Towards a potent and rapidly reversible Dexmedetomidine-based general anesthetic

Abstract

Clinically useful anesthetics are associated with delirium and cognitive decline in the elderly. Dexmedetomidine (Dex), an α2 adrenergic receptor agonist, is an intravenous sedative with analgesic properties. Dex is associated with a lower incidence of delirium in the elderly. In this study, we first assessed whether a high dose of Dex alone was a clinically useful anesthetic. Finding that it was not, we sought to determine whether supplementation of Dex with low doses of two common anesthetics, propofol or sevoflurane, created an effective general anesthetic. Rats were sedated with a bolus followed by a continuous infusion of Dex and a low dose of a second agent—propofol, or sevoflurane. A strong noxious stimulus was applied every 15 minutes while monitoring vital signs. A combination of the α2 competitive antagonist, atipamezole, and caffeine was administered to reverse the anesthesia. Abdominal surgery was used to validate the efficacy of these dosing regimens. The animals responded to noxious stimuli when receiving Dex alone. Supplementing Dex with either a low dose of propofol or sevoflurane completely suppressed responses to the noxious stimulus and allowed the rats to tolerate abdominal surgery with complete immobility and no alterations in vital signs, suggesting that the drug combinations were effective anesthetics. EEG recordings showed suppression of high frequency activity suggesting that awareness and memory were impaired. Previously we found that combination of atipamezole and caffeine rapidly and completely reversed the sedation and bradycardia elicited by Dex. In this study, atipamezole and caffeine accelerated the time to emergence from unconsciousness by >95% in Dex supplemented with either propofol or sevoflurane. In conclusion Our results suggest that Dex supplemented with a low dose of a second agent creates a potent anesthetic that is rapidly reversed by atipamezole and caffeine.