Emergence from anesthesia marks the transition from an anesthetized state to consciousness and normal physiological function. During emergence, complex changes in the brain occur as the effects of anesthesia wane.¹ The timing and quality of emergence can significantly impact patient outcomes, including the incidence of post-operative complications including delirium, psychological dysfunctions, respiratory failures, and cardiovascular instabilities. Understanding the factors that affect emergence, including patient-specific variables and anesthetic techniques, is essential for improving safety and recovery in surgical patients.

While there is not a consensus on the mechanism of action behind emergence from anesthesia, one hypothesis is that the wake-promoting systems in the brain are the cause of the return of consciousness. In general, the cortical structures targeted by anesthetic agents include the thalamus, hypothalamus, basal forebrain, brainstem, and cerebral cortex. The ascending reticular activating system (ARAS) is a network of nerve fibers from the brainstem that activates the basal forebrain during wake and sleep cycles.² If the connectivity strength of ARAS, an interconnected network, falls below a threshold, loss of consciousness will occur. When its strength returns above threshold, consciousness will return.³ The dorsal pathway of ARAS begins in the pontine and midbrain reticular formations, specifically in the cholinergic and glutamatergic neurons of the lateral dorsal tegmentum. These neurons then project to thalamic nuclei that further innervate separate areas of the cerebral cortex. In the ventral pathway, neurons from the lateral hypothalamic area send their axons to the basal forebrain, where they ascend to the cortex.³

Wake-promoting neurotransmitter systems are thoroughly interconnected, forming a close-knit network where one system will often compensate for the shortcomings of another. These systems include the cholinergic basal forebrain, the orexinergic lateral hypothalamus, the serotonergic raphe nuclei, the noradrenergic locus coeruleus, and the histaminergic tuberomammillary nuclei.⁴ Endogenous orexin is one of the most important molecules in sleep regulation. These hypothalamic neuropeptides have been shown to promote wakefulness, suppressing both REM and NREM sleep.⁵ A number of studies also indicate orexin reduces the anesthetic duration of several agents, including thiopental, pentobarbital, phenobarbital, propofol, isoflurane, and sevoflurane.^6,7,8

Noradrenaline is another neurotransmitter with a role in physiological arousal. In 2011, a group of Japanese researchers performed a study on 47 male mice and found that DSP-4, a selective neurotoxin, had a destructive effect on the noradrenergic locus coeruleus neurons. Additionally, DSP-4 was found to increase the effective duration of thiopental anesthesia and decrease the duration of ketamine. As thiopental is a GABA-mediated agent and ketamine is an NMDA-mediated anesthetic, the paper concludes the noradrenergic neurons from the locus coeruleus must play a role in blocking anesthesia that predominantly works through GABA and promoting anesthesia that strongly works through NMDA.⁹ 

Successful emergence from anesthesia is pivotal to patient recovery, influencing both short- and long-term outcomes. While modern medicine has certainly advanced the clinical understanding of what happens in the brain during anesthesia emergence, continued research is essential for further improvement in the safety and efficiency of this critical period.

References 

1. Cascella, Marco, Sabrina Bimonte, and Raffaela Di Napoli. “Delayed Emergence From Anesthesia: What We Know and How We Act.” Local and Regional Anesthesia, vol. 13, 2020, pp. 195-206. 
2. Jones, Barbara E. “From Waking to Sleeping: Neuronal and Chemical Substrates.” Trends in Pharmacological Sciences, vol. 26, no. 11, Nov. 2005, pp. 578–86. https://doi.org/10.1016/j.tips.2005.09.009.
3. Kushikata, Tetsuya, and Kazuyoshi Hirota. “Mechanisms of Anesthetic Emergence: Evidence for Active Reanimation.” Current Anesthesiology Reports, vol. 4, no. 1, Mar. 2014, pp. 49–56. https://doi.org/10.1007/s40140-013-0045-2 
4. Brown, Ritchie E., et al. “Control of Sleep and Wakefulness.” Physiological Reviews, vol. 92, no. 3, July 2012, pp. 1087–187, https://doi.org/10.1152/physrev.00032.2011 
5. Mieda, Michihiro, et al. “Differential Roles of Orexin Receptor-1 and -2 in the Regulation of Non-REM and REM Sleep.” Journal of Neuroscience, vol. 31, no. 17, Apr. 2011, pp. 6518–26. https://doi.org/10.1523/JNEUROSCI.6506-10.2011 
6. Kushikata, T., et al. “Orexinergic Neurons and Barbiturate Anesthesia.” Neuroscience, vol. 121, no. 4, Nov. 2003, pp. 855–63. https://doi.org/10.1016/S0306-4522(03)00554-2 
7. Zhang, Li-Na, et al. “Orexin-A Facilitates Emergence from Propofol Anesthesia in the Rat.” Anesthesia & Analgesia, vol. 115, no. 4, Oct. 2012, pp. 789–96. https://doi.org/10.1213/ANE.0b013e3182645ea3 
8. Kelz, Max B., et al. “An Essential Role for Orexins in Emergence from General Anesthesia.” Proceedings of the National Academy of Sciences, vol. 105, no. 4, Jan. 2008, pp. 1309–14. https://doi.org/10.1073/pnas.0707146105
9. Kushikata, T., et al. “Role of Coerulean Noradrenergic Neurones in General Anaesthesia in Rats.” British Journal of Anaesthesia, vol. 107, no. 6, Dec. 2011, pp. 924–29. https://doi.org/10.1093/bja/aer303