The study examined the effect of alpha.sub.2-adrenoreceptor (alpha.sub.2-AR) activation against the background of preliminary blockage of I.sub.f on the performance of Langerndorff-isolated rat ...heart. Stimulation of alpha.sub.2-AR in isolated rat hearts against the background of ZD7288 in concentrations of 10.sup.-9 M and 3x10.sup.-5 M changed the negative dynamics of myocardial inotropy to positive (by 25 and 38%; p<0.05). Activation of alpha.sub.2-AR produced opposite effects on HR. I.sub.f blockade abolished tachycardia caused by activation of alpha.sub.2-AR; HR deceleration in response to alpha.sub.2-AR agonist against the background of I.sub.f blocker in a concentration 10.sup.-9 M was 41% (p<0.05). We observed negative dynamics of coronary flow (by 38%; p<0.05) in isolated adult rat hearts after application of alpha.sub.2-AR agonist against the background of I.sub.f blockade (10.sup.-9 M). Key Words: alpha2-adrenergic receptors; I.sub.f; isolated heart; rat
Summary
Background : Dexmedetomidine has shown sedative, analgesic, and anxiolytic effects after intravenous (IV) administration. Sevoflurane is associated with a high incidence of emergence ...agitation in preschool children. In this placebo‐controlled study, we examined the effect of single dose dexmedetomidine on emergence agitation in children undergoing adenotonsillectomy.
Methods : In a double‐blinded trial, 60 children (age 3–7 years) were randomly assigned to receive dexmedetomidine 0.5 μg·kg−1 IV or placebo, 5 min before the end of surgery. All patients received a standardized anesthetic regimen. For induction and maintenance of anesthesia we used sevoflurane. After surgery, the incidence and severity of agitation was measured 2 h postoperatively. The incidence of untoward airway events after extubation, such as breath holding, severe coughing, or straining were recorded. After surgery, the children's behavior and pain were assessed with a 5‐point scale.
Results : The agitation and pain scores in the dexmedetomidine group were better than those in the placebo group (P < 0.05). The incidence of severe agitation (a score of 4 or more), and severe pain (a score of 3 or more) were significantly less in the dexmedetomidine group (P < 0.05). The number of severe coughs per patient in the dexmedetomidine group was significantly decreased compared with the control group (P < 0.05). Postoperative vomiting was similar in both groups. Times to emergence and extubation were significantly longer in the dexmedetomidine group (P < 0.05).
Conclusions : We conclude that 0.5 μg·kg−1 dexmedetomidine reduces agitation after sevoflurane anesthesia in children undergoing adenotonsillectomy.
Intranasal dexmedetomidine produces safe, effective sedation in children and adults. It may be administered by drops from a syringe or by nasal mucosal atomisation (MAD NasalTM).
This prospective, ...three-period, crossover, double-blind study compared the pharmacokinetic (PK) and pharmacodynamic (PD) profile of i.v. administration with these two different modes of administration. In each session each subject received 1 μg kg−1 dexmedetomidine, either i.v., intranasal with the atomiser or intranasal by drops. Dexmedetomidine plasma concentration and Ramsay sedation score were used for PK/PD modelling by NONMEM.
The i.v. route had a significantly faster onset (15 min, 95% CI 15–20 min) compared to intranasal routes by atomiser (47.5 min, 95% CI 25–135 min), and by drops (60 min, 95%CI 30–75 min), (P<0.001). There was no significant difference in sedation duration across the three treatment groups (P=0.88) nor in the median onset time between the two modes of intranasal administration (P=0.94). A 2-compartment disposition model, with transit intranasal absorption and clearance driven by cardiac output using the well-stirred liver model, was the final PK model. Intranasal bioavailability was estimated to be 40.6% (95% CI 34.7–54.4%) and 40.7% (95% CI 36.5–53.2%) for atomisation and drops respectively. Sedation score was modelled via a sigmoidal Emax model driven by an effect compartment. The effect compartment had an equilibration half time 3.3 (95% CI 1.8–4.7) min−1, and the EC50 was estimated to be 903 (95% CI 450–2344) pg ml−1.
There is no difference in bioavailability with atomisation or nasal drops. A similar degree of sedation can be achieved by either method.
HKUCTR-1617.
Dexmedetomidine (Precedex®), a pharmacologically active dextroisomer of medetomidine, is a selective α(2)-adrenergic receptor agonist. It is indicated in the US for the sedation of mechanically ...ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of dexmedetomidine in randomized, double-blind, placebo-controlled, multicentre studies in these indications. Post-surgical patients in an intensive care setting receiving dexmedetomidine required less rescue sedation with intravenous propofol or intravenous midazolam to achieve and/or maintain optimal sedation during the assisted ventilation period than placebo recipients, according to two randomized, double-blind, multinational studies. Moreover, significantly more dexmedetomidine than placebo recipients acquired and/or maintained optimal sedation without rescue sedation. Sedation with dexmedetomidine was also effective in terms of the total dose of morphine administered, with dexmedetomidine recipients requiring less morphine than placebo recipients; with regard to patient management, dexmedetomidine recipients were calmer and easier to arouse and manage than placebo recipients. Intravenous dexmedetomidine was effective as a primary sedative in two randomized, double-blind, placebo-controlled, multicentre studies in adult patients undergoing awake fibre-optic intubation or a variety of diagnostic or surgical procedures requiring monitored anaesthesia care. In one study, significantly fewer dexmedetomidine than placebo recipients required rescue sedation with intravenous midazolam to achieve and/or maintain optimal sedation; conversely, in another study, rescue sedation with intravenous midazolam was not required by significantly more dexmedetomidine than placebo recipients. Primary sedation with intravenous dexmedetomidine was also effective in terms of the secondary efficacy endpoints, including the mean total dose of midazolam and fentanyl administered and the percentage of patients requiring further sedation (in addition to dexmedetomidine or placebo and midazolam), with, for the most part, significant between-group differences observed in favour of dexmedetomidine over placebo. In general, no significant differences were observed between the dexmedetomidine and placebo treatment groups in the anaesthesiologists' assessment of ease of intubation, haemodynamic stability, patient cooperation and/or respiratory stability. Intravenous dexmedetomidine is generally well tolerated when utilized in mechanically ventilated patients in an intensive care setting and for procedural sedation in non-intubated patients. Dexmedetomidine is associated with a lower rate of postoperative delirium than midazolam or propofol; it is not associated with respiratory depression. While dexmedetomidine is associated with hypotension and bradycardia, both usually resolve without intervention. Thus, intravenous dexmedetomidine provides a further option as a short-term (<24 hours) primary sedative in mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures.
Nerve blocks improve postoperative analgesia, but their benefits may be short-lived. This quantitative review examines whether perineural dexmedetomidine as a local anaesthetic (LA) adjuvant for ...neuraxial and peripheral nerve blocks can prolong the duration of analgesia compared with LA alone. All randomized controlled trials (RCTs) comparing the effect of dexmedetomidine as an LA adjuvant to LA alone on neuraxial and peripheral nerve blocks were reviewed. Sensory block duration, motor block duration, block onset times, analgesic consumption, time to first analgesic request, and side-effects were analysed. Results were combined using random-effects modelling. A total of 516 patients were analysed from nine RCTs. Five trials investigated dexmedetomidine as part of spinal anaesthesia and four as part of a brachial plexus (BP) block. Sensory block duration was prolonged by 150 min 95% confidence interval (CI): 96, 205, P<0.00001 with intrathecal dexmedetomidine. Perineural dexmedetomidine used in BP block may prolong the mean duration of sensory block by 284 min (95% CI: 1, 566, P=0.05), but this difference did not reach statistical significance. Motor block duration and time to first analgesic request were prolonged for both intrathecal and BP block. Dexmedetomidine produced reversible bradycardia in 7% of BP block patients, but no effect on the incidence of hypotension. No patients experienced respiratory depression. Dexmedetomidine is a potential LA adjuvant that can exhibit a facilitatory effect when administered intrathecally as part of spinal anaesthesia or peripherally as part of a BP block. However, there are presently insufficient safety data to support perineural dexmedetomidine use in the clinical setting.
Dexmedetomidine (Dexdor(®)) is a highly selective α2-adrenoceptor agonist. It has sedative, analgesic and opioid-sparing effects and is suitable for short- and longer-term sedation in an intensive ...care setting. In the randomized, double-blind, multicentre MIDEX and PRODEX trials, longer-term sedation with dexmedetomidine was noninferior to midazolam and propofol in terms of time spent at the target sedation range, as well as being associated with a shorter time to extubation than midazolam or propofol, and a shorter duration of mechanical ventilation than midazolam. Patients receiving dexmedetomidine were also easier to rouse, more co-operative and better able to communicate than patients receiving midazolam or propofol. Dexmedetomidine had beneficial effects on delirium in some randomized, controlled trials (e.g. patients receiving dexmedetomidine were less likely to experience delirium than patients receiving midazolam, propofol or remifentanil and had more delirium- and coma-free days than patients receiving lorazepam). Intravenous dexmedetomidine had an acceptable tolerability profile; hypotension, hypertension and bradycardia were the most commonly reported adverse reactions. In conclusion, dexmedetomidine is an important option for sedation in the intensive care setting.
Background The alpha.sub.2 adrenergic receptor agonist dexmedetomidine is an important intravenous sedative with analgesic properties. Currently available dexmedetomidine reversal agents, like the ...alpha.sub.2-receptor antagonist atipamezole, cause serious adverse effects at the large dosages required for effective reversal; they are not used clinically. Without reversal agents, emergence times from dexmedetomidine sedation are slow. In this study we tested the ability of low-dose atipamezole, in combination with caffeine, to reverse dexmedetomidine sedation. The low dose of atipamezole employed should not be associated with unwanted effects. Methods Two different sedation protocols were employed. In the first protocol, a bolus of dexmedetomidine was rapidly applied and the drug was allowed to equilibrate for 10 min before rats received either saline (as control) or low-dose atipamezole with caffeine. Following this procedure, rats were placed on their backs. Emergence from sedation was the time for rats to recover their righting reflex and stand with 4 paws on the floor. A second sedation protocol simulated a pediatric magnetic resonance imaging (MRI) scan. Adult rats were sedated with dexmedetomidine for one hour followed by 30 min with both dexmedetomidine and propofol. At the end of 90 min, rats received either saline (control) or a combination of low-dose atipamezole, and caffeine. Recovery of the righting reflex was used as a proxy for emergence from sedation. Results Emergence from sedation, the time for rats to recover their righting reflex, decreased by ~ 90% when using an atipamezole dose ~ 20 fold lower than manufacturer's recommendation, supplemented with caffeine. Using an atipamezole dose ~ tenfold lower than recommended, with caffeine, emergence times decreased by ~ 97%. A different stimulant, forskolin, when tested, was as effective as caffeine. For the MRI simulation, emergence times were decreased by ~ 93% by low-dose atipamezole with caffeine. Conclusions Low dose atipamezole with caffeine was effective at reversing dexmedetomidine sedation. Emergence was rapid and the rats regained not only their righting reflex but also their balance and their ability to carry out complex behaviors. These findings suggest that the combination of low dose atipamezole with caffeine may permit rapid clinical reversal of dexmedetomidine without unwanted effects. Keywords: Dexmedetomidine, Atipamezole, Sedation, Emergence from sedation, cAMP, alpha.sub.2 receptor agonist, alpha.sub.2 receptor antagonist, Caffeine, Forskolin
Atomised intranasal dexmedetomidine administration is an attractive option when sedation is required for paediatric diagnostic procedures, as vascular access is not required. The risk of haemodynamic ...instability caused by dexmedetomidine necessitates better understanding of its pharmacokinetics in young children. To date, intranasal dexmedetomidine pharmacokinetics has only been studied in adults.
Eighteen paediatric patients received dexmedetomidine 1 or 2 μg kg−1 intranasally or 1 μg kg−1 i.v. Plasma concentrations were determined by liquid chromatography/mass spectrometry. Non-compartmental analysis provided estimates of Cmax and Tmax. Volume of distribution, clearance, and bioavailability were estimated by simultaneous population PK analysis of data after intranasal and i.v. administration. Dexmedetomidine plasma concentration-time profiles were evaluated by simulation for intranasal and i.v. administration.
An average peak plasma concentration of 199 pg ml−1 was achieved 46 min after 1 μg kg−1 dosing and 355 pg ml−1 was achieved 47 min after 2 μg kg−1 dosing. A two-compartment pharmacokinetic model, with allometrically scaled parameters, adequately described the data. Typical bioavailability was 83.8% (95% confidence interval 69.5–98.1%).
Mean arterial plasma concentrations of dexmedetomidine in infants and toddlers approached 100 pg ml−1, the low end reported for sedative efficacy, within 20 min of an atomised intranasal administration of 1 μg kg−1. Doubling the dose to 2 μg kg−1 reached this plasma concentration within 10 min and achieved almost twice the peak concentration. Peak plasma concentrations with both doses were reached within 47 min of intranasal administration, with an overall bioavailability of 84%.
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