Abstract
D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.
Highlights
Patients emerging from general anesthesia can present numerous challenges including airway and oxygenation problems (Fasting and Gisvold, 2002), hemodynamic instability (Miyazaki et al, 2009), and delirium (Mason, 2017)
Bonferroni post-hoc comparisons revealed that d-amphetamine (3 mg/kg over 2 min, median emergence time 1.8, interquartile ranges (IQR) [1.3, 2.2]) reduced mean time to emergence by 111.0 min compared to saline
The arousal effect of d-amphetamine (1 mg/kg) was blocked by pretreatment with 0.2 mg/kg SCH-23390, increasing the mean time to emergence by 99.7 min (Figure 1B)
Summary
Patients emerging from general anesthesia can present numerous challenges including airway and oxygenation problems (Fasting and Gisvold, 2002), hemodynamic instability (Miyazaki et al, 2009), and delirium (Mason, 2017). We previously reported that intravenous d-amphetamine dose-dependently induces emergence from propofol and sevoflurane anesthesia in rats (Kenny et al, 2015). Consistent with a dopaminergic mechanism of action, we found that administration of chloro-APB, a D1 dopamine receptor agonist, induces emergence from isoflurane anesthesia (Taylor et al, 2013). Propofol, isoflurane and sevoflurane act primarily by enhancing GABAA receptor function (Brown et al, 2011), and it is unknown if d-amphetamine reverses the effects of other anesthetics that have non-GABAergic mechanisms of action
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