Discussion
To the best of our knowledge, this is the first meta-analysis to evaluate the effects of DEX on postoperative sleep quality based on PSG data. The results of our systematic review and meta-analysis of RCTs showed that perioperative administration of DEX may be adequate to improve postoperative sleep quality within a short period by increasing the percentage of stage N2 sleep and sleep efficiency, prolonging the duration of TST, and decreasing the percentage of stage N1 sleep and sleep arousals. Additionally, the administration of DEX could provide effective postoperative analgesia by reducing the VAS score.
Many variables can be used to measure sleep quality. PSG can assess sleep architecture objectively and accurately reflect the percentage of each sleep stage, which is more helpful for our subsequent meta-analysis. In addition to PSG, objective tools include portable sleep monitor and the bispectral index (BIS). A portable sleep monitor can evaluate sleep efficiency, percentage of REM sleep, and unstable and stable sleep, whereas the BIS measures the level of sedation, sleep depth, SEI, and TST. Subjective tools are mostly questionnaires and scales, including the Pittsburgh Sleep Quality Index (PSQI), Richards Campbell Sleep Questionnaire (RCSQ), St. Mary Hospital Sleep Questionnaire (SMH), numeric rating scale (NRS), insomnia severity index (ISI), Athens insomnia scale (AIS), consensus sleep diary (CSD), and other simple questions. Apart from our results using PSG, other questionnaires of the above-mentioned tools also showed positive effects of DEX on postoperative sleep quality.[21–28]
A normal sleep pattern and cycle are crucial to maintain normal physiological and mental functions. Stage N1 is regarded as light sleep (drowsiness) and stages N2 and N3 represent deeper sleep. Slow-wave sleep (SWS) is considered to be the deepest sleep stage. Dreaming usually occurs in REM sleep.[29] Previous studies have reported that patients experienced severe sleep disturbances with a pronounced decrease in REM sleep immediately after surgery and a tendency for a rebound phenomenon within the first week after surgery,[30] even in some fast-track surgeries involving regional anesthesia, opioid-sparing multimodal analgesia, mobilization on the day of surgery, and a planned length of stay of 1–3 days.[31] At the same time, stage N1 sleep was significantly longer.[1,13] Electroencephalogram (EEG) patterns associated with DEX-induced sleep include spindle and slow-delta oscillations, which are similar to physiological stage N2 sleep.[32] DEX binds to receptors in the locus coeruleus and inhibits norepinephrine release, which causes GABA output from the ventrolateral preoptic nucleus, resulting in NREM sleep patterns.[10] Norepinephrine plays a permissive role during REM sleep;[33] therefore, inhibition of its release by DEX may make REM sleep difficult to achieve. These results are consistent with our meta-analysis findings that DEX provides a slightly deeper and more physiological sleep pattern and improves postoperative sleep architecture by shortening stage N1 sleep and prolonging stage N2 sleep with no significant effect on REM sleep. Additionally, increased stage N2 sleep and decreased REM sleep were found in healthy volunteers using an oral dosage formulation of DEX.[34] Stage N3 sleep is promoted by DEX in a dose-dependent manner,[35,36] which may be beneficial for cognitive function and synaptic plasticity.[37]
The dosage and timing of administration were related to the effects of DEX on postoperative sleep quality. A real-world cohort study covering 7418 patients undergoing non-cardiac major surgery demonstrated that the incidence of severe sleep disturbance in the low-dose (0.2–0.4 μg/kg/h) DEX group was significantly lower than that in the medium- (0.4–0.6 μg/kg/h) and high-dose (0.6–0.8 μg/kg/h) DEX groups.[26] Jiang et al.[18] compared the effects of oxycodone in combination with different doses of DEX on postoperative sleep quality, and the results indicated that larger doses of DEX did not further improve sleep but increased the risk of hypotension. From these results, it can be concluded that low-dose DEX may be the optimal treatment for postoperative sleep disturbance. Song et al.[28] found that intraoperative use of DEX during the daytime (8:00–12:00) operation could improve sleep efficiency and subjective sleep quality and promote the analgesic property of sufentanil-based PCA than that during the nighttime (18:00–22:00) operation under general anesthesia, which might be explained by the pharmacologic sensitivity influenced by chronobiology and time-dependent variations in pain.[38] However, Tan et al.[39] reported worse sleep on the night of surgery using DEX under spinal anesthesia than with midazolam. A possible explanation is that the natural sleep cycle of patients is disturbed during the daytime with the deeper sedative state provided by DEX. Similar results were obtained in the ICU.[10] Given the above, further studies should focus on the optimal dosage of DEX and the timing of administration to better treat postoperative sleep disturbances.
Postoperative sleep disturbances can lead to hyperalgesia.[40] Therefore, effective postoperative analgesia may positively affect sleep quality. As widely used analgesics, opioids have been reported to negatively impact sleep architecture by decreasing REM and stable sleep, resulting in deteriorated sleep quality in post-surgical patients.[1] The result of our meta-analysis on postoperative analgesia is also consistent with previous studies.[28,41,42] DEX, used as an adjuvant for pain management, can contribute to the recovery-promoting effect and treat postoperative sleep disturbances induced by pain.
Critically ill patients exhibit disorganized and poor sleep quality, as evidenced by the lack of sequential progression through sleep stages and low percentages of SWS and REM sleep.[5,6,43] Even after discharge, patients report sleep disturbances and continue to experience poor sleep quality.[44] Oto et al.[10] first performed PSG to assess sleep with DEX sedation in mechanically ventilated patients and concluded that night-time infusion of DEX preserved the day-night cycle of sleep but induced severely disturbed sleep architecture without evidence of SWS and REM sleep. However, the absence of a control group and poor control of sedation depth complicates the interpretation of these results. Subsequently, a pilot study[45] demonstrated that night-time DEX administration to achieve the recommended light sedation in critically ill patients increased sleep efficiency and improved sleep quality by reducing sleep fragmentation and shifting sleep from stage N1 to stage N2. DEX modified the 24-h sleep pattern by shifting sleep mainly to the night, partly restoring the normal circadian rhythm. In addition, this study found that DEX sedation did not increase most restorative sleep stages (SWS and REM), which is in line with our meta-analysis. As shown in Figure 2, two studies involving ICU patients reported longer TST but very low percentages or even the absence of stage N3 and REM sleep. A possible explanation is that the sleep quality of critically ill patients remains low even during sedation with this agent. This result suggests that although the TST may be normal or even increased, critically ill patients are considered to have qualitatively disrupted sleep. Recent studies have reported positive effects of DEX on sleep quality in critically ill patients with or without surgical procedures.[12,46] Future studies should focus on the duration or frequency of DEX administration to improve the sleep quality in these patients.
The side effects of the perioperative administration of DEX remain controversial. Some studies have suggested that DEX could cause hypotension or bradycardia,[13,18,20,47] while others have reported similar respiratory and hemodynamic safety of DEX compared to placebo or other sedatives.[23,39,42] Of the included studies in our meta-analysis, two studies reported that the use of DEX slightly increased the occurrence of hypotension and bradycardia without the requirement of intervention,[13,18] while the other studies showed no significant differences with regard to those side effects or the percentage of drug interruption because of the above side effects. Although we did not conclude that DEX had significant side effects or unsafe outcomes, dosage and infusion rate should be considered, since hypotension and bradycardia caused by DEX are common in clinical settings, especially in aged population.
Limitations
The present meta-analysis had several limitations. First, considering the unified evaluation of sleep quality, only studies using PSG were included, which led to the small sample size of our meta-analysis. The limited number of studies for the majority of outcomes precluded effective comparisons, exploration of heterogeneity, and assessment of small-study effects. Second, DEX regimens and timing of administration, patient population, the severity of illness, type of surgery, and follow-up varied widely across the included trials, which explains the high heterogeneity of most parameters in our results. Furthermore, in our assessment of the risk of bias, some trials had high risk in at least one domain. Due to the lack of detailed reporting, the risk of bias was rated as unclear in several domains. Last but not least, the inclusion and exclusion criteria were strictly observed by all our reviewers, however, the final included studies were all from China. We have done the egger test and begg test, which showed no publication bias.
BMC Anesthesiol. 2023;23(88) © 2023 BioMed Central, Ltd.
