Effects of dexmedetomidine on early postoperative cognitive function and postoperative inflammatory response: a systematic review and network meta-analysis

Background Dexmedetomidine (DEX) has demonstrated potential as an effective agent for enhancing early postoperative cognitive function. However, there is ongoing debate regarding its optimal dosage and impact on early postoperative inflammatory response. This study aimed to assess and prioritize the effects of varying doses of DEX on early postoperative cognitive function and inflammatory response, in order to identify the most effective intervention dosage. Methods Randomised controlled trials (RCTs) and retrospective cohort studies (RCS) from PubMed, Embase, and Cochrane Library up to January 28, 2024, were included. The Mini-Mental State Examination (MMSE) was utilized to assess the impact of varying doses of DEX on cognitive function during the early postoperative period as the primary outcome, peripheral blood levels of IL-6 and TNF-α were considered as secondary outcomes. Meta-analysis and Bayesian Network Meta-Analysis (NMA) were conducted using R. Funnel plots were generated using Stata 15.0. Results A total of 29 studies involving 2,807 patients and 25 different doses of DEX were included. DEX was given at a loading dose of 0.3–1.0 μg/kg followed by a maintenance dose of 0.1–0.5 μg/kg/h, or at a uniform intraoperative dose of 0.4–0.7 μg/kg/h. Network meta-analysis revealed most doses of DEX were significantly more effective than normal saline (NS) in improving postoperative MMSE scores (on days 1, 3, and 7) and lowering IL-6 and TNF-α levels. Probability results showed that a 1 μg/kg loading dose followed by a 0.6 μg/kg/h maintenance dose was the best dosing regimen for improving MMSE scores on postoperative days 1 (97.3%), 3 (100%), and 7 (99.9%), as well as for reducing postoperative blood IL-6 levels (1.3%). On the other hand, 0.3 μg/kg followed by 0.2 μg/kg/h was the optimal dosing regimen for reducing postoperative blood TNF-α levels (6.6%). Conclusion Compared with NS, intraoperative intravenous DEX improved early postoperative cognitive function and postoperative inflammatory response in patients undergoing elective surgery. In particular, a 1 μg/kg loading dose and a 0.6 μg/kg/h maintenance dose resulted in the best improvement in postoperative MMSE scores and blood IL-6 levels, while a 0.3 μg/kg loading dose followed by a 0.2 μg/kg/h maintenance dose is the optimal regimen for lowering postoperative blood TNF-α levels. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=433932, identifier CRD42023433932.


Introduction
Abnormalities in postoperative cognitive function can manifest in the anaesthesia recovery room, during hospitalization, or up to 1 year after surgery.These abnormalities may include memory loss, poor concentration, and delayed thinking.Notably, postoperative cognitive abnormalities can result in long-term cognitive impairment, extended hospital stays, increased mortality, and negative socioeconomic consequences.The efficacy and safety of dexmedetomidine (DEX) in treating postoperative cognitive abnormalities and inflammatory response have been supported by numerous randomised, double-blind, placebo-controlled trials (1,2).DEX has been shown to impact cognitive function and inflammatory outcomes through various mechanisms.Zhao et al. (3) found that DEX inhibited PSD95-NMDA receptor interactions in mice with traumatic brain injury (TBI), leading to improved functional recovery after TBI.Chen et al. (4) reported that DEX enhanced mitochondrial autophagy via PINK1, attenuated hippocampal focal neuroapoptosis, and improved postoperative cognitive dysfunction.Research on epigenetic mechanisms of postoperative cognitive impairment has also indicated that DEX is linked to a lower risk of cognitive decline compared to other substances (5).Kho et al. (6) examined the effects of DEX on autophagic flux, microRNA, and cholinergic anti-inflammatory pathways in LPS-treated rats.The authors revealed that DEX prevented impairment of autophagic flux and reduced apoptosis-associated proteins in the spleen.This suggests that DEX may modulate inflammation through multiple pathways, potentially contributing to its cognitive benefits (6).Furthermore, DEX has been found to play an important role in improving neuroinflammation-induced cognitive dysfunction.Recent studies indicate that DEX ameliorates postoperative cognitive dysfunction (POCD) by activating the c-Jun N-terminal kinase (JNK)/p-38 signaling pathway through CEBPB as a pharmacological target to inhibit M1-mediated inflammation in CNS microglia (7).In a retrospective propensity score study involving patients undergoing lobectomy, DEX prevented cognitive dysfunction and delirium by attenuating neuroinflammation (8).Additionally, a meta-analysis of 17 randomised-controlled trials (RCTs) with 1,619 patients demonstrated that DEX not only ameliorates perioperative immune dysfunction but also reduces POCD and associated neuroinflammation.These findings demonstrate that DEX can enhance postoperative recovery and clinical outcomes in patients undergoing gastrointestinal cancer surgery (9).Clinical guidelines recommend intraoperative DEX infusion for high-risk patients or continuous postoperative infusion for ICU patients to reduce postoperative cognitive abnormalities.However, high doses of DEX as an anaesthetic adjuvant to general intravenous anaesthesia can lower blood pressure and heart rate due to its sympathetic effects.Recovery from these effects may be slow and persistent even after general anaesthesia.Furthermore, there is limited research directly comparing the effects of different DEX doses on postoperative cognitive function and inflammation.
We therefore performed network meta-analyses (NMA) of different doses of DEX.NMA is an extension of traditional metaanalysis, a technique that combines direct and indirect evidence in a network of trials comparing multiple treatments or different doses.In the absence of head-to-head trials, these indirect comparisons provided insights into the optimal dose of DEX to mitigate postoperative cognitive abnormalities and early inflammatory responses.

Methods
The analyses were conducted in accordance with a pre-specified protocol registered in PROSPERO (CRD42023433932), and the results were reported following the Preferred Reporting Items for Systematic Evaluation and Meta-Analysis (PRISMA) extension statement for NMA (10).

Search strategy and eligibility criteria
Relevant studies were systematically search in Embase, Pubmed, and the Cochrane Library from inception to January 28, 2024 using free-text keywords and MeSH related to DEX and postoperative cognitive disorder without language restrictions (see Appendix A).The retrieved articles were identified and screened by two independent reviewers (RMY and XLX).The relevant procedures for systematic appraisal were in accordance with the PRISMA guidelines.The articles were further selected to assess the expression of postoperative inflammatory markers.The inclusion criteria for this study were: (

Data extraction
Data were extracted independently by two authors (CFH, XLX) and entered into a standardized Excel spreadsheet (Microsoft, Redmond, WA, United States).In cases where trials were published in languages other than English, Google Translate was utilized.The extracted trial characteristics included the number of patients in each study group, age, surgical procedure, anesthesia, DEX dose, usage, and duration.The primary endpoints were postoperative MMSE scores on postoperative days 1, 3, and 7, and the secondary endpoints were postoperative blood IL-6 and TNF-α levels.The results were extracted as means and standard deviations.Data presented in graphical form were converted to numerical format using Plot Digitizer (version 2.1, Free Software Foundation, Boston, MA, United States).The median was assumed to be equal to the mean, and the standard deviation was calculated based on the interquartile spacing and extreme deviation (1.35 and 4, respectively) (11).In cases where information was unclear or incomplete, clarification was sought by sending an email to the authors of the included trials.
The quality of all included studies was independently assessed by the investigators (RMY and HJD) according to the Cochrane risk-ofbias tool for randomized trials (RoB2) and Newcastle-Ottawa Scale (NOS).The quality of randomized-controlled trials (RCTs) was assessed using the RoB2 tool in five domains, namely randomization process, deviation from intended intervention, missing outcome data, measurement of outcomes, and selection of reported outcomes.Each domain was scored low risk, some level of concern, or high risk.Any disagreements were resolved through discussion.The NOS scale was used to rate the quality of retrospective cohort studies (RCS), with scores ranging from 1 to 3 indicating low quality, 4 to 6 indicating moderate quality, and 7 to 9 indicating high quality.

Statistical analysis
Meta-analysis and Bayesian NMA were performed using the 'gemtc' and 'rjags' packages of R v4.3.1 (12).Network graphs were generated for each outcome displaying different DEX doses as nodes and direct comparisons as connecting lines.Indirect comparisons were derived from direct comparison estimates of a common comparison dose, and the results of both direct and indirect comparisons were summarized in a network leaderboard.MMSE scores (postoperative days 1, 3, 7) and postoperative blood IL-6 and TNF-α levels are expressed as ratios (OR) and 95% confidence intervals (CI) (13).The advantages and disadvantages of different DEX doses were ranked according to the surface under the cumulative ranking curve (SUCRA).The intervention dose is absolutely effective if SUCRA is ≥0 and ≤ 1, and absolutely ineffective if SUCRA is 0. For IL-6 and TNF-α, a larger area under the curve (AUC) indicates a more detrimental effect of postoperative inflammatory markers on recovery.
Heterogeneity among the results of the included studies was determined by the χ 2 test (significance level α = 0.1) and quantitated by I 2 .The fixed effects model was used if there was no heterogeneity between studies (I 2 ≤ 50%); otherwise, a random effects model was used (I 2 > 50%).Significant clinical heterogeneity was addressed through methods such as subgroup analysis, sensitivity analysis, or descriptive analysis only.
The robustness of results can be influenced by the size of the study and the likelihood of publishing negative results.In addition, we conducted one-way sensitivity analyses to evaluate the influence of the included studies on the combined results, considering the significantly heterogeneous outcomes.Funnel plots were created using Stata version 15.0 (Stata Corp, College Station, TX, United Sates), and Egger's test were conducted to visually assess publication bias for outcomes that included 10 or more studies.

Characteristics of included studies
A total of 1,484 relevant articles were collected from the three databases.After removing duplications, the title of the remaining 667 articles was screened by two independent reviewers and 495 studies were excluded due to inappropriate study type, including animal studies, case reports, reviews, protocols, and studies unrelated to postoperative cognition.Upon further examination of the abstracts, 126 studies were excluded due to failure to meet the inclusion criteria, including 61 with unrelated study outcomes, 33 with unrelated study interventions, and 32 with unrelated study controls.Following a thorough review of the full text, 17 studies were eliminated, comprising 9 articles with unextractable data, 6 articles lacking raw data, and 2 retracted articles.Ultimately, 29 studies involving 2,807 patients were included.The included studies had comparable baseline characteristics, such as sex, age, and sample size.The screening process is depicted in Figure 1.

Results of risk of bias, heterogeneity and sensitivity analysis
Of the 26 RCTs, 17 (65.3%)utilized a method to generate a randomized sequence of appropriate methods, 3 (11.5%)deviated from the intervention, and 3 (11.5%)experienced loss of data.Additionally, 19 (26.9%)RCTs had outcome measurement bias and 2 (7.6%) reported selection bias in the outcome.Quality assessment of the included studies revealed that 38.5% were of low risk, 23.1% were of unknown risk of bias, and 38.5% were of high risk (Figure 2).The overall quality of the included studies ranged from low to moderate.In addition, quality assessment of the 3 RCSs using the NOS scale showed that they were all high-quality (Table 2).
The included studies were heterogeneous (I 2 >50%), except for the MMSE scores on postoperative days 3 and 7 (Supplementary Figures 1a-e).The heterogeneity test indicated an I 2 value greater than 50%, with no significant variations observed in study design, region, participant characteristics, interventions, or methodology.Subsequent sensitivity analyses identified the Li et al. (25) and Li et al. (26) studies as the primary sources of heterogeneity (Supplementary Figure 1).Upon re-evaluation, it was discerned that both studies exhibited bias due to small sample sizes in each group.After excluding these studies, the I 2 value dropped below 50%, leading to enhanced consistency and stability in the results of the net meta-analysis.
The pooled results of our network meta-analyses may have been influenced by several confounding factors, including the type of surgery, age, and method of assessment.To ensure the reliability of our findings, we performed a series of sensitivity analyses.The results of these analyses, presented in Supplementary Figures 2a-e, did not reveal any significant changes in the pooled results for all comparisons.

Selection of cohorts
Visual inspection of the comparative adjusted funnel plots did not reveal publication bias in the postoperative day 1, 3, 7 MMSE scores and blood IL-6 lever in our network meta-analysis.The results of Egger's test (p = 0.964, 0.993, 0.339 and 0.126) also negated the presence of a small study effect.Because there were no more than 10 studies on TNF-α, the publication bias analysis did not employ the inverted funnel plot method and the Egger's test (Supplementary Figures 3a-d).

Discussion
The results of this study demonstrated that a 1 μg/kg LD followed by a 0.6 μg/kg/h MD was the best dosing regimen for improving postoperative MMSE scores on days 1, 3, and 7. Conversely, an IOD of 0.5 μg/kg/h had the least favorable effect.Additionally, the 1 μg/kg LD followed by 0.6 μg/kg/h MD regimen exhibited the greatest efficacy in reducing postoperative blood IL-6 level, while the 0.3 μg/kg LD followed by a 0.8 μg/kg/h MD regimen was the best approach for lowering postoperative blood TNF-α level.NS had the last effect on postoperative blood levels of IL-6 and TNF-α.Collectively, our findings demonstrate that a 1 μg/kg LD Although the certainty of evidence was low, these results nonetheless indicated that there is an optimal DEX dosing regimen that can improve postoperative cognitive function and postoperative blood IL-6 level.It is interesting to note that the optimal dose converges while the worst dose does not.Does DEX exert neuroprotective effects through its antiinflammatory action?DEX inhibits the production and release of key inflammatory mediators, such as cytokines IL-6 and TNF-α (43).These mediators are crucial in the inflammatory response, and their reduction diminishes the intensity and extent of inflammation.DEX  Inflammatory responses can harm the blood-brain barrier, increasing its permeability and worsening neurological damage.Dexmedetomidine's anti-inflammatory effect helps maintain and restore the blood-brain barrier's integrity (45), preventing harmful substances from entering brain tissue.These pathways demonstrate DEX's significant neuroprotective and nerve repair effects, with its anti-inflammatory action being a crucial mechanism.Further research could delve into these mechanisms and assess DEX's therapeutic potential in various neurological disorders.
We included studies in which DEX was used in different surgical and anaesthesia modalities.Our meta-analysis showed that DEX improves neurological outcomes in different surgical and anesthesia approaches, consistent with previous studies.A study comparing pre-anesthetic doses of ketamine and DEX in older patients undergoing emergency surgery showed promising results in reducing cognitive dysfunction (46).In addition, a study assessing the impact of DEX combined with etomidate on postoperative cognitive function in older patients undergoing ureteroscopic holmium laser lithotripsy revealed decreased incidences of cognitive dysfunction, emergent agitation, depression, and anxiety (47).Furthermore, a recent network meta-analysis involving 24 RCTs reported that intravenous DEX infusion during non-cardiac and non-neurosurgical procedures led to significantly reduced incidences of postoperative delirium (POD) and cognitive deficits when compared to alternative interventions (1).DEX has also demonstrated neuroprotective effects across different anesthesia modalities.It was found that the incidence of POD was lower in patients using DEX in spinal anaesthesia than in those using propofol (48).Additionally, a meta-analysis of 18 RCTs suggested that intravenous DEX sedation during surgery could play a crucial role in preventing POD and cognitive dysfunction in older patients (≥ 60 years old) receiving regional anesthesia.Moreover, transnasal administration of DEX has been shown to be effective for improving sleep disturbances, preventing neurocognitive impairment and POD, reducing anxiety, and minimizing adverse effects and complications in older patients undergoing general anaesthesia (49).Taken together, DEX is a promising sedative for enhancing cognitive function in various surgical procedures, anaesthesia modalities, and administration routes.DEX has demonstrated favourable outcomes in postoperative sedation (50), pain management, anxiety reduction (51), cognitive function, and postoperative inflammation.Additionally, it has a unique and manageable mechanism of action that results in a low risk of respiratory depression (52) compared to other sedatives.However, DEX can also pose several adverse effects, including hypotension (53), bradycardia (54), and over-sedation.These risks may vary between different patient populations and should be closely monitored in the clinical setting.
Due to the presence of potential heterogeneity, the ranking of DEX doses in the NMA may not be directly applicable to future clinical treatment rankings.Therefore, our findings should be interpreted with caution, and randomized-controlled trials will be required to directly  compare the effect of different DEX doses on postoperative cognitive function and inflammatory response.This study has two strengths.First, this is the first and largest systematic review using a NMA approach to determine the effect of different DEX doses on postoperative cognitive function and inflammatory markers.The findings of this work provide valuable insight into the optimal DEX dosing regimen for reducing the incidences of postoperative cognitive dysfunction and postoperative inflammation.Second, the results of this systematic review and NMA can serve as support for future studies on the same topic.
Several limitations should be noted for this study.Differences in study design between RCTs and retrospective comparative studies (RCS) can impact result interpretation, since the latter is prone to selection bias and information bias due to its non-randomized nature.Additionally, high heterogeneity could indicate variations in populations, interventions, and outcome measures, which may impact result stability and interpretation.Lastly, potential limitations in data availability and study quality should be considered.Nonetheless, further large-cohort RCTs are warranted to minimize heterogeneity, improve internal validity, and assess the long-term safety and tolerability of DEX in different patient populations.

Conclusion
In conclusion, our NMA demonstrates the benefits of perioperative DEX use in improving postoperative cognitive function and postoperative inflammatory response.In addition, a 1 μg/kg LD then 0.6 μg/kg/h MD of DEX is the optimal dosing regimen for improving postoperative cognitive function and lowering blood IL-6 levels, whereas a 0.3 μg/kg LD then 0.2 μg/ kg/h MD is the best regimen for lowering postoperative blood TNF-α level.Due to the limitations of this study and the heterogeneity among the included studies, these findings should be interpreted with caution.Nevertheless, we hope that our findings will provide valuable insights into the selection of appropriate DEX regimens for elective surgery patients.

FIGURE 1 Flow
FIGURE 1Flow chart of the study selection procedure.

9 ★
: appropriate study design; ★★: one for the most important factor; the other for another factor.
followed by a 0.6 μg/kg/h MD of DEX is superior for reducing postoperative blood IL-6 level and improving postoperative MMSE scores, while caution should be exercised when considering the 0.5 μg/kg/h IOD or 0.3 μg/kg LD then 0.2 μg/kg/h MD regimens.

FIGURE 3
FIGURE 3 Network estimates of total MMSE score on day 1 after surgery.(A) Network plot showing direct comparisons between nodes.(B) Forest plot of different DEX doses compared with NS in NMA.(C) Estimated probability (%) of each dose level.(D) Description of individual DEX doses in this analysis.LD, Load dose; MD, Maintenance dose; IOD, Intraoperative dose.

FIGURE 4
FIGURE 4 Network estimates of total MMSE score on day 3 after surgery.(A) Network plot showing direct comparisons between nodes.(B) Forest plot of different DEX doses compared with NS in NMA.(C) Estimated probability (%) of each dose level.(D) Description of individual DEX doses in this analysis.LD, Load dose; MD, Maintenance dose; IOD, Intraoperative dose.

FIGURE 5
FIGURE 5 Network estimates of total MMSE score on day 7 after surgery.(A) Network plot showing direct comparisons between nodes.(B) Forest plot of different DEX doses compared with NS in NMA.(C) Estimated probability (%) of each dose level.(D) Description of individual DEX doses in this analysis.LD, Load dose; MD, Maintenance dose; IOD, Intraoperative dose.

FIGURE 6
FIGURE 6 Network estimates of blood IL-6 level after surgery.(A) Network plot showing direct comparisons between nodes.(B) Forest plot of different DEX doses compared with NS in NMA.(C) Estimated probability (%) of each dose level.(D) Description of individual DEX doses in this analysis.LD, Load dose; MD, Maintenance dose; IOD, Intraoperative dose.

TABLE 1
Characteristics of the included trials.