Dexmedetomidine in Trauma Anesthesiology and Critical Care

Dexmedetomidine (Precedex) is an α2-adrenergic agonist that is currently approved by the Food and Drug Administration for the short-term (<24 hours) sedation of adult patients in the intensive care unit. Its clinical effects include sedation, anxiolysis, analgesia, a decrease of the minimum alveolar concentration of inhalational anesthetic agents, blunting of the sympathetic nervous response to surgery, and lowering of heart rate and blood pressure. These beneficial physiologic effects, combined with its relatively low incidence of adverse hemodynamic and respiratory effects, have led to its use in various intraoperative and postoperative clinical scenarios, including sedation during mechanical ventilation, prevention of emergence agitation following general anesthesia, provision of procedural sedation, and prevention of the withdrawal following the prolonged use of opioids and benzodiazepines. This article reviews the basic pharmacology of dexmedetomidine, its end-organ effects including its adverse effect profile, and reports of its use in various clinical scenarios. Its potential applications in the practice of trauma anesthesiology and critical care are explored. Dexmedetomidine (Precedex), the pharmacologically active dextroisomer of medetomidine, is an α2-adrenergic agonist with physiologic effects similar to those of clonidine. The α2-adrenergic agonists are subclassified into three groups: imidazolines, phenylethylamines, and oxalozepines. Both dexmedetomidine and clonidine are members of the imidazole compounds, which exhibit a high ratio of specificity for the α2 versus the α1 receptor. Clonidine exhibits an α2:α1 specificity ratio of 200:1, and that of dexmedetomidine is 1600:1. As such, dexmedetomidine is considered a complete agonist at the α2-adrenergic receptor. Another difference between the two agents is that dexmedetomidine has a short half-life (2-3 hours vs. 12-24 hours with clonidine) and is commercially available for intravenous administration as opposed to the epidural formulation for clonidine. The physiologic actions of dexmedetomidine are mediated via stimulation of postsynaptic α2-adrenergic receptors that activate a pertussis toxin-sensitive guanine nucleotide regulatory protein (G protein), resulting in inhibitory feedback and decreased activity of adenylyl cyclase. This results in a reduction of intracellular cyclic adenosine monophosphate (cAMP) and cAMP-dependent protein kinase activity, resulting in a dephosphorylation of ion channels. This process subsequently modifies ion translocation and membrane conductance, resulting in decreased neuronal activation and the clinical effects of sedation and anxiolysis. The centrally acting α2adrenergic agonists including dexmedetomidine also activate receptors in the medullary vasomotor center, reducing norepinephrine turnover and decreasing central sympathetic outflow, resulting in decreased heart rate and blood pressure. Additional effects result from the central stimulation of parasympathetic outflow and inhibition of sympathetic outflow from the locus ceruleus in the brainstem. The latter effect plays a prominent role in the sedation and anxiolysis produced by these agents as decreased noradrenergic output from the locus ceruleus allows for increased firing of inhibitory neurons including the α-amino butyric acid (GABA) system. The activation of α2-adrenergic receptors in the dorsal horn of the spinal cord inhibits the release of substance P, resulting in primary analgesic effects as well as potentiation of opioid-induced analgesia. The latter effect has been shown in clinical trials to result in opioid-sparing and analgesia in acute pain syndromes and during intraoperative anesthetic care (see following discussion). The interactions with α2-adrenergic receptors throughout the central nervous system and spinal cord result in physiologic effects in various organs systems including sedation, anxiolysis, analgesia, a decrease of the minimum alveolar concentration of inhalational anesthetic agents, decreased renin and vasopressin levels leading to diuresis, blunting of the sympathetic nervous response to surgery, and lowering of heart rate and blood pressure. Currently, the only Food and Drug Administration (FDA)approved indication for dexmedetomidine is the provision of sedation in adult patients in the intensive care unit (ICU) setting for up to 24 hours. However, given its favorable physiologic effects as well as its limited adverse effect profile, there is increasing interest in the use of this agent in patients of all ages and various clinical scenarios. This article reviews the basic pharmacology of dexmedetomidine, its endorgan effects and adverse effect profile, and reports from the literature regarding its use in various clinical scenarios.