Alpha₂ adrenergic agonists provide sedation and analgesia with maintained cardiorespiratory function. Large doses of ₂ adrenergic agonists such as clonidine have been used, but the MAC-sparing effects are complicated by persistent hypotension requiring treatment as well as hypertension arising from ₂ -receptor mediated vascular constriction. The availability of a drug with a shorter half-life, dexmedetomidine (dex), may widen use of this class of drugs into postoperative or intensive care unit sedation. This study examined human volunteers in good health to establish some of the dose effect relationships of relatively low concentrations of dex that have few cardiovascular effects, given as a continuous infusion. The purpose of this research in volunteers was to evaluate the effect of dex on sedation, cognitive function, analgesia, and cardiorespiratory function, in order to assess the safety and efficacy of dex for its proposed use in postoperative sedation.

The study design included three sessions in which seven subjects received, in random order, either placebo or a 6 µg per kg per hour dex load followed by infusions of either 0.2 or 0.6 µg per kg per hour. Both the investigators and the subjects were blinded to the randomization schedule. Sedation level was measured by the bispectral index, the Observer Assessment of Alertness/Sedation (OAA/S) and the visual analog scale for sedation (VAS). Cognition was tested by using the digit symbol substitution test and a memory recall test. Pain perception was assessed using the cold pressor test, which consists of immersion of the hand into ice water for one minute. Pain response was assessed by heart rate, mean arterial pressure, and a subjective VAS for pain.

Both small and moderate doses of dex produced significant sedation compared with placebo. Sedation level had reached the maximum by 10 minutes after starting the infusion. Subjects were aroused to assess sedation and perform their various tests; once stimulated, verbally and/or physically, the subjectsÕ alertness rose to baseline levels and then returned. The level of sedation achieved after this 60 minute infusion was the same for both doses by all indicators. Recovery from sedation showed BIS and VAS values that were not yet normal by 2 hours after end infusion but had returned to normal by 4 hours recovery. Dex also produced partial lack of recall of events occurring during the infusion. Digit symbol substitution test results showed impairment of psychomotor function during the infusion, which had lessened by one hour postop and was gone by 4 hours postop. Dex also produced a significant decrease in pain perception (approximately 30% less response than baseline), with some analgesia remaining up to the first hour of recovery (approximately 15% lower than baseline). Again, both doses of dex were significantly different from placebo but were not different from each other. Although pronounced cardiorespiratory effects were not expected, some changes were seen. Small but statistically significant decreases in mean arterial pressure were seen at the end of infusion and one and two hours into recovery. There were also 20% decreases in heart rate from baseline. Spo₂ declined during infusion, but did not go below 95%.

These results suggest that dex may prove useful in a postoperative setting or in the intensive care unit to provide sedation/analgesia. In conclusion, administration of dexmedetomidine in small doses provided sedation that could be easily reversed with verbal or physical stimuli. It also provided some analgesia and concurrent memory impairment without significant effect on cardiorespiratory variables.

ABSTRACT Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. AUTHORS: Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ SOURCE: Anesth Analg 2000 Mar;90(3):699-705 ABSTRACT: This research determined the safety and efficacy of two small-dose infusions of dexmedetomidine by evaluating sedation, analgesia, cognition, and cardiorespiratory function. Seven healthy young volunteers provided informed consent and participated on three occasions with random assignment to drug or placebo. Heart rate, blood pressure, respiratory rate, ETCO(2), O(2) saturation, and processed electroencephalogram (bispectral analysis) were monitored. Baseline hemodynamic measurements were acquired, and psychometric tests were performed (visual analog scale sedation; observer's assessment of alertness/sedation scale; digit symbol substitution test; and memory). The pain from a 1-min cold pressor test was quantified with a visual analog scale. After a 10-min initial dose of saline or 6 microg. kg(-1). h(-1) dexmedetomidine, volunteers received 50-min IV infusions of saline, or 0.2 or 0.6 microg. kg(-1). h(-1) dexmedetomidine. Measurements were repeated at the end of infusion and during recovery. The two dexmedetomidine infusions resulted in similar and significant sedation (30%-60%), impairment of memory (approximately 50%), and psychomotor performance (28%-41%). Hemodynamics, oxygen saturation, ETCO(2), and respiratory rate were well preserved throughout the infusion and recovery periods. Pain to thecold pressor test was reduced by 30% during dexmedetomidine infusion. Small-dose dexmedetomidine provided sedation, analgesia, and memory and cognitive impairment. These properties might prove useful in a postoperative or intensive care unit setting. IMPLICATIONS: The alpha(2) agonist, dexmedetomidine, has sedation and analgesic properties. This study quantified these effects, as well as cardiorespiratory, memory and psychomotor effects, in healthy volunteers. Dexmedetomidine infusions resulted in reversible sedation, mild analgesia, and memory impairment without cardiorespiratory compromise.

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