Sleep and Anesthesia

03/22/2022

Anesthesia is a reversible state of unconsciousness, often medically induced and used for surgery. Many studies have indicated that being under anesthesia and sleep share similar biological mechanisms, predominantly through the GABAA pathway [1]. Sleep involves GABAA-containing neurons in the ventrolateral preoptic nucleus (VLPO) that innervate the tuberomammillary nucleus (TMN), a region in the hypothalamus known to be critical in promoting arousal and regulating sleep-wake states [2]. Anesthetic agents also initiate this cascade, first activating the VLPO, then the GABAA receptors in the TMN, producing an effect similar to sleep [2]. However, there are still marked differences between the two states. EEG studies indicate the neural waves produced by propofol show less sleep spindle activity, but more slow wave activity (prominent in N-REM sleep) and a greater network of origin hotspots (for these slow waves) compared to spontaneous sleep [3,4].

Benzodiazepines are a class of anesthetic drugs that operate via GABA receptors, much like spontaneous sleep [5]. In a murine study, Radulovacki et. al. demonstrated both midazolam and diazepine significantly increased the lighter stage of slow wave sleep (SWS1) but not the subsequent, deeper stage (SWS2). Similarly, diazepine also reduced sleep latency for SWS1 but not SWS2 [6]. A clinical study on 22 ICU patients found those receiving less midazolam exhibited shorter overall sleep time and more arousal during sleep. These patients also showed greater REM sleep, a sleep stage known to be important for learning and memory [7]. Benzodiazepines also have a noteworthy effect on the respiratory system. Research has shown midazolam to lower muscle activity during deep anesthesia; midazolam-induced sedation may affect pharyngeal collapsibility [5,8]. Additionally, diazepam potentially leads to adverse side effects including hypothermia, hypertension, and tachycardia [9].

The intravenous anesthetic agent propofol is one of the most used anesthetics in the medical field due to its uniquely short half-life, which generally prevents prolonged effects [5]. However, its effect on sleep proves to be a conflicting element, with propofol administration to healthy participants delaying sleep latency and particularly Stage 2 sleep, the stage where your body prepares to enter deep sleep [10]. In critically ill patients, propofol also exacerbated poor sleep quality and reduced REM sleep [11]. Contrastingly, in patients with chronic insomnia, propofol therapy improved polysomnographic and Leeds Sleep Evaluation Questionnaire results [12]. Taken together, these studies imply the effect of propofol on sleep varies by circumstance.

Anesthesia for sleep-disordered patients requires careful consideration, given the current lack of consensus in the scientific field as to the neural mechanisms of anesthesia and how those might interact with sleep disorders. Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness which is thought to be a result of orexin (OX) deficiency. This peptide produced in the hypothalamus projects to virtually all subcortical arousal systems to maintain and regulate wakefulness [13]. Many anesthetic agents are involved somewhat with orexin; for example, barbiturates target orexinergic neurons by inhibiting OX-evoked norepinephrine release to maintain the anesthetic state [14]. Inhalational anesthetics such as isoflurane and sevoflurane inhibit c-Fos expression (a marker of neuronal activity) in orexinergic neurons, and loss of orexinergic neurons led to significantly delayed anesthesia emergence time [15]. For these reasons, a recent systematic review listed recommendations for clinical anesthesia practices on narcoleptic patients. Treatment of narcolepsy should be continued until the day of operation, and short-acting anesthetic agents, such as propofol and remifentanil, are advised because they cause the least damage to orexinergic pathways [16].

Acknowledging the consequences of anesthesia on sleep means considering the shared neural regions they act upon as well as biological mechanisms which fuel their impact. Since they are so interconnected, collaborative research in sleep and anesthesia may open new avenues in both areas of study.

References 

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  1. Sherin, J. E., Elmquist, J. K., Torrealba, F., & Saper, C. B. (1998). Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. Journal of Neuroscience, 18(12), 4705–4721. https://doi.org/10.1523/JNEUROSCI.18-12-04705.1998  
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