Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and pharmacokinetic interactions

Abstract

Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with anaesthetic-sparing effects. We have determined the pharmacodynamic and pharmacokinetic interactions between dexmedetomidine and isoflurane in volunteers. Nine male subjects were allocated randomly to receive isoflurane anaesthesia preceded by infusion of dexmedetomidine on three separate occasions, 2 weeks apart. Dexmedetomidine target plasma concentrations were 0.0 (placebo), 0.3 ng ml-1 (low-dex) and 0.6 ng ml-1 (high-dex). End-tidal isoflurane concentrations at which gross purposeful movement and response to verbal commands occurred were identified. In the recovery period, sedation scores and digit symbol substitution tests were recorded. Venous blood samples were obtained before, during and after anaesthesia at predetermined intervals for measurement of plasma concentrations of dexmedetomidine and calculation of standard pharmacokinetic indices (AUC, Cl, Vss, T1/2 alpha, T1/2 beta). The end-tidal isoflurane concentration at which 50% of subjects first responded to the tetanic stimulus was 1.05% in the placebo group, 0.72% in the low-dex group and 0.52% in the high-dex group. We conclude that dexmedetomidine decreased isoflurane requirements in a dose-dependent manner and reduced heart rate, systolic and diastolic arterial pressures. Sedation and slight impairment of cognitive function persisted for several hours after anaesthesia and the end of infusion of dexmedetomidine. Isoflurane did not appear to influence the pharmacokinetics of dexmedetomidine.

Dexmedetomidine used to provide hypotensive anesthesia during middle ear surgery

“…These fi ndings confi rm with a previous study which showed that use of DEX reduces requirement of inhalational anesthetics [7,8]. The probable mechanism of reducing blood pressure by DEX is attributed to stimulation of peripheral alpha 2 adrenoceptors of vascular smooth muscle .This results in decrease in blood pressure and heart rate secondary to inhibition of central sympathetic outfl ow.…”

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

“…Kahn et al [11] showed a left shift in isoflurane dose±response curves in volunteers receiving an infusion of dexmedetomidine. Dexmedetomidine 0.35 ng.ml 21 decreased isoflurane requirements to prevent movement in response to a noxious stimulus by 35%; dexmedetomidine 0.75 ng.ml 21 decreased isoflurane requirements by < 50% [11].…”

“…Kahn et al [11] showed a left shift in isoflurane dose±response curves in volunteers receiving an infusion of dexmedetomidine. Dexmedetomidine 0.35 ng.ml 21 decreased isoflurane requirements to prevent movement in response to a noxious stimulus by 35%; dexmedetomidine 0.75 ng.ml 21 decreased isoflurane requirements by < 50% [11]. Fragen & Fitzgerald [12] used dexmedetomidine infusions to produce target blood concentrations of 0.3 ng.ml 21 and 0.6 ng.ml 21 in adult patients, the response to surgical stimulus was assessed; sevoflurane MAC was reduced by 17% in the high-dose dexmedetomidine group only.…”

“…Recently, the dose-dependent effects of dexmedetomidine on isoflurane [11] and sevoflurane [12] requirements have been assessed in humans. However, to date, no studies have explored the shift of a dose±response curve for intravenous agents in conjunction with the a 2 -agonists.…”

“…Other recent studies [11,12] using dexmedetomidine infusions to achieve concentrations of 0.35±0.75 ng.ml 21 have shown reductions in the MAC of volatile agents of up to 50% [11]. Although it is extremely difficult to make interspecies comparisons it does appear that the dose of dexmedetomidine required to produce the profound reductions in anaesthetic requirements (.…”