1. Introduction
Postoperative cognitive dysfunction (POCD) is a very common disorder in patients undergoing surgery, especially in elderly subjects over 65 years old.[1–3] It is often characterized by a decline in performance on neuropsychiatric tests and lasts from days to weeks after operation.[4–7] Its incidence is reported to be 26% and 10% to 12.7% at 7 days and 3 months post-surgery, respectively, in the elderly population.[8–10] If this disorder cannot be managed in a timely manner, it can result in permanent cognitive decline in some patients,[11] poor functional recovery, prolonged hospitalization, long-term rehabilitation, and increased overall mortality rate.[12–14] Thus, it is important to detect and prevent POCD in elderly patients undergoing surgery.
Dexmedetomidine, as a highly selective α2 adrenoreceptor agonist, not only has a sedation, algesia, antagonistic effect, but also effectively protects the nervous system by restricting inflammatory response and decreasing incidence of delirium and POCD during sedation.[15–20] Previous studies have reported that dexmedetomidine may benefit POCD in elderly population.[21–30] However, no systematic review comprehensively has addressed this topic. Thus, the present study systematically investigated the effectiveness and safety of dexmedetomidine on POCD in elderly with fracture undergoing surgery.
2. Methods
2.1. Ethical statement
This study does not require ethical approval since no individual data was involved in this study.
2.2. Literature search
This study identified eligible randomized controlled trials (RCTs) of dexmedetomidine on POCD in elderly patients with fracture. Electronic databases of PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wang Fang and China Science and Technology Journal Database were searched from inception to July 1, 2022. We utilized search terms of “dexmedetomidine,” “cognition,” “cognitive,” “dementia,” “postoperative cognitive dysfunction,” “cognitive dysfunction,” “postoperative,” “fracture,” “limb fracture,” “lower limb fracture,” “upper limb fracture,” “random,” “randomized,” “randomly” “allocated,” “placebo,” “clinical trial,” “controlled study.” The detailed search strategy of PubMed was presented in Table 1. In addition, reference lists of included trials were manually identified for relevance and suitability.
Table 1 -
Search strategy of PUBMED.
| Number |
Search terms |
| 1 |
Postoperative cognitive dysfunction |
| 2 |
Cognition |
| 3 |
Cognitive |
| 4 |
Dementia |
| 5 |
Cognitive dysfunction |
| 6 |
Postoperative |
| 7 |
Limb fracture |
| 8 |
Or 1–7 |
| 9 |
Dexmedetomidine |
| 10 |
Alpha-2 agonist |
| 11 |
Or 9–10 |
| 12 |
Clinical trial |
| 13 |
Controlled trial |
| 14 |
Case-control study |
| 15 |
Randomized |
| 16 |
Random |
| 17 |
Allocated |
| 18 |
Placebo |
| 19 |
Or 12–18 |
| 20 |
8 AND 11 AND 19 |
2.3. Eligibility criteria
1.2.3. Inclusion criteria.
All eligible studies met the following criteria: Published RCTs of dexmedetomidine on POCD; Patients aged over 65 years; Patients were diagnosed with a fracture; Subjects in the treatment group underwent general anesthesia (GA) and dexmedetomidine, whereas those in the control group received GA and normal saline or GA alone; and Full article was available.
Studies were excluded if they met the following criteria: Studies of duplicates, irrelevant studies, not clinical trial, wrong comparison, not RCT and quasi-RCT; Study patients underwent managements other than GA and dexmedetomidine in the treatment group; and Studies with insufficient data.
2.4. Outcome measurements
Primary outcome included mini-mental state examination (MMSE).[31,32] This tool covers 7 domains, consisting of 30 items. Each item ranges from 0 to 1, and the total score ranges from 0 to 30, with a lower score indicating worse condition.[31,32] Secondary outcomes consisted of total occurrence rate of POCD (TORPOCD), occurrence rate of delirium (ORD), visual analogue scale (VAS) and occurrence rate of adverse events (ORAE). The scale of VAS ranges from 0 (no pain) to 10 (worst pain), with a higher score indicating worse pain intensity.[33]
2.5. Study selection and data extraction
Two authors (TZ and QZ) independently carried out study selection and data extraction. Any disagreement was resolved by a third author (JL or YC) through discussion to reach a consensus. All records were identified by screening titles/abstracts and irrelevant records were eliminated. Then, full text of remaining papers was cautiously read against the eligibility criteria. Data extraction was performed based on the previously defined data extraction sheet. It included the title, first author, publication time, country/region, age, gender, sample size, study design information, interventions, controls, outcomes, results, and findings.
2.6. Risk of bias assessment
Two authors (TZ and QZ) independently assessed risk of bias of all included RCTs using Cochrane risk of-bias tool through 7 domains. Each 1 was further rated as low, unclear or high risk of bias. Any divergence was solved through discussion by a third author (X-FL).
2.7. Statistical analysis
RevMan 5.3 (Cochrane Collaboration, London, UK) was used to perform statistical analysis in this study. Continuous data were calculated using mean difference (MD) and 95% confidence interval (CI), and dichotomous data were expressed using odds ratio (OR) and 95% CI. Statistical heterogeneity across eligible RCTs were explored using I² test as follows: I² <50% signified reasonable heterogeneity and the data were pooled using a fixed-effects model, while I² ≥50% denoted substantial heterogeneity and the data were synthesized using a random-effects model. We conducted a meta-analysis based on the sufficient available data on the same outcome.
3. Results
3.1. Trial selection results
In the initial record search, a total of 250 literature was searched (Fig. 1). After removing duplicates and irrelevant studies, we carefully read 46 articles with full papers (Fig. 1). Then, 36 articles were excluded because of not clinical trial (n = 1), combined other disorder (n = 1), wrong comparison (n = 27), not RCTs (n = 5) and quasi-RCTs (n = 2). Finally, 10 eligible RCTs were included in this study[21–30] (Fig. 1).
;)
Figure 1.: Flowchart of trial selection.
3.2. Trial characteristics
The characteristics of the included trials are listed in Table 2. This study included a total of 10 eligible trials involving 969 elderly subjects with fracture. It shows detailed information on each eligible trial, comprising of first author, year of publication, sample size, fracture location, year, administrations for treatment and control patients, and outcomes.
Table 2 -
General characteristics of included trials.
| Study |
No. of patients (T/C) |
Fracture location |
Age (yr, T/C) |
Treatment |
Control |
Outcomes |
| Chen 2021[21]
|
30/30 |
Hip |
T:71.2 ± 10.9; C: 70.2 ± 13.3 |
GA plus dexmedetomidine |
GA plus NS |
① ② ③ ④ ⑤ |
| Du 2020[22]
|
107/107 |
Femur |
T:68.9 ± 4.5; C: 69.8 ± 5.2 |
GA plus dexmedetomidine |
GA plus NS |
① ⑤ |
| Huang 2021[23]
|
75/75 |
Femur |
T:69.8 ± 4.3; C: 69.8 ± 4.3 |
GA plus dexmedetomidine |
GA plus NS |
① ④ |
| Li 2019[24]
|
35/35 |
Lower limb |
70 ± 7 |
GA plus dexmedetomidine |
GA |
① ④ ⑤ |
| Li 2021[25]
|
36/36 |
Upper and lower limb |
T:67.5 ± 2.2; C: 67.1 ± 2.6 |
GA plus dexmedetomidine |
GA plus NS |
① |
| Li 2022[26]
|
25/25 |
Femur |
T:71.9 ± 3.0; C: 70.6 ± 2.9 |
GA plus dexmedetomidine |
GA |
① ③ ⑤ |
| Luo 2021[27]
|
60/61 |
Thoracolumbar spine |
T:69.2 ± 5.7; C: 69.5 ± 5.5 |
GA plus dexmedetomidine |
GA plus NS |
① ④ |
| Ma 2022[28]
|
40/40 |
Lower limb |
T:73.1 ± 5.9; C: 73.3 ± 5.8 |
GA plus dexmedetomidine |
GA |
① ④ ⑤ |
| Mao 2019[29]
|
30/30 |
Femur |
T:71.5 ± 5.0; C: 73.5 ± 5.6 |
GA plus dexmedetomidine |
GA plus NS |
① |
| Qin 2020[30]
|
46/46 |
Femur |
T:58.7 ± 6.3; C: 59.1 ± 6.5 |
GA plus dexmedetomidine |
GA plus NS |
① ② ⑤ |
C = control group, GA = general anesthesia, NS = normal saline, T = treatment group.
① Mini-mental state examination; ② total occurrance rate of postoperative cognitive dysfunction; ③ occurrence rate of delirium; ④ visual analogue scale; ⑤ occrrence rate of adverse events.
3.3. Risk of bias assessment
Risk of bias of all included RCTs was assessed using Cochrane risk of-bias tool[21–30] (Fig. 2). All 10 eligible RCTs reported sufficient randomization details, incomplete outcome data, selective reporting, and other bias.[21–30] However, all of them failed to provide sufficient information on allocation concealment, blinding to participants and investigators, and outcome assessment.[21–30]
Figure 2.: Risk of bias summary.
3.4. Meta-analysis of MMSE
Ten trials with 969 patients investigated the effectiveness of dexmedetomidine on MMSE at 1-day, 3-day and 7-day post-surgery.[21–30] Meta-analysis result showed statistically significant difference at 1-day post-surgery (7 studies with 655 patients, MD = 2.17; random 95% CI, 1.06, 3.28; P < .001; I²=98%; Fig. 3), 3-day post-surgery (8 studies with 778 patients, MD = 2.70; random 95% CI, 1.51, 3.89; P < .001; I²=98%; Fig. 3), and 7-day post-surgery (5 studies with 442 patients, MD = 1.21; random 95% CI, 0.50, 1.93; P < .001; I²=86%; Fig. 3) between the 2 groups.
Figure 3.: Meta-analysis of MMSE. MMSE = mini-mental state examination.
3.5. Meta-analysis of TORPOCD
Two trials involving 152 patients investigated TORPOCD. Statistically significant difference on TORPOCD (OR = 0.26; fixed 95% CI, 0.11, 0.60; P = .002; I²= 0%; Fig. 4) was detected between the 2 groups.
Figure 4.: Meta-analysis of TORPOCD. TORPOCD = total occurrence rate of postoperative cognitive dysfunction.
3.6. Meta-analysis of ORD
Two eligible trials with 110 patients assessed ORD. Meta-analysis result showed a significant difference on ORD (OR = 0.29; fixed 95% CI, 0.11, 0.78; P = .01; I²= 0%; Fig. 5).
Figure 5.: Meta-analysis of ORD. ORD = occurrence rate of delirium.
3.7. Meta-analysis of VAS
Five studies involving 481 patients evaluated VAS. Significant differences were identified between 2 types of managements on VAS (MD = −1.23; random 95% CI, −1.74, −0.72; P < .001; I²=95%; Fig. 6).
Figure 6.: Meta-analysis of VAS. VAS = visual analogue scale.
3.8. Meta-analysis of ORAE
Six trials involving 566 patients explored ORAE. The meta-analysis result showed significant difference on ORAE (OR = 0.32; fixed 95% CI, 0.20, 0.50; P < .001; I²= 0%; Figure 7).
Figure 7.: Meta-analysis of ORAE. ORAE = occurrence rate of adverse events.
4. Discussion
POCD is one of the common complications of GA in patients undergoing surgery, which can prolong the recovery time, increase disability and mortality, and decrease the quality of life. At present, although age, immunosuppression and anesthesia modality are reported as risk factors of POCD, its specific pathogenesis has not been fully elucidated.[34,35] Therefore, the appropriate and effective anesthesia choice for elderly patients with postoperative recovery to reduce the incidence of POCD is very important.
Dexmedetomidine is a α2 receptor agonist that is effective against sedation and analgesia. It works quickly by inhibiting sympathetic nervous system activity and glutamate concentration, reducing stress injury to the brain protects the brain tissue and keeps it hemodynamics stable during surgery, which can greatly reduce pain, risk of proceeding with POCD and delirium.[36] Previous studies have explored the effectiveness of dexmedetomidine on POCD in elderly patients with fracture. However, no systematic review and meta-analysis has comprehensively investigated this topic.
In this study, a total of 10 eligible trials involving 969 elderly subjects with fracture undergoing surgery. We synthesized and analyzed outcome data of MMSE, TORPOCD, ORD, VAS and ORAE. There were significant differences on MMSE at 1-day post-surgery (MD = 2.17; random 95% CI, 1.06, 3.28; P < .001; I²=98%), 3-day post-surgery (MD = 2.70; random 95% CI, 1.51, 3.89; P < .001; I²=98%), and 7-day post-surgery (MD = 1.21; random 95% CI, 0.50, 1.93; P < .001; I²=86%), TORPOCD (OR = 0.26; fixed 95% CI, 0.11, 0.60; P = .002; I²= 0%), ORD (OR = 0.29; fixed 95% CI, 0.11, 0.78; P = .01; I²= 0%), VAS (MD = −1.23; random 95% CI, −1.74, −0.72; P < .001; I²=95%), and ORAE (OR = 0.32; fixed 95% CI, 0.20, 0.50; P < .001; I²= 0%) between the 2 modalities. These results indicated that dexmedetomidine was more effective in relieving MMSE, TORPOCD, ORD, VAS and ORAE.
The present study may suffer from several limitations. First, the overall quality of included trials is not too high, which may have affected our results. Second, the sample size of most included RCTs is pretty small, which may have impacted this study. Third, all studies were carried out in China and were published in Chinese journals, which may have increased risk of publication bias in this study. Finally, this study only assessed outcomes in a short term within 7 days after surgery. Thus, long-term assessment is still needed in the further studies.
5. Conclusion
This study demonstrated that dexmedetomidine could relieve POCD in elderly patients with fracture. However, the present findings should be cautiously applied because the overall quality of included trials is not too high.
Author contributions
Conceptualization: Ting Zeng, Jie Lv, Yang Cui, Qi Zhang.
Data curation: Ting Zeng, Jie Lv, Yang Cui, Xue-Feng Li, Qi Zhang.
Formal analysis: Ting Zeng, Jie Lv, Xue-Feng Li, Qi Zhang.
Investigation: Qi Zhang.
Methodology: Ting Zeng, Jie Lv, Yang Cui, Xue-Feng Li, Qi Zhang.
Project administration: Qi Zhang.
Resources: Ting Zeng, Jie Lv, Yang Cui, Xue-Feng Li.
Software: Ting Zeng, Yang Cui, Xue-Feng Li.
Supervision: Qi Zhang.
Validation: Jie Lv, Yang Cui, Xue-Feng Li, Qi Zhang.
Visualization: Jie Lv, Yang Cui, Xue-Feng Li, Qi Zhang.
Writing – original draft: Ting Zeng, Qi Zhang.
Writing – review & editing: Ting Zeng, Jie Lv, Yang Cui, Qi Zhang.
References
[1]. Desai R, Patel K, Krishnan S, et al. Postoperative cognitive dysfunction in the elderly: a role for modafinil. Cureus. 2022;14:e26204.
[2]. Wang W, Ma Y, Liu Y, et al. Effects of dexmedetomidine anesthesia on early postoperative cognitive dysfunction in elderly patients. ACS Chem Neurosci. 2022;13:2309–14.
[3]. Tan XX, Qiu LL, Sun J. Research progress on the role of inflammatory mechanisms in the development of postoperative cognitive dysfunction. Biomed Res Int. 2021;2021:3883204.
[4]. Xiao QX, Liu Q, Deng R, et al. Postoperative cognitive dysfunction in elderly patients undergoing hip arthroplasty. Psychogeriatr. 2020;20:501–9.
[5]. Deiner S, Luo X, Lin HM, et al. Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing major elective noncardiac surgery: a randomized clinical trial. JAMA Surg. 2017;152:e171505.
[6]. Brown CT, Deiner S. Perioperative cognitive protection. Br J Anaesth. 2016;117(suppl 3):iii52–61.
[7]. Urits I, Orhurhu V, Jones M, et al. Current perspectives on postoperative cognitive dysfunction in the ageing population. Turk J Anaesthesiol Reanim. 2019;47:439–47.
[8]. Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ispocd1 study. Ispocd investigators. International study of post-operative cognitive dysfunction. Lancet. 1998;351:857–61.
[9]. Johnson T, Monk T, Rasmussen LS, et al. Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology. 2002;96:1351–7.
[10]. Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008;108:18–30.
[11]. Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a
systematic review. Anesth Analg. 2006;102:1255–66.
[12]. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–81.
[13]. Carro E, Trejo JL, Spuch C, et al. Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer’s like neuropathology in rodents: new cues into the human disease? Neurobiol Aging. 2006;27:1618–31.
[14]. Zhang Y, Bao HG, Lv YL, et al. Risk factors for early postoperative cognitive dysfunction after colorectal surgery. BMC Anesthesiol. 2019;19:6.
[15]. Song B, Li Y, Teng X, et al. The effect of intraoperative use of dexmedetomidine during the daytime operation vs the nighttime operation on postoperative sleep quality and pain under general anesthesia. Nat Sci Sleep. 2019;11:207–15.
[16]. Su X, Meng ZT, Wu XH, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016;388:1893–902.
[17]. Lin X, Chen Y, Zhang P, et al. The potential mechanism of postoperative cognitive dysfunction in older people. Exp Gerontol. 2020;130:110791.
[18]. Endesfelder S, Makki H, von Haefen C, et al. Neuroprotective effects of dexmedetomidine against hyperoxia-induced injury in the developing rat brain. PLoS One. 2017;12:e0171498.
[19]. Li Y, He R, Chen S, et al. Effect of dexmedetomidine on early postoperative cognitive dysfunction and peri-operative inflammation in elderly patients undergoing laparoscopic cholecystectomy. Exp Ther Med. 2015;10:1635–42.
[20]. Li WX, Luo RY, Chen C, et al. Effects of propofol, dexmedetomidine, and midazolam on postoperative cognitive dysfunction in elderly patients: a randomized controlled preliminary trial. Chin Med J (Engl). 2019;132:437–45.
[21]. Chen ZL, Li ZW, Li SJ. Effects of dexmedetomidine on postoperative cognitive function, cerebral oxygen metabolism and delirium in elderly patients with hip fracture. Hainan Med. 2021;32:2762–5.
[22]. Du J, Li J, He L, et al. Effect of dexmedetomidine on early cognitive function and recovery after total hip arthroplasty in elderly patients with osteoporosis and femoral neck fracture. Chin J Front Med (electronic edition). 2020;12:67–70.
[23]. Huang HM, Xu SC. Effects of dexmedetomidine on Hemodynamics, postoperative cognitive function and stress response in elderly patients with intertrochanteric fractures. Chin J Gerontol. 2021;41:4971–3.
[24]. Li XM, Li J, Li DK, et al. Effects of dexmedetomidine-assisted general anesthesia on postoperative cognitive function and immune function in elderly patients with lower extremity fracture. Chin Med. 2019;14:91–5.
[25]. Li XL. Effect of continuous infusion of dexmedetomidine on postoperative cardiac function and anesthetic effect in elderly patients with coronary heart disease and limb fracture. Med Theory Pract. 2021;34:1528–30.
[26]. Li HF, Xu YQ, Zhu RF. Evaluation of the effect of dexmedetomidine after operation in elderly patients with intertrochanteric fracture of femur complicated with diabetes mellitus. Shenzhen J Integr Chin Western Med. 2022;32:12–5.
[27]. Luo K, Wang YS, Lei MW, et al. The neuroprotective effect of dexmedetomidine in the elderly patients with thoracolumbar fractures after internal fixation. Gerontol Health. 2021;27:834–7.
[28]. Ma HL. Effects of dexmedetomidine-assisted general anesthesia on postoperative cognitive function and immune function in elderly patients with lower extremity fracture. Syst Med. 2022;7:75–9.
[29]. Mao GT. Effect of Dexmedetomidine on Early Postoperative Cognitive Function in Elderly Patients with Femoral Shaft Fracture. Jinlin, China: Jilin University; 2019.
[30]. Qin MJ, Zhang ZJ. Effect of lumbar block anesthesia with dexmedetomidine on postoperative cognitive function in patients with intertrochanteric fracture of femur. Northwestern Pharm J. 2020;35:426–30.
[31]. Horton AM Jr, Alana S. Validation of the mini-mental state examination. Int J Neurosci. 1990;53:209–12.
[32]. Aytaç I, Güven Aytaç B, Demirelli G, et al. Comparison of postoperative cognitive decline using the mini-mental state examination and Montreal cognitive assessment after minor elective surgery in elderly. Cureus. 2021;13:e18631.
[33]. Hawksley H. Pain assessment using a visual analogue scale. Prof Nurse. 2000;15:593–7.
[34]. Zhang GF, Yang P, Wang Q, et al. Effect of perioperative continuous femoral nerve block on postoperative cognitive impairment in elderly patients with femoral neck fracture. Chin J Anesthesiol. 2018;38:66–9.
[35]. Ye J. Effects of propofol combined with sevoflurane on perioperative oxidative stress and postoperative cognitive function in elderly patients with femoral neck fracture complicated with mild cognitive impairment. Shaanxi Med J. 2019;48:1298–301.
[36]. Zuo D, Zhou M. Application of ultrasound-guided lumbar plexus combined with paracral sciatic nerve block in internal fixation of femoral neck fracture in elderly patients. J Trauma Surg. 2017;19:503–7.
