Intravenous infusion of dexmedetomidine during the surgery to prevent postoperative delirium and postoperative cognitive dysfunction undergoing non-cardiac surgery: A meta- analysis of randomized controlled trials

doi:10.21203/rs.3.rs-2707738/v1

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Research Article

Intravenous infusion of dexmedetomidine during the surgery to prevent postoperative delirium and postoperative cognitive dysfunction undergoing non-cardiac surgery: A meta- analysis of randomized controlled trials

https://doi.org/10.21203/rs.3.rs-2707738/v1

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published 18 Apr, 2024

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Background

Dexmedetomidine is crucial for preventing postoperative delirium and cognitive dysfunction and improving the quality of life of surgical patients. However, the effects of dexmedetomidine on these complications in different anesthesia methods have not been thoroughly evaluated. Thus, we conducted a meta-analysis to assess its impact on postoperative delirium and cognitive dysfunction.

Methods

We searched PubMed, Embase, and Cochrane Library for randomized controlled trials comparing intravenous dexmedetomidine to other interventions in preventing postoperative delirium and cognitive dysfunction in non-cardiac and non-neurosurgical patients. Statistical analysis and graphing were performed using Review Manager, STATA, the second version of the Cochrane risk-of-bias tool for randomized controlled trials, and GRADE profiler.

Main results

This meta-analysis comprised a total of 24 randomized controlled trials, including 20 trials assessing postoperative delirium and 6 trials assessing postoperative cognitive dysfunction. In these 20 studies, a positive correlation was found between intravenous infusion of dexmedetomidine and the lower incidence of postoperative delirium (RR: 0.55; 95%CI: 0.47 to 0.64, p＜ 0.00001, I² = 2%) and postoperative cognitive dysfunction(RR: 0.60; 95%CI: 0.38 to 0.96, p = 0.03, I² = 60%). Subgroup analysis did not reveal a significant difference in the incidence of postoperative delirium between the general anesthesia and non-general anesthesia groups, but a significant difference was observed in the incidence of postoperative cognitive dysfunction. However, pooled data showed that the use of dexmedetomidine increased the incidence of hypotension (RR: 1.42; 95%CI:1.08 to 1.86, p =0.01, I² = 0%) and bradycardia (RR: 1.66; 95%CI: 1.23 to 2.26, p =0.001, I² = 0%) compared with other interventions but there is no significantly higher occurrence of hypertension in DEX groups (RR=1.35, 95% CI :0.81–2.24, p=0.25, I²= 0%).

Conclusion

Intravenous dexmedetomidine infusion during non-cardiac and non-neurosurgical procedures may significantly reduce the risk of postoperative delirium and cognitive dysfunction compared to other interventions. Subgroup analysis revealed a consistent preventive effect on postoperative delirium in both general and non-general anesthesia groups, while continuous infusion during general anesthesia was more effective in reducing the risk of cognitive dysfunction. However, hypotension and bradycardia were more frequent in patients who received dexmedetomidine during surgery.

dexmedetomidine

non-cardiac surgery and non-neurosurgery

postoperative delirium

postoperative cognitive dysfunction

Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are postoperative phenomena associated with a variety of surgical complications. Some believed that POD and POCD can be referred to both simultaneously as "postoperative cerebral dysfunction". However, others considered POCD to be a different disease from POD.As a prevalent and serious acute neuropsychiatric syndrome, delirium is characterized primarily by cognitive impairment and inattention, along with changes in arousal, altered sleep-wake cycles, and other changes to mental state^[1] .In a meta-analysis, the incidence of POD ranged from 8.4%-18.1% in patients with total hip replacement and slightly higher 12.8%-30.5% after total knee arthroplasty, depending on the patient population and the means to assess^[2]. In a study conducted in a tertiary care center in Taipei, China, the prevalence of delirium was 5.1% among 701 patients (aged > 65 years) undergoing elective orthopedic or urologic surgery^[3].Similarly, older patients who have undergone non-cardiac surgery often experience POCD which is often accompanied by a deterioration in cognitive ability and increased mortality. Monk's study reported that among patients aged 60 and above who underwent non-cardiac surgery, the incidence of POCD was 41.4% on leaving the hospital and 12.7% at 3 months ^[4]. Several independent risk factors for early POCD were identified, including increased age, lower levels of education, longer duration of anesthesia, postoperative infections, a history of previous surgery, and respiratory complications. However, only age was found to be a significant factor in long-term cognitive impairment following surgery^[5] .POD is usually evaluated by the confusion assessment method (CAM), but different from POD, there is no universally accepted and standardized method for assessing POCD in the medical community^[6]. The Mini-Mental State Examination (MMSE) is a useful tool in quantitatively assessing the level of cognitive impairment and tracking changes in cognitive function, and the MMSE scores are positively correlated with the patient's cognitive function^[7].

Dexmedetomidine (DEX) is an alpha2-adrenergic agonist with high selectivity, which can inhibit sympathetic excitability, enhances vagal excitability, decreases blood pressure, makes heart rate slower, and reduces myocardial oxygen consumption; and has sedative, analgesic, anti-anxiety, hypnotic amnesic and narcotic effects. It reduces the patient's pain and anxiety by inhibiting neuronal firing, thus achieving sedation. The pharmacological properties of dexmedetomidine include rapid absorption, rapid distribution, rapid metabolism and rapid excretion. In clinical practice, dexmedetomidine can be used for sedation, analgesia and tranquillization, as well as intra- and post-operative sedation and analgesia. In addition, dexmedetomidine also inhibits the activity of the central nervous system, thereby reducing the patient's pain. Some literature suggests a neuroprotective effect of DEX^[8–10]. Previous studies have examined the impact of dexmedetomidine (DEX) on postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). However, due to the lack of exclusion of confounding factors such as the type of surgery and anesthesia protocol, the results are not always applicable to clinical practice. Therefore, we conducted a meta-analysis to evaluate the effectiveness of DEX in reducing the incidence of POD and POCD in patients undergoing non-cardiac surgery and non-neurosurgery. Furthermore, a subgroup analysis was conducted based on the type of anesthesia administered to account for any potential variations in results. As a secondary outcome, we also sought to determine if dexmedetomidine affected the stability of the circulatory system.

2.1 Search strategy

A systematic search was conducted in the databases of PubMed, Embase, and The Cochrane Library to identify all relevant studies from their inception to February 10, 2023.The PubMed basic search strategy is as follows: (("delirium"[MeSH Terms] OR "delirium"[All Fields] OR ("Postoperative Cognitive Complications"[MeSH Terms] OR "Postoperative Cognitive Complications"[All Fields])) AND ("dexmedetomidine"[MeSH Terms] OR "dexmedetomidine"[All Fields])). Our search strategy only included randomized controlled trials (RCTs), and we limited the language to English and Chinese. Species restriction was only human, and the present meta-analysis was prospectively registered in the PROSPERO database with the registration number CRD42023402004.

2.2 Study selection

The inclusion criteria and requirements for the studies incorporated into this meta-analysis were as follows: (1) designed as RCTs; (2) published in English or Chinese; (3) patients who underwent non-cardiac surgery and non-neurosurgery;(4) intravenous infusion of dexmedetomidine or the drugs used in the control group during the surgery. We ruled out reviews, study protocol, observational studies, the outcomes or adverse effects of the study didn’t include POD and POCD, studies including critically ill patients or sedates of patients in ICU, studies including DEX given to patients by other means, and repeated reports.

2.3 Endpoints

The primary outcome was the occurrence of POD and POCD during the seventh post-operative day, and the secondary outcomes were the occurrence of hypertension, hypotension, and bradycardia during the surgery.

2.4 Data extraction

We extracted data according to the standard forms. If there is doubt, we discussed it with the corresponding author to resolve the problem. The data we have extracted are as follows: first author, publication year and country, design of experiments, the sample size of the intervention and comparison groups, range of age, and Grade of ASA, anesthetic type, surgery procedure, drugs applied in the control group, the anesthesia depth monitoring, the strategy of DEX infusion, cognitive problem and the assessment method.

2.5 Assessment of trial quality

We assess the risk of bias through the Risk bias assessment tool RoB2 (revised version 2019) for RCTs in six areas: the process of randomization, departures from the intended interventions, lack of outcome data, measurement of the outcome, selection of the reported outcome, and overall risk of bias^[11].

2.6 Statistical analysis

For statistical analysis and graphing, we used Review Manager software (RevMan version 5.4.1), STATA software (Version 12.0), and GRADE profiler. We analyzing dichotomous data by using risk ratios (RR) with 95% confidence interval (CI). There were three levels of heterogeneity determined by the I² statistics: low (I² < 50%), moderate (50%≤I² ≤ 75%), and high (I² > 75%)^[12] .When I² < 50%, we will choose the fixed effect model as the approach to pool the data; conversely, if the conclusion is that the study has moderate or high heterogeneity, we chose the random effect model as the approach to pool the data and conducted subgroup analysis to identify sources of heterogeneity. We assessed publication bias by examining funnel plots and conducting Egger's test, with p-values greater than 0.05 indicating no significant publication bias. Additionally, we conducted a sensitivity analysis to evaluate the stability of the results. Finally, we utilized the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) technique to classify the major results of the degree of certainty.

3.1. Search results

The process for searching and including literature in the database is illustrated in Fig. 1. After searching by our previously defined search strategy, 436 articles were discovered throughout the database search, and no article was discovered using other sources.319 of them were retrieved after duplicated records were taken out. According to titles and abstracts, 227 of them were later excluded, mainly because of the low correlation between these studies and the aim of the meta-analysis. We did a full read-through of the other 92 articles and eliminated a further 67 articles as pointed out in Fig. 1. In the end, a total of 24 RCTs fully met our inclusion criteria and were ultimately incorporated into the meta-analysis (Fig. 1).

3.2. Characteristics of trials

This meta-analysis included trials published from 2014 to 2023, involving 5207 participants (2638 patients received intraoperative intravenous DEX for sedation and 2569 patients received other medication for sedation or saline as a control group). Among them, two studies^[13][14] assessed both POD and POCD, while a study^[15] used two different methods for assessing POCD and reached different conclusions, so we included them in the analysis as two outcomes independently. 23 studies were reported in English and one studies were published in Chinese. There are 17, 3, 1,1 and 2 experiments in China, Korea, Egypt, Japan and India respectively. In our meta-analysis, 20 studies enrolling a total of 4304 patients examined in depth whether there was a link between DEX and a reduction in the incidence of POD, and 7 studies recruiting 690 participants examined whether DEX reduced the incidence of POCD. In Table 1, detailed descriptions of the included trials are provided. All patients included in the study were over the age of 18 and drugs used in the control group included saline, midazolam and propofol. Table 1 also demonstrated that DEX doses and administration times were different. Although POCD evaluation instruments varied, the process for evaluating POD is generally consistent.

3.3. Risk of bias in included studies

Based on the main result, we used the RoB 2.0 to assess 24 RCTs, and the result is that 5 trials were judged to have "some concerns”, 19 trials were deemed to have "low risk of bias" and no trial was "high risk of bias”. (Fig. 2).

3.4. Meta-analysis for the studies of cognitive problem

3.4.1. the occurrence of POD

Twenty studies^{[13,14][16–33]} with a total of 4304 patients, studied the incidence of POD, with no statistical heterogeneity between studies(P = 0.43, I² = 2%), were analyzed using a fixed-effects model, and it was found that in the case of non-cardiac surgery and non-neurosurgery, DEX significantly associated with reduced incidence of POD in the comparison with the control group (19 trials, RR: 0.54; 95%CI: 0.46 to 0.64 ;p < 0.0001) (Fig. 3).

3.4.2. the occurrence of POCD

Six studies^{[13–15][34–36]} reported the occurrence of POCD in seventh post-operative day, for which neuropsychological tests, Stroop color word interference test, Montreal Cognitive Assessment (MoCA) and Mini-mental State Examination (MMSE) were each chosen as the evaluation method. A study^[15] used two different methods for assessing POCD and reached different conclusions, so we included them in the analysis as two outcomes independently. The results of meta-analyses using a random-effects model revealed statistical differences in preventing POCD undergoing non-cardiac surgery and non-neurosurgery compared with the control group (7 trials, RR: 0.60; 95%CI: 0.38 to 0.96, p = 0.03) with moderate heterogeneity (P = 0.02, I² = 60%) (Fig. 4).

3.4.3 Secondary outcomes

Four studies^{[20] [23][28] [33]} with 694 participants (DEX group: 349 patients; control group: 345 patients) reported the occurrence of hypertension during the surgery. We applied a fixed effect model with no statistical heterogeneity between studies (P = 0.70, I² = 0%) in our analysis. There is no significantly higher occurrence of hypertension in DEX groups in included studies (RR = 1.35, 95% CI :0.81–2.24, p = 0.25) (Fig. 5). In addition, seven studies^{[13 ,14][20][23] [28] [32, 33]}with 994 patients (DEX group: 519 patients; control group: 475 patients) examined the occurrence of hypotension and showed that intravenous infusion of DEX for sedation causes intraoperative hypotension in patients in comparison to the group that received other sedatives or normal saline with the low heterogeneity (RR: 1.42; 95%CI:1.08 to 1.86, p = 0.01, I² = 0%) (Fig. 6). Likewise, these seven studies^{[13 ,14][20][23] [28] [32, 33]} also examined the occurrence of bradycardia and showed that Intravenous infusion of DEX for sedation causes intraoperative bradycardia in patients in comparison to the group that received other sedatives or normal saline with the low heterogeneity (RR: 1.66; 95%CI: 1.23 to 2.26, p = 0.001, I² = 0%) (Fig. 7).

3.5 Subgroup analysis

We divided the studies on the incidence of POD into two subgroups according to the type of anesthesia. Fourteen studies were conducted with patients only receiving general anesthesia, and four studies were tested under non-general anesthesia plus sedation and assessed the effect on postoperative delirium. We note that regardless of the type of anesthesia, DEX significantly reduced the prevalence of POD with low heterogeneity (Fig. 8).

For POCD, we also assigned subgroups according to the type of anesthesia in the respective studies. 5 studies were conducted with patients only receiving general anesthesia, and two studies were tested under regional anesthesia plus sedation and assessed the preventive effect on the incidence of POCD. We noted compared with regional anesthesia plus sedation, continuous intravenous injection of DEX during general anesthesia (5 trials, RR: 0.50; 95%CI: 0.34 to 0.74, p = 0.0005, I² = 31%) may be more beneficial in reducing the risk of POCD (2 trials, RR: 0.84; 95%CI: 0.60 to 1.19, p = 0.03, I² = 80%) (Fig. 9). We consider the type of anesthesia as a source of obvious heterogeneity (I² = 74.4%).

3.6. Level of certainty for outcomes (GRADE)

GRADE profiler was used to assess the level of certainty in the outcomes of the meta-analysis we conducted, following the GRADE methodology., and ranked them as ranging from low to high as shown in Table 2.

3.7. Publication bias and sensitivity analysis

We conducted a sensitivity analysis to assess the impact of each individual study on the overall meta-analysis. By excluding one study at a time from the included research, we observed that the pooled results of the primary outcomes remained robust. Furthermore, the funnel plots (Fig. 10 and Fig. 11) and Egger's tests (with a P value of 0.448 for POD and 0.098 for POCD) suggested that there was no significant publication bias in the studies that investigated the effects of DEX administration on both POD and POCD.

By analyzing all available RCTs, we found out that intraoperative intravenous DEX infusion reduces the incidence of POD and POCD compared to other sedatives or normal saline. In addition, our subgroup analysis showed that DEX had a consistent preventive effect on POD in patients undergoing non-cardiac or non-neurosurgery, regardless of the type of anesthesia used. And another subgroup analysis also suggested that continuous intravenous injection of DEX during general anesthesia appeared to be more effective in reducing the risk of POCD compared to regional anesthesia. However, in contrast to the control group receiving normal saline or other sedatives, patients receiving DEX during surgery were more prone to experiencing hypotension and bradycardia, whereas the occurrence of hypertension during surgery did not differ significantly between the two groups.

POD and POCD have become major concerns in clinical practice due to their potential to cause prolonged hospital stays, higher medical expenses and lower quality of life for patients. Risk factors for these complications include advanced age, pain, anemia, and hypoxemia^[37]. The use of certain anesthetic drugs has also been implicated as a risk factor for POD^[38–40], and proposed mechanisms for these complications include disruption of normal neurotransmitter function, tau protein, inflammatory response, disrupted calcium homeostasis, and impaired mitochondrial function. In addition, POD has been recognized as a significant risk factor for adverse outcomes in hip fracture patients, with the risk of mortality increases two-fold observed in patients with POCD or POD ^[41] Thus, it is crucial to recognize patients who are susceptible to POD and POCD and take preventive measures to mitigate their incidence.

Fortunately, some literature suggested that 40% of POD cases can be prevented^[42] .One method of prevention is administering DEX the perioperative period, a highly selective alpha-2 adrenergic receptor agonist that has been shown to have neuroprotective effects. DEX does not interact with γ-aminobutyric acid receptors, does not possess anticholinergic activity, and has been shown to promote natural sleep patterns, which may account for its potential anti-delirium effects^[43].Several interventions, including multimodal analgesia techniques, cognitive stimulation programs, and early mobilization, have also been proposed for the prevention of POD and POCD^[42].

Two meta-analyses published in 2019^[44]and 2022^[45]were conducted to investigate the impact of DEX on postoperative neurocognitive function of elderly patients who underwent non-cardiac surgery. Regarding the elderly patients who had non-cardiac surgery, both studies found that DEX administration during the perioperative period was more effective than other sedatives in maintaining cognitive function after the surgical intervention. However, it is important to note that these meta-analyses only included the elderly population and did not apply to all patients. Although POD and POCD are more common in older patients, they can still occur in relatively young patients and middle-aged people after major surgery. Furthermore, neither meta-analysis included a subgroup analysis based on anesthetic modality to assess whether the efficacy of DEX in preventing POD and POCD was influenced by differences in the type of anesthesia. This is an important consideration, as different types of anesthesia may have different effects on neurocognitive function. Therefore, a new meta-analysis was conducted to address these limitations and provide a more comprehensive analysis of the effect of DEX on POD and POCD.

In this new meta-analysis, databases were added for up-to-date literature searches, resulting in a much larger number of RCTs and patients included in the meta-analysis compared to the previous studies. Additionally, a subgroup analysis was carried out to evaluate the influence of DEX on POD and POCD under different types of anesthesia. The meta-analysis concentrated on the impact of administering DEX continuously via intravenous infusion during the surgery on the prevention of POD and POCD in patients of all ages, providing a more comprehensive and reliable analysis of the neuroprotective effects of DEX.

Our meta-analysis supports previous findings that the administration of DEX to patients undergoing non-cardiac and non-neurosurgical procedures has a significant beneficial effect on postoperative cognitive function. Furthermore, our analysis demonstrates that a continuous intraoperative infusion of DEX is effective in preventing both POD and POCD. The subgroup analysis revealed that DEX had a consistent preventive effect on POD regardless of anesthesia type, and continuous intravenous injection of DEX during general anesthesia was more effective in reducing the risk of POCD than regional anesthesia. These results suggest that DEX could be a valuable tool in perioperative care for this population and warrants further investigation in future studies.

However, the meta-analysis conducted in this study demonstrated that DEX leads to bradycardia, hypertension and hypotension, of which are linked to its α2-adrenoreceptor agonist. When DEX is administered, it produces a distinct two-phase hemodynamic response, whereby lower plasma concentrations lead to a reduction in blood pressure, while higher plasma concentrations result in an increase in blood pressure ^[46] .Notably, the hypotension and bradycardia associated with DEX are both intraoperative adverse effects, and there is a lack of sufficient studies to demonstrate a relationship between these adverse effects and long-term postoperative adverse effects in patients. Perhaps there will be a better drug that prevents both POD and POCD while better maintaining the patient's hemodynamic stability.

This study still has a little limitations and shortcomings. Firstly, it should be emphasized that there was considerable heterogeneity in both the assessment measures employed to evaluate POCD and the types of drugs administered to the control group among the studies incorporated in the analysis. Secondly, more precise studies are needed to determine if there is an optimal dosing regimen and dosage to protect the patient's cognitive function with less hemodynamic impact on the patient. Thirdly, the accuracy of the results is compromised by the under-representation of certain groups of studies.

In summary, intravenous infusion of DEX during surgery has a risk-reducing effect on POD and POCD in the elderly undergoing non-cardiac surgery and non-neurosurgery. It seems that compared to regional anesthesia, continuous intravenous infusion of DEX during general anesthesia may be better in reducing the risk of POCD; but in terms of reducing the occurrence of POD, DEX can achieve the same good effect regardless of whether the patient receives general anesthesia or regional anesthesia. However, intravenous infusion of DEX during surgery may lead to intraoperative hypotension and bradycardia. Although this study provides strong evidence that intraoperative intravenous DEX infusion is effective in preventing the development of POD and POCD, the heterogeneity and insufficient number of research findings in some areas leads to limitations of this meta-analysis, and therefore a meta-analysis incorporating more RCTs will be performed in the future to help confirm the occurrence of POD and POCD with anesthesia.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

Di Wang participated in the design, collected the data, performed the quality assessment ，statistical analyses and draft the manuscript. Congjie Bi participated in the design and draft the manuscript. Wenhui Zhang and Zhi Liu collected the data and performed the quality assessment. Guo Zu, He Tao helped to perform statistical analyses and search strategy. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

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Tables 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

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Intravenous infusion of dexmedetomidine during the surgery to prevent postoperative delirium and postoperative cognitive dysfunction undergoing non-cardiac surgery: A meta- analysis of randomized controlled trials

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Abstract

Background

Methods

Main results

Conclusion

Figures

1. Background

2. Methods

2.1 Search strategy

2.2 Study selection

2.3 Endpoints

2.4 Data extraction

2.5 Assessment of trial quality

2.6 Statistical analysis

3. Results

3.1. Search results

3.2. Characteristics of trials

3.3. Risk of bias in included studies

3.4. Meta-analysis for the studies of cognitive problem

3.4.1. the occurrence of POD

3.4.2. the occurrence of POCD

3.4.3 Secondary outcomes

3.5 Subgroup analysis

3.6. Level of certainty for outcomes (GRADE)

3.7. Publication bias and sensitivity analysis

4. Discussion

5. Conclusion

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding:

Authors' contributions

Acknowledgements

References

Tables

Additional Declarations

Supplementary Files

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Journal Publication

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