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EDITORIAL

Expecting the Unexpected

Pekka O. Talke, MD^*, and Mervyn Maze, MB ChB, FRCP, FRCA, FMedSci

From the *Department of Anesthesia and Perioperative Medicine, University of California, San Francisco, California; Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.

Address correspondence to Pekka O. Talke, MD, Department of Anesthesia and Perioperative Medicine, University of California, San Francisco, 521 Parnassus Ave., C450, San Francisco, CA 94143-0648. Address e-mail to talkep{at}anesthesia.ucsf.edu.

Dexmedetomidine is a highly selective ₂ adrenergic receptor agonist that has similar affinity at each of the three receptor subtypes. Of the numerous physiologic effects mediated by ₂ adrenergic receptors,1 the properties of sedation, sympatholysis, and analgesia are most sought after for the more than 1 million patients who have received dexmedetomidine. The fact that healthy volunteers tolerate 15–20 times higher dexmedetomidine concentrations than those intended for clinical use2 presaged its relative safety and wide therapeutic window.

In this issue of Anesthesia & Analgesia, Sichrovsky et al. describe a cardiovascular system-related death associated with use of dexmedetomidine3 that follows a similar report from the same institution.4 Both patients had preexisting cardiac conduction abnormalities.

Dexmedetomidine has well-described cardiovascular effects that are due in large part to its centrally mediated sympatholytic effect in combination with peripherally mediated vasoconstriction. In healthy volunteers, these cardiovascular effects are dose-related and highly predictable.2 However, physiologically "normal" individuals are not dependent on sympathetic tone and tolerate sympatholysis without sequelae. Small doses of dexmedetomidine reduce heart rate and arterial blood pressure, helping limit perioperative stress-induced tachycardia and hypertension.5 At higher concentrations, ₂ adrenergic receptor-mediated peripheral vasoconstriction increases arterial blood pressure.2 Within the usual clinical range, ₂ agonist-induced sympatholytic effects predominate and thereby yield a putative cardioprotective effect.

The hemodynamic side effect profile of dexmedetomidine (including hypotension, bradycardia, peripheral vasoconstriction, and decreased cardiac output) is due to an extension of its pharmacologic action via the ₂ adrenergic receptor that can be largely avoided by carefully titrating the dose to the desired effect. Hypertension and the associated reflex bradycardia can be minimized by avoiding high dexmedetomidine plasma concentrations. Therefore, dexmedetomidine administration should proceed through an initial loading infusion, followed by a maintenance infusion, rather than rapid IV bolus.

Even with careful titration, rare but potentially dangerous hemodynamic side effects have been observed. Sinus pauses and/or arrests were observed in studies involving volunteers who were often young and otherwise healthy.6,7 These adverse events had been precipitated by a vagal stimulus or standing up toward the end of experimental studies while dexmedetomidine plasma concentrations were within the range advocated for clinical use. The explanation provided was that this clinical scenario was due to vagotonia that was not offset by sympathetic tone, which had been obtunded at the relatively low concentrations of dexmedetomidine. Although a few intraoperative sinus pauses and/or arrests have been reported,8 to our knowledge, these events have not been seen in the postoperative setting in which sympathetic tone is relatively high. However, we anticipate that sinus pauses and arrest may be seen in settings in which sedation with dexmedetomidine is being used for procedures that are not associated with stress, such as radiologic imaging or minor surgical procedures performed with nerve conduction blocks.

Germane to the current report, dexmedetomidine has been associated with conduction blocks resulting in atrioventricular dissociation that can progress to third degree heart block. These rare events have usually occurred during general anesthesia. Clonidine, another ₂ adrenergic receptor agonist, has also been associated with defects in cardiac conduction, such as high-grade A-V block and A-V dissociation.9–11 Electrophysiologic studies have demonstrated that clonidine and dexmedetomidine depress sinus and A-V nodal function in some subjects having striking prolongation of sinus nodal recovery time.9,12 The clonidine-induced conduction effects appear to be more profound in patients whose sinus function is already impaired before administration of clonidine. Although we suspect that clonidine and dexmedetomidine induce similar changes in cardiac conduction, future electrophysiologic studies should document the mechanisms of dexmedetomidine-induced cardiac conduction blocks.

The case reported in this issue strongly suggests that the profound sympatholytic effect of dexmedetomidine may be dangerous for patients who rely on high sympathetic tone. Dexmedetomidine-induced reduction in sympathetic tone will decrease heart rate, arterial blood pressure, and cardiac output. This may be life-threatening in patients with coronary artery disease and/or cardiac conduction abnormalities who rely on high sympathetic nervous system tone to maintain adequate cardiovascular function. The inability to resuscitate these patients cannot be completely explained by the previously discussed cardiac effects of dexmedetomidine. It is possible that exogenously administered catecholamines may not reach and stimulate the myocardium as well as expected during profound sympatholysis, increasing pacing thresholds and making resuscitation more difficult in patients receiving dexmedetomidine.

Although the dexmedetomidine package insert points out the potential for these cardiac side effects, little published data describe these events. Case reports are the only source of data to help us understand how dexmedetomidine provokes these rare, life-threatening events. What can we learn from the report by Sichrovsky et al.? First, it is important to select the appropriate patients and clinical settings for the safest use of dexmedetomidine, particularly as use expands to include off-label indications. We advise against the use of dexmedetomidine in patients with (i) known sinus and A-V conduction problems, (ii) no stress-induced stimulation of the sympathetic nervous system (e.g., sedation in patients with regional anesthesia), and (iii) insufficient cardiovascular reserve requiring continuous high sympathetic nervous system tone. We also advise against any dosing regimen that might produce abruptly high concentrations. Clinicians who do not respect the sympatholytic potency of dexmedetomidine should expect the unexpected.

	Footnotes

 
Accepted for publication January 23, 2008.

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