ALPHA2-adrenergic receptor agonists, as a class of compounds, have been widely used as adjuncts in the perioperative period to exploit their sedative/hypnotic, analgesic, anxiolytic, and sympatholytic properties for the benefit of surgical patients.1–3In this issue of Anesthesiology, Ramsay and Luterman have provided three interesting case reports involving the use of high doses of the alpha2-adrenoceptor agonist, dexmedetomidine, as a sole agent for anesthesia.4The rationale for this new, off-label use of dexmedetomidine is based on known properties of alpha2-agonists to provide analgesia5–7while avoiding depression of respiratory function.2,8–10In all three cases, airway control or ventilatory dysfunction was an issue of concern. That dexmedetomidine could be used for general anesthesia had been alluded to by Ebert et al. ,2who earlier demonstrated that two volunteers who received a targeted infusion to a concentration of 8 ng/ml could not be aroused. Although Ramsay and Luterman have reported successful results from the use of dexmedetomidine in high doses for surgical procedures, several caveats need to be highlighted if the application of this technique is to be more commonly applied to select patients. There are potential side effects of large concentrations of dexmedetomidine that could result in undesirable effects on the cardiovascular system. A brief review of the attributes of dexmedetomidine seems warranted.

The alpha2-receptors are involved in regulating the autonomic and cardiovascular systems. Alpha2-receptors are located on blood vessels, where they mediate vasoconstriction, and on sympathetic terminals, where they inhibit norepinephrine release.11,12Alpha2-receptors also are located within the central nervous system,13and their activation leads to sedation, a 60–80% reduction of tonic levels of sympathetic outflow and catecholamines,2,10–14and an augmentation of cardiac-vagal activity.15In addition, alpha2-receptors within the spinal cord modulate pain pathways, thereby providing some degree of analgesia.5–7 

Alpha2-induced sedation qualitatively resembles normal sleep;10specifically, the endogenous, nonrapid eye movement, sleep-promoting pathways may mediate alpha2-mediated sedation. Nelson et al.  used a combination of immunohistochemistry (to monitor activity in brain nuclei), discrete application of ibotenic acid (to lesion specific nuclei), and pharmacologic antagonists as well as genetically-altered mice (to probe the participation of specific receptors) to show that endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation (fig. 1).16Thus, the participation of nonrapid eye movement sleep pathways seems to explain why patients who appear to be “deeply asleep” from dexmedetomidine are relatively easily aroused in much the same way as occurs with natural sleep.

However, the mechanisms that have been elucidated in rodents do not completely explain why arousal was not possible in both Ebert et al.'  s two volunteers and now in Ramsay and Luterman's three patients. Possibly, at very high levels of dexmedetomidine, nociceptive transmission is sufficiently blocked to prevent the arousing signal from disrupting the patient's hypnotic state. Dexmedetomidine and other alpha2-agonists are known to interrupt nociceptive processing in the periphery, in the spinal cord, and in supraspinal sites.3 

The respiratory sparing effects of alpha2-agonists have been closely examined.2,8–10,17–21They are associated with minimal respiratory depression and a preservation of the ventilatory and occlusion pressure response to CO2. In healthy volunteers, plasma levels of dexmedetomidine eightfold to 10-fold higher than the clinical range resulted in unarousable volunteers who did not respond to a painful stimulus but maintained their respiratory drive.2The Paco2increased from a baseline of 43 mm Hg to only 47 mm Hg. However, several reports indicate that obstructive apnea can occur with either a bolus administration or high doses of dexmedetomidine.2,9This first caveat suggests that patients with a history of obstructive sleep apnea might also obstruct during high concentrations of dexmedetomidine.

The second concern with the use of high concentrations of dexmedetomidine is the potential for both systemic and pulmonary hypertension and direct or reflex bradycardia. In the previously mentioned volunteer study, central pressures responded to increasing concentrations of dexmedetomidine in a biphasic manner. In the lower, clinical range, infusions decreased pressure, presumably as a result of a central sympatholytic effect. At higher plasma levels, peripheral alpha2-receptor mediated vasoconstriction overrode the sympatholytic effects, resulting in increased pulmonary artery and systemic blood pressures. In healthy patients with intact baroreflexes, this can lead to bradycardia. Reflex bradycardia in conjunction with the vagal mimetic property of alpha2-agonists could lead to severe bradycardia or asystole. In the three case reports from Ramsay and Luterman describing the use of high doses of dexmedetomidine in surgical patients, decreases, rather than increases, in blood pressure were noted. Perhaps in an older population, the alpha2-receptor vascular effects of dexmedetomidine are diminished. Nonetheless, a second caveat with administering high doses of dexmedetomidine is to be wary of increases in blood pressure and excessive slowing of heart rate.

Although both Ebert et al.  2and now Ramsay and Luterman4have described the possible monotherapeutic application of alpha2-agonists to provide an anesthetic state suitable for general anesthesia, it is much more likely that this class of compound will be used in combination with other anesthetic adjuvants in the perioperative period. Clinical studies in humans have validated the long-practiced veterinary anesthetic technique of combining alpha2-agonists with ketamine to obviate both the cardiostimulatory and psychomimetic effects of the latter drug.22Furthermore, combining alpha2-agonists with opiate narcotics or nonsteroidal antiinflammatory drugs can enhance the analgesic efficacy without increasing the respiratory depressant effect of the latter. Past studies have revealed that the dose of many induction and maintenance agents for anesthesia can be significantly reduced when combined with alpha2-agonists without adverse effects.23 

Ramsay and Luterman's interesting series of cases provides another arrow in the quiver of clinicians for the management of surgical patients with compromised airways. We anticipate further comparative studies to establish the clinical role of dexmedetomidine in difficult airway algorithms.

* Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin. † Department of Anesthetics and Intensive Care, Imperial College School of Medicine, London, United Kingdom.

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