Extraction of ketamine and dexmedetomidine by extracorporeal life support circuits☠.

BACKGROUND: Patients supported with extracorporeal life support (ECLS) circuits such as ECMO and CRRT often require high doses of sedatives and analgesics, including ketamine and dexmedetomidine. Concentrations of many medications are affected by ECLS circuits through adsorption to the circuit components, dialysis, as well as the large volume of blood used to prime the circuits. However, the impact of ECLS circuits on ketamine and dexmedetomidine pharmacokinetics has not been well described. This study determined ketamine and dexmedetomidine extraction by extracorporeal circuits in an ex-vivo system. METHODS: Medication was administered at therapeutic concentration to blood-primed, closed-loop ex-vivo ECMO and CRRT circuits. Drug concentrations were measured in plasma, hemofiltrate, and control samples at multiple time points throughout the experiments. At each sample time point, the percentage of drug recovery was calculated. RESULTS: Ketamine plasma concentration in the ECMO and CRRT circuits decreased rapidly, with 43.8% recovery (SD = 0.6%) from ECMO circuits after 8 h and 3.3% (SD = 1.8%) recovery from CRRT circuits after 6 h. Dexmedetomidine was also cleared from CRRT circuits, with 20.3% recovery (SD = 1.8%) after 6 h. Concentrations of both medications were very stable in the control experiments, with approximately 100% drug recovery of both ketamine and dexmedetomidine after 6 h. CONCLUSION: Ketamine and dexmedetomidine concentrations are significantly affected by ECLS circuits, indicating that dosing adjustments are needed for patients supported with ECMO and CRRT.

Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

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.

Dexmedetomidina, tendencias y actuales aplicaciones / Dexmedetomidine, trends and current applications

Dexmedetomidine (DXM), is a potent, versatile and highly selective a-2 adrenergic receptor agonist, currently described as an agent with sedative, anxiolytic, sympatholytic, and hypnotic effects that preserve the integrity of respiratory functions. It has highly lipophilic chemical characteristics and conforms to a two-compartment distribution and elimination model. Among its unique pharmacodynamic characteristics, at the cardiac level there is a biphasic hemodynamic effect, with a transient increase in blood pressure and reflex bradycardia determined by its plasma concentration, at the renal level it improves ischemic damage by improving external medullary blood flow through local renal vasodilation and allowing an increase in glomerular filtration. At the respiratory level, it induces a minimal depressant effect, allowing a wide margin of safety in various surgical and sedation scenarios outside the operating room. From its neuroprotective characteristics, it is suggested that the catecholamine pathways at the level of a-2 adrenoceptors modulate the release of neurotransmitters in the central and peripheral sympathetic nervous system. They are diverse clinical applications from a "cooperative sedation", anxiolysis in pediatric patients, during the intubation process in difficult airways, as well as its use in cardiovascular and neurological surgery and management of the critical patient.

La dexmedetomidina (DXM), un agonista de los receptores adrenérgicos a-2 potente, versátil y altamente selectivo, actualmente descrito como un agente con efectos sedantes, ansiolíticos, simpaticolíticos e hipnóticos que permite conservar la integridad de las funciones respiratorias. De características químicas altamente lipofilicas se ajusta a un modelo de distribución y eliminación bicompartimental. Entre sus rasgos farmacodinámicos únicos, a nivel cardíaco se produce un efecto hemodinámico bifásico, con un aumento transitorio de la presión arterial y bradicardia refleja determiando por su concentración plasmática, a nivel renal mejora el daño por isquemia, mejorando el flujo sanguíneo medular externo, a través de la vasodilatación renal local y permitiendo un aumento en la filtración glomerular. A nivel respiratorio, induce un mínimo efecto depresor, permitiendo un amplio margen de seguridad en diversos escenarios quirurgicos y de sedación fuera de quirófano. Su propiedad de neuroprotección, modulan la liberación de neurotransmisores en el sistema nervioso simpático central y periférico. Resalta un amplio expectro de aplicaciones clínicas desde una "sedación cooperativa", ansiolisis en pacientes pediátricos, durante el proceso de intubación en vías áreas difíciles, al igual que su uso en cirugía cardiovascular, neurológica y manejo del paciente crítico.

Simultaneous Determination of Celecoxib, Dezocine and Dexmedetomidine in Beagle Plasma Using UPLC-MS/MS Method and the Application in Pharmacokinetics.

BACKGROUND: An efficient, fast and sensitive ultra high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for simultaneous determination of celecoxib (CEL), dezocine (DEZ) and dexmedetomidine (DEX) in beagle plasma were established. METHODS: The beagle dogs plasmawas precipitated by acetonitrile. The column was Acquity UPLC BEH C18 column and the mobile phase was acetonitrile-formic acid with gradient mode, and the flow rate was set at 0.4 mL/min. Under the positive ion mode, CEL, DEZ, DEX and Midazolam (internal standard, IS) were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 381.10→282.10 for CEL, m/z 246.20→147.00 for DEZ, m/z 201.10→94.90 for DEX, and m/z 326.10→291.10 for IS. RESULTS: This UPLC-MS/MS method had good linearity for CEL, DEZ and DEX. The RSDs of inter-day and intra-day precision were the values of 0.31-7.66% and 0.11-9.63%, respectively; the RE values were from -6.05% to 10.98%. The extraction recovery was more than 79%, and the matrix effect was around 100%. The RSDs of stability were less than 8.96%. All of them met the acceptance standard of biological analysis method recommended by FDA. CONCLUSION: This UPLC-MS/MS method is an effective tool for the simultaneous determination of CEL, DEX and DEX, and has been successfully applied to the study of pharmacokinetics in beagle dogs.

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.

A Pharmacokinetic and Pharmacodynamic Study of Oral Dexmedetomidine.

BACKGROUND: Dexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation may broaden the use and benefits of dexmedetomidine to numerous care settings. The authors hypothesized that oral dexmedetomidine (300 mcg to 700 mcg) would result in plasma concentrations consistent with sedation while maintaining hemodynamic stability. METHODS: The authors performed a single-site, open-label, phase I dose-escalation study of a solid oral dosage formulation of dexmedetomidine in healthy volunteers (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg). The primary study outcome was hemodynamic stability defined as lack of hypertension, hypotension, or bradycardia. The authors assessed this outcome by analyzing raw hemodynamic data. Plasma dexmedetomidine concentrations were determined by liquid chromatograph-tandem mass spectrometry. Nonlinear mixed effect models were used for pharmacokinetic and pharmacodynamic analyses. RESULTS: Oral dexmedetomidine was associated with plasma concentration-dependent decreases in heart rate and mean arterial pressure. All but one subject in the 500-mcg group met our criteria for hemodynamic stability. The plasma concentration profile was adequately described by a 2-compartment, weight allometric, first-order absorption, first-order elimination pharmacokinetic model. The standardized estimated parameters for an individual of 70 kg was V1 = 35.6 [95% CI, 23.8 to 52.8] l; V2 = 54.7 [34.2 to 81.7] l; CL = 0.56 [0.49 to 0.64] l/min; and F = 7.2 [4.7 to 14.4]%. Linear models with effect sites adequately described the decreases in mean arterial pressure and heart rate associated with oral dexmedetomidine administration. However, only the 700-mcg group reached plasma concentrations that have previously been associated with sedation (>0.2 ng/ml). CONCLUSIONS: Oral administration of dexmedetomidine in doses between 300 and 700 mcg was associated with decreases in heart rate and mean arterial pressure. Despite low oral absorption, the 700-mcg dose scheme reached clinically relevant concentrations for possible use as a sleep-enhancing medication.

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.

Effects of Dexmedetomidine on the Pharmacokinetics of Parecoxib and Its Metabolite Valdecoxib in Beagles by UPLC-MS/MS.

A sensitive and reliable ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagles. The effects of dexmedetomidine on the pharmacokinetics of parecoxib and valdecoxib in beagles were studied. The plasma was precipitated by acetonitrile, and the two analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm); the mobile phase was acetonitrile and 0.1% formic acid with gradient mode, and the flow rate was 0.4 mL/min. In the negative ion mode, the two analytes and internal standard (IS) were monitored by multiple reaction monitoring (MRM), and the mass transition pairs were as follows: m/z 369.1 → 119.1 for parecoxib, m/z 313.0 → 118.0 for valdecoxib, and m/z 380.0 → 316.0 for celecoxib (IS). Six beagles were designed as a double cycle self-control experiment. In the first cycle, after intramuscular injection of parecoxib 1.33 mg/kg, 1.0 mL blood samples were collected at different times (group A). In the second cycle, the same six beagles were intravenously injected with 2 µg/kg dexmedetomidine for 7 days after one week of washing period. On day 7, after intravenous injection of 2 µg/kg dexmedetomidine for 0.5 hours, 6 beagle dogs were intramuscularly injected with 1.33 mg/kg parecoxib, and blood samples were collected at different time points (group A). The concentration of parecoxib and valdecoxib was detected by UPLC-MS/MS, and the main pharmacokinetic parameters were calculated by DAS 2.0 software. Under the experimental conditions, the method has a good linear relationship for both analytes. The interday and intraday precision was less than 8.07%; the accuracy values were from -1.20% to 2.76%. C max of parecoxib in group A and group B was 2148.59 ± 406.13 ng/mL and 2100.49 ± 356.94 ng/mL, t 1/2 was 0.85 ± 0.36 h and 0.85 ± 0.36 h, and AUC(0-t) was 2429.96 ± 323.22 ng·h/mL and 2506.38 ± 544.83 ng·h/mL, respectively. C max of valdecoxib in group A and group B was 2059.15 ± 281.86 ng/mL and 2837.39 ± 276.78 ng/mL, t 1/2 was 2.44 ± 1.55 h and 2.91 ± 1.27 h, and AUC(0-t) was 4971.61 ± 696.56 ng·h/mL and 6770.65 ± 453.25 ng·h/mL, respectively. There was no significant change in the pharmacokinetics of parecoxib in groups A and B. C max and AUC(0 - ∞) of valdecoxib in group A were 37.79% and 36.19% higher than those in group B, respectively, and t 1/2 was increased from 2.44 h to 2.91 h. V z /F and CL z /F were correspondingly reduced, respectively. The developed UPLC-MS/MS method for simultaneous determination of parecoxib and valdecoxib in beagle plasma was specific, accurate, rapid, and suitable for the pharmacokinetics and drug-drug interactions of parecoxib and valdecoxib. Dexmedetomidine can inhibit the metabolism of valdecoxib in beagles and increase the exposure of valdecoxib, but it does not affect the pharmacokinetics of parecoxib.

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

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

Population analysis to assess the influence of age and body weight on pharmacokinetics and pharmacodynamics of dexmedetomidine in New Zealand White rabbits.

The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 µg kg-1 . Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min-1 and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.

Population Pharmacokinetic Model of Dexmedetomidine in a Heterogeneous Group of Patients.

Dexmedetomidine is a hepatically eliminated drug with sedative, anxiolytic, sympatholytic, and analgesic properties that has been increasingly used for various indications in the form of a short or continuous intravenous infusion. This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed-effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single-nucleotide polymorphisms were tested. A 2-compartment model was used to describe dexmedetomidine PK. An allometric/isometric scaling was used to account for body weight difference in PK parameters, and the Hill equation was used to describe the maturation of clearance. Typical values of the central and peripheral volume of distribution and the systemic and distribution clearance for a theoretical adult patient were central volume of distribution = 22.50 L, peripheral volume of distribution = 86.1 L, systemic clearance = 34.7 L/h, and distribution clearance = 40.8 L/h. The CYP1A2 genetic polymorphism and noradrenaline administration were identified as significant covariates for clearance. A population PK model of dexmedetomidine was successfully developed. The proposed model is well calibrated to the observed data. The identified covariates account for <5% of interindividual variability and consequently are of low clinical significance for the purpose of dose adjustment.

Dexmedetomidine and worsening hypoxemia in the setting of COVID-19: A case report.

Emergency department management of hypoxemia in the setting of COVID-19 is riddled with uncertainty. The lack of high-quality research has translated to an absence of clarity at the bedside. With disease spread outpacing treatment consensus, provider discretion has taken on a heightened role. Here, we report a case of dexmedetomidine use in the setting of worsening hypoxemia, whereby oxygenation improved and intubation was avoided. Well known pharmacologic properties of the drug, namely the lack of respiratory depression and its anti-delirium effects, as well as other possible physiologic effects, suggest potential benefit for patients being managed with a delayed intubation approach. If dexmedetomidine can improve compliance with non-invasive oxygen support (the current recommended first-line therapy) while promoting better oxygenation, it may also decrease the need for mechanical ventilation and thus improve mortality.

Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration.

BACKGROUND AND OBJECTIVE: Dexmedetomidine is a potent agonist of α2-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing. METHODS: Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion. RESULTS: The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals. CONCLUSIONS: Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34.

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 alfaxalone with or without dexmedetomidine in rabbits.

This study aimed to investigate the specific pharmacokinetic profile and effects of alfaxalone after intravenous (IV) and intramuscular (IM) administration to rabbits and evaluate the potential interaction with dexmedetomidine. The study design was a blinded, randomized crossover with a washout period of 2 weeks. Five New Zealand white rabbits were used. Each animal received single IV and IM injections of alfaxalone at a single dose of 5 mg/kg, and single IV and IM injections of alfaxalone (5 mg/kg) combined with dexmedetomidine (100 µg/kg) administered intramuscularly. Blood samples were collected at predetermined times and analysed by high-performance liquid chromatography. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation/anaesthesia scores were evaluated by a modified numerical rating scale. At pre-determined time points heart and respiratory rates were measured. Times to sternal recumbency and standing position during the recovery were recorded. Concentrations of alfaxalone alone were very similar (slighty smaller) to concentrations when alfaxalone was combined with dexmedetomidine, after both routes of administration. Dexmedetomidine enhanced and increase the duration of the sedative effects of alfaxalone. In conclusion, alfaxalone administered in rabbits provides rapid and smooth onset of sedation. After IV and IM injections of alfaxalone combined with dexmedetomidine, a longer MRT and a deeper and extended sedation have been obtained compared to alfaxalone alone. Consequently, alfaxalone alone or in combination with dexmedetomidine could be useful to achieve respectively moderate to deep sedation in rabbits.

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.