Effect of dexmedetomidine on postoperative delirium in patients undergoing type A aortic dissection surgery: a prospective cohort study

Introduction

Background

Delirium is a complex symptom group characterized by an acute change in state of mind, manifesting a range of cognitive and behavioral clinical features. These symptoms encompass disturbances in consciousness (such as decreased orientation to the environment), impaired attention (such as decreased ability to focus, shift, and maintain attention), and cognitive disorders (such as disorientation, reduced language, visuospatial abilities, and perceptual abilities) (1). Postoperative delirium (POD) is one of the most common neurocognitive complications after cardiac surgery, which is usually related to delayed functional recovery, long-term cognitive decline, and increased mortality. Additionally, it prolongs intensive care unit (ICU) stays and incurs additional healthcare costs (2,3). It is reported that the occurrence rate of POD following cardiac surgery is estimated at 6–46% (3-6). POD in cardiac surgery is influenced by various patient-specific factors, including dangerous factors such as advanced age, atrial fibrillation (AF), cerebral vascular diseases, diabetes mellitus, and chronic renal disease, as well as inciting factors such as anesthetic medications, intraoperative deep hypothermic circulatory arrest (DHCA), low cardiac output, use of extracorporeal circulation, and perioperative medications (particularly benzodiazepines) (7-9). Cardiac surgery and cardiopulmonary bypass (CPB) activate the sympathetic system, with the consequent systemic inflammation and metabolic changes leading to delirium. Other mechanisms can also lead to the emergence of delirium (10).

Rationale and knowledge gap

Type A aortic dissection (TAAD) represents a highly critical surgical disease necessitating prompt intervention. Despite improvements in surgical and anesthetic techniques, surgical mortality and complications remain significant (11-13). Compared to patients undergoing other cardiac surgeries, TAAD patients are more prone to experiencing neuropsychiatric complications, which can negatively impact postoperative outcomes. This disparity arises from the preoperative neurological dysfunction frequently observed in TAAD patients, along with poor intraoperative cerebral perfusion and cerebral and nervous system ischemia induced by hypothermia (14,15).

Dexmedetomidine, an effective and exceptionally selective α2 adrenoceptor activator, exhibits sympatholytic and anti-inflammatory effects, as well as anti-anxiety, sedation, and mild analgesic properties, yet with minimal respiratory depression (16-19). A previous study (5) showed that prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first seven days after surgery in patients aged over 65 years who are admitted to the ICU after non-cardiac surgery. A randomized placebo-controlled trial (DECADE) published in the Lancet in 2020 showed that dexmedetomidine infusion, which was initiated during anesthesia induction and continued for 24 hours, did not decrease postoperative atrial arrhythmia or delirium in patients recovering from cardiac surgery (10). Then, a recent meta-analysis demonstrated that perioperative dexmedetomidine administration in heart surgery patients decreased the occurrence rate of POD, although it may increase the occurrence of bradycardia (20). Furthermore, a retrospective analysis indicated that postoperative dexmedetomidine infusion in patients accepting TAAD surgery significantly decreased the risk of critical severe acute renal injury, with a comparable occurrence rate of POD between the two groups (13). However, POD was not the main outcome in this retrospective analysis, and the impact of POD on TAAD patients was not further explored.

Objective

Currently, there is a shortage of prospective evidence regarding the impact of dexmedetomidine on POD in TAAD patients, and the research advances and implications of POD remain unclear. Therefore, this study aimed to discuss the effect of intraoperative dexmedetomidine infusion on POD in patients undergoing TAAD surgery. We hypothesize that intraoperative dexmedetomidine administration in patients accepting TAAD surgery will mitigate the risk of POD and improve overall prognosis. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1219/rc).

Methods

Research design and ethics

We conducted a prospective, single-center, observational cohort study at the Affiliated Drum Tower Hospital, Medical School of Nanjing University. The study was conducted by the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of Nanjing Drum Tower Hospital (approval No. 2022-034-01). Each participant provided written informed consent before being included in the study. The trial was registered with the Chinese Clinical Trials Registry before the start of the trial (ChiCTR2200055980).

Patients

This study enrolled patients diagnosed with TAAD based on computed tomography (CT) angiography and scheduled for surgery. The inclusion period spanned from February 2022 to March 2023, and patients aged 18 to 85 years were eligible for participation. The exclusion criteria were as follows: (I) preoperative coma or inability to communicate due to severe vision or hearing impairment; (II) previous mental illness, cerebrovascular disease, or craniocerebral trauma; (III) preoperative sick sinus syndrome, atrioventricular block, sinus bradycardia; (IV) severe liver dysfunction (Child-Pugh C) or severe renal insufficiency (dialysis before surgery); (V) allergy to α2-adrenergic agonists or opioids or allergic to dexmedetomidine; (VI) recent use of sedatives, antidepressants, or immunosuppressive drugs; (VII) history of emergency surgery; (VIII) perioperative death; (XI) incomplete data collection.

Therapeutic procedures

The decision to use dexmedetomidine was based on the anesthesia treatment strategy determined by the anesthesiologist. Patients who took dexmedetomidine during the operation were assigned to the dexmedetomidine group, whereas those who did not take the drug were assigned to the control group. Intravenous infusion of dexmedetomidine was initiated immediately following CPB in the dexmedetomidine group. The administration of dexmedetomidine involved diluting 50 mL of normal saline to a final concentration of 4 µg/mL before injection, then the drug delivery was slowly administered at a dose of 1 µg/kg for more than 10 minutes. Subsequently, a maintenance dosage of 0.2–0.7 µg/kg/h was infused. If the patient’s hemodynamics were unstable, the injection dose was omitted. The infusion of dexmedetomidine was continued until the end of the surgery. Other positive inotropic drugs and vasopressors were administered as part of the routine treatment strategy. The same treatment approach was employed for patients in the control group, except for the exclusion of dexmedetomidine.

Study endpoint

POD evaluation and postoperative data recording were performed through regular rounds of the ICU. The primary outcome was delirium within five days after surgery. Delirium was evaluated twice using the confusion assessment method (CAM) between 8 and 10 am and 4 and 8 pm by the same investigator who had been trained before the research and was not involved in the clinical nursing care of the patient. CAM is a standardized tool that identifies delirium mainly through diagnostic algorithms based on the four main characteristics of delirium: (I) acute episodes of mental state changes or fluctuations; (II) lack of concentration; (III) confused thought; (IV) change of consciousness level. CAM-ICU has at least two features (features 1 and 2+3 or 4), and it is defined as delirium (21).

Secondary outcomes assessed included intubation time, ICU hospitalization time, postoperative hospital stay, the incidence of non-delirium complications (e.g., bradycardia, hypotension, AF), and all-cause mortality within seven days. Non-delirium complications are commonly defined as medical incidents other than mental disorders that require therapeutic intervention during postoperative hospitalization.

Statistical analysis

The sample size estimation was informed by previous studies. In previous research, when dexmedetomidine was used in the ICU for sedating mechanically ventilated patients, the incidence of postoperative confusion was 22.6%, which was a reduction of approximately one-third compared to that of other drugs (5). Based on this, we hypothesized that the incidence of delirium in the dexmedetomidine group would also decrease by one-third. Using PASS 15.0 software (NCSS LLC, Kaysville, UT, USA), we determined that a minimum sample size of 121 patients is required to assess significant differences in the incidence of delirium with a power of 0.90 and an alpha level (α) of 0.05 and a relative risk (RR) of approximately 0.35. To account for a follow-up loss rate of around 20%, we planned to include 152 patients in each group.

Successive variables were described using mean ± standard deviation (SD) or median [interquartile range (IQR)], whereas categorical variables were expressed as the number of patients and corresponding percentages. The normal distribution of the data was tested by the Kolmogorov-Smirnov test, and the successive variables were analyzed by the independent t-test or Mann-Whitney U test. Categorical variables were analyzed by chi-square test or Fisher exact test, and frequency and percentage were reported.

As the large number of prospectively collected confounders adjusted using multivariate regression models challenging, to account for potential confounding factors, we conducted a propensity score matching (PSM) analysis to balance the baseline concomitant variables between the two groups. A 1:1 matching ratio was employed, comparing the probability of receiving dexmedetomidine for each patient with that of patients who did not receive it, with the closest propensity score selected for matching, allowing a difference of ±0.01.

For evaluating the outcome of POD, a logarithmic binomial regression model was constructed, reporting odds ratios (ORs) or hazard ratios (HRs) along with 95% confidence intervals (CIs) to assess the effect size between the dexmedetomidine group and the control group. All bilaterally statistical tests with P<0.05 were deemed statistically significant. Statistical analysis was performed utilizing the software SPSS 26.0 (IBM Corp., Armonk, NY, USA).

Results

During the study period, 181 patients aged 18 to 85 years who underwent surgery for TAAD were carefully selected for inclusion. However, 14 patients were excluded from the study due to specific reasons. Of these excluded patients, 10 required emergency surgery (including six who were in a coma), whereas four had a prior history of chronic kidney disease. As a result, the final cohort included 167 patients for analysis (see Figure 1). To minimize potential biases caused by confounding factors and ensure comparability between groups, we employed PSM analysis. This process generated a dataset of 84 patients, evenly divided into two groups of 42. Importantly, this matching procedure successfully balanced all baseline characteristics between the two groups.

Figure 1 Flowchart of the study. TAAD, type A aortic dissection; BMI, body mass index.

Baseline and characteristics

This study presents the demographic, preoperative, and intraoperative characteristics of eligible patients, as outlined in Table 1. Prior to conducting the PSM analysis, we observed no significant differences in preoperative medical history or surgical information between the two groups. The average age of patients in the dexmedetomidine group was 52.6 years, slightly higher than the average age of 50.1 years in the control group. It is worth noting that there was a higher proportion of patients with island-total replacement surgery in the dexmedetomidine group (P=0.01), whereas there was a higher proportion of patients in the control group who underwent total arch replacement surgery (P<0.01). In addition, patients in the dexmedetomidine group had less blood transfusions during surgery than those in the control group (P=0.04). After performing PSM, the demographic characteristics and preoperative and intraoperative characteristics were effectively balanced between the two groups, and no significant differences were observed (see Table 1).

Outcomes in the pre-matched patients

In the pre-matched patient population, the occurrence of delirium within five days after surgery was 35.0% in the dexmedetomidine group and 42.6% in the control group. Before conducting the PSM analysis, dexmedetomidine had no notable impact on the incidence rate of POD (OR 0.73; 95% CI: 0.37–1.45; P=0.36). Furthermore, there were no significant differences in secondary outcomes such as intubation time, ICU hospitalization time, and hospital stay after operation between the two groups (see Table 2). Subgroup analysis yielded consistent results across various categories, as shown in Figure 2. Regarding non-delirium-related complications, the overall incidence was 38.3% in the dexmedetomidine group and 46.8% in the control group, as detailed in Table 3. However, no statistically significant differences were noted between the two groups.

Figure 2 Forest plot of pre-match. Before PSM analysis, subgroup analysis of delirium in intubation time and postoperative eGFR. The black square indicates the estimated odds ratio, and the line indicates the CI. CI, confidence interval; ICU, intensive care unit; eGFR, estimated glomerular filtration rate; PSM, propensity score matching.

Outcomes in the propensity-matched patients

In the propensity-matched patient cohort, 12 patients (28.6%) in the dexmedetomidine group and 19 patients (45.2%) in the control group experienced POD within five days of the surgery. There was no statistically significant difference between the two groups (OR 0.48; 95% CI: 0.20–1.20; P=0.12). The dexmedetomidine group displayed a trend towards a shorter ICU stay and postoperative hospitalization duration, but there was no statistical significance (P=0.13, P=0.12). Notably, the control group exhibited higher postoperative creatinine levels than the dexmedetomidine group (P=0.04) (see Table 2). In the dexmedetomidine group, the incidence of POD was lower in patients with moderate estimated glomerular filtration rate (eGFR) compared to the control group (P=0.03). However, no significant heterogeneity was found among the other subgroups (see Figure 3). The overall rate of non-delirium complications was 52.4% in the control group and 45.2% in the dexmedetomidine group. Additionally, AF occurred more frequently in the dexmedetomidine group (P=0.14). No significant differences were observed in other adverse events between the two groups (see Table 3).

Figure 3 Forest plot of PSM. After propensity score matching, subgroup analysis of delirium in intubation time and postoperative eGFR. The black square indicates the estimated odds ratio, and the line indicates the CI. CI, confidence interval; ICU, intensive care unit; eGFR, estimated glomerular filtration rate; PSM, propensity score matching.

Discussion

Key findings

Prior to conducting PSM analysis, our initial findings indicated that the intraoperative infusion of dexmedetomidine did not reduce the incidence of POD within five days following TAAD surgery. Furthermore, no statistically significant differences were identified between the two groups regarding intubation time, ICU hospitalization time, or postoperative hospital stay. Subsequently, we performed a 1:1 PSM analysis to further evaluate the outcomes while minimizing potential biases. The outcomes from this analysis reaffirmed that dexmedetomidine did not lower the incidence rate of POD compared to the control group. Additionally, there were no significant differences in intubation time, ICU hospitalization time, postoperative hospital stay, and the occurrence of complications unrelated to POD between the two groups. Overall, these findings suggest that the intraoperative infusion of dexmedetomidine did not yield significant benefits in reducing POD or impacting other relevant outcomes in patients undergoing TAAD surgery.

Explanations of findings

Research exploring the relationship between dexmedetomidine and POD in patients undergoing TAAD surgery is limited, with only one published retrospective study available. This retrospective study found that the occurrence rate of delirium was 22.1% in the dexmedetomidine group compared to 18.4% in the non-dexmedetomidine group. However, it did not specifically focus on the correlation between dexmedetomidine and POD, as POD was considered a secondary outcome. Notably, the study indicated that intraoperative administration of dexmedetomidine after TAAD surgery was likely to significantly reduce the incidence of serious kidney injury and the need for blood dialysis (13). In line with previous research, our current study showed lower rates of POD in the propensity-matched dexmedetomidine group than in the control group (28.6% vs. 45.2%). However, this difference did not reach statistical significance, suggesting that the intraoperative use of dexmedetomidine did not effectively decrease the occurrence rate of POD. Importantly, to our knowledge, no prospective study has previously investigated the impact of dexmedetomidine on POD in aortic dissection surgery, which represents the primary innovation of our investigation.

Comparison with similar researches

Studies evaluating the impact of dexmedetomidine on POD have included patients undergoing various types of heart surgery, such as coronary artery bypass graft (CABG) or valve surgery. For instance, a multicenter randomized controlled trial (RCT) published in the Lancet, which involved 798 patients undergoing cardiopulmonary bypass surgery (including valve-aorta and CABG), found no reduction in the occurrence rate of AF or POD with dexmedetomidine infusion. This deficiency of results may be attributed to the complexity of brain function disorders and the controversial effects of a single drug administration on these disorders (10). A meta-analysis of 10 RCTs conducted a subgroup analysis based on the type of surgery. This analysis showed that dexmedetomidine significantly decreased the occurrence rate of POD in patients undergoing valvular or mixed cardiac surgery (CABG and valvular surgery). In contrast, its preventive effect was diminished when limited to CABG alone. Another study indicated that POD had a higher incidence in heart valve operations compared to coronary artery bypass surgery. This difference may be due to the increased risk of cognitive impairment associated with cerebral microemboli in valve replacement procedures (20). Additionally, evidence suggests that the incidence of mental disorders after heart valve surgery is higher than that following CABG, also attributed to the prevalence of cerebral microemboli (22). Another meta-analysis (6) encompassing 19 studies involving 3,266 patients evaluated the occurrence of POD as the primary outcome. The analysis revealed that patients treated with dexmedetomidine had a lower rate of POD compared to the control group. However, the wide heterogeneity among the included studies limited the efficacy of dexmedetomidine. In studies (23-26) with a high risk of bias excluded, dexmedetomidine did not demonstrate a significant effect.

Researchers have reported various findings regarding the effect of dexmedetomidine on postoperative outcomes. In particular, a study involving elderly patients admitted to the ICU after non-cardiac surgery indicated that dexmedetomidine administration was associated with shorter intubation times and higher early discharge rates (5). Additionally, a RCT revealed that adding dexmedetomidine to standard treatment reduced the need for ventilation in ICU patients with agitated delirium requiring mechanical ventilation within seven days (27). However, a meta-analysis found no significant decrease in the length of postoperative clinic stays, ICU stays, or catheterization times in the dexmedetomidine group (20). A retrospective analysis evaluating the impact of dexmedetomidine on patients with aortic dissection also noted no meaningful differences in ventilation times, ICU hospitalization, overall hospitalization, and medical expenses between the dexmedetomidine and control groups (13). These inconsistencies may be due to factors such as limited sample size or the influence of advanced age on treatment outcomes. Similarly, in line with a previous retrospective study on aortic dissection surgery, our study demonstrated no significant differences in intubation times, postoperative ICU hospitalization time, and postoperative hospitalization time between the dexmedetomidine and control groups. This lack of difference may be related to the complexity of aortic arch repair surgery, which requires specialized techniques for cerebral perfusion and DHCA can significantly impact the function of various organs, particularly the nervous system and kidneys. Consequently, even if dexmedetomidine is administered during the operation, it may not effectively mitigate the complications associated with this intricate procedure (28).

Recent research has shown varying effects on heart rate conditions—tachycardia, bradycardia, and AF—associated with the administration of dexmedetomidine. Wu et al. conducted a meta-analysis involving 1,387 patients and found that a prophylactic intraoperative injection of dexmedetomidine increased the occurrence of bradycardia but did not elevate the risk of hypotension (20). Another study examined intraoperative dexmedetomidine infusion for preventing delirium in elderly patients undergoing significant non-cardiac surgery. This study indicated that although the infusion could reduce the rates of tachycardia and acute agitation, it did increase the likelihood of bradycardia. Notably, patients in the dexmedetomidine group experienced fewer complications unrelated to delirium, particularly surgery-related complications, compared to the control group (29). Additionally, a cohort study involving 8,015 patients demonstrated that dexmedetomidine administration decreased the risk of new-onset atrial fibrillation (NOAF) in emergency patients (30). A randomized placebo-controlled trial with 795 patients indicated that injection of dexmedetomidine could decrease the incidence of AF and delirium following heart surgery. However, the study did not confirm that dexmedetomidine prevented AF (10). In our study, the rates of tachycardia and bradycardia were similar between the dexmedetomidine and control groups. After PSM, the occurrence rate of AF was 14.3% in the dexmedetomidine group compared to 4.8% in the non-dexmedetomidine group. It is important to mention that the incidence of postoperative AF was notably higher in patients undergoing TAAD surgery than in those with general heart disease. However, our study found no effect of dexmedetomidine infusion on the occurrence rate of postoperative AF.

Strengths and limitations

We acknowledge several limitations in our research. Firstly, although we employed PSM to adjust for baseline characteristics, there may still be confounding factors that could affect our outcomes, such as intraoperative use of anesthetic medications, pre-admission medications, and concomitant medications during ICU hospitalization. Additionally, the use of PSM may have resulted in a smaller sample size, which can introduce statistical error. Secondly, since our research was conducted at a single center, the generalizability of our findings to other settings remains uncertain. Thirdly, although delirium was assessed twice daily by well-trained medical professionals, there is a possibility that occurrences of delirium at different times may have been overlooked, including cases of mild cognitive impairment. Lastly, our study focused exclusively on patients undergoing TAAD surgery who received intraoperative dexmedetomidine infusion. We did not investigate the impact of continuing dexmedetomidine or using other sedatives postoperatively, which could potentially affect the incidence of POD. The most important limitation of this study is the lack of randomization. In the future, we need to carry out prospective, randomized, double-blind, and multicenter studies to understand better the prevalence of POD and other clinical outcomes in patients with TAAD.

Conclusions

This prospective observational study demonstrated that intraoperative dexmedetomidine did not decrease the occurrence rate of POD, intubation time, ICU hospitalization time, hospital stay after operation, and the incidence of non-delirium adverse reactions in TAAD patients. Dexmedetomidine’s effect on POD in TAAD will need to be determined through high-quality, large-scale trials in the future.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (82100289), the Natural Science Foundation of Jiangsu Province (BK202104051), the China Postdoctoral Science Foundation (2019M651804), and the Jiangsu Province Capability Improvement Project through Science, Technology and Education (ZDXK202229).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1219/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1219/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1219/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1219/coif). Y.P.W. reports that this research was supported by the foundation of Jiangsu Province Capability Improvement Project through Science, Technology and Education (ZDXK202229). J.X.Y. reports that this research was supported by the foundation of the National Natural Science Foundation of China (82100289), the Natural Science Foundation of Jiangsu Province (BK202104051), China Postdoctoral Science Foundation (2019M651804). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted by the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics committee of Nanjing Drum Tower Hospital (approval No. 2022-034-01). Written informed consent was signed by all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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