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• W1584639503 abstract "In this issue of Anaesthesia, Yuen et al. report on their investigation of the use of intranasal dexmedetomidine for premedicating children [1]. It is an example of the burgeoning interest in this somewhat unusual compound, which is still in the process of finding its niche in anaesthetic and intensive care practice. After quite a long gestation, dexmedetomidine was introduced into clinical practice about ten years ago, but only became available in the UK in October 2011 (see http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=2690). Dexmedetomidine is a full agonist on the α2b-adrenoceptor subtype [2] and is a more powerful hypnotic than clonidine. It has been used both as a single agent for sedation, and in combination with other drugs for sedation and for general anaesthesia. Before it could be released in Europe, the European Medicines Agency required further studies to be undertaken comparing dexmedetomidine with existing sedative drugs (M. Maze, personal communication). There were some delays in completing these studies, hence the drug’s relatively late arrival in Europe. In order to use any drug effectively, clinicians must have realistic expectations of its capabilities and failings. Dexmedetomidine is not the magic bullet for sedation, but its relative specificity for adrenergic modulation allows the anaesthetist to alter the central nervous system in ways that are impossible to achieve with other existing sedative drugs. The aim of this editorial is to highlight briefly a few of its clinical strengths and limitations. In particular I will concentrate on: (i) the idea of ‘arousable sedation’; (ii) the importance of adrenergic suppression as a specific therapeutic goal for sedation and anaesthesia; and (iii) the problems with the slow onset and offset of dexmedetomidine. For more detailed descriptions of the drug, and its use in specific clinical situations, I would direct the reader to a number of comprehensive review articles [3-10]. When used as a sole agent, the immediate appeal of dexmedetomidine lies in the promise of analgesia and sedation without respiratory depression or paradoxical confusion. However, the practitioner must be aware that it provides a type of sedation that is qualitatively different to that produced by commonly used γ-amino-butyric-acid(GABA)-ergic hypnotics, such as propofol and midazolam. These differences in sedation are the direct consequence of the profound differences in neuropharmacology. The somewhat oxymoronic term ‘arousable sedation’ has been used to describe the state produced by dexmedetomidine. It refers to the observation that patients sedated with the recommended dosage of dexmedetomidine appear asleep, but are rousable and co-operative to verbal command – and then go back to sleep. The contrast with propofol or sevoflurane sedation is most graphically demonstrated in a figure (no. 3) in a paper by Kasinoro and co-workers [11]. In this figure, the electroencephalographic indices (bispectral index (BIS) and spectral entropy) follow the state of dexmedetomidine sedated patients, abruptly flipping between wakefulness (BIS ∼80) and sleep (BIS ∼40) each time their sedation score is assessed. Eventually, at relatively high blood concentrations (above 2 ng ml−1), the patient becomes unresponsive to verbal command. This arousable sedation phenomenon is an indicator that one is literally ‘putting the patient to sleep’ with dexmedetomidine. The neuromodulator milieu that characterises natural sleep is marked by low levels of amines and orexin. At the risk of over-simplification, dexmedetomidine is a potent drug that acts specifically to suppress the effects of brainstem adrenergic activity, thus producing a neuromodulator profile most similar to that of natural sleep. In contrast, classical GABA-ergic hypnotics have more widespread targets. Whilst part of their action is to facilitate natural sleep mechanisms in the hypothalamus and brainstem, they also have direct inhibitory effects on higher brain regions (striatum, thalamus, cerebral cortex and hippocampus), and propofol sedation is probably associated with minimal suppression of brainstem amine activity [12, 13]. The clinical relevance of this neurobiology is that it explains the fact that the amnesic and anxiolytic effects of dexmedetomidine are in direct proportion to the hypnotic effects, unlike midazolam and propofol which commonly induce amnesia without much sedation. It also explains the relatively modest anti-nociceptive effects of dexmedetomidine when used alone – but the powerful synergistic effects when used in conjunction with low doses of opioids and midazolam or propofol. Like clonidine, dexmedetomidine is often used most effectively in conjunction with other drugs – to augment their actions, and hence enable a reduction in their dosage and side effects. Finally, it explains why dexmedetomidine strongly reduces confusion and delirium [14]. The relationship between dexmedetomidine dose and its cardiovascular effects is complex and somewhat unpredictable [15]. Compared with clonidine, dexmedetomidine will tend to cause more bradycardia and less hypotension – and sometimes even hypertension at higher doses. In some patient populations this profile protects against myocardial ischaemia [7], but there are numerous reports of significant sinus arrests in both healthy volunteers and frail patients [16]. These events seem to be often associated with additional vagotonic stimuli or interaction with concomitant β-blockade; and are usually responsive to conventional anticholinergic treatment. For this reason, dexmedetomidine should never be given as a single large bolus dose, and, if infused for a long duration, the possibility of drug accumulation should be detected by using regular cardiovascular monitoring. It has been suggested that a 30% decrease in heart rate would be a threshold for stopping the infusion. α2-Adrenoceptors are involved in the control of the classical centrifugal sympathetic nervous system, which is manifest most obviously in the changes in blood pressure and heart rate as described above. But, perhaps more importantly, these receptors also have critical roles in the sympathetic control of nociception, cognition, and apoptosis within the brain and spinal cord [17]. Probably the biggest clinical benefits of the drug are likely to be seen in its ability to control central aminergic activity when the drug is used as an adjunct to more conventional general anaesthesia techniques. Dexmedetomidine has MAC-sparing effects of between 25% and 70% [18]. The resultant reduction in dosage of volatile anaesthetic and opioid drugs has been shown to have a beneficial effect for a plethora of postoperative problems. There are significant decreases in the incidence of: delirium and agitation (and possibly cognitive impairment); opioid requirements (and opioid-induced hyperalgesia); and nausea and vomiting [19]. The term ‘immunosedation’ has been coined to describe techniques that minimise the immune depression associated with traditional sedative drugs [20, 21]. The role of dexmedetomidine for sedation in the intensive care unit results in less critical illness-induced immune dysfunction [22] and possibly, improved mortality in septic patients – although this is being investigated further. When compared with existing GABA-ergic hypnotics, it is immediately apparent that dexmedetomidine has a slow onset time and a variable offset. It is not a drug that is easy to use if you are in a hurry, or during an operating list that requires a rapid turnover. The time to achieve a peak effect is at least 10 minutes after the attainment of adequate plasma levels of the drug [15]. As a result, it is very easy to overshoot when titrating dosage to clinical effect. Analogous to fentanyl, the offset of action is also strongly context sensitive. In both healthy subjects and critically ill patients, the plasma half-life varies from about 15 minutes after a small dose (∼0.5 μg.kg−1) to over two hours after a large cumulative dose (>3 μg.kg−1) [23-25]. Examples of effect-site concentrations for three simulated dosages are shown in Fig. 1. Assuming that significant hypnosis occurs at blood levels of over ∼0.7 ng.ml−1, it can be seen that, at the highest dose, sedation might be expected to last for some hours. Simulated effect-site (Ce) concentration of dexmedetomidine for three different dosages. The simulated drug was modelled as being administered in short infusions, resulting in a cumulative dosage of 2.0 μg.kg−1 given over 40 min (upper); 1.0 μg.kg−1 given over 20 min (middle); and 0.5 μg.kg−1 given over 10 min (lower). The infusions are shown by the thick horizontal lines. To overcome the problems of prolonged sedation and bradycardia, the availability of an effective α2-receptor antagonist would be very useful. The compound atipamezole has shown some promise, but for undisclosed reasons, is not available outside veterinary practice [26]. Dexmedetomidine has been available in New Zealand for the best part of a decade. This is therefore a short summary of my practice, distilled from published studies and my personal experience of using the drug as an adjunct to general anaesthesia and for sedation in the intensive care unit, the interventional radiology suite, and the operating theatre. Dexmedetomidine would be my choice for procedural sedation if I was concerned about risks of respiratory embarrassment (e.g. obesity, airway obstruction) and restlessness (e.g. the elderly, those patients on – or withdrawing from – psychoactive drugs). I would be less likely to use dexmedetomidine as a single drug for sedation if: (i) rapid changes in depth of sedation were required; (ii) the patient was dependent on sympathetic drive for an adequate cardiac output; (iii) reliable amnesia is required; or (iv) a strong noxious stimulus is anticipated. I would consider the inclusion of dexmedetomidine as part of a general anaesthetic technique if I was particularly worried about postoperative respiratory compromise and wanted to minimise opioid requirements (e.g. obesity, opioid sensitivity, neurosurgery, perhaps a history of postoperative nausea and vomiting), or about the deleterious effects of postoperative delirium (e.g. pre-operative dementia, drug abuse, ischaemic heart disease, critical disruption of surgical wounds). A practical guide that might be useful to readers unfamiliar with this fascinating drug, based on my own practice, is provided in Box 1. No external funding and no competing interests declared." @default.
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• W1584639503 date "2012-09-05" @default.
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• W1584639503 title "All hands on dex" @default.
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