Table 1.

The Risk Factors and Consequences of Perioperative Sleep Disturbances

Risk Factors	Mechanisms	References
Preoperative anxiety or depression	The transition into REM sleep is accompanied by a rapid decrease in monoamines and a concomitant increase in cholinergic tone.	Pace‐Schott EF et al23 Wang YQ et al24
	A marked disruption in the circadian rhythm was observed in patients with MDD. Genes known to be crucial in the generation and regulation of circadian rhythm was found to be involved in depression. Clock genes dysregulation was assumed as an important factor associated with the development of both insomnia and depression.	Li JZ et al26 Lamont EW et al27 Satyanarayanan SK et al28
	In depressed patients, markers of inflammation have been shown to be higher than in non‐depressed individuals, and in patients with an inflammatory disorder, comorbid depression has been shown to be high. Sleep loss may increase markers of inflammation (eg IL‐6 and CRP) by activating the sympathetic nervous system and β‐adrenergic signalling, which further promoted the occurrence and progression of depression.	Krysta K et al31
Intraoperative general anesthetics	General anesthesia has a strong effect on main neurotransmitter systems (such as GABA/NMDA) that are related to the control of circadian rhythms and may interfere with light-entrainment of the clock.	Brosnan RJ et al38 Hummer DL et al 39
	Expression of the core clock gene per2 is inhibited by general anesthesia (possibly via a NMDA/glycogen synthase kinase 3b (GSK3b) pathway). Four other studies describe a reduction in per2 expression following in vivo sevoflurane, dexmedetomidine or propofol treatment.	Kadota K et al40 Anzai M et al41 Ohe Y et al42 Kobayashi K et al43
	Anaesthetics could act via the promotion of proteosomal degradation of BMAL1. Bellet et al found that ketamine inhibited per1 expression in vitro by preventing binding of the CLOCK:BMAL1 complex to the per1 promoter.	Bellet MM et al44
Postoperative pain	Chronic pain could dysregulate serotonergic raphe cells signaling, which would then contribute to prolonged sleep deprivation and greater disruption of sleep continuity. Due to the abundance of dopamine receptors in this region of the brain stem and the relationship between serotonergic and dopaminergic neurotransmission, pain-induced alterations in dopamine signaling may influence the raphe nuclei modulation of the sleep/wake cycle.	Foo H et al52
	Compromised pain inhibitory capacity has been demonstrated in many idiopathic clinical pain conditions with prominent sleep disturbance components. Opioid receptors are located in multiple nuclei that actively regulate both sleep and pain, including the preoptic suprachiasmatic nuclei, which controls sleep–wake cycles, and the periaqueductal gray, which plays a major role in descending pain inhibition. Moreover, sleep deprivation could also alter m- and d-opioid receptor function in mesolimbic circuits, diminishe basal endogenous opioid levels, and downregulate central opioid receptors.	Julien N et al53 Staud R et al54 Finan PH et al55
Consequences of perioperative sleep disturbances
Neurodegenerative disease	Lack of sleep could increase Aβ peptides in the brain interstitial fluid, which had a direct relationship with wakefulness. Furthermore, injections of orexin, a major neuropeptide related to wakefulness, increased Aβ, whereas the orexin antagonist almorexant decreased Aβ levels.	Kang JE et al60
	Parkinson’s disease dementia is caused by the aggregation of the protein α-synuclein, deposits of which are known as Lewy bodies (DLBs). Rapid eye movement sleep behavioral disorder is strongly associated with PD and dementia with DLBs.	Pringsheim T et al62 Braak H et al63
cogitive function	The consolidation of memory and normal brain functioning require high sleep quality, and sleep disturbance could interfere with the function of neuronal pathways, especially those of GABA and cAMP, which in turn impair synaptic plasticity. Poor sleep might contribute to neurodegeneration by causing neuroinflammation and disrupting neurogenesis, especially in the hippocampal areas, a key neuroanatomical region for learning and memory.	Diekelmann S et al71 Stickgold R et al72 Havekes R et al73 Zhu B et al74 Meerlo P et al75
	Increased sleep fragmentation and hypoxia are two consequences of disordered breathing during sleep, which may impair cognitive function. In animal models, hypoxia increased apoptosis and hippocampal atrophy through oxidative and inflammatory pathways.76 Hypoxia increases the concentration of amyloid β, number of amyloid plaques, and tau phosphorylation in the brain, which are key components of Alzheimer’s disease pathology.	Nair D et al76 Gao L et al77 Li L et al78
	Melatonin, a hormone associated with the sleep–wake cycle and produced by the pineal gland in a circadian manner, might be involved in another mechanism by which circadian rhythm dysregulation might contribute to cognitive impairment. Melatonin might have neuroprotective properties and is altered in patients with Alzheimer’s disease. Therefore, changes in circadian rhythms and melatonin concentrations might occur before the onset of clinical symptoms and thus might serve as an early marker for risk of Alzheimer’s disease and other dementias	Macchi, M.M et al79 Pandi-Perumal, S.R et al80 Ohashi, Y et al89 Wu, Y. H et al90 Zhou, J. N et al91