Advances in the use of dexmedetomidine during the perioperative period to improve postoperative sleep quality in patients undergoing surgery

Abstract

There is a high incidence of postoperative sleep and sleep architecture disorders in patients undergoing surgery, and dexmedetomidine (DEX) is commonly used to improve postoperative sleep quality and ameliorate the adverse effects of poor sleep on various organ systems. The continuous intraoperative intravenous infusion of DEX, the addition of DEX to postoperative intravenous analgesia pumps, and the continuous infusion of DEX after admission to the intensive care unit are often used clinically to improve postoperative sleep quality at doses of 0.1 to 0.7 μg/kg/hour, but the effects of DEX on sleep quality and structure identified in these studies have been inconsistent. Thus, it is unclear whether DEX improves postoperative sleep quality. The various methods of administering DEX to improve postoperative sleep quality have differing effects, the route used modifies the effect of DEX on sleep structure, and the intrinsic mechanism whereby DEX improves sleep quality remains to be fully investigated. In the present review, we describe new directions for future research into the effects of DEX on postoperative sleep quality and the mechanisms involved, which should help guide the design of further studies. This narrative review was completed according to the Scale for the Assessment of Narrative Review Articles (SANRA).

Introduction

Sleep issues are increasingly prevalent. Seven major categories of sleep disorders are defined by the International Classification of Sleep Disorders, third edition, ¹ and disordered sleep architecture, characterized by inappropriate proportions of the various sleep phases or frequent waking, can be identified using polysomnography (PSG). A previous meta-analysis revealed that the prevalence of sleep disorders in the general populations of several countries, including Japan, Germany, and China, is very high, and that there is a significantly higher prevalence (60%) in individuals who undergo surgery than in the general population. ²

Sleep is composed of non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM), and NREM is composed of N1, N2, N3, and N4 phases. Sleep usually cycles through these phases in the order N1 → N2 → N3 → N4 → REM sleep. Stages N1 and N2 are also referred to as light sleep, and N3 and N4 are collectively referred to as slow-wave sleep (SWS) or deep sleep. REM sleep typically accounts for 20% to 25% of total sleep in adults.^3,4 With increasing age, the total duration of sleep decreases, the N1 and N2 phases lengthen, and the amount of REM sleep decreases. Abnormal postoperative sleep architecture is common in patients who undergo surgery, although one study showed no significant change in total waking time or the number of times patients awoke during the night following surgery. REM sleep decreases or disappears during the first postoperative night, but this is followed by a rebound in REM sleep intensity and duration during the following nights.^5–7 In addition, SWS significantly decreases and the N2 phase increases during the night following surgery. These disturbances in postoperative sleep structure are similar to those that characterize the sleep of older people.

Disordered postoperative sleep architecture increases cardiovascular risk: a reduction or absence of REM sleep on the first night after surgery, followed by an REM rebound on subsequent nights, accompanied by paroxysmal hypoxemia and hemodynamic instability, may lead to postoperative myocardial ischemia, infarction, and ultimately, unexpected death. ⁸ In addition, procedural memory retention, synaptic plasticity, ⁹ the role of the glymphatic system in the clearing of metabolic waste from the brain, ¹⁰ the severity of cognitive impairment in patients with Alzheimer’s disease, ¹¹ depression, ¹² and the risks of developing type 2 diabetes and obesity ¹³ are all associated with critical components of sleep architecture, such SWS and REM sleep. ⁴ Postoperative sleep disorders can lead to greater postoperative pain, psychiatric disease, neurocognitive dysfunction, and delirium, and also affect the postoperative recovery of various systems.^8,14,15

To prevent and treat the adverse consequences of sleep disorders in patients, various methods are currently employed in clinical settings to improve postoperative sleep quality. Pharmacologic methods include the administration of benzodiazepines (BZDs), zolpidem (a non-benzodiazepine drug), gabapentin, melatonin, and dexmedetomidine (DEX). However, these medications vary in their effectiveness in improving sleep. ¹⁴ These differences will be discussed below. Of these drugs, DEX has significant advantages. In healthy individuals, DEX-induced sleep resembles physiologic human sleep and DEX dose-dependently promotes N2 or N3 sleep.^16,17 Furthermore, in perioperative patients, DEX improves both subjective and objective postoperative sleep quality. ¹⁴

Sleep and wakefulness behavior is determined by two main neuroanatomical regions: the mesopontine reticular activating system (RAS) and the hypothalamus. The neurotransmitters that control sleep and wakefulness are glutamate, acetylcholine, histamine, norepinephrine, and gamma-aminobutyric acid (GABA). The structure that initiates sleep is thought to be the ventrolateral preoptic nucleus (VLPO), which is located in the anterior part of the hypothalamus. The VLPO suppresses the activities of the brainstem, pons, and locus coeruleus (LC), dorsal raphe nucleus (RN), and laterodorsal tegmental pedinculopontine tegmental nucleus through the secretion of GABA and galanine. In the central nervous system (CNS), catecholaminergic neurons, which secrete norepinephrine (NE), are most abundant in the LC. Noradrenergic neurons in the LC have diffuse projections in the brain, including to the cortex. However, the medullar reticular formation secretes the largest amounts of epinephrine and contains β1 and 2 receptors, which are widespread in the CNS. Binding to α1 receptors has a behavioral effect, increasing vigilance. In contrast, α2 receptors act as an autoreceptor at the presynaptic level and are inhibitory in nature, causing sedation. ¹⁸ Most anesthetics principally act on GABAa receptors, and sedation and natural sleep are the result of enhanced GABAergic transmission, which in turn affects the release of a number of excitatory transmitters, such as acetylcholine, excitatory amino acids, and histamine, thereby also affecting the level of arousal in this way. Antidepressants with sedative effects (tricyclic antidepressants, trazadone, nefazadone, and mitrazapine) have effects on the emotional state via 5-hydroxytryptamine (HT) NE receptors, and their sedative effects are mediated through antagonistic effects at the H1, 5-HT2, and α1 receptors. In contrast, the drugs used for the treatment of insomnia (melatonin and melatonin analogs) exert their effects via MT1 and MT2 receptors. ¹⁹

DEX is an α2-adrenergic receptor agonist, and although α2 adrenergic receptors are also expressed post-synaptically, classical α2 adrenergic receptors are considered to be presynaptic autoreceptors that are expressed on sympathetic nerve terminals, where they inhibit the release of NE. ²⁰ The mechanism by which DEX improves sleep quality may be related to its direct action via α2 adrenergic receptors in the CNS. Thus, α2 adrenergic receptor agonist drugs reduce the depolarization rate of neurons in the locus coeruleus, and this lower neuronal activity plays a key role in the initiation and maintenance of sleep by reducing wakefulness-promoting adrenergic inputs to the cortex, basal forebrain, thalamus, and the hypothalamic preoptic area of the cerebral cortex. Less adrenergic signaling in the preoptic area leads to the activation of sleep-active neurons, which inhibit brainstem arousal nuclei through GABA and alanine secretion. In addition, α2 adrenoreceptor agonists also have direct effects on noradrenergic neurons in the thalamus and basal forebrain to promote sleep. ¹⁸

For this narrative review, we followed the Scale for the Assessment of Narrative Review Articles (SANRA). ²¹ We searched several major databases (PubMed, Cochrane Library, and Embase) and found that there has been a considerable amount of research regarding the effects of perioperative DEX on postoperative sleep quality, but that there is no consensus regarding the optimal method of using DEX. Therefore, the aim of the present review is to summarize the effects of DEX when used clinically to improve postoperative sleep quality in patients who undergo surgery, and to discuss whether the administration of this drug at various times during the perioperative period has differing effects on postoperative sleep quality.

Common clinical applications of DEX

Continuous intravenous infusion of DEX during surgery

DEX is often administered intravenously during surgery to assist with sedation, reduce stress, and improve postoperative sleep quality. It is typically administered as a loading dose of 1 μg/kg over 10 to 15 minutes, followed by intravenous infusion at 0.2 to 0.7 μg/kg/hour until 30 minutes before the commencement of surgery. Previous studies have shown that the continuous intravenous infusion of DEX during the maintenance phase of general anesthesia^22–27 improves postoperative subjective sleep quality.^22,23,26,27 However, one previous study showed that DEX does not significantly affect postoperative sleep quality. ²⁵ Only a few of these studies have involved the assessment of postoperative objective sleep quality using PSG,^24,26,27 finding that the continuous intravenous infusion of DEX during surgery improves postoperative sleep efficiency and the proportion of REM sleep, ²⁷ but with no study of its effects on other phases of sleep.

An increase in nighttime NREM sleep and the duration of N3 sleep and a decrease in the duration of REM sleep were identified in healthy individuals who were administered a single intravenous dose of DEX, without a significant effect on subjective sleep quality. ¹⁶ The differing effects of DEX on the sleep architecture of patients who undergo surgery and healthy individuals may be related to their trauma, stress response, incomplete metabolism of anesthetic drugs following surgery, and the longer duration and/or higher total dosage of medication administered to the former. A study of patients undergoing an endovascular intervention showed no effect of intraoperative DEX administration on postoperative subjective sleep quality, ²⁵ possibly because the relatively minor trauma associated with endovascular interventional procedures does not significantly affect postoperative sleep quality, and therefore the scope for a DEX-induced improvement in sleep quality is limited. A six-point scale was used in this study to assess subjective sleep quality, whereas other studies that yielded different results mostly involved the use of the Numeric Rating Scale (NRS) for sleep quality. For example, in a real-world study by Duan et al., the continuous intraoperative intravenous infusion of DEX at 0.2 to 0.8 µg/kg/hour in patients undergoing major non-cardiac surgery was found to improve subjective sleep quality, assessed using the NRS, on the day after surgery vs. patients who were administered a low-dose (0.2 to 0.4 µg/kg/hour) continuous intraoperative infusion. ²² Furthermore, in patients undergoing elective abdominal surgery, Lu et al. found that those who were administered a continuous intraoperative infusion of DEX (loading dose of 0.5 μg/kg over 15 minutes, followed by a maintenance dose of 0.2 μg/kg/hour) had superior NRS-assessed sleep quality on the second and fifth postoperative days than control patients. ²⁷

General anesthetic drugs and sleep circadian rhythms

In their study, Song et al. divided patients undergoing general anesthesia and abdominal surgery into daytime and nighttime groups according to the timing of their surgery, and better subjective sleep quality was achieved by the nighttime group when they were administered a continuous intraoperative intravenous infusion of DEX, but the daytime group showed higher sleep efficiency and proportion of REM sleep, ²⁴ suggesting that sleep quality may be related to the timing of surgery and of DEX administration, and perhaps also the effect of general anesthesia on the sleep–wake cycle. ²⁸

Inflammatory response

The relationship between DEX and sleep may be mediated by effects on the inflammatory response, and DEX can alter the expression of inflammatory molecules. Inflammatory responses are risk factor for sleep disorders. In general, pro-inflammatory cytokines induce sleep, whereas anti-inflammatory cytokines inhibit sleep. Some pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, are associated with shorter REM sleep and longer deep sleep (SWS). IL-2, IL-15, IL-18, interferon (IFN)-α, and IFN-γ typically prolong sleep, whereas IL-4, IL-10, and IL-13 usually inhibit spontaneous sleep. ²⁹ DEX has been shown to alleviate systemic inflammation, and especially neuroinflammation, through various pathways. ²⁰ The study by Hu et al. showed that patients who undergo total intravenous anesthesia (TIVA) using DEX experience a smaller surgery-induced increase in IL-6 concentration than those who do not. ³⁰ Furthermore, a meta-analysis showed that DEX reduces the postoperative concentrations of pro-inflammatory cytokines, such as IL-6 and TNF-α, as well as that of C-reactive protein, increases the numbers of natural killer (NK) cells, B cells, and cluster of differentiation (CD)4+ cells, and increases the CD4+/CD8+ and T helper (Th)1/Th2 ratios. ³¹ Thus, DEX both improves postoperative sleep quality and reduces the concentrations of pro-inflammatory cytokines, even though pro-inflammatory factors are known to promote sleep. ²⁹ Therefore, it is likely that DEX improves sleep quality through other mechanisms than a simple reduction in inflammation.

Stress

Surgical stress is also a risk factor for sleep disorders. DEX may improve postoperative sleep quality by reducing the stress response associated with surgery. Similar changes in sleep patterns have been identified in patients who experience stress because of acute ischemic stroke, acute myocardial infarction, or congestive heart failure, and in those who are in medical and trauma ICUs, ³² suggesting that stress responses during surgery are risk factors for postoperative sleep disorders. Post-surgical injury triggers a complex stress response involving hormones and other humoral mediators, immunosuppression, and inflammatory responses. Postoperative increases in sympathetic activity and catecholamine concentrations can lead to postoperative sleep disorders because the transition from wakefulness to sleep typically involves a shift from sympathetic to parasympathetic regulation, with high levels of noradrenergic activity maintaining wakefulness. Cortisol is another key mediator of the post-surgical endocrine response, and when it is administered to healthy volunteers, it leads to a reduction in REM sleep and an increase in NREM sleep. In addition, corticotropin-releasing hormone secretion increases during surgical stress, and this has been shown to lead to a dose-dependent decrease in NREM sleep and an increase in wakefulness in rabbits and rats. ³² Compared with the use of a transversus abdominis plane block (TAPB) alone, combining TAPB with the administration of a low dose of DEX can ameliorate these responses. ³³ A recent meta-analysis showed that the perioperative use of DEX attenuates these stress responses: it significantly reduces the circulating concentrations of epinephrine, NE, cortisol, and glucose in patients undergoing surgery, possibly because of reductions in the activation of the hypothalamic–pituitary–adrenal axis and sympathetic tone. ³¹ However, the exact mechanism by which DEX improves sleep quality has not been elucidated.

Opioids

Opioids cause disorders of sleep structure, leading to reductions in SWS and REM sleep and increases in the duration of the N1 and N2 phases. ³⁴ Therefore, the intraoperative use of DEX, which reduces the required dose of opioids, may be another reason why intraoperative DEX improves postoperative sleep quality.

In summary, the studies performed to date have shown that the continuous intraoperative use of DEX improves postoperative subjective sleep quality. However, the specific mechanisms mediating this effect are unclear, and the objective sleep quality of postoperative patients has been assessed in relatively few studies. Thus, the exact effects of the continuous intravenous infusion of DEX on postoperative objective sleep quality remain uncertain.

Addition of DEX to postoperative intravenous analgesia infusions

The addition of DEX to postoperative patient-controlled intravenous analgesia (PCIA) regimens can improve postoperative subjective sleep quality,^35,36 but its effects on objective sleep quality have not been well characterized. We identified only one study of patients undergoing hysterectomy who were monitored overnight using PSG, which showed that adding DEX to PCIA pumps increases postoperative sleep efficacy, reduces the arousal index, reduces the proportion of N1 sleep, and increases the proportion of N2 sleep, but has no effects on the proportions of N3 and REM sleep. ³⁷

Sedation

The subjective sleep quality of the patients in the study of the use of DEX in intravenous postoperative analgesia pumps was improved ¹⁸ , which may be related to the sedative effect of DEX mentioned above and the direct effect of DEX on the central nervous system to promote sleep.

Pain

The improvement in sleep quality may be related to the direct effect of DEX to promote sleep or its analgesic effects. DEX inhibits the facilitation of the pain pathway by blocking the presynaptic release of NE in excitatory interneurons of the spinal cord, and inhibition of the central noradrenergic pathway may also enhance the analgesic effect mediated by the postsynaptic dorsal root ganglion. ³⁸ The use of DEX did not significantly change the patients’ levels of pain, according to the visual analog scale (VAS) pain score, but it was shown that the addition of DEX to the analgesia pump reduced the required dose of opioids. Because opioids have adverse effects on sleep, this may be one of the mechanisms by which the postoperative administration of DEX improves sleep quality, but further studies are required to confirm this.

Timing of sleep assessment

In most studies, objective sleep quality is monitored during the first night after surgery. However, for procedures that end late in the day, the sleep data might be confounded by the incomplete metabolism of the general anesthesia drugs used. Severe pain during the first night following surgery is one reason for the inability to achieve deep sleep, including N3 and REM sleep. Therefore, researchers should consider these factors when selecting the most appropriate timing of postoperative sleep quality assessments.

Continuous intravenous DEX administration in patients admitted to the ICU after surgery

The continuous intravenous infusion of DEX at various doses in patients, both intubated and non-intubated, in the ICU has previously been evaluated in a number of studies,^39–42 which have shown that this reduces the incidence of postoperative delirium. Various scales were used to assess subjective sleep quality and differing effects of DEX on subjective sleep quality were identified. In patients not undergoing cardiac surgery who were in the ICU and did not require mechanical ventilation, Wu et al. found that a low dose of DEX (0.1 μg/kg/hour) improved subjective sleep quality, assessed using the NRS sleep rating scale. ³⁹ However, when Alexopoulou et al. studied patients not undergoing cardiac surgery who were on mechanical ventilation in the ICU and were administered a higher maintenance dose of DEX (0.2 μg/kg/hour), no significant effect on sleep quality was identified using the Richards–Campbell Sleep Questionnaire. ⁴⁰ Regarding objective sleep quality, these two studies showed that DEX reduces the proportion of N1 sleep and increases the proportion of N2 sleep in patients in ICU, but has no significant effects on N3 or REM sleep.^39,40 However, the study of mechanically ventilated patients by Sun et al. showed that DEX had no significant effect on any index of sleep structure. ⁴¹ This difference from the findings of Alexopoulou et al. may be explained by the small sample size of this study (n = 13) and that the DEX was titrated according to each patient’s level of sedation.^40,41 It is possible that the effect of DEX on the sleep quality of patients in the ICU varies according to whether or not they are mechanically ventilated and intubated, but we have not identified any studies that shed light on this. When performing PSG, it is recommended to make recordings using at least three channels (F4-M1, C4-M1, and O2-M1). The M1 electrode is placed on the left mastoid process, and the F3, C3, O1, and M2 electrodes are attached as a backup. For the required minimum three-channel recordings used for PSG monitoring, the O1 and O2 electrodes are placed on the occipital region, which is uncomfortable for conscious patients. Therefore, further objective studies of the effects of DEX on sleep are required. Furthermore, more studies of patients who return to the ward after surgery without being admitted to the ICU or being sedated in which objective sleep quality is assessed using PSG monitoring are required. ⁴³

Discussion

Factors influencing sleep quality and the effects of DEX

The factors affecting postoperative sleep quality include preoperative factors such as high Pittsburgh Sleep Quality Index score; high pain ratings; anxiety or depression; advanced age; pre-existing conditions, such as obstructive sleep apnea and coronary artery disease; intraoperative factors, such as autonomic reflexes and inflammatory stress responses, the surgical site and type, and the level of surgical trauma; and anesthesia-related risks, such as the method of anesthesia used, the anesthetics, opioids, and nonsteroidal anti-inflammatory drugs used, the use of gabapentin or ketamine, and the use of DEX. The postoperative release of cytokines also affects sleep quality; TNF-α, IL-1, and IL-6 have been shown to be associated with less REM sleep and longer SWS. ²⁹ Other external factors, such as hospital staff entering and exiting wards at night, noise made by other patients, medical equipment, and lighting, also affect postoperative sleep. The administration of DEX may reduce the inflammatory stress response, reduce the dose of intraoperative or postoperative intravenous analgesia required, reduce postoperative pain score, reduce the release of proinflammatory factors, and inhibit autonomic nerve reflexes. All of these are possible mediators of the effect of DEX to improve sleep quality.

Superiority of DEX to other drugs with respect to an improvement in sleep quality

DEX has significant advantages over the drugs mentioned above with respect to a beneficial effect on sleep structure. DEX-induced sleep resembles physiologic human sleep and DEX dose-dependently promotes N2 or N3 sleep.^15,16 As mentioned above, a shortage of sleep predisposes to many health problems, especially in patients undergoing surgery. Many pharmaceutical methods of improving sleep quality have been described previously. Therefore, we next compared the effects of these drugs with those of DEX. BZDs increase the duration of N2 sleep, but shorten the N3, N4, and REM phases of sleep and increase drowsiness during the day. ⁴⁴ In a study of healthy volunteers, zolpidem was shown to reduce the frequency of θ waves (5 to 8 Hz; N2 and N3) and increase the frequency of β waves (13 to 25 Hz; N2 and REM sleep), but not to improve SWS of REM sleep. ¹⁶ Another study showed that zolpidem improves sleep efficiency by increasing the respiratory arousal threshold, which counteracts the arousal-inducing effect of atomoxetine in patients with obstructive sleep apnea. ⁴⁵ Some previous studies have shown that gabapentin does not significantly alter sleep structure, but one showed that gabapentin reduces sleep latency and improves sleep efficiency. ⁴⁶ Finally, melatonin induces sleep and modifies circadian rhythms.^47–49

Sleep structure and the means of administration of DEX

The specific effects of DEX on sleep structure depend on the mode of administration used. As mentioned in the previous paragraph, DEX induces sleep that is similar to human physiologic sleep of phases N2 or N3. However, the effect of DEX to improve sleep quality may depend on the route of administration. A single dose of intravenous DEX was found to induce sleep that is similar to human physiologic sleep in healthy volunteers, promoting N3 sleep in a dose-dependent manner. ¹⁶ However, in another study, the oral administration of DEX to healthy volunteers promoted N2 sleep to a greater extent. ¹⁷ Thus, the effect of DEX on sleep structure depends on whether it is administered orally or intravenously, which may reflect the absorption rate or circulating concentration of the drug, but this hypothesis was not confirmed in the two quoted studies.

Sleep structure and the timing of DEX administration

The effect of DEX on the sleep architecture of patients undergoing surgery may be related to the timing of administration. To date, objective sleep quality monitoring using PSG has been performed in only a few studies of the effects of a continuous intravenous infusion of DEX during surgery, and only one of these studies showed that this improved the proportion of postoperative REM sleep in these patients, with no significant effects on other parameters describing sleep structure. ²⁷ Therefore, there are not enough data to draw conclusions regarding the effect of intraoperative DEX infusion on postoperative sleep structure in such patients. However, several other studies have shown that DEX improves postoperative N2 sleep, when added to postoperative analgesia pumps or administered continuously via the intravenous route in the ICU,^37,39,40 although a machine learning study by Ramaswamy et al. of a poorly characterized group of patients also showed that DEX promotes N3 sleep. ⁵⁰ Thus, the effect of DEX on the sleep architecture of patients undergoing surgery may be related to the timing of administration, whether DEX is administered via a continuous intraoperative infusion, added to a postoperative intravenous analgesia pump, or administered via a continuous intravenous infusion after admission to the ICU, but this requires confirmation in further studies.

Sleep spindles are produced by the thalamus, and the N2 stage of sleep is identified by the presence of sleep spindles and K-complexes on electroencephalography. It is possible that they are induced by the action of DEX on α2 adrenergic receptor in the LC of the thalamus. ⁴³

Other clinical effects of DEX

DEX when administered at 0.6 ± 0.3 μg/kg/hour increases the risk of bradycardia, but in a study of its effects on sleep quality, 0.2 to 0.7 μg/kg/hour DEX did not cause statistically significant hypotension or bradycardia. ⁵⁰ Furthermore, a meta-analysis of the efficacy and safety of the use of DEX as part of postoperative PCIA vs. the use of analgesics alone showed that the former significantly improves analgesia; reduces postoperative nausea, vomiting, and pruritus; limits postoperative inflammation; reduces the required dose and incidence of adverse reactions to analgesics; reduces the incidence of postoperative delirium; and increases patient satisfaction. ⁵¹ DEX also affects the immune system, and the impact of the immunosuppressive effects of DEX on patient outcomes requires further study.

In conclusion, DEX significantly improves postoperative sleep quality. However, it is unclear as yet whether DEX specifically promotes the N2 or N3 phases of sleep and how its effects on sleep are related to the timing and duration of its administration and the total dose administered. Therefore, future clinical studies should evaluate these aspects and investigate the specific mechanisms by which DEX improves sleep quality.