Glasgow Meeting - May 2003

Dexmedetomidine for ICU sedation

Prof M Maze, Sir Ivan Magill Professor of Anaesthetics and Intensive Care, Imperial College, London

a2-adrenoceptor agonists (e.g. clonidine, dexmedetomidine, xylazine) are anesthetic agents used widely in clinical and veterinary settings for their sedative, or hypnotic, and analgesic effects. One of the highest densities of a2-adrenoceptor has been detected in the pontine locus coeruleus (LC),1 a key source of noradrenergic innervation of the forebrain and an important modulator of vigilance.2,3 The sedative effects of a2-adrenoceptor activation have been attributed to the inhibition of this nucleus.4,5 Dexmedetomidine (marketed as PrecedexÔ by Abbott Laboratories, Abbott Park, Illinois, USA) is the pharmacologically active dextroisomer of medetomidine and displays specific and selective a2-adrenoceptor agonism. It was approved by the U.S. Food and Drug Administration in 1999 as a short-term medication (<24 hr) for sedation in the intensive care unit and has also been shown to act as a general anesthetic.6 Its specificity for the a2-adrenoceptor, and relative selectivity for the a2Aadrenoceptor subtype (which is responsible for its sedative properties7), provides for a more effective sedative and analgesic agent than clonidine and makes it an ideal probe with which to investigate anesthetic mechanisms. After dexmedetomidine binds to a2-adrenoceptors in the LC, transmembrane signalling results in activation of an inwardly rectifying potassium channel facilitating a K+ efflux and inhibition of voltage-gated Ca2+ channels. The resulting hyperpolarization decreases the firing rate of LC neurons and allows presynaptic inhibition of their terminals.8-10 Hyperpolarization of noradrenergic LC neurons appears to be a key factor in initiating the anesthetic mechanism of action of dexmedetomidine.5,11

Qualitatively, dexmedetomidine induces a sedative response that exhibits properties similar to natural sleep, unlike other anesthetics. Patients receiving dexmedetomidine experience a clinically effective sedation yet are still easily and uniquely arousable, an effect not observed with any other clinically available sedative.12 Data from our recent fMRI study in human volunteers indicates that the Blood Oxygen Level Dependent (BOLD) signal, which positively correlates with local brain activity, changes during dexmedetomidine sedation in a similar fashion to that seen during natural sleep while changes induced by the benzediazepine midazolam were markedly different.13 We investigated whether dexmedetomidine -induced decrease in firing of noradrenergic LC neurons leads to loss of consciousness, at least in part via activation of an endogenous sleep-promoting pathway. Dexmedetomidine-induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal sleep (i.e., a decrease in the locus coeruleus (LC) and tuberomammillary nucleus (TMN) and an increase in the ventrolateral preoptic nucleus (VLPO). These changes were attenuated by atipamezole, and were not seen in mice lacking functional a2Aadrenoceptors, which do not show a sedative response to dexmedetomidine. Bilateral VLPO lesions attenuated the sedative response to dexmedetomidine and the doseresponse curve was shifted right by gabazine administered systemically or directly into the TMN. Both VLPO lesions and gabazine pre-treatment altered c-Fos expression in the TMN but not the LC following dexmedetomidine administration, indicating a hierarchical sequence of changes. Thus the endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation; dexmedetomidine’s sedative mechanism involves inhibition of the LC, which disinhibits VLPO firing. The increased release of GABA at the terminals of the VLPO inhibits TMN firing, which is required for the sedative response.

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13. Jones MEP, Coull JT, Egan TD, Maze M: Are subjects more easily aroused during sedation with the a2 agonist, dexmedetomidine?, Anaesthetic Research Society 2000 Meeting. London, Br J Anaesth 2002; 86(2): 324P