Electroencephalographic (EEG) activity is used to monitor the neurophysiology of the brain, which is a target organ of general anaesthesia. Besides its use in evaluating hypnotic states, neurophysiologic reactions to noxious stimulation can also be observed in the EEG. Recognising and understanding these responses could help optimise intraoperative analgesic management. This review describes three types of changes in the EEG induced by noxious stimulation when the patient is under general anaesthesia: (1) beta arousal, (2) (paradoxical) delta arousal, and (3) alpha dropout. Beta arousal is an increase in EEG power in the beta-frequency band (12-25 Hz) in response to noxious stimulation, especially at lower doses of anaesthesia drugs in the absence of opioids. It is usually indicative of a cortical depolarisation and increased cortical activity. At higher concentrations of anaesthetic drug, and with insufficient opioids, delta arousal (increased power in the delta band [0.5-4 Hz]) and alpha dropout (decreased alpha power [8-12 Hz]) are associated with noxious stimuli. The mechanisms of delta arousal are not well understood, but the midbrain reticular formation seems to play a role. Alpha dropout may indicate a return of thalamocortical communication, from an idling mode to an operational mode. Each of these EEG changes reflect an incomplete modulation of pain signals and can be mitigated by administration of opioid or the use of regional anaesthesia techniques. Future studies should evaluate whether titrating analgesic drugs in response to these EEG signals reduces postoperative pain and influences other postoperative outcomes, including the potential development of chronic pain.

Background: Preexisting factors such as age and cognitive performance can influence the electroencephalogram (EEG) during general anesthesia. Specifically, spectral EEG power is lower in elderly, compared to younger, subjects. Here, the authors investigate age-related changes in EEG architecture in patients undergoing general anesthesia through a detailed examination of spectral and entropic measures. Methods: The authors retrospectively studied 180 frontal EEG recordings from patients undergoing general anesthesia, induced with propofol/fentanyl and maintained by sevoflurane at the Waikato Hospital in Hamilton, New Zealand. The authors calculated power spectral density and normalized power spectral density, the entropic measures approximate and permutation entropy, as well as the beta ratio and spectral entropy as exemplary parameters used in current monitoring systems from segments of EEG obtained before the onset of surgery (i.e., with no noxious stimulation). Results: The oldest quartile of patients had significantly lower 1/f characteristics (P < 0.001; area under the receiver operating characteristics curve, 0.84 [0.76 0.92]), indicative of a more uniform distribution of spectral power. Analysis of the normalized power spectral density revealed no significant impact of age on relative alpha (P = 0.693; area under the receiver operating characteristics curve, 0.52 [0.41 0.63]) and a significant but weak effect on relative beta power (P = 0.041; area under the receiver operating characteristics curve, 0.62 [0.52 0.73]). Using entropic parameters, the authors found a significant age-related change toward a more irregular and unpredictable EEG (permutation entropy: P < 0.001, area under the receiver operating characteristics curve, 0.81 [0.71 0.90]; approximate entropy: P < 0.001; area under the receiver operating characteristics curve, 0.76 [0.66 0.85]). With approximate entropy, the authors could also detect an age-induced change in alpha-band activity (P = 0.002; area under the receiver operating characteristics curve, 0.69 [0.60 78]). Conclusions: Like the sleep literature, spectral and entropic EEG features under general anesthesia change with age revealing a shift toward a faster, more irregular, oscillatory composition of the EEG in older patients. Age-related changes in neurophysiological activity may underlie these findings however the contribution of age-related changes in filtering properties or the signal to noise ratio must also be considered. Regardless, most current EEG technology used to guide anesthetic management focus on spectral features, and improvements to these devices might involve integration of entropic features of the raw EEG. Editor’s Perspective: What We Already Know about This Topic: What This Article Tells Us That Is New:

Flumazenil had a modest effect on accelerating emergence from isoflurane anesthesia. Prolongation of sleep time in the first day after isoflurane anesthesia was significantly reduced by flumazenil. The data suggest that inhibition of γ-aminobutyric acid type A receptors can not only hasten emergence but can mitigate postanesthesia sleep disturbances. Background: Transitions into conscious states are partially mediated by inactivation of sleep networks and activation of arousal networks. Pharmacologic hastening of emergence from general anesthesia has largely focused on activating subcortical monoaminergic networks, with little attention on antagonizing the γ-aminobutyric acid type A receptor (GABA_AR). As the GABA_AR mediates the clinical effects of many common general anesthetics, the authors hypothesized that negative GABA_AR modulators would hasten emergence, possibly via cortical networks involved in sleep. Methods: The authors investigated the capacity of the benzodiazepine rescue agent, flumazenil, which had been recently shown to promote wakefulness in hypersomnia patients, to alter emergence. Using an in vivo rodent model and an in vitro GABA_AR heterologous expression system, they measured flumazenil’s effects on behavioral, neurophysiologic, and electrophysiologic correlates of emergence from isoflurane anesthesia. Results: Animals administered intravenous flumazenil (0.4 mg/kg, n = 8) exhibited hastened emergence compared to saline-treated animals (n = 8) at cessation of isoflurane anesthesia. Wake-like electroencephalographic patterns occurred sooner and exhibited more high-frequency electroencephalography power after flumazenil administration (median latency ± median absolute deviation: 290 ± 34 s) compared to saline administration (473 ± 186 s; P = 0.042). Moreover, in flumazenil-treated animals, there was a decreased impact on postanesthesia sleep. In vitro experiments in human embryonic kidney-293T cells demonstrated that flumazenil inhibited isoflurane-mediated GABA current enhancement (n = 34 cells, 88.7 ± 2.42% potentiation at 3 μM). Moreover, flumazenil exhibited weak agonist activity on the GABA_AR (n = 10 cells, 10.3 ± 3.96% peak GABA EC₂₀ current at 1 μM). Conclusions: Flumazenil can modulate emergence from isoflurane anesthesia. The authors highlight the complex role GABA_ARs play in mediating consciousness and provide mechanistic links between emergence from anesthesia and arousal.

Recent interest in reversal of the hypnotic effects of anesthesia has mainly focused on overcoming a surge in GABA-mediated inhibitory signaling through activation of subcortical arousal circuits or antagonizing GABA receptors. Here we examine the reversal of anesthesia produced from non-GABA agents ketamine/xylazine and the effects of antagonists of adrenoreceptors. These antagonists vary in selectivity and produce temporally unique waking behavior post-anesthesia. We compared two antagonists with differential selectivity for α₁- vs. α₂-receptors, yohimbine (YOH, 1:40 selectivity) and atipamezole (ATI, 1:8500). Adult mice received intraperitoneal injections of either YOH (4.3 mg/kg), ATI (0.4 mg/kg), or saline after achieving sustained loss of righting following injection of ketamine/xylazine (ketamine: 65.0 mg/kg; xylazine: 9.9 mg/kg). Behaviors indicative of the post-anesthesia, re-animation sequence were carefully monitored and the timing of each behavior relative to anesthesia induction was compared. Both YOH and ATI hastened behaviors indicative of emergence, but ATI was faster than YOH to produce certain behaviors, including whisker movement (YOH: 21.9±1.5 min, ATI: 17.5±0.5 min, p = 0.004) and return of righting reflex (RORR) (YOH: 40.6±8.8 min, ATI: 26.0±1.2 min, p<0.001). Interestingly, although YOH administration hastened early behavioral markers of emergence relative to saline (whisking), the completion of the emergence sequence (time from first marker to appearance of RORR) was delayed with YOH. We attribute this effect to antagonism of α₁ receptors by yohimbine. Also notable was the failure of either antagonist to hasten the re-establishment of coordinated motor behavior (e.g., attempts to remove adhesive tape on the forepaw placed during anesthesia) relative to the end of emergence (RORR). In total, our work suggests that in addition to pharmacokinetic effects, re-establishment of normal waking behaviors after anesthesia involves neuronal circuits dependent on time and/or activity.