45 minutes (40-48 minutes) after dosing. Median (IQR) decrease in heart rate was 15% (9%-23%) from the baseline. CONCLUSIONS: Dexmedetomidine is relatively rapidly absorbed after IN administration and provides clinically meaningful but short-lasting sedation in pediatric patients.

Target-controlled infusion of dexmedetomidine effect-site concentration for sedation in patients undergoing spinal anaesthesia.

WHAT IS KNOWN AND OBJECTIVE: Dexmedetomidine has been a preferred sedative for patients undergoing regional anaesthesia and is mostly administered via conventional zero-order infusion. Recently, a pharmacokinetic-pharmacodynamic (PKPD) model of dexmedetomidine has been published, but no external validation has been reported in clinical trials. We aimed to administer target-controlled infusion (TCI) of dexmedetomidine at the effect-site concentration (Ce) to patients undergoing spinal anaesthesia and investigate the relationship between dexmedetomidine Ce and the sedative effects. METHODS: Forty-five patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. After confirmation of sensory block level, we initiated effect-site TCI of dexmedetomidine using Colin's model and assessed sedation levels using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and bispectral index (BIS) with each stepwise increase in the dexmedetomidine Ce. We used a non-linear mixed-effects model to determine the PD relationships between the dexmedetomidine Ce and sedation level. RESULTS: The dexmedetomidine Ce associated with 50% probability (Ce50 ) of the MOAA/S scale ≤4, 3 and 2 was 0.57, 0.89 and 1.19 ng/mL, respectively. Mean dexmedetomidine Ce when BIS decreased ≤70 was 0.99 ± 0.15 ng/mL. As dexmedetomidine Ce increased, the MOAA/S scale decreased significantly (correlation coefficient [r] = -.832, P < .0001). BIS decreased significantly with increasing dexmedetomidine Ce (r = -.811, P < .0001) and decreasing MOAA/S scale (r = .838, P < .0001). The most common side effects were hypertension (26.67%) and bradycardia (20%). WHAT IS NEW AND CONCLUSION: We applied effect-site TCI of dexmedetomidine in patients undergoing spinal anaesthesia for the first time. Dexmedetomidine Ce correlated significantly with MOAA/S scale and BIS, and was 0.89 and 1.19 ng/mL for moderate and deep sedation, respectively.

Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass.

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.

Probing the Role of Ion-Pair Strategy in Controlling Dexmedetomidine Penetrate Through Drug-in-Adhesive Patch: Mechanistic Insights Based on Release and Percutaneous Absorption Process.

The purpose of present study was to develop a controlled release drug-in-adhesive patch for transdermal delivery of dexmedetomidine (Dex) using ion-pair technique. Based on the in vitro transdermal experiment, the role of ion-pair on the Dex release behavior and percutaneous absorption process was also investigated. Fourier transform infrared spectroscopy (FTIR), molecular modeling, differential scanning calorimetry (DSC), and rheological test were conducted to probe the effect of ion-pair on the Dex release from patch. Besides, the tape stripping test, attenuated total reflectance Fourier transform infrared (ATR-FTIR), and molecular simulation were carried out to elaborate the action of ion-pair on the Dex percutaneous permeation process. Results showed that the optimized patch prepared with Dex-salicylic acid (SA) showed zero-order skin permeation profile within 24 h; Dex-SA had greater hydrogen bonding formation potential with pressure sensitive adhesive (PSA) than Dex, which resulted in the decrease in the formation ability of free volume of PSA and the increase with the improvement of mechanical strength and chain stiffness of PSA and thus controlled the release rate of Dex from transdermal patch. Besides, the physicochemical properties of Dex such as molecular weight and octanol/water partition coefficient were changed after forming ion-pair with SA, which decreased the permeation ability of Dex. In conclusion, a controlled release drug-adhesive patch for Dex was developed and the mechanism study of ion-pair on the Dex release and percutaneous permeation process was proposed at molecular level.

Effects of serum from breast cancer surgery patients receiving perioperative dexmedetomidine on breast cancer cell malignancy: A prospective randomized controlled trial.

Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α2 -AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 µg kg-1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF-7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF-7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF-7 cells. Clinical trial registration: NCT03108937.

Effect of bupivacaine versus bupivacaine plus intrathecal dexmedetomidine in postoperative pain

Background: Pain is defined as "unpleasant sensory and sensory experience", associated with actual or potential tissue domage or described in terms of such damage. Objetive: To assess the effect of bupivacaine versus bupivacaine plus intrathecal dexmedetomidine in postoperative pain. Patients and method: An experimental design was made of a controlled clinical trial type, in patients scheduled for lower abdomen surgery or lower extremities. A sample of 60 patients was studied during the period from October 1 to december 15, 2018, who agreed to participate in the study through of signing consent under information. Results: It was observed that the time of the rescue analgesia was prolonged in more than 120 min in the case of dexmedetomidine when compared with bupivacaine (p<0.0001); also VAS scores at the time of analgesia rescue for the group with dexmedetomidine were 3.71 ± 1.27 and in the bupivacaine group of 5.7 ± 1.59, the difference of two pints of the VAS (p= <0.001) was significant, which demonstrates that dexmedetomidine is effective for prolong postoperative analgesia and decrease the analgesia requirements. Conclusions: Dexmedetomidine at a dose of 5 ug associated with bupivacaine administered intrathecally is more Effective in postoperative analgesia compared with this substance alone in abdominal surgery inferior and lower extremities (AU)

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.

Recovery time after oral and maxillofacial ambulatory surgery with dexmedetomidine: an observational study.

OBJECTIVES: To evaluate the relationship between pharmacokinetic descriptors of dexmedetomidine (predicted area under the curve during the procedure, predicted plasma level at the end of the procedure, and duration of procedure) and sedation depth (proportion of time with bispectral index < 85 during the procedure) with recovery time after ambulatory procedures. MATERIALS AND METHODS: Clinical observational study of patients undergoing oral and maxillofacial ambulatory surgery with dexmedetomidine as sole sedative agent. Patients received a loading dose of dexmedetomidine (0.25-1 µg kg-1) followed by a maintenance infusion (0.2-1.4 µg kg-1 h-1) to keep a bispectral index < 85 until 5 min before the end of the procedure, and were transferred to a post-anesthesia care unit until criteria for discharge were met. RESULTS: Data from 75 patients was analyzed. Sedation depth was directly associated with recovery time (Pearson correlation coefficient [r] = 0.26; p = 0.024). Around 7% of the variation in recovery time was explained by the proportion of time with bispectral index < 85. No association with procedure duration (r = 0.01; p = 0.9), predicted area under the curve (r = 0.1; p = 0.4), or predicted plasma level of dexmedetomidine at the end of the procedure (r = 0.12; p = 0.3) with recovery time was observed. CONCLUSIONS: Sedation depth with dexmedetomidine could play a role in increasing recovery time after oral and maxillofacial ambulatory surgery. In our study, the pharmacokinetic descriptors of dexmedetomidine did not seem to influence recovery time. CLINICAL RELEVANCE: Sedation depth with dexmedetomidine could play a role in increasing recovery time after ambulatory procedures.

Enhanced Perioperative Safety and Comfort During Airway-Related Surgeries and Procedures With Dexmedetomidine-A Brief Review and Clinical Practice Experience.

Dexmedetomidine, an α-2 adrenergic receptor agonist, provides analgesia, sedation, anxiolysis, sympatholysis and anesthetic-sparing effect, without inducing significant respiratory depression. Due to these properties, its clinical use is no longer limited to serving as a sedative agent in the intensive care unit. Proper airway management and the avoidance of cardiac and respiratory complications are common goals of everyday anesthesia practice. Ensuring airway safety is pivotal during the anesthesia stages of induction, maintenance and recovery. In this review, we focus on the advantages of dexmedetomidine in awake fiberoptic intubation (AFOI), diagnostic examinations and surgeries of patients with obstructed airways, and reducing emergence delirium effectively without causing further adverse events. With increasing implementation in different anesthetic scenarios, dexmedetomidine provides a favorable option to enhance patient safety and comfort.

Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication.

BACKGROUND: Dexmedetomidine is a widely used sedative in clinic, which is mainly metabolized by cytochrome P450 2A6 (CYP2A6). Dexmedetomidine was rarely reported for off-label usage of premedication, but lacking relevant pharmacokinetic investigations. Therefore, our study determined the dexmedetomidine pharmacokinetics of CYP2A6*4 allele in Chinese patients pretreated with dexmedetomidine whose mutation frequency of CYP2A6*4 are high, in order to provide clinical references. METHODS: Thirty-one elective surgery patients received premedication with 0.5 µg/kg dexmedetomidine via intravenous pump. Their plasma concentrations at multiple time-points and polymorphism of CYP2A6*4 were determined and statistically analyzed. RESULTS: 9 patients were *1/*4 or *4/*4, and 22 patients were *1/*1. The main pharmacokinetic parameters were area under curve (AUC) 1396.19 ± 332.47h· ng· l-1, peak blood concentration (Cmax) 495.50 ± 104.90ng· l-1, distribution volume (V) 0.68 ± 0.20 L/kg, clearance (CL) 0.38 ± 0.11 L/h/kg, distribution half-life (t1/2α) 0.05 ± 0.01h, elimination half-life (t1/2ß) 2.53 ± 0.04h. No significant pharmacokinetic differences were found among CYP2A6*1/*1, *1/*4, and *4/*4 patients. CONCLUSIONS: In Chinese patients pretreated with dexmedetomidine, T1/2ß was consistent with that published, but T1/2α, V and Cl were lower. It was unnecessary to consider the mutation when developing the precision regimen of dexmedetomidine.

Efficacy and pharmacokinetics of bupivacaine with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy.

The aim of this study was to determine the efficacy and pharmacokinetics of bupivacaine in combination with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy. Sixteen healthy adult cats (3.3 ± 0.6 kg) were included in a prospective, randomized, masked clinical trial after obtaining owners' consent. Anesthetic protocol included buprenorphine-propofol-isoflurane. Meloxicam [0.2 mg/kg body weight (BW)] was administered subcutaneously before surgery. Cats were randomly divided into 2 groups to receive 1 of 2 treatments. Intraperitoneal bupivacaine 0.25% (2 mg/kg BW) was administered with epinephrine (BE group; 2 µg/kg BW) or dexmedetomidine (BD group; 1 µg/kg BW) before ovariohysterectomy (n = 8/group). A catheter was placed in the jugular vein for blood sampling. Blood samples were collected for up to 8 h after bupivacaine was administered. Plasma concentrations and pharmacokinetics of bupivacaine were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) and non-compartmental model, respectively. Pain was evaluated using the UNESP-Botucatu multidimensional composite pain scale (MCPS), the Glasgow composite feline pain scale (GPS), and a dynamic visual analog scale up to 8 h after extubation. Rescue analgesia was provided with buprenorphine if MCPS was ≥ 6. Repeated measures linear models were used for analysis of pain and sedation scores (P < 0.05). Maximum bupivacaine plasma concentrations (Cmax) for BE and BD were 1155 ± 168 ng/mL and 1678 ± 364 ng/mL (P = 0.29) at 67 ± 13 min (Tmax) and 123 ± 59 min (P = 0.17), respectively. Pharmacokinetic parameters and pain scores were not different between treatments (P > 0.05). One cat in the BE group received rescue analgesia (P = 0.30). Intraperitoneal bupivacaine with epinephrine or dexmedetomidine produced concentrations below toxic levels and similar analgesic effects. It is therefore safe to administer these drug combinations in cats undergoing ovariohysterectomy.

L'objectif de cette étude était de déterminer la pharmacocinétique de la bupivacaïne avec de l'épinéphrine ou de la dexmedetomidine après son administration intrapéritonéale chez des chats subissant une ovariohystérectomie. Seize chats adultes en bonne santé (3,3 ± 0,6 kg) ont été inclus dans un essai prospectif, randomisé et «à l'aveugle¼. Le protocole anesthésique comprenait la buprénorphine-propofol-isoflurane. Méloxicam (0,2 mg/kg) a été administré par voie sous-cutanée avant la chirurgie. Un cathéter a été placé dans la veine jugulaire pour l'échantillonnage du sang. La bupivacaïne 0,25 % a été administrée intrapéritonéale (2 mg/kg) avec de l'épinéphrine (BE, 2 µg/kg) ou de la dexmedetomidine (BD, 1 µg/kg) avant l'ovariohystérectomie (n = 8/groupe). Des échantillons de sang ont été prélevés jusqu'à 8 heures après l'administration de bupivacaïne. Les concentrations plasmatiques et les données pharmacocinétiques de la bupivacaïne ont été déterminées par l'aide de la chromatographie liquide-spectrométrie de masse (LC-MS) et la représentation graphique avec un modèle noncompartimentale. La douleur a été évaluée à l'aide de l'échelle composite multidimensionnelle de la douleur (MCPS), de l'échelle composite de Glasgow de la douleur féline (GPS) et d'une échelle visuelle analogique dynamique jusqu'à 8 heures après l'extubation. L'analgésie de secours a été fournie avec la buprénorphine si MCPS ≥ 6. Les modèles linéaires de mesures répétées ont été utilisés pour l'analyse des scores de douleur et de sédation (P < 0,05). Les concentrations plasmatiques maximales de bupivacaïne (Cmax) pour BE et BD étaient de 1155 ± 168 ng/mL et 1678 ± 364 ng/mL (P = 0,29) à 67 ± 13 minutes (Tmax) et 123 ± 59 minutes (P = 0,17), respectivement. Les paramètres pharmacocinétiques et les scores de douleur n'étaient pas différents entre les traitements (P > 0,05). Un chat de BE a reçu analgésie de secours (P = 0,30). La bupivacaïne avec de l'épinéphrine ou de la dexmedetomidine intra-péritonéale a produit des concentrations inférieures aux niveaux toxiques et des effets analgésiques similaires. Il est donc sécuritaire d'administrer ces combinaisons de médicaments chez les chats subissant une ovariohysterectomie.(Traduit par les auteurs).

Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery.

BACKGROUND: Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures. METHODS: Thirty children 2-18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 µg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK-PD models were constructed using the Monolix program. RESULTS: A 2-compartment model adequately described the concentration-time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK-PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml. CONCLUSIONS: Our results suggest that in Mexican children 2-18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.

Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients.

BACKGROUND: Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance. METHODS: Forty patients, ASA I-III, 18-60 yr old, weighing 47-126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X-ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non-linear mixed-effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (ΔOFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. RESULTS: A total of 637 dexmedetomidine serum samples were obtained. A two-compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (ΔOFV=-5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (ΔOFV<3.84). CONCLUSIONS: We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance. CLINICAL TRIAL REGISTRATION: NCT02557867.