Editorial Views  |   June 2004
Rested and Refreshed after Anesthesia? Overlapping Neurobiologic Mechanisms of Sleep and Anesthesia
Author Affiliations & Notes
  • Laura E. Nelson, Ph.D.
  • Department of Biological Sciences, Imperial College London; and Department of Anaesthetics and Intensive Care, Imperial College School of Medicine; London, United Kingdom. *Current address: Neuroscience Research Centre, Merck Sharp & Dohme, Harlow, United Kingdom.
Article Information
Editorial Views
Editorial Views   |   June 2004
Rested and Refreshed after Anesthesia? Overlapping Neurobiologic Mechanisms of Sleep and Anesthesia
Anesthesiology 6 2004, Vol.100, 1341-1342. doi:
Anesthesiology 6 2004, Vol.100, 1341-1342. doi:
A RAPIDLY growing field of recent research focuses on the potential mechanistic similarities between the behavioral states of endogenous nonrapid eye movement (NREM) sleep and anesthesia. In this month's issue of the Journal, Tung et al.  move this field a large step forward, reporting research suggesting that pharmacologic “sleep” may be able to fulfill some functions of natural sleep. 1 The authors previously reported that on emergence from prolonged propofol-induced sedation, no electroencephalographic (rebound increases in rapid eye movement [REM] or NREM sleep) or behavioral signs of sleep deprivation are observed, 2 and that 24 h of sleep deprivation decreases the latency to loss of righting reflex by 40% for propofol and 55% for isoflurane and prolongs the time to recovery from both. 3 
What is the relationship between sleep and anesthesia?  Although there are obvious significant physiologic differences between sleep and anesthesia (e.g.  , the ability to fulfill an essential biologic need, arousability from noxious stimuli, and cyclical variability), the two states have many similarities ranging from a generalized reduction in responsiveness to external stimuli to subtle changes in encephalographic activity. K-complexes (single, episodic, large-amplitude waves), sleep spindles (0.5- to 3.0-s runs of 12 to 14 Hz), and an increasing predominance of slow waves (delta 1–4 Hz and theta 4–7 Hz) are features of both NREM sleep and light anesthesia.
Both human and animal research suggest that NREM sleep and anesthesia may share certain mechanistic features. Labeled positron emission tomography scans of human brains during anesthesia have demonstrated regional changes in brain images similar to those seen during sleep. 4 Positron emission tomography with metabolic scanning 4 and microelectrode recordings of thalamic relay neuronal activity 5 show distinctive reductions in thalamic activity during anesthesia, which are also known to stimulate natural sleeplike changes in thalamocortical electrical activity.
On a neural substrate level, animal experiments 6,7 demonstrate that anesthetic agents that are proved, or postulated, to act on α2-adrenoceptors (dexmedetomidine), and γ-aminobutyric acid A receptors (muscimol, propofol, and pentobarbital, isoflurane), induce a loss of consciousness, at least in part, via  activation of endogenous NREM sleep-promoting hypothalamic pathways. Importantly, different classes of anesthetics seem to converge differentially on sleep-promoting circuitry; noradrenergic neurons within the locus ceruleus maintain their “awake” activity during hypnosis produced by γ-aminobutyric acid A–mediated (GABAergic) compounds but are inhibited during hypnosis induced by α2-adrenoceptor agonists, whereas histaminergic neurons in the tuberomamillary nucleus appear critical to the hypnotic action of both types of agents. 6,7 
How important is it to understand the overlap between natural and pharmacologic “sleep”?  Sleep disruption and deprivation create problems for patients recovering from surgical interventions. Although the causes are multifactorial, appropriate control of pain and anxiety are necessary to prevent the negative consequences that unfavorably affect recovery. However, commonly used medications to treat pain and anxiety may themselves alter sleep architecture and quality. For example, aspirin (acetylsalicylic acid) decreases the duration of slow-wave sleep (stages 3 and 4 NREM sleep) and stage 2 NREM, and it decreases sleep continuity 8; selective serotonin reuptake inhibitors decrease REM sleep duration and increase REM latency 9; classic benzodiazepines decrease slow-wave sleep duration, decrease delta power during slow-wave sleep, and increase stage 2 NREM sleep 10; and opioids increase the duration of stage 2 NREM and decrease slow-wave sleep and REM. 11 Prolonged sleep deprivation alters electrocortical, respiratory as well as carbon dioxide and oxygen homeostasis, and psychiatric and immune functions (all of which are reversible with physiologic sleep), and can ultimately result in death when taken to an extreme in animal experiments. 12 Can we find hypnotic agents to combat these detrimental effects in settings where natural sleep is not possible? Could any of our existing anesthetics/hypnotics be helpful?
The rapid-acting anesthetic propofol  , originally developed for use as an intravenous anesthetic for outpatients, was recently introduced as a sedative during intensive care. Its rapid onset and offset allows physicians to sedate patients to near unresponsiveness for extended periods while retaining the ability to wake them up rapidly 13; and these properties have led to the advocacy of its use to promote sleep in the intensive care setting, although there is little evidence to support such a strategy. Propofol is thought to act by binding to the γ-aminobutyric acid A receptor at a site distinct from the benzodiazepine binding site and allosterically enhancing the activity of γ-aminobutyric acid. 14 Does propofol-induced sedation promote or mimic physiologic sleep? Unlike endogenous sleep, propofol sedation does not demonstrate an orderly progression of electroencephalogram states and is not entirely reversible with external stimuli. In addition, little evidence exists suggesting that propofol-induced sedation can satisfy the biologic need for natural sleep. Might prolonged periods of continuous sedation, overlapping with naturally occurring sleep periods, result in sleep deprivation?
Tung et al.  administered 6 h of propofol anesthesia to electroencephalogram-telemetered rats after inducing 24 h of sleep deprivation by the disk-over-water paradigm (animals are placed on a 45-cm elevated disk that rotates when sleep is detected by computerized electroencephalogram/electromyogram monitoring, causing the rat to wake up to avoid falling in a water hazard 15); unexpectedly, Tung et al.  observed that propofol anesthesia induced the hallmark features of natural sleep deprivation recovery (increases in NREM and REM duration as well as NREM delta power). Their results suggest for the first time a functional relevance to the phenotypical, electrical, and neuroanatomic similarities between NREM sleep and anesthesia reported by others in recent years. Might anesthetic practice be refined such that, one day, patients will emerge from anesthesia or prolonged sedation feeling refreshed and rested?
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