A comparison of dexmedetomidine, moxonidine and alpha-methyldopa effects on acute, lethal cocaine toxicity

Background: The treatment of cocaine toxicity is an important subject for emergency physicians. We investigated the effects of dexmedetomidine, moxonidine and alpha-methyldopa on acute cocaine toxicity in mice. Objectives: The aim of this study was to evaluate the effects of dexmedetomidine, moxonidine and alpha-methyldopa in a mouse model of acute cocaine toxicity. Materials and Methods: We performed an experiment consisting of four groups (n = 25 each). The first group received normal saline solution, the second group received 40 μg/kg of dexmedetomidine, the third group received 0.1 mg/kg of moxonidine and the fourth group received 200 mg/kg of alpha-methyldopa, all of which were intraperitoneally administered 10 minutes before cocaine hydrochloride (105 mg/kg). All animals were observed for seizures (popcorn jumping, tonic-clonic activity, or a loss of the righting reflex) and lethality over the 30 minutes following cocaine treatment. Results: The ratio of animals with convulsions was lower in all treated groups when compared to the control (P 0.05). In addition, the time to lethality was also longer in the same group (P < 0.001). Conclusions: The present study provides the first experimental evidence in support of dexmedetomidine treatment for cocaine-induced seizures. Premedication with dexmedetomidine reduces seizure activity in a mouse model of acute cocaine toxicity. In addition, while dexmedetomidine may be effective, moxonidine and alpha-methyldopa did not effectively prevent cocaine-induced lethality. © 2015, Iranian Red Crescent Medical Journal

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns : impact of design optimisation

Purpose: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population

Review of the effects of anesthetic agents used as premedication for patients undergoing electroconvulsive therapy with diagnoses of bipolar disorder or major depression on convulsion, recovery period, and hemodynamic parameters

Objective: The aim of this study was to examine the effects of anesthetic agents used as premedication in patients undergoing electroconvulsive therapy (ECT) for diagnoses of bipolar disorder or major depression in terms of convulsion, recovery period, and hemodynamic parameters. Materials and Method: This retrospective study was carried out by screening the anesthesia forms of patients in a psychiatry clinic in Turkey. Results: Researchers reviewed 104 patient files, of which 39 fit the inclusion criteria. 26 patients were given premedication; 13 patients were not given premedication. The study found a significant difference between the group to which dexmedetomidine was given and the non-premedication group in terms of mean arterial blood pressure and heart rate. A significant difference was also found between the group to which midazolam was given and the non-premedication group in terms of peripheral oxygen saturation. Conclusion: Premedication before ECT may be used to reduce the side effects after ECT without affecting convulsions and the recovery period

Dexmedetomidine post-treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF-1α signalling.

Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in the apoptotic process during cardiac ischaemia/reperfusion (I/R) injury. This study aimed to investigate whether post-treatment with dexmedetomidine (DEX) could protect against I/R-induced cardiac apoptosis in vivo and in vitro via regulating HIF-1α signalling pathway. Rat myocardial I/R was induced by occluding the left anterior descending artery for 30 minutes followed by 6-hours reperfusion, and cardiomyocyte hypoxia/reoxygenation (H/R) was induced by oxygen-glucose deprivation for 6 hours followed by 3-hours reoxygenation. Dexmedetomidine administration at the beginning of reperfusion or reoxygenation attenuated I/R-induced myocardial injury or H/R-induced cell death, alleviated mitochondrial dysfunction, reduced the number of apoptotic cardiomyocytes, inhibited the activation of HIF-1α and modulated the expressions of apoptosis-related proteins including BCL-2, BAX, BNIP3, cleaved caspase-3 and cleaved PARP. Conversely, the HIF-1α prolyl hydroxylase-2 inhibitor IOX2 partly blocked DEX-mediated cardioprotection both in vivo and in vitro. Mechanistically, DEX down-regulated HIF-1α expression at the post-transcriptional level and inhibited the transcriptional activation of the target gene BNIP3. Post-treatment with DEX protects against cardiac I/R injury in vivo and H/R injury in vitro. These effects are, at least in part, mediated via the inhibition of cell apoptosis by targeting HIF-1α signalling

Behavioral and cardiopulmonary effects of dexmedetomidine alone and in combination with butorphanol, methadone, morphine or tramadol in conscious sheep

Objective: To compare cardiopulmonary and sedative effects following administration of dexmedetomidine alone or with butorphanol, methadone, morphine or tramadol in healthy sheep. Study design: Randomized crossover study. Animals: Six Santa Inês sheep, five females, one male, aged 12–28 months and weighing 40.1 ± 6.2 kg. Methods: Sheep were assigned treatments of dexmedetomidine (0.005 mg kg−1; D); D and butorphanol (0.15 mg kg−1; DB); D and methadone (0.5 mg kg−1; DM); D and morphine (0.5 mg kg−1; DMO); or D and tramadol (5.0 mg kg−1; DT). All drugs were administered intravenously with at least 7 days between each treatment. Rectal temperature, heart rate (HR), respiratory rate (fR), invasive arterial pressure, blood gases and electrolytes were measured prior to administration of drugs (baseline, T0) and every 15 minutes following drug administration for 120 minutes (T15–T120). Sedation was scored by three observers blinded to treatment. Results: HR decreased in all treatments and fR decreased in DM at T30 and DMO at T30 and T45. PaCO2 was increased in D, DB and DM compared with baseline, and PaO2 decreased in D at T15 and T45; in DB at T15 to T75; in DM at T15 to T60; in DMO at T15; and in DT at T15, T30 and T75. There was a decrease in temperature in D, DB and DM. An increased pH was measured in D at all time points and in DT at T30–T120. inline image and base excess were increased in all treatments compared with baseline. There were no statistical differences in sedation scores. Conclusions and clinical relevance: The combination of dexmedetomidine with butorphanol, methadone, morphine or tramadol resulted in similar changes in cardiopulmonary function and did not improve sedation when compared with dexmedetomidine alone

Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs

Intranasal ketamine has recently gained interest in human medicine, not only for its sedative, anaesthetic or analgesic properties, but also in the management of treatment resistant depression, where it has been shown to be an effective, fast acting alternative treatment. Since several similarities are reported between human psychiatric disorders and canine anxiety disorders, intranasal ketamine could serve as an alternative treatment for anxiety disordered dogs. However, to the authors knowledge, intranasal administration of ketamine and its pharmacokinetics have never been described in dogs. Therefore, this study aimed to examine the pharmacokinetics, absolute bioavailability and tolerability of intranasal ketamine administration compared with intravenous administration. Seven healthy, adult laboratory Beagle dogs were included in this randomized crossover study. The dogs received 2 mg/kg body weight ketamine intravenously (IV) or intranasally (IN), with a two-week washout period. Prior to ketamine administration, dogs were sedated intramuscularly with dexmedetomidine. Venous blood samples were collected at fixed times until 480 min post-administration and ketamine plasma concentrations were determined by liquid chromatographytandem mass spectrometry. Cardiovascular parameters and sedation scores were recorded at the same time points. Non-compartmental pharmacokinetic analysis revealed a rapid (Tmax = 0.25 +/- 0.14 h) and complete IN bioavailability (F = 147.65 +/- 49.97%). Elimination half-life was similar between both administration routes (T1/2el IV = 1.47 +/- 0.24 h, T1/2el IN = 1.50 +/- 0.97 h). Heart rate and sedation scores were significantly higher at 5 and 10 min following IV administration compared to IN administration, but not at the later time-points

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units : a systematic review

Funding The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.Peer reviewedPublisher PD

A comparison of medetomidine and its active enantiomer dexmedetomidine when administered with ketamine in mice

Medetomidine-ketamine (MK) and dexmedetomidine-ketamine (DK) are widely used to provide general anaesthesia in laboratory animals, but have not been compared directly in many of these species, including rodents. This study aimed to compare the onset and depth of anaesthesia, and changes in vital signs, after intraperitoneal (IP) or subcutaneous (SC) administration of ketamine (75 mg kg-1) combined with medetomidine (1 mg kg-1) or dexmedetomidine (0.5 mg kg-1) using a randomised semi-crossover design with >= 48 hours between treatments in 10 male and 10 female mice. Each mouse was anaesthetised twice using the same administration route (IP or SC): once with each drug-ketamine combination. Anaesthetised mice were monitored on a heating pad without supplemental oxygen for 89 minutes; atipamezole was administered for reversal. The times that the righting reflex was lost post-injection and returned post-reversal were analysed using general linear models. Tail-pinch and pedal reflexes were examined using binomial generalized linear models. Pulse rate (PR), respiratory rate (fr), and arterial haemoglobin saturation (SpO2) were compared using generalized additive mixed models. There were no significant differences among treatments for the times taken for loss and return of the righting reflex, or response of the tail-pinch reflex. The pedal withdrawal reflex was abolished more frequently with MK than DK over time (P = 0.021). The response of PR and SpO2 were similar among treatments, but fr was significantly higher with MK than DK (P <= 0.0005). Markedly low SpO2 concentrations occurred within 5 minutes post-injection (83.8 +/- 6.7 %) in all treatment groups and were most severe after 89 minutes lapsed (66.7 +/- 7.5 %). No statistical differences were detected in regards to administration route (P <= 0.94). This study failed to demonstrate clinical advantages of the enantiomer dexmedetomidine over medetomidine when combined with ketamine to produce general anaesthesia in mice. At the doses administered, deep surgical anaesthesia was not consistently produced with either combination; therefore, anaesthetic depth must be assessed before performing surgical procedures. Supplemental oxygen should always be provided during anaesthesia to prevent hypoxaemia

Managing Opioid-Tolerant Patients in the Perioperative Surgical Home.

Management of acute postoperative pain is important to decrease perioperative morbidity and improve patient satisfaction. Opioids are associated with potential adverse events that may lead to significant risk. Uncontrolled pain is a risk factor in the transformation of acute pain to chronic pain. Balancing these issues can be especially challenging in opioid-tolerant patients undergoing surgery, for whom rapidly escalating opioid doses in an effort to control pain can be associated with increased complications. In the perioperative surgical home model, anesthesiologists are positioned to coordinate a comprehensive perioperative analgesic plan that begins with the preoperative assessment and continues through discharge