Plasma Concentrations Of Dexmedetomidine Research Articles

Absorption pharmacokinetics and feasibility of intranasal dexmedetomidine in patients under general anaesthesia.

The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics. We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 μg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (CMAX) and time (TMAX) were estimated using simulation (n = 1000) with parameter estimates and their associated variability. There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) μg kg-1. CMAX 0.273 μg L-1 was achieved at 98 min after intranasal administration (TMAX). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (TABS = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable. Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after TMAX for several hours.

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants.

Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.

Pharmacokinetics of dexmedetomidine in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass.

Cardiopulmonary bypass can affect the pharmacokinetics of anesthetic agents. We aimed to evaluate the pharmacokinetics of dexmedetomidine for infants and small children undergoing cardiac surgery with cardiopulmonary bypass based on population pharmacokinetics. We enrolled 30 pediatric cardiac surgical patients in this study. After anesthetic induction with atropine (0.02 mg/kg), thiopental sodium (5mg/kg), and fentanyl (2-3μg/kg), we administered 1μg/kg of dexmedetomidine for 10min, followed by administration of 0.5μg/kg of dexmedetomidine per hour during surgery. At the initiation of cardiopulmonary bypass, 1μg/kg of dexmedetomidine was infused over 5min. Arterial blood was obtained at predefined time points. A pharmacokinetic model was developed using NONMEM. Theory-based allometric scaling with fixed exponents was applied. Weight, age, post-menstrual age, fat-free mass, whether to implement cardiopulmonary bypass and temperature were explored as covariates. A total of 376 blood samples were obtained from 29 children (age: 20.3 ± 19.3months, weight: 9.7 ± 4.1kg). A two-compartment mammillary model with third compartment associated cardiopulmonary bypass procedure best explained the pharmacokinetics of dexmedetomidine. The pharmacokinetic parameter estimates (95% CI) standardized to a 70-kg person were as follows: V1 (L)=31.6 (17.9-39.5), V2 (L)=90.1 (44.0-330), Cl (L/min)=1.08 (0.70-1.25), Q (L/min)=2.0 (1.05-3.46). Volume for third compartment associated cardiopulmonary bypass procedure (L)=39.4 (19.3-50.9). Clearance was not influenced by the presence of cardiopulmonary bypass in this model. When cardiopulmonary bypass is applied, the plasma concentration of dexmedetomidine decreases due to an increase in the volume of distribution, so a loading dose is required to maintain the previous concentration.

Justification Of Empiric Methodology to Determine Dexmedetomidine Dose for the TREX Study.

Dexmedetomidine is the sedative agent administered in combination with remifentanil and low dose of sevoflurane in the interventional arm of the ongoing TREX trial (Trial Remifentanil DExmedetomidine). The TREX pilot study (published in Paediatr Anaesth 2019;29:59-67) established infusion rates higher than those initially proposed. This could be attributed to an inappropriate target concentration for sedation or incorrect initial pharmacokinetic parameter estimates. The TREX study is a Phase III, randomized, active controlled, parallel group, blinded evaluator, multicentre, superiority trial comparing neurological outcome after standard sevoflurane anaesthesia with dexmedetomidine/remifentanil and low dose sevoflurane anaesthesia in children aged less than 2 years undergoing anaesthesia of 2 hours or longer. In this report, dexmedetomidine pharmacokinetics were analysed in the interventional arm of the Italian population. There were 162 blood samples from 32 infants (22 male and 10 female). The median (IQR) age was 12 (5.2-15.5) months, weight 9.9 (7.3-10.8) kg. Duration of anaesthesia ranged from 2-6 hours. None of the children were born premature (median postnatal age 39 weeks, IQR 38-40 weeks). A 3-compartment PK model that incorporated allometric scaling and a maturation function demonstrated plasma concentration observations from the current Italian arm of the TREX study were consistent with those predicted by a "universal" model using pooled data obtained from neonates to adults. This current PK analysis from the Italian arm of the TREX study confirms that plasma concentration of dexmedetomidine is predictable using known covariates such as age and size. The initial target concentration (0.6 μg.L-1 ) used to sedate children cared for in the intensive care after cardiac surgery was inadequate for infants in the current TREX study. A target concentration 1 mcg.L-1 , corresponding to a loading dose of 1 mcg.kg-1 followed by an infusion of 1 mcg.kg-1 .hour-1 , provided adequate sedation.

CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response.

Background: Dexmedetomidine is a commonly used clinical sedative; however, the drug response varies among individuals. Thus, the purpose of this study was to explore the association between dexmedetomidine response and gene polymorphisms related to drug-metabolizing enzymes and drug response (CYP2A6, UGT2B10, UGT1A4, ADRA2A, ADRA2B, ADRA2C, GABRA1, GABRB2, and GLRA1). Methods: This study was a prospective cohort study. A total of 194 female patients aged 18–60 years, American Society of Anesthesiologists (ASA) score I-II, who underwent laparoscopy at the Third Xiangya Hospital of Central South University, were included. The sedative effect was assessed every 2 min using the Ramsay score, and the patient’s heart rate decrease within 20 min was recorded. Peripheral blood was collected from each participant to identify genetic variants in the candidate genes of metabolic and drug effects using the Sequenom MassARRAY® platform. Furthermore, additional peripheral blood samples were collected from the first 99 participants at multiple time points after dexmedetomidine infusion to perform dexmedetomidine pharmacokinetic analysis by Phoenix® WinNonlin 7.0 software. Results: Carriers of the minor allele (C) of CYP2A6 rs28399433 had lower metabolic enzyme efficiency and higher plasma concentrations of dexmedetomidine. In addition, the participants were divided into dexmedetomidine sensitive or dexmedetomidine tolerant groups based on whether they had a Ramsay score of at least four within 20 min, and CYP2A6 rs28399433 was identified to have a significant influence on the dexmedetomidine sedation sensitivity by logistic regression with Plink software [p = 0.003, OR (95% CI): 0.27 (0.11–0.65)]. C allele carriers were more sensitive to the sedative effects of dexmedetomidine than A allele carriers. GABRA2 rs279847 polymorphism was significantly associated with the degree of the heart rate decrease. In particular, individuals with the GG genotype had a 4-fold higher risk of heart rate abnormality than carriers of the T allele (OR = 4.32, 95% CI: 1.96–9.50, p = 0.00027). Conclusion: CYP2A6 rs28399433 polymorphism affects the metabolic rate of dexmedetomidine and is associated with susceptibility to the sedative effects of dexmedetomidine; GABRA2 rs279847 polymorphism is significantly associated with the degree of the heart rate decrease.

Perioperative Low Dose Dexmedetomidine and Its Effect on the Visibility of the Surgical Field for Middle Ear Microsurgery: A Randomised Controlled Trial.

Background and Purpose: There are many benefits of administering dexmedetomidine perioperatively. The pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous, intranasal and oral dexmedetomidine that was administered before anesthesia were compared in this study, and the effects of dexmedetomidine on the surgical field visibility in tympanoplasty was evaluated. Methods: A single-blind, randomized controlled trial was conducted in a university-affiliated hospital where 45 patients who underwent tympanoplasty under general anesthesia were randomly allocated into three groups. Dexmedetomidine was administered by intravenous infusion at 0.8 μg.kg−1 for 10 min, intranasal instillation at a drop rate of 1 μg.kg−1 and oral intake at 4 μg.kg−1 ten minutes before the induction of anesthesia. The PK and PD of dexmedetomidine after a single low dose administration and its effect on the surgical field in tympanoplasty were analysed. Results: A plasma concentration of dexmedetomidine of 220 pg/ml was achieved immediately after intravenous infusion and at 13.2 and 70.3 min for intranasal and oral administration, respectively. Dexmedetomidine decreased the heart rate (HR) and mean arterial pressure (MAP) in all three groups, although these values remained higher in the oral dexmedetomidine group at all eight time points. Intravenous dexmedetomidine provided the best visualization of the surgical field for opening of the tympanic sinus, 30 min after the start of the infusion (p < 0.05). Intranasal dexmedetomidine provided a significantly better visual field than oral dexmedetomidine for the repair of a tympanic membrane perforation using the fascia temporal muscle (p < 0.05). Conclusion: A single low dose of dexmedetomidine administered intravenously or intranasally could decrease HR and MAP, improve surgical field visibility and be appropriate for deliberate hypotension for surgical procedures of 1–2 h in length. Trial registration: Clinicaltrials.gov identifier: NCT03800641.

This Month in Anesthesiology

This Month in Anesthesiology

Pharmacokinetics and Pharmacodynamics of Dexmedetomidine Administered as an Adjunct to Bupivacaine for Transversus Abdominis Plane Block in Patients Undergoing Lower Abdominal Cancer Surgery.

BackgroundDespite the growing interest in dexmedetomidine as an adjunct to truncal blocks, little is known about the systemic absorption of dexmedetomidine after these blocks and its role in analgesia and in hemodynamics.ObjectiveWe investigated the pharmacokinetics and pharmacodynamics of dexmedetomidine as an adjunct to transversus abdominis plane (TAP) block in patients undergoing lower abdominal cancer surgery.MethodsTwenty-four adult patients were randomized to receive a bilateral single-injection TAP block before surgery with 20 mL of bupivacaine 0.5% (TAP group, n = 12) or combined with 1 µg/kg dexmedetomidine (TAP-DEX group, n = 12) and diluted with saline to a volume of 40 mL (20 mL on each side). Plasma concentrations of dexmedetomidine and its pharmacokinetics were investigated using non-compartmental methods, postoperative analgesia, hemodynamics, and adverse events (nausea, vomiting, itching, hypotension, bradycardia, and respiratory depression).ResultsDexmedetomidine was detected in the plasma of 11 patients in the TAP-DEX group. The mean dexmedetomidine peak plasma concentration (Cmax) was 0.158 ± 0.085 (range, 0.045–0.31) ng/mL. The median time to reach peak plasma concentration of dexmedetomidine (Tmax) was 15 (15–45) min. From 2 to 8 h postoperatively, visual analog pain scale (VAS) scores at rest and during movement were significantly lower in the TAP-DEX group. Analgesia time was (11.3 ± 3.12 vs 9.0 ± 4.69 h; P = 0.213) and postoperative morphine consumption was (7.4 ± 3.24 vs 11.5 ± 4.46 mg; P = 0.033) in TAP-DEX and TAP groups, respectively. Lower mean heart rate and mean blood pressure were recorded in the TAP-DEX group intraoperatively and 2 h postoperatively (P < 0.05). Except for mild nausea and vomiting, no adverse events were recorded in either group.ConclusionSystemic absorption of dexmedetomidine administered in a TAP block is common. Direct central effects on the locus coeruleus caused by this systemic absorption may play a role in the analgesia and hemodynamic effects produced by TAP-dexmedetomidine in addition to local mechanisms.Trial RegistrationClinicalTrial.gov (identifier: NCT03328299).

Cardiopulmonary function and intestinal blood flow in anaesthetised, experimentally endotoxaemic horses given a constant rate infusion of dexmedetomidine.

Endotoxaemia causes untoward inflammatory-mediated effects that might be attenuated by dexmedetomidine. To evaluate the effects of a dexmedetomidine intravenous (IV) infusion on systemic and intestinal haemodynamics and arterial blood gas values in sevoflurane-anaesthetised horses administered Escherichia coli O55:B5 lipopolysaccharides (LPS). Randomised controlled in vivo experiment. A total of 13 horses weighing 456±86kg (mean±standard deviation) and aged 13.9±9.0years donated for euthanasia underwent ventral midline celiotomy using sevoflurane anaesthesia. Baseline physiological variables were recorded after a 90-minute equilibration period. All horses were given 0.1mcg/kgbwt LPS IV. Horses were randomly assigned to no further treatment (group LPS; seven horses) or IV administration of dexmedetomidine (loading dose 1.75mcg/kgbwt followed by 1.75mcg/kgbwt/h; group LPS-Dex; six horses) with concurrent target sevoflurane dose reduction of 50%. Cardiac index (CI; thermodilution), intestinal blood flow, arterial blood parameters and plasma dexmedetomidine concentration measurements were recorded every 30minutes until euthanasia at 390minutes. Data were compared between and within groups to baseline using a mixed model analysis (significance P<.05). In LPS-Dex horses, intestinal blood flow and CI were transiently decreased after the dexmedetomidine loading dose, but no significant differences were found compared with baseline during the infusion. Sevoflurane dose was reliably reduced by approximately 40%. Significant differences were identified in creatinine (115 umol/L LPS-Dex; 195umol/L LPS), bicarbonate (29.7mmol/L LPS-Dex; 23mmol/L LPS) and base excess (2.0mmol/L LPS-Dex; -5.3mmol/L LPS). Dexmedetomidine plasma concentrations were highest after the loading dose and stable during infusion dosing. Experimental conditions are not reflective of clinical colic management. A dexmedetomidine infusion with sevoflurane dose reduction attenuated some deleterious changes in anaesthetised horses administered LPS without sustained negative cardiovascular effects and may be beneficial during colic surgery.

Pharmacodynamics and plasma concentrations of dexmedetomidine with or without vatinoxan as a constant-rate infusion in horses anaesthetized with isoflurane-A pilot study.

The aim was to determine the effects of vatinoxan on dexmedetomidine plasma concentrations and effects on cardiovascular and intestinal tissue pharmacodynamics. In a prospective randomized study, six horses were premedicated intravenously with dexmedetomidine 3.5µgkg-1 followed by a constant-rate infusion of 7µgkg-1 h-1 (group DEX) and six horses with dexmedetomidine of the same dose (bolus and constant-rate infusion) combined with vatinoxan 130µgkg-1 followed by 40µgkg-1 h-1 (group VAT). Anaesthesia was induced with ketamine and diazepam and maintained with isoflurane. Venous blood samples were withdrawn before and at predefined points in time after drug application. During sedation and anaesthesia, cardiopulmonary variables, gastrointestinal tissue perfusion and oxygenation were recorded. Data were analysed using two-way-ANOVA, unpaired-t-test and Dunnett's-t-test (p<0.05). Group VAT had significantly higher oxygen delivery and lower oxygen extraction ratio, venous admixture, alveolar dead space and alveolar-arterial-oxygen difference. Tissue perfusion of buccal mucosa was reduced during anaesthesia in group DEX. Plasma concentrations of dexmedetomidine in group VAT (n=6) and group DEX (n=5) were comparable between groups. In the present pilot study, co-administration of vatinoxan with dexmedetomidine did not alter plasma concentrations of dexmedetomidine but ameliorated tissue perfusion and global oxygenation variables.

Effects of perineural administration of ropivacaine combined with perineural or intravenous administration of dexmedetomidine for sciatic and saphenous nerve blocks in dogs.

To evaluate the effects of using ropivacaine combined with dexmedetomidine for sciatic and saphenous nerve blocks in dogs. 7 healthy adult Beagles. In phase 1, dogs received each of the following 3 treatments in random order: perineural sciatic and saphenous nerve injections of 0.5% ropivacaine (0.4 mL/kg) mixed with saline (0.9% NaCl) solution (0.04 mL/kg; DEX0PN), 0.5% ropivacaine mixed with dexmedetomidine (1 μg/kg; DEX1PN), and 0.5% ropivacaine mixed with dexmedetomidine (2 μg/kg; DEX2PN). In phase 2, dogs received perineural sciatic and saphenous nerve injections of 0.5% ropivacaine and an IV injection of diluted dexmedetomidine (1 μg/kg; DEX1IV). For perineural injections, the dose was divided equally between the 2 sites. Duration of sensory blockade was evaluated, and plasma dexmedetomidine concentrations were measured. Duration of sensory blockade was significantly longer with DEX1PN and DEX2PN, compared with DEX0PN; DEX1IV did not prolong duration of sensory blockade, compared with DEX0PN. Peak plasma dexmedetomidine concentrations were reached after 15 minutes with DEX1PN (mean ± SD, 348 ± 200 pg/mL) and after 30 minutes DEX2PN (816 ± 607 pg/mL), and bioavailability was 54 ± 40% and 73 ± 43%, respectively. The highest plasma dexmedetomidine concentration was measured with DEX1IV (1,032 ± 415 pg/mL) 5 minutes after injection. Results suggested that perineural injection of 0.5% ropivacaine in combination with dexmedetomidine (1 μg/kg) for locoregional anesthesia in dogs seemed to balance the benefit of prolonging sensory nerve blockade while minimizing adverse effects.

Age-Specific Dose Regimens of Dexmedetomidine for Pediatric Patients in Intensive Care Following Elective Surgery: A Phase 3, Multicenter, Open-Label Clinical Trial in Japan.

To demonstrate the efficacy, safety, and pharmacokinetics of dexmedetomidine as a potential sedative for pediatric surgery patients in the ICU. Phase 3, multicenter, open-label study. This study included 61 patients at 13 tertiary hospitals in Japan. Pediatric patients (≥ 45 wk corrected gestational age to < 17 yr) undergoing intensive care treatment with mechanical ventilation requiring greater than 6 hours estimated duration of sedation following elective cardiac surgery. Dexmedetomidine was IV administered without a loading dose at age-specific dose regimens 0.2-1.4 (< 6 yr) and 0.2-1.0 µg/kg/hr (≥ 6 yr). The primary endpoint was the percentage of patients who did not require a rescue sedative (midazolam) infusion during mechanical ventilation or for the first 24 hours of a greater than 24 hours ventilation following the commencement of dexmedetomidine administration. Overall, 47 of the 61 patients (77.0%) did not require rescue midazolam. Adverse events were reported in 53 patients (86.9%). Frequently observed adverse events were hypotension (47.5%), bradycardia (31.1%), and respiratory depression (26.2%). Most of these adverse events were mild, a few moderate, and none severe. Although serious adverse events occurred in four patients, including one cardiac tamponade resulting in the withdrawal of dexmedetomidine, none of the adverse events resulted in mortality or were directly related to dexmedetomidine. The plasma dexmedetomidine concentration generally reached the target concentration of 0.3-1.25 ng/mL at 1-2 hours prior to completion of administration or immediately prior to the commencement of tapering. The age-specific dose regimens of dexmedetomidine without an initial loading dose achieved an adequate sedation level during mechanical ventilation and caused no clinically significant adverse events in the intensive care pediatric patients. These effects were achieved within the therapeutic range of dexmedetomidine plasma concentration and were accompanied by minimal effects on hemodynamics and respiration.

Pharmacokinetics and pharmacodynamics of intravenous continuous rate infusion and repeated intramuscular administration of dexmedetomidine in standing horses.

An ideal dexmedetomidine protocol has yet to be determined for standing sedation in horses. It was hypothesized that an IV bolus followed by CRI dexmedetomidine would have a quicker increase in plasma concentrations compared with repeated IM injections. In a crossover design, eight adult, female horses were randomly placed into two groups: the CRI group (IV bolus dexmedetomidine at 0.005mg/kg followed by a CRI at 0.01mg/kg/h for 15min then 0.005mg/kg/h for 60min) and the IM group (dexmedetomidine at 0.01mg/kg, followed by 0.005mg/kg in 30-min intervals for 60min). Clearance and elimination half-life were 134±67.4ml/kg/min and 44.3±26.3min, respectively, in the CRI group, and apparent clearance and half-life were 412±306ml/kg/min (Cl/F) and 38.9±18.6min, respectively, in the IM group. Analgesia was evaluated using mechanical pressure threshold. Intravenous dexmedetomidine produced faster onset of sedation and increased pressure threshold compared with IM administration. Individual horses had a large variability in dexmedetomidine plasma concentrations between CRI and IM administration. The odds of a decreased GI motility following IV administration was 12.34 times greater compared with IM administration.

Combined effects of dexmedetomidine and vatinoxan infusions on minimum alveolar concentration and cardiopulmonary function in sevoflurane-anesthetized dogs

ObjectiveTo evaluate the effects of combined infusions of vatinoxan and dexmedetomidine on inhalant anesthetic requirement and cardiopulmonary function in dogs. Study designProspective experimental study. MethodsA total of six Beagle dogs were anesthetized to determine sevoflurane minimum alveolar concentration (MAC) prior to and after an intravenous (IV) dose (loading, then continuous infusion) of dexmedetomidine (4.5 μg kg–1 hour–1) and after two IV doses of vatinoxan in sequence (90 and 180 μg kg–1 hour–1). Blood was collected for plasma dexmedetomidine and vatinoxan concentrations. During a separate anesthesia, cardiac output (CO) was measured under equivalent MAC conditions of sevoflurane and dexmedetomidine, and then with each added dose of vatinoxan. For each treatment, cardiovascular variables were measured with spontaneous and controlled ventilation. Repeated measures analyses were performed for each response variable; for all analyses, p < 0.05 was considered significant. ResultsDexmedetomidine reduced sevoflurane MAC by 67% (0.64 ± 0.1%), mean ± standard deviation in dogs. The addition of vatinoxan attenuated this to 57% (0.81 ± 0.1%) and 43% (1.1 ± 0.1%) with low and high doses, respectively, and caused a reduction in plasma dexmedetomidine concentrations. Heart rate and CO decreased while systemic vascular resistance increased with dexmedetomidine regardless of ventilation mode. The co-administration of vatinoxan dose-dependently modified these effects such that cardiovascular variables approached baseline. Conclusions and clinical relevanceIV infusions of 90 and 180 μg kg–1 hour–1 of vatinoxan combined with 4.5 μg kg–1 hour–1 dexmedetomidine provide a meaningful reduction in sevoflurane requirement in dogs. Although sevoflurane MAC-sparing properties of dexmedetomidine in dogs are attenuated by vatinoxan, the cardiovascular function is improved. Doses of vatinoxan >180 μg kg–1 hour–1 might improve cardiovascular function further in combination with this dose of dexmedetomidine, but beneficial effects on anesthesia plane and recovery quality may be lost.

The efficacy and safety of intrathecal dexmedetomidine for parturients undergoing cesarean section: a double-blind randomized controlled trial

BackgroundThe efficacy and safety of spinal anesthesia by intrathecal dexmedetomidine (DEX) for parturients undergoing cesarean section are still lack of evidence. This aim of our study was to evaluate the efficacy and safety of intrathecal DEX for parturients undergoing cesarean section to provide more data evidence for intrathecal applications.MethodsThree hundred parturients undergoing cesarean section under spinal anesthesia were randomly assigned into three groups: group B: 9.0 mg (1.2 ml) of 0.75% bupivacaine with saline (1 ml); group FB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 20 μg of fentanyl (1 ml); group DB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 5 μg of DEX (1 ml). Intraoperative block characteristics, parturients’ postoperative quality of recovery, maternal and neonatal outcomes and the plasma concentration of DEX were measured. All parturients were followed up for 30 days to determine whether nerve injury occurred.ResultsCompared with group B, the duration of sensory block in group FB and group DB were significantly prolonged (108.4 min [95% Confidence Interval (CI) = 104.6–112.3] in group B, and 122.0 min [95% CI = 116.8–127.3] in group FB, 148.2 min [95% CI = 145.3–151.1] in group DB). The overall score of quality recovery in group DB (71.6 [95% CI = 71.0–72.2]) was significantly higher than that in group FB (61.5 [95% CI = 60.8–62.2]) and group B (61.7 [95% CI = 61.0–62.4]). There was no statistically significant difference among the three groups for PH, PaO2, and PaCO2 of newborn. The plasma concentration of DEX in umbilical artery and umbilical vein was low and cannot be detected. The 30-days follow-up of parturients did not show any new onset of back, buttock or leg pain or paresthesia.ConclusionsDEX is a potential local anesthetic adjuvant that the intrathecal combination of 5 μg DEX can safely exhibit a facilitatory block effect and improve parturients’ recovery quality.Trial registrationChinese Clinical Trial Registry (Registration number # ChiCTR1900022019; Date of Registration on March 20th, 2019).

Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs

To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone. 8 healthy Beagles. Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 μg/kg], medetomidine [20 μg/kg] and vatinoxan [400 μg/kg], and medetomidine [40 μg/kg] and vatinoxan [800 μg/kg]; M20, M20V400, and M40V800, respectively). Sedation, visceral and somatic nociception, and plasma drug concentrations were assessed. Somatic and visceral nociception measurements and sedation scores were compared among treatments and over time. Sedation, visceral antinociception, and somatic antinociception effects of M20V400 and M40V800 were analyzed for noninferiority to effects of M20, and plasma drug concentration data were assessed for equivalence between treatments. Plasma dexmedetomidine concentrations after administration of M20 and M40V800 were equivalent. Sedation scores, visceral nociception measurements, and somatic nociception measurements did not differ significantly among treatments within time points. Overall sedative effects of M20V400 and M40V800 and visceral antinociceptive effects of M40V800 were noninferior to those produced by M20. Somatic antinociception effects of M20V400 at 10 minutes and M40V800 at 10 and 55 minutes after injection were noninferior to those produced by M20. Results suggested coadministration with vatinoxan did not substantially diminish visceral antinociceptive effects of medetomidine when plasma dexmedetomidine concentrations were equivalent to those produced by medetomidine alone. For somatic antinociception, noninferiority of treatments was detected at some time points.

Intranasal dexmedetomidine in elderly subjects with or without beta blockade: a randomised double-blind single-ascending-dose cohort study

BackgroundThe aim of this double-blind, placebo-controlled, single-ascending-dose study was to determine the safety and tolerability of intranasal dexmedetomidine in the elderly. MethodsWe randomly assigned 48 surgical patients ≥65 yr of age to receive single intranasal doses of dexmedetomidine or placebo (5:1 ratio) in four sequential dose cohorts: 0.5, 1.0, 1.5, and 2.0 μg kg−1. Each dose cohort comprised two groups of six subjects: a group of subjects using β-blockers and a group not taking β-blockers. Vital signs and sedation depth (Modified Observer's Assessment of Alertness and Sedation [MOAA/S] and bispectral index) were measured for 2 h after administration. Blood samples were taken to determine dexmedetomidine plasma concentrations. ResultsOne subject (1.0 μg kg−1) had acute hypotension requiring ephedrine. Systolic arterial BP decreased >30% in 15 of 40 subjects (37.5%) receiving dexmedetomidine, lasting longer than 5 min in 11 subjects (27.5%). The MAP decreased >30% (>5 min) in 10%, 20%, 50%, and 30% of subjects receiving dexmedetomidine 0.5, 1.0, 1.5, and 2.0 μg kg−1, respectively, irrespective of β-blocker use. HR decreased 10–26%. MOAA/S score ≤3 occurred in 18 (45%) subjects; eight (20%) subjects receiving dexmedetomidine showed no signs of sedation. Tmax was 70 min. Cmax was between 0.15 ng ml−1 (0.5 μg kg−1) and 0.46 ng ml−1 (2.0 μg kg−1). ConclusionsIntranasal dexmedetomidine in elderly subjects had a sedative effect, but caused a high incidence of profound and sustained hypotension irrespective of β-blocker use. The technique is unsuitable for routine clinical use. Clinical trial registrationNTR5513 (The Netherlands Trial Registry 5513).

Pharmacokinetics of dexmedetomidine during administration of vatinoxan in male neutered cats anesthetized with isoflurane

Dexmedetomidine is an alpha-2 adrenoceptor agonist, and vatinoxan is an alpha-2 antagonist believed to poorly cross the blood-brain barrier in cats. Dexmedetomidine-vatinoxan combinations are of interest in anesthetized cats because the anesthetic sparing effect of dexmedetomidine may be preserved while vatinoxan attenuates the adverse cardiovascular effects of dexmedetomidine. The aim of this study was to characterize the pharmacokinetics of dexmedetomidine in cats during administration of isoflurane and vatinoxan. Six healthy adult male castrated cats were anesthetized with isoflurane in oxygen. Vatinoxan was administered using a target-controlled infusion system intended to maintain a plasma concentration of 4 µg/ml. Dexmedetomidine, 35 µg/kg was administered intravenously over 5 min. Plasma dexmedetomidine and vatinoxan concentrations were measured at selected time points ranging from prior to 8 hr after dexmedetomidine administration using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed-effect modeling. A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three-compartment volumes (ml/kg), the metabolic clearance and the two intercompartment distribution clearances (ml min-1 kg-1 ) were 168 (259), 318 (35), 1,425 (18), 12.4 (31), 39.1 (18), and 29.6 (17), respectively. Mean ± standard deviation plasma vatinoxan concentration was 2.6 ± 0.6 µg/ml.

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.

Effects of vatinoxan on cardiorespiratory function, fecal output and plasma drug concentrations in horses anesthetized with isoflurane and infusion of medetomidine

A constant rate infusion (CRI) of medetomidine is used to balance equine inhalation anesthesia, but its cardiovascular side effects are a concern. This experimental crossover study aimed to evaluate the effects of vatinoxan (a peripheral α2-adrenoceptor antagonist) on cardiorespiratory and gastrointestinal function in anesthetized healthy horses. Six horses received medetomidine hydrochloride 7μg/kg IV alone (MED) or with vatinoxan hydrochloride 140μg/kg IV (MED+V). Anesthesia was induced with midazolam and ketamine and maintained with isoflurane and medetomidine CRI for 60min. Heart rate, carotid and pulmonary arterial pressures, central venous pressure, cardiac output and arterial and mixed venous blood gases were measured. Selected cardiopulmonary parameters were calculated. Plasma drug concentrations were determined. Fecal output was measured over 24h. For statistical comparisons, repeated measures analysis of covariance and paired t-tests were applied.Heart rate decreased slightly from baseline in the MED group. Arterial blood pressures decreased with both treatments, but significantly more dobutamine was needed to maintain normotension with MED+V (P=0.018). Cardiac index (CI) and oxygen delivery index (DO2I) decreased significantly more with MED, with the largest difference observed at 20min: CI was 39±2 and 73±18 (P=0.009) and DO2I 7.4±1.2 and 15.3±4.8 (P=0.014)mL/min/kg with MED and MED+V, respectively. Fecal output or plasma concentrations of dexmedetomidine did not differ between the treatments. In conclusion, premedication with vatinoxan induced hypotension, thus its use in anesthetized horses warrants further studies. Even though heart rate and arterial blood pressures remained clinically acceptable with MED, cardiac performance and oxygen delivery were lower than with MED+V.