Effects of Dexmedetomidine on Postoperative Sleep Quality

Methods

Standard Protocol Approval and Registration

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.^[15] The protocol was registered in PROSPERO (registration number: CRD42022373253).

Search Strategy

The search was conducted using PubMed/MEDLINE, EMBASE, Cochrane Library and Web of Science from inception to November 20, 2022. The full search strings for each database are available in Appendix S1. Medical Subject Headings (MeSH) terms and corresponding keywords were combined to find potentially available articles. For instance, researches about DEX were searched using "dexmedetomidine" (MeSH term) OR "MPV-1440" OR "MPV 1440" OR "MPV1440" OR "Precedex" OR "Dexmedetomidine Hydrochloride" OR "Hydrochloride Dexmedetomidine". All terms were explored in the "Title/Abstract" or "Keywords" sections. Moreover, references from identified studies and relevant published reports were manually searched to identify possibly eligible trials in the present topic.

Study Selection

Studies were included in our meta-analysis according to the following criteria: (1) participants: adult patients who underwent elective surgery; (2) intervention: pre-, peri-, or postoperative administration of DEX; (3) comparison: placebo (normal saline), other sedative drugs or analgesics; (4) outcome: sleep quality should be objectively evaluated through PSG or its derivatives, including at least one of the following parameters: sleep efficiency index (SEI) or total sleep time (TST), arousal index (AI), the percentages of stage N1, N2, and N3 of NREM sleep and REM sleep; (5) study design: patients should be randomly allocated to different treatments or different sequences of treatments; (6) studies should be published or accepted for publication in a peer-reviewed journal; (7) studies should be theses or dissertations with full-text access. We made no restrictions on sample size, treatment duration, or publication date because of the anticipated small number of studies that used PSG data. We also made no geographical or cultural restrictions because we were interested in a global perspective on postoperative sleep quality and its treatments.

Duplicate articles were removed, and the titles and abstracts of potentially eligible articles were independently screened by two reviewers (Huizi Liu and Hanwei Wei). The full-text articles from the remaining studies were retrieved and reviewed. Only studies that fulfilled the inclusion criteria were selected for our systematic review and meta-analysis. Any discrepancies during article selection were reassessed by another author (Fang Cai) and resolved through discussion to reach a consensus.

Data Extraction and Risk of Bias Assessment

Data for assessing the outcomes were independently extracted and recorded by two reviewers (Huizi Liu and Hanwei Wei) from the included studies. Any discrepancies were reassessed by another author (Fang Cai) and resolved through discussion and consensus. The following information of each selected article was collected: first author; year of publication; study design; geographical location; sample size; participant characteristics, including mean age, gender distribution, American Society of Anesthesiologists (ASA) classification, type of surgery; inclusion and exclusion criteria; intervention strategies (type, dosage, approach, frequency and duration); primary and secondary outcomes; sleep evaluation tool; results data and statistical data.

The following outcomes were used to evaluate sleep quality: (1) SEI or TST: SEI was calculated as the ratio of TST/total recording time; (2) AI was defined as the average number of arousals per hour of sleep; and (3) the percentages of stage N1, N2, and N3 of NREM sleep and REM sleep. The primary outcome should include at least one of these parameters. The secondary outcomes included postoperative Ramsay sedation scores, Visual Analog Scale (VAS) scores, postoperative delirium (POD), and postoperative nausea and vomiting (PONV). We attempted to contact the authors by e-mail if there were missing data. If a study did not report standard deviations (SDs), we imputed the SDs of the included trial comparing the same treatments.

Two reviewers (Huizi Liu and Hanwei Wei) independently evaluated the methodological quality of the included studies using the Cochrane risk-of-bias tool. The risk of bias for each RCT covered seven domains: random sequence generation, allocation concealment, blinding, outcome assessment, incomplete outcome data, selective reporting and other biases. The risk of bias for each item was rated as "high," "low" or "unclear". Discrepancies were resolved through consensus.

Data Synthesis and Analysis

Data synthesis and statistical analyses were performed using the Review Manager (RevMan, version 5.4) software (Cochrane Library, Oxford, UK). The data extracted from the literature in the present review were continuous variables; therefore, we calculated the mean differences (MDs) and 95% confidence intervals (CIs). If the primary outcomes were reported as median (interquartile range, IQR), the methodology of Wan et al.^[16] and Luo et al.^[17] was used to convert the median (IQR) to mean ± SD. Statistical differences were not considered significant if the 95% CI included zero for the MD. Forest plots were used to present the pooled results and corresponding 95% CIs. Cochrane Q test (p < 0.10 for a statistical significance) and I ² test were conducted to evaluate the heterogeneity among included research. As described in the Cochrane review guidelines, I ² > 50% indicated a significantly high heterogeneity, and the corresponding outcome was analyzed with a random effects model, whereas the fixed effects model was applied. In addition, an egger test and begg test were performed to explore possible publication bias. A trial sequential analysis of PSG parameter was performed to determine whether the sample size was adequate and the results were stable.

Subgroup analysis was performed according to the severity of illness, administration regimen of DEX, type of surgery, ward environment, etc. Heterogeneity was resolved by subgroup analysis when two or more studies were included in each subgroup. Additionally, based on the results of the quality evaluation, a sensitivity analysis was performed by excluding articles with a significantly high risk of bias.

Table 1. Baseline characteristics of included trials
First author, year of publication	Country	Type of surgery	Age range(yr)	Males(%)	Control group	No. randomized	No. in DEX group	No. in control group	ICU stay	DEX starting time	DEX dosage	Variables provided
Wu XH²⁰, 2016	China	Non-cardiac Surgery	≥ 65	57.9	Placebo	61	31	30	Yes	Postoperative	0.1 μg/kg/h, lasting 15 h	SEI, TST, AI, N1, N2, N3, REM
Chen ZC¹³, 2017	China	Abdominal hysterectomy	30–55	NR	Placebo	59	30	29	No	PCA	Continuous dose: 0.05 μg/kg/h Bolus dose: 0.05 μg/kg	SEI, AI, N1, N2, N3, REM, Ramsay, VAS
Jiang ZM¹⁸, 2018	China	Abdominal surgery	60–70	58.8	Placebo	97	Low dose group: 32 High dose group: 33	32	No	PCA	Low dose group: 0.072 μg/kg/h continuous dose, 0.024 μg/kg bolus dose High dose group: 0.144 μg/kg/h continuous dose, 0.048 μg/kg bolus dose	SEI, AI, N1, N2, N3, REM, VAS
Sun YM¹⁹, 2022	China	Non-cardiac surgery	≥ 18	51.4	Placebo	68	33	35	Yes	Postoperative	0.1–0.2 μg/kg/h, lasting 72 h	SEI, TST, AI, N1, N2, N3, REM
Wu Y¹⁴, 2022	China	Endoscopic sinus surgery	18–65	55	Placebo	96	48	48	No	Intraoperative	Loading dose: 0.5 μg/kg, continuous infusion: 0.2 μg/kg/h	SEI, AI, REM, Ramsay, VAS, PONV, POD

NR, not reported; PCA, patient controlled analgesia; SEI, sleep efficiency index; TST, total sleep time; AI, arousal index; N1, stage 1 of non-rapid eye movement sleep; N2, stage 2 of non-rapid eye movement sleep; N3, stage 3 of non-rapid eye movement sleep; REM, rapid eye movement sleep; VAS, visual analogue scale; PONV, postoperative nausea and vomiting; POD, postoperative delirium

Table 2. Subgroup analysis stratified by severity of illness
	Subgroup	Sample size		Weight (%)	MD with [95%CI]	Z	I ²(%)	P value
	Subgroup	DEX	Control	Weight (%)	MD with [95%CI]	Z	I ²(%)	P value
SEI	ICU	64	65	35.5	9.98 [3.48, 16.47]	3.01	0	0.003
SEI	Non-ICU	143	109	64.5	11.64 [-0.39, 23.66]	1.90	98	0.06
AI	ICU	64	65	21.9	-1.27 [-2.73, 0.18]	1.72	0	0.09
AI	Non-ICU	143	109	78.1	-2.51 [-4.17, -0.86]	2.98	96	0.003
N1	ICU	64	65	37.6	-8.09 [-14.93, -1.26]	2.32	0	0.02
N1	Non-ICU	95	61	62.4	-12.88 [-26.83, 1.08]	1.81	99	0.07
N2	ICU	64	65	24.4	7.21 [-7.88, 22.30]	0.94	39	0.35
N2	Non-ICU	95	61	75.6	17.82 [13.53, 22.12]	0.13	79	< 0.00001
N3	ICU	64	65	0	NE	NA	NA	NA
N3	Non-ICU	95	61	100	-2.09 [-7.51, 3.33]	0.76	92	0.45
REM	ICU	33	35	30.6	0 [-0.04, 0.04]	0	NA	1
REM	Non-ICU	143	109	69.4	-0.34 [-2.32, 1.64]	0.33	92	0.74

SEI, sleep efficiency index; AI, arousal index; N1, stage 1 of non-rapid eye movement sleep; N2, stage 2 of non-rapid eye movement sleep; N3, stage 3 of non-rapid eye movement sleep; REM, rapid eye movement sleep; MD, mean difference; CI, confidence interval; NE, not estimable; NA, not applicable