To the Editor: Delirium is a common postoperative complication associated with multiple adverse clinical outcomes in older patients.[1] According to the time of onset, delirium in the postoperative stage can be divided into emergence delirium (ED) and postoperative delirium (POD). ED occurs during or immediately after awakening from general anesthesia, whereas POD is usually found during postoperative days 1–7. Assessing patients for ED provides the first clue of a possible postoperative neurocognitive disorder.[2] Dexmedetomidine (DEX) is a highly selective α-2 receptor agonist that is increasingly used in the perioperative period to induce sedation, analgesia, anxiolysis, and sympathetic tone suppression. Previous studies suggested that DEX may be an effective intraoperative adjuvant drug, which can reduce agitation and improve recovery after orthopedic surgery in older patients.[3,4] However, few studies focused on the relationships between DEX and ED. This randomized controlled trial (RCT) aims to explore the relationships between intraoperative DEX administration and the incidence of ED in older patients undergoing lower limb orthopedic surgery, and examine the effects of DEX on the electroencephalogram (EEG) trajectories of older patients during the emergence period and its correlation with ED occurrence. We analyzed 240 older patients who aged ≥60 years (DEX-group, n = 120; saline [SA] group, n = 120). The confusion assessment method for the intensive care unit and the Richmond Agitation and Sedation scale were used to evaluate the occurrence of delirium during emergence. We also recorded and analyzed EEG trajectories during awakening, compared the differences in emergence trajectories between the two groups, and explored possible mechanisms. This study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. PJ2021-14-16). The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2100053491, Date of registration: November 22, 2021). Written informed consent were obtained from all the participants or their legal representatives. The inclusion criteria were as follows: aged ≥60 years, body mass index (BMI) 18–30 kg/m2, older patients scheduled to undergo lower extremity orthopedic surgery under general anesthesia combined with nerve block anesthesia. The exclusion criteria were as follows: (1) refused to participate in the study; (2) diagnosed with a psychiatric disease; (3) preoperative cognitive impairment (defined as Mini-CogTM score ≤2), language barrier, or inability to communicate; (4) preoperative history of chronic pain or opioid abuse; (5) oral intake of levodopa, donepezil hydrochloride, and antidepressants; or history of stroke or brain tumor; and (6) inability to complete the neuropsychological tests. DEX or SA were diluted in 0.9% saline up to a volume of 50 mL in identical syringes yielding a concentration of DEX of 1 µg/mL. Each group of patients received DEX or saline 0.4 mL/kg loading volume (pumped within 15 min), etomidate 0.2 mg/kg, sufentanil 0.4–0.5 μg/kg, and cis-atracurium 0.15–0.20 mg/kg for anesthesia induction. After the patients lost consciousness and the muscle relaxation was satisfactory, a laryngeal mask was placed. Tidal volume (6–8 mL/kg) and inspiratory ratio (1:2) were set to maintain end-tidal carbon dioxide at 35–45 mmHg. Combined with a lower extremity nerve block, DEX or saline 0.3 mL·kg−1·h−1, remifentanil 0.1–0.3 μg·kg−1·min−1, and propofol 4–6 mg·kg−1·h−1 were used to maintain the depth of anesthesia (anesthesia index [Ai]) at 40–60 in each group. DEX and SA stopped 20 min before the end of the surgery. At the end of the operation, the patients were transferred to the post-anesthesia care unit (PACU) after spontaneous breathing was restored. The patients received the standard emergence program after stopping the anesthetic drugs to minimize external stimuli (such as noise and oral sputum suction) during the emergence period. EEG data for the whole emergence period (from the cessation of intravenous anesthetics to PACU discharge) were extracted and analyzed. For each patient, the EEG spectrograms were computed using the multi-taper method implemented in Chronux toolbox. The time-series plots of α (8–12 Hz) and δ (1–4 Hz) peak power were extracted from the EEG spectrogram. Then, the hypnograms depicting changes in these states over time were evaluated to determine emergence trajectories. Hypnograms were drawn using three types of anesthesia: non-slow-wave anesthesia (nSWA), δ-dominant slow-wave anesthesia (ddSWA), and α-dominant slow-wave anesthesia (adSWA). nSWA was defined as both δ and α power ≤7 dB; otherwise, δ or α power >7 dB, and ddSWA and adSWA were defined as δ power >α power and δ power ≤α wave power, respectively. Spectrograms with corresponding hypnotic maps were visually assessed by the observer. Patients must remain in a specific state (such as ddSWA, adSWA, or nSWA) for at least 60 s to be included in the appropriate trajectory category: (1) ddSWA to adSWA to nSWA to wake, (2) ddSWA to nSWA to wake, (3) adSWA to nSWA to wake, (4) ddSWA to adSWA to wake, (5) ddSWA to wake, (6) adSWA to wake, and (7) nSWA to wake [Supplementary Figure 1, https://links.lww.com/CM9/C58].[5] Continuous variables were compared using the unpaired two-tailed t-test or the Mann–Whitney test, and categorical variables were compared using the chi-squared test or Fisher's exact test. Correlation between ED and POD was performed as a post hoc exploratory analysis based on a univariable logistic regression model. P <0.05 was statistically significant. Statistical analysis was performed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA). A total of 260 participants were randomly allocated to the group [Supplementary Figure 2, https://links.lww.com/CM9/C58]. No statistically significant differences in the basic characteristic data, surgery type, and duration of surgery or anesthesia were found between the two groups [Supplementary Table 1, https://links.lww.com/CM9/C58]. Intraoperative data (including anesthetic or vasoactive drug use) did not differ significantly between the two groups [Supplementary Table 2, https://links.lww.com/CM9/C58]. According to the modified intention-to-treat analysis (n = 246), ED occurred in 23.39% (29/124) of cases in the DEX group and in 36.07% (44/122) of cases in the SA group (P = 0.030). According to the per-protocol analysis (n = 240), the DEX group had a lower incidence of ED than the SA group (24.17% [29/120] vs. 36.67% [44/120], P = 0.035) [Supplementary Table 3, https://links.lww.com/CM9/C58]. Despite the lack of difference in the patterns of emergence trajectory between the two groups (P = 0.173), more patients in the SA group experienced a similarly sudden transition from the slow-wave sleep (include emergence trajectories ddSWA to [adSWA], ddSWA, or adSWA) directly to wakefulness (P = 0.033) [Supplementary Table 4, https://links.lww.com/CM9/C58]. Postoperative plasma concentrations of interleukin (IL)-6, IL-8, tumor necrosis factor-α, and C-reactive protein increased significantly in both groups although the incremental change was significantly smaller in the DEX group (P <0.001) [Supplementary Figure 3, https://links.lww.com/CM9/C58]. Exploratory analysis showed a significant correlation between ED and POD (odds ratio [OR]: 8.60, 95% confidence interval [CI]: 3.75–19.72, P <0.001). Our results suggested that intraoperative use of DEX in older patients who underwent joint replacement (including knee and hip) reduced the incidence of ED but did not reduce the incidence of POD during the first 3 days after surgery. These results may support the adjuvant use of DEX for smooth emergence from anesthesia and further evaluation of the potential of DEX to reduce long-term cognitive dysfunction in older patients.[6] DEX reduced the levels of inflammatory factors after surgery. However, few patients in the DEX group experienced a similarly sudden transition from slow-wave anesthesia (include emergence trajectories ddSWA to adSWA, ddSWA, or adSWA) directly to wakefulness. The occurrence of ED was independently associated with an increased risk of developing POD. The possible mechanism by which DEX reduces ED in elderly patients is related to the reduction of perioperative inflammatory response in the DEX group and its effect on the emergence trajectory of EEG during the recovery period. The emergence trajectory of an abrupt transition from SWA to wakefulness can be compared to arousal during non-rapid eye movement (NREM) sleep. It was demonstrated to be often associated with parasomnias or sleep disturbances resulting from fragmented sleep.[7] Consistent with the common characteristics between sleep and anesthesia, the transition from deep sleep to wakefulness can also be observed in some NREM sleep abnormalities, such as, night terrors or sleepwalking.[8] In our research, more subjects of control group emerging from general anesthesia were observed to move progressively from SWA to awake [38 (50.7%) vs. 27 (33.8%)].The patients who spent emergence time less in nSWA were more likely to have severe pain, and express a degree of agitation in recovery.[9] The "non-preferred" type of emergence trajectory in which the brain transitions directly from SWA to waking status, as compared with the sleepness status, would characterize as a parasomnic or less desirable trajectory and re-establish conscious awareness.[10] This may be one of the explanations for a larger number of patients with ED in the control group during postoperative recovery. Whether effective measures to prevent ED can reduce POD and improve perioperative outcomes remains to be further validated by more high-quality RCT studies in the future.Our observations could help anesthesiologists identify patients at ED risks before the patients fully emerge from general anesthesia. Intraoperative EEG monitoring can provide a method to predict and prevent delirium in PACU, thereby improving postoperative prognosis. To summarize, further researches on the delirium interventions of the patients with delirium-related EEG patterns need to be explored. Funding This work is partially supported by grants from National Natural Science Foundation of China (Nos. 81870841 and 82171192). Conflicts of interest None.
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