Reversal of the Sedative and Sympatholytic Effects of Dexmedetomidine with a Specific α2-Adrenoceptor Antagonist Atipamezole

Abstract

Background Specific and selective alpha2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an alpha2-antagonist, in healthy persons. Methods The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 microg/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 microg/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h. Results The mean +/- SD atipamezole dose needed in part 1 was 104+/-44 microg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 microg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 microg/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. Conclusions The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusion rate (75 microg x kg(-1) x min(-1)) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.

The effect of intravenous dexmedetomidine premedication on the dose requirement of propofol to induce loss of consciousness in patients receiving alfentanil

“…Significant bradycardias, including sinus pauses of 3 s [22], related to dexmedetomidine have been reported in up to 40% of patients in other studies [8,9,22]. Sinus arrest has occurred in a young healthy volunteer 3.5 h after receiving dexmedetomidine [23].…”

“…A recent publication hailed in an accompanying editorial [26] as the`Beginning of a new era of anesthesia', described receptor-specific reversal of the sedative and sympatholytic effects of dexmedetomidine [23]. The multicentre report of dexmedetomidine in the ICU appears to show promise for its role as a sedative agent [10].…”

Dexmedetomidine in Current Anaesthesia Practice- A Review

“…Its onset of action is less than 5 min and the peak effect occurs within 15 min. Dexmedetomidine provides a titratable form of hypnotic sedation that can be easily reversed by α2-AR antagonist atipamezole [10].…”

Uso de dexmedetomidina em anestesiologia

“…Karhuvaara et al 49 have evaluated the effects of three different atipamezole doses (6.7 µg.kg atipamezole doses were effective in totally reverting sedation and dexmedetomidine-related hemodynamic changes. Scheinin et al 50 have studied the atipamezole dose needed to revert sedation obtained with 2.5 µg.kg -1 muscular dexmedetomidine in healthy volunteers. Alpha-2 adrenergic infusion was started one hour after dexmedetomidine.…”