In recent years, studies have found that general anesthetics are closely associated with the development of ED. Propofol and sevoflurane, the most widely used anesthetics in clinical practice, are widely used in the induction and maintenance of general anesthesia by activating the functional Cl-channels formed by the β-subunit of GABA A receptor, and the increase in the inward Cl-current causes the post-synaptic neuron to hyperpolarize and agonize the GABA A receptor, exerting central inhibitory effects (Sanna et al., 1995).

Clinical studies have shown a higher ED incidence in children induced with inhalational than with intravenous anesthetics (Peker and Polat, 2020). Furthermore, the incidence of ED after sevoflurane administration is higher than that after desflurane (Wu et al., 2019b); however, propofol can reduce the incidence of ED after sevoflurane anesthesia (Wu et al., 2019a; Ramlan et al., 2020). Wu et al. retrospectively analyzed the data of 200 children undergoing inguinal hernia, where the experimental group received 2 mg/kg propofol intravenously, 5 min after discontinuation of sevoflurane, and the control group received sodium chloride 0.9%. Using the PAED scale, they concluded that propofol administered after discontinuation of sevoflurane inhalation anesthesia could prevent the development of pediatric ED (Wu et al., 2019a). This corresponds with the results of a double-blind RCT conducted by Ramlan and colleagues. The Aono and PAED scales were used to assess the incidence and severity of ED in children aged 1–5 years in the PACU within 30 min. They found that propofol 0.5 mg/kg administration immediately after resumption of spontaneous breathing following cessation of inhaled sevoflurane was effective in reducing the incidence of ED (Ramlan et al., 2020).

Previously, Ching et al. demonstrated that propofol can stimulate increased alpha wave power in the frontal cortex as well as hypersynchronous neurobiological manifestations. They hypothesized that propofol-induced increases in thalamocortical hypersynchrony and alpha wave power may interfere with the flexible cortical communication required for brain consciousness, causing selective inhibition of frontoparietal feedback connectivity and ultimately loss of consciousness (Ching et al., 2010; Dehaene and Changeux, 2011). Therefore, combined with previous findings on the relationship between alpha waves and neurological connectivity of the brain regions and ED occurrence, we believe that the propofol-induced increased alpha wave power and reduced brain connectivity may have a protective effect on ED occurrence.

Magnesium is a noncompetitive blocker of NMDA receptors (Mayer et al., 1984), reduces the incidence of postoperative shivering, and has good analgesic properties (Lysakowski et al., 2007). Clinically, the most commonly used magnesium-containing drug is magnesium sulfate (MgSO4). Recently, MgSO4 has been used as an adjunct to general anesthetic agents for sedation and analgesia, and may potentially prevent ED.

There is no consensus on whether MgSO4 can reduce the incidence of postoperative ED in children (Abdulatif et al., 2013; Lee et al., 2020; Koo et al., 2022; Shen et al., 2022). An RCT by Lee et al. included 66 children aged 2–5 years undergoing daytime strabismus surgery who received MgSO4 30 mg/kg as an initial loading dose after anesthesia induction, followed by continuous infusion of 10 mg/kg/h. They found no significant effect of magnesium supplementation during anesthesia on the incidence of ED (Lee et al., 2020). A meta-analysis by Shen et al. including 635 patients aged <18 years from eight RCTs also concluded that MgSO4 did not reduce the incidence of ED in children (Shen et al., 2022). However, Abdulatif et al. observed 65 children undergoing adenotonsillectomy with sevoflurane induction followed by intravenous administration of MgSO4 and found the incidence of ED in the experimental group and the control group was 36% and 72%, respectively. They concluded that MgSO4 reduced the incidence and severity of ED in these children (Abdulatif et al., 2013). A meta-analysis by Koo et al. on the effect of intraoperative MgSO4 administration on postoperative agitation and delirium in pediatric patients also reported that MgSO4 has a positive effect on reducing ED incidence (Koo et al., 2022). The discrepancy in the results of these RCTs may be owing to the different types of surgery—the high ED incidence following ENT surgery is more likely to deliver positive results—and the different induction methods and doses of MgSO4 administered. Overall, we believe that MgSO4 has a role in preventing the occurrence of ED in children.

Magnesium is involved in energy metabolism, preserving brain glucose or pyruvate in tissues to meet energy demands during cerebral ischemia and reperfusion, and suppressing brain lactate and elevated glutamate levels (Lin et al., 2002; Bariskaner et al., 2003). Brain tissue energy metabolism is closely related to EEG grading. An increase in EEG grading is manifested by a decrease in EEG wave amplitude, a decrease in alpha band activity, and a gradual increase in theta or delta band activity. As the grading continues to increase, the EEG reveals an absence of brain wave activity (Oğün et al., 2002). Bariskaner et al. found that brain lactate and malondialdehyde concentrations positively correlate with EEG grading. Thus, when the brain lactate and malondialdehyde concentrations were suppressed after intravenous MgSO4 injection, the EEG grading decreased, EEG amplitude increased, alpha band activity increased, and delta band activity decreased (Bariskaner et al., 2003). As mentioned above, the decrease in alpha RP and increase in delta RP during the emergence period is one of the main EEG manifestations of ED in children. Therefore, we speculate that MgSO4 changes the delta/alpha ratio on the EEG during the emergence period by inhibiting the production of lactate and malondialdehyde in the brain, thus reducing ED occurrence. Further research is required to elucidate how lactate and malondialdehyde affect ion channels or protein receptors in neuronal cells, affecting EEG conduction and thus cortical EEG waveforms.

Dexmedetomidine is a selective α2-adrenoceptor agonist with sedative, analgesic, anxiolytic, and sympatholytic effects. It may produce sedative effects by agonizing endogenous pro-sleep pathways through presynaptic mechanisms (Weerink et al., 2017). Under physiological conditions, the LC acts as an inhibitor on the hypothalamus-preoptic area (HPOA) via adrenergic neurons, inhibiting the brainstem and thalamus via GABAergic neurons. The activity of the brainstem reticular formation is associated with arousal. The LC also transmits excitation to the cerebral cortex via adrenergic neurons. The binding of dexmedetomidine to the α2 receptors hyperpolarizes LC neurons, decreasing norepinephrine release. This weakens HPOA inhibition by the LC, and neuron activation in the HPOA inhibits the brainstem arousal center, while cortical excitability decreases, resulting in a sedated state in patients (Brown et al., 2010; Brown et al., 2011). Recently, an increasing number of research related to dexmedetomidine and ED have demonstrated its diverse positive effects on ED (Yao et al., 2015; Lin et al., 2017; Sun et al., 2017; Sadeghi et al., 2022).

ENT surgery is a known risk factor for pediatric ED. In 2020, a meta-analysis by Jiao et al. showed that dexmedetomidine reduced the incidence of ED in children undergoing adenotonsillectomy under sevoflurane anesthesia and was superior to other drugs (Jiao et al., 2020). However, large, high-quality RCTs are required to confirm its superiority, because the included studies did not standardize the administration dose, route, or timing, and did not limit the age of inclusion. A subsequent RCT conducted by Lin et al. demonstrated that intravenous dexmedetomidine 1 μg/kg for maintenance of anesthesia in children undergoing odontotherapy significantly reduced the incidence of ED (Lin et al., 2017). Dexmedetomidine can be administered intranasally and intravenously. In an RCT conducted among 90 children aged 3–7 years who underwent unilateral strabismus surgery, Yao and colleagues found that intranasal administration of dexmedetomidine 1 μg/kg and 2 μg/kg 45 min before induction reduced the incidence of pediatric ED (Yao et al., 2015). Sadeghi et al. reported that, for ED prevention, intravenous dexmedetomidine 1 μg/kg 10 min before the end of adenotonsillectomy or cleft palate repair surgery was superior to the equivalent dose 10 min after the start of surgery (Sadeghi et al., 2022). Besides the administration route and timing, the dose is also a factor influencing the effect of dexmedetomidine. Intravenous administration of dexmedetomidine 0.25 μg/kg, 0.5 μg/kg, and 1.0 μg/kg 10 min before the end of laparoscopic hernia repair in children prevented ED occurrence—the fewest cases occurred in the 1.0 ug/kg group (Sun et al., 2017).

In 2016, Akeju et al. assessed EEG changes throughout the cortex during intravenous infusion of dexmedetomidine 1 μg/kg (within 10 min) followed by continuous infusion at 0.7 μg/kg/h for 50 min in eight healthy adult volunteers aged 18–36 years by 64-channel EEG. They found an increase in delta oscillations, a decrease in beta oscillations, an increase in occipital theta oscillations, and an increase in frontal spindle waves. These changes are similar to those in the second phase of NREM. They further found that intravenous dexmedetomidine 0.5 μg/kg or 1 μg/kg alone promoted NREM stage III in a dose-dependent manner (Akeju et al., 2018). The NREM stage III EEG waves were dominated by delta waves. Dexmedetomidine prolongs NREM and reduces wakefulness time, and this effect is dose-dependent (Feng et al., 2018). In 2020, Chamadia et al. found that oral dexmedetomidine increased the duration of NREM stage II and decreased the duration of REM sleep in an RCT conducted among 15 adults. They also suggested that dexmedetomidine promotion of NREM stage II or III may be related to the route and time of administration (Chamadia et al., 2020).

Overall, EEG characteristics after dexmedetomidine administration are unclear in children. Therefore, we hypothesize that dexmedetomidine may increase EEG spindle waves and prolong N2 sleep duration. Although delta oscillations may also increase, low CNS excitability persists, thereby preventing ED occurrence.

Ketamine is a non-competitive NMDA receptor antagonist with dose-dependent sedative and analgesic effects (Mihaljević et al., 2020). The analgesic action of ketamine is multimodal and mainly produced by blocking NMDA receptors in the spinal cord (Oye et al., 1992); secondly, it acts on opioid receptors to produce analgesic effects (Pacheco Dda et al., 2014). More studies on ketamine are emerging, aimed at preventing pediatric ED (Dalens et al., 2006; Ali et al., 2020).

Ali et al. analyzed the data of 120 children aged 3–15 years who underwent adenotonsillectomy and found that the incidence of ED in children who were given 0.15 mg/kg ketamine intravenous 10min before the end of the operation was 13.33% and that in the control group was 48.33% (Ali et al., 2020). Similarly, a randomized controlled study involving 90 children undergoing MRI found that 0.25 mg of ketamine at the end of surgery reduced the incidence of ED by about 13% compared with a control group (Dalens et al., 2006). However, a study by Schmitz et al., involving 351 children aged 3 months to 10 years undergoing MRI, found no difference in the incidence of ED between ketamine given 1 mg/kg at induction of anesthesia and the control group (Schmitz et al., 2018). In the former study, sevoflurane was used for induction and maintenance of anesthesia, while propofol was used for maintenance of anesthesia in the latter, and the incidence of ED after propofol was lower than that after sevoflurane. Secondly, different doses of ketamine, different time points of administration, and different ages of included children may cause inconsistent conclusions.

Lee et al. observed changes in frontal and parietal EEG among 30 surgery patients after intravenous induction with ketamine 2 mg/kg, and found an increase in delta, theta, and gamma RP (25–35 Hz) and a decrease in alpha and beta RP, with diminished brain connectivity (Lee et al., 2013). In 2015, by observing changes in the EEG of rats under ketamine anesthesia, Pal et al. found that gamma activity in the mid-high range (65–175 Hz) was significantly decreased after ketamine-induced loss of consciousness compared to the awake state; activity in other frequency bands did not markedly change. Delta activity was decreased and gamma wave activity was increased during the emergence period. They also found that cortical connectivity was reduced under ketamine anesthesia (Pal et al., 2015). An EEG after ketamine sedation is characterized by beta and gamma oscillations (Purdon et al., 2015). From the abovementioned study, we found that low-frequency gamma activity is a characteristic EEG manifestation of ketamine sedation. Although the EEG pattern under ketamine action is relatively active and different from that of propofol, Lee et al. suggested that both ketamine and propofol result in reduced frontoparietal connectivity and thus a sedated, unconscious state.

We hypothesize that cortical connectivity is reduced after intravenous ketamine administration, which reduces CNS excitability even though EEG activity appears relatively active. Ketamine may prevent ED occurrence by reducing the cortical connectivity of the child and its analgesic effect.

Opioids can be divided into three categories: natural (morphine, codeine, papaverine), synthetic (methadone, meperidine, fentanyl, alfentanil, sufentanil, remifentanil), and semisynthetic (hydromorphone). They produce analgesic effects by acting on μ, κ, and δ receptors. Opioids are widely used in clinical practice and are one of the essential drug classes used for general anesthesia. Recently, several opioids have been used to prevent ED in children (An et al., 2017; Kim et al., 2017; Choi et al., 2018; Chu and Pan, 2018).

Fentanyl is commonly used in pediatric anesthesia. In 2017, Kim et al. analyzed 10 RCTs and found that intravenous fentanyl before and after the end of surgery reduced the incidence of pediatric ED with sevoflurane general anesthesia (Kim et al., 2017). In addition to fentanyl, remifentanil, and sufentanil are commonly used in pediatric anesthesia and positively affect ED incidence. An RCT by Choi et al. revealed that, in children aged 3–7 years, remifentanil 0.05 μg/kg/min infusion at the end of strabismus surgery after discontinuation of sevoflurane, the incidence of ED was reduced by 35% (Choi et al., 2018). It has also been reported that administration of 0.1 mg/kg dezocine at the end of surgery has reduced the incidence of ED in children undergoing laparoscopic inguinal hernia repair (An et al., 2017) and that intravenous infusion of 0.01 mg/kg hydromorphone 10 min before surgery prevented ED in children undergoing strabismus surgery (Chu and Pan, 2018).

We believe that the mechanism of opioid prevention of ED is inextricably linked to its analgesic effect, which reduces the incidence of ED by suppressing pain, reduces sensitivity to external stimuli, and more closely resembles the natural arousal of NREM sleep.

Acupuncture is a type of acupuncture therapy that involves the insertion of fine needles into acupuncture points on the skin to a certain depth and for a sustained period of time in order to alleviate symptoms and cure diseases (Nakajima et al., 2022). In recent years, some studies have reported that acupuncture therapy can prevent the occurrence of postoperative ED in pediatric patients. Yuanchi Lin et al. observed 80 children aged 1–6 years who underwent tympanotomy with tympanic ventricular tubing, and acupuncture treatment was performed for 10 min at bilateral Hegu and Senmen points after induction of sevoflurane anesthesia, and it was found that the acupuncture therapy significantly reduced the severity of postoperative pain and agitation in children (Lin et al., 2009). However, contrastingly, a study by Martin et al. employed acupuncture at bilateral HT-7 and ear shen men points of children after anesthesia induction until the end of surgery and showed no significant difference in ED incidence between the two groups (Martin et al., 2020). The discrepancy in results may be due to the difference in acupuncture points and duration. Some studies have shown that acupuncture therapy may activate the release of opioid peptides in the adult CNS (Chernyak and Sessler, 2005; Zhao, 2008). Others have suggested that it can affect the release of visceral pain–modulating substances, such as increasing the secretion of β-endorphin and decreasing epinephrine, cortisol, and prostaglandin E2 levels (Lee et al., 2019). We believe that acupuncture therapy may prevent ED occurrence by reducing pain. However, it is unclear how it affects EEG changes, and the optimal acupuncture site, timing of initiation, and duration of treatment for the prevention of pediatric ED need to be further explored.

In summary, these interventions alter the EEG during wakefulness through their respective sedative and analgesic effects, increase the power of spindle or alpha waves, reduce the connectivity of t the brain, so that the EEG during the emergence period will be closer to the natural awakening EEG changes, and render the childless perceptive to external stimuli and reduce CNS excitability, thereby preventing the occurrence of pediatric ED. Furthermore, other interventions such as colistin, benzodiazepines, melatonin, gabapentin (Pinto Filho et al., 2019; Archana et al., 2022; Yang et al., 2022) and recorded maternal voice during emergence, and regional block can reduce the incidence of ED (Byun et al., 2018; Zhong et al., 2018; Yang et al., 2020). Interestingly, after intravenous administration of clonidine to achieve sedation in healthy volunteers, their EEG showed a decrease in dominant alpha activity and an increase in delta oscillations (Bischoff et al., 2004; Miyazaki et al., 2004). However, this EEG change is inconsistent with our previous findings that the increase in delta RP and decrease in alpha RP are associated with a high ED incidence. Nevertheless, sufficient clinical evidence supports the beneficial effect of clonidine on ED outcomes; more relevant studies are required to elaborate on the EEG changes after clonidine administration in children.