
==== Front
Int J Surg
Int J Surg
JS9
International Journal of Surgery (London, England)
1743-9191
1743-9159
Lippincott Williams & Wilkins Hagerstown, MD

IJS-D-23-02907
10.1097/JS9.0000000000001642
00020
3
Original Research
Diurnal variation of postoperative delirium in elderly patients undergoing esketamine anesthesia for elective noncardiac surgery: a randomized clinical trial
Zhang Yuan MM abRM002876@whu.edu.cn

Chen Rong MD, PhD abr.chen-rm@whu.edu.cn

Tang Shan MM b1060925829@qq.com

Sun Tao MM b1406257573@qq.com

Yu Yanli MD bliliyu2012@163.com

Shi Ruoshi MM abshirs1020@163.com

Wang Kai MM abwangk2019@126.com

Zeng Zi MM 732898589@qq.com
ab
Liu Xinhang BN b524563006@qq.com

Meng Qingtao MD, PhD ab*mengqingtao2018@126.com

Xia Zhongyuan MD, PhD abxiazhongyuan200501@126.com

a Department of Anesthesiology, Renmin Hospital of Wuhan University
b Department of Anesthesiology, East Hospital, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
* Corresponding author. Address: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, People’s Republic of China. Tel.: +86 139 955 695 60. E-mail: mengqingtao2018@126.com (Q.T. Meng).
9 2024
28 5 2024
110 9 54965504
13 12 2023
6 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Background:

Postoperative delirium (POD) is a serious and common complication. The aim of present study is to investigate the diurnal variation of POD and the effects of esketamine in elderly patients.

Methods:

A randomized, double-blind, placebo-controlled clinical trial with factorial design was conducted. Patients (aged 65 to 85 years) with normal Mini-Mental State Examination (MMSE) score were stratified by age (≤70 vs. >70) and American Society of Anesthesiologists physical status classification (Ⅱ vs. Ⅲ), then randomly assigned to either morning (08:00–12:00) or afternoon (14:00–18:00) noncardiac operation under general anesthesia with or without esketamine administration (0.2 mg/kg). The primary outcome was the incidence of POD (3-Minute Diagnostic Interview for Confusion Assessment Method-defined Delirium, 3D-CAM) on postoperative days 1, 3, and 7. The secondary outcomes were the scores of MMSE and Hospital Anxiety and Depression Scale. The intention-to-treat analysis of the outcomes were performed by generalized estimating equation.

Results:

Six patients who did not receive an intervention because of canceled operation were excluded after randomization. The datasets containing 426 cases were analyzed following the intention-to-treat principle after handling missing data via multiple imputation method. The incidence of POD declined from about 55% on postoperative day 1 to 31 and 18% on postoperative days 3 and 7, respectively. Afternoon operation [B=−0.583, OR (95% CI) 0.558 (0.319–0.976); P=0.041], but not esketamine, significantly decreased the incidence of POD. Both esketamine and operation time failed to significantly affect MMSE, HAD, and NRS score. There was no interaction among operation time, esketamine, and follow up time.

Conclusion:

Elderly patients undergoing elective noncardiac surgery in the afternoon displayed lower POD incidence than those operated in the morning. A single low-dose of esketamine before general anesthesia induction failed to significantly decrease the risk of POD but decrease the risk of intraoperative hypotension and emergence agitation.

Keywords:

diurnal rhythm
elderly patient
esketamine
noncardiac surgery
postoperative delirium
OPEN-ACCESSTRUE
SDCT
==== Body
pmcIntroduction

Highlights

Elderly patients undergoing elective noncardiac surgery in the afternoon displayed lower postoperative delirium incidence than those operated in the morning.

Subanesthesia dose of esketamine did not decrease the incidence of postoperative delirium.

A single dose of esketamine injection before general anesthesia induction decreased the risk of intraoperative hypotension and emergence agitation.

Postoperative delirium (POD) is a serious and common complication in elderly patients. As reported, an overall pooled frequency of POD was 23.8% in adults aged over 60 years undergoing any noncardiac surgery requiring hospitalization. The POD estimates increased between 1995 and 2020 at an average rate of 3% per year1. However, the aetilolgy and pathophysiology of POD have not been described completely, which makes it challenging to prevent and treat.

The diurnal variation has been associated with a multitude of postoperative adverse consequences. Previous study suggested that afternoon surgery could provide perioperative myocardial protection and improve clinical outcomes compared with morning surgery in patients undergoing aortic valve replacement2. Although there was no diurnal variation in perioperative myocardial injury in patients undergoing noncardiac surgery, the incidence of acute myocardial infarction during 1-year follow-up increased in afternoon surgery3. Additionally, a clinically relevant diurnal variation was advocated in the postoperative mortality4 and short-term sleep quality5, the length of stay in post anesthesia care unit (PACU)6 and hospital7, the incidence of postoperative blood transfusion8, delayed extubation and nonhome discharge9. Yet available data on diurnal variation of POD in the ageing population is limited.

The N-methyl-D-aspartate receptor (NMDAR) antagonist esketamine has anesthetic, analgesic, and sympathomimetic properties and is known to cause less cardiorespiratory depression than ketamine. Recent studies have confirmed the clinical effectiveness and safety of low-dose esketamine for general anesthesia (GA) induction and maintain10–12. What is more, esketamine could reduce the incidence of delayed neurocognitive recovery (DNR) and improve early postoperative neurocognition in elderly patients undergoing gastrointestinal surgery13,14. There is growing concern over esketamine on postoperative neurocognition in surgical patients.

It has been well demonstrated that GA may mimic the mechanism involved in adaptation of the molecular clock to changes in entrained conditions, which linked with the inhibition of core clock gene PER2 via NMDAR-related pathway15. Moreover, traumatic brain injury recovery depended on the time of day at which the damage occurred. The circadian rhythmicity of NMDAR subunit NR1 expression in motor cortex is more minimum in rats who subjected to traumatic brain injury during night-time hours16. Thus, we hypothesized that the incidence of POD displayed a diurnal variation in elderly patients undergoing elective noncardiac surgery and sub-anesthetic doses of esketamine could improve postoperative neurocognition.

Methods

Study design and patients

A randomized, double-blind, placebo-controlled clinical trial with factorial design was conducted and reported in line with Consolidated Standards of Reporting Trials (CONSORT, Supplemental Digital Content 1, http://links.lww.com/JS9/C672) Guidelines17. Patients [aged between 65 and 85 years, American Society of Anesthesiologists (ASA) physical status classification Ⅱ to Ⅲ] with normal Mini-Mental State Examination (MMSE) score (illiterateness ≥17, primary school ≥20, and middle school and above ≥24) undergoing GA for scheduled operation (anesthesia duration ≤4 h) were enrolled between 4 January 2022 and 7 March 2023. Patients were excluded as follows: history of alcohol or drug abuse, psychiatric disorders, traumatic brain injury or brain surgery, admitted to ICU after operation, esketamine or any of their formulation ingredient allergies or contraindications. The medical and demographic data, anesthesia management protocol, and monitoring records were recorded in case report files.

Randomization and masking

Eligible patients were stratified by age (≤70 vs. >70) and ASA physical status classification (Ⅱ vs. Ⅲ), then randomly assigned (block size=4 or 8) in a 1:1:1:1 ratio to either morning (08:00 to 12:00) or afternoon (14:00 to 18:00) operation with or without esketamine administration. The code sequence was generated by computer and kept in sealed envelopes by a staff who was not involved in the outcomes assessment. The investigators not involved in the perianesthetic management were in charge of enrolling participants. Operation time was open-label for the anesthesiologists who were responsible for GA management, but esketamine assignment was masked. The investigators who were blinded to both interventions (operation time and medication regimen) and not involved in the GA management were in charge of assessing primary and secondary outcomes. Data were monitored by a data checker who was not involved in the study and centrally reviewed by two independent investigators who were kept unaware of the randomized assignment profiles. In case of disagreement, the data were discussed with the third investigator.

GA procedures

The procedures of GA were performed according to the routine protocols of the department of anesthesiology and adjusted depending on the clinical practices guidelines and existing experiences. Patients were given physiological liquid requirement using intravenous acetate Ringer’s solution on the ward. The clear liquids were allowed to drink until 2 h before GA. Before induction, 5-channel electrocardiogram (ECG), heart rate (HR), peripheral pulse oximetry (SpO2), pulse rate, respiratory rate, end-tidal carbon dioxide (ETCO2), arterial blood pressure (ABP), nasopharyngeal temperature and bispectral index (BIS) were monitored with PHILIPS medicine system (IntelliVue, 866064). ABP was monitored from either continuous noninvasive blood pressure management device (TL-400 Tensysmeter, Shanshi Medical Co Ltd) or invasive pressure monitoring set (Pressure Transducer Kit #PX260, Edwards Lifesciences).

After preoxygenation, a single intravenous injection of esketamine (5 mg/ml, 0.2 mg/kg, Jiangsu Hengrui Pharmaceutical Co Ltd.,) or normal saline was employed before induction according to the grouping information. Immediately, propofol (10 mg/ml) was injected via infusion pumps at a rate of 240 ml/h to minimize the diversity of manual delivery. When BIS value (<60) reached the endpoint of induction, sufentanil (5 mcg/ml) and cisatracurium (1 mg/ml) were given as appropriate for induction. GA was maintained with inhaled sevoflurane (0.6–1.2 vol % of the expired fraction), propofol (2–4 mg/kg/h), remifentanil (4–8 μg/kg/h), and cisatracurium (0.05 mg/kg/h). The specific regimen for each patient was fully at the discretion of the anesthesiologists until the desired clinical effect was achieved.

Outcomes

The primary outcome was the incidence of POD. The secondary outcomes were the score of MMSE and Hospital Anxiety and Depression Scale (HAD). The profiles of anesthesia management (vital signs, anesthetic consumption, vasoactive drugs intervention, the total amount of fluid infusion, and blood loss), adverse events (injection pain, cough, hypotension, hypertension, low BIS value (<40), hypoxemia (SpO2 <95%), arrhythmia, emergence agitation, nausea, vomiting, dizziness, etc.), and postoperative Numerical Rating Scale (NRS) score were also recorded.

POD was detected in the morning at 1, 3, and 7 days postoperatively via the scale of 3-Minute Diagnostic Interview for Confusion Assessment Method-defined Delirium (3D-CAM). The scores of MMSE and HAD were obtained via corresponding scales at preoperation and 1, 3, and 7 days postoperatively. Before the first follow up initiation, patients had at least 20 h and 14 h recovery period in morning and afternoon operation group, respectively. Hypotension or hypertension was defined as the fluctuation of MAP over 20% of the baseline value (the mean of measurements during 5 min before induction).

Statistical analysis

In the pilot study, a total of 115 cases were initially enrolled. Among of them, 67 cases were excluded, 48 cases were randomly assigned to four groups at a ratio of 1:1:1:1. Wherein, the time-averaged incidences of POD were 33, 25, 25, 17% for four groups. Then, an estimated sample size was calculated based on the results by PASS version 2021 (NCSS) for present study. A total of 432 cases allowed for a power of 80%, a two-tailed alpha level of 5%, a dropout rate of 10%, an assigned ratio of 1:1:1:1and the effect size over 0.2. Standard ITT analyses would be performed after handling missing data via multiple imputation method. The data on patients can be excluded, as long as allocation to treatment arm cannot influence the likelihood that patients receive the intervention18.

Continuous variables were expressed as mean (standard difference, SD) or median (interquartile range, IQR), and categorical variables were expressed as number (proportion). Normality of data was assessed using Shapiro–Wilk’s test. The repeated measurements and the impact of study factors on study objectives were assessed using generalized estimating equation (GEE) models to estimate population-averaged effects. All models were adjusted for prespecified potential covariates, including age, sex, ASA physical status classification, years of education, working years of anesthesiologists, surgery type and complexity grading, anesthesia duration, interoperative low BIS value, hypoxemia and hypotension, type of mechanical ventilation, and postoperative analgesia methods. As for continuous dependent variable, the partial regression coefficient B of GEE gives the mean amount by which the dependent variable changes when one independent variable is changed by one unit and all the other independent variables are held constant. As for binary dependent variable, B is the natural logarithm of OR of the two groups when the independent variable changes by one unit. Besides, the general linear models, Kruskal–Wallis test, Scheirer–Ray–Har test, χ² test, Fisher’s exact test, and Cochran–Mantel–Haenszel test were employed as appropriate.

A two-tailed P-value less than 0.05 was judged to be statistically significant. All statistical analyses were performed via SPSS version 26 (IBM).

Results

A total of 873 cases were initially enrolled. Among of them, 427 cases were excluded, 432 cases were randomly assigned to four groups. The types of deviations from the ITT analysis were shown in the flowchart (Fig. 1). Among of them, two cases fell into double types of deviations. The data on patients who did not receive an intervention because of canceled operation were excluded. Finally, the datasets containing 426 cases were analyzed.

Figure 1 Study flow chart.

In the present study, these participants were comparable with similar baseline characteristics (Supplementary Table 1, Supplemental Digital Content 2, http://links.lww.com/JS9/C673). As shown in Table 1, the incidence of POD declined gradually from about 55% on postoperative day 1 to 31 and 18% on postoperative days 3 and 7, respectively. GEE analysis of POD revealed that afternoon operation [B=−0.583, OR (95% CI) 0.558 (0.319–0.976); P=0.041], but not esketamine administration, significantly decreased the incidence of POD (Table 2). Besides, ASA physical status classification, follow up time points, surgery type, grading of surgical complexity, education years, age, and working years of anesthesiologist significantly influenced the incidence of POD.

Table 1 The incidence of POD during follow up.

	Afternoon operation	Morning operation				
Follow up time point	Esketamine (n=106)	Normal Saline (n=108)	Esketamine (n=107)	Normal Saline (n=105)	χ 2	P	OR (95% CI)	
Postoperative day 1	57 (53.8%)	51 (47.2%)	64 (59.8%)	62 (59.0%)	0.61	0.44	0.86 (0.59–1.23)	
Postoperative day 3	34 (32.1%)	24 (22.2%)	40 (37.4%)	35 (33.3%)	2.46	0.12	0.85 (0.70–1.09)	
Postoperative day 7	13 (12.3%)	18 (16.7%)	23 (21.5%)	23 (21.9%)	0.40	0.53	1.17 (0.72–1.92)	
POD, postoperative delirium.

Data presented as number (proportion) were compared using Cochran–Mantel–Haenszel test.

Table 2 The GEE analysis of POD.

Parameter	B	SE	P	OR (95% CI)	
Intercept	−0.790	0.568	0.164	0.454 (0.149–1.381)	
Esketamine vs normal saline	0.128	0.301	0.670	1.137 (0.631–2.050)	
Afternoon operation vs morning operation	−0.583	0.285	0.041	0.558 (0.319–0.976)	
ASA physical status II vs III	−1.033	0.1815	<0.001	0.356 (0.249–0.508)	
Follow up time point	
 Postoperative day 7	−2.074	0.303	<0.001	0.126 (0.069–0.228)	
 Postoperative day 3	−1.479	0.286	<0.001	0.228 (0.130–0.399)	
 Postoperative day 1	0			1	
Type of surgery	
 Breast/Vascular	−0.081	0.393	0.836	0.922 (0.427–1.992)	
 Ears/Nose/Throat/Ophthalmology	0.193	0.443	0.663	1.213 (0.509–2.890)	
 Gastrointestinal/Gynecology	0.213	0.343	0.534	1.238 (0.632–2.424)	
 Hepatobiliary/Pancreatic	0.639	0.461	0.166	1.894 (0.767–4.678)	
 Neurosurgical	1.217	0.392	0.002	3.378 (1.566–7.288)	
 Orthopedic/Spine	0.286	0.372	0.442	1.331 (0.642–2.758)	
 Thoracic	1.252	0.383	0.001	3.497 (1.653–7.401)	
 Urologic	0			1	
Grading of surgical complexity	
 1	−1.596	0.341	<0.001	0.203 (0.104–0.395)	
 2	−0.83	0.258	0.001	0.436 (0.263–0.723)	
 3	−0.461	0.258	0.074	0.631 (0.381–1.045)	
 4	0			1	
Years of education	
 ≤5 years	2.378	0.430	<0.001	10.785 (4.646–25.036)	
 6–8 years	2.441	0.407	<0.001	11.49 (5.173–25.523)	
 9–11 years	1.576	0.390	<0.001	4.835 (2.252–10.383)	
 12–15 years	−0.014	0.470	0.976	0.986 (0.393–2.474)	
 >15 years	0			1	
Age	0.629	0.090	<0.001	1.876 (1.574–2.236)	
Working years of anesthesiologist	−0.202	0.099	0.042	0.817 (0.673–0.993)	
ASA, American society of anesthesiologists; GEE, generalized estimating equation; POD, postoperative delirium.

At preoperative assessment, the median of MMSE score was about 24, and no significant differences were found among groups. At postoperative visits, the median of MMSE scores restored gradually from about 18 on postoperative day 1 to 20 and 22 on postoperative days 3 and 7, respectively. There was a significant difference in MMSE score among groups on postoperative days 7. The median of HAD scores changed from preoperative 4 to 8, 8 and 7 on postoperative days 1, 3, and 7, respectively. No significant differences were found across groups in the median of HAD scores (Table 3).

Table 3 The MMSE and HAD score during follow up.

Follow up time point	Group	MMSE	Z	P	HAD	Z	P	
Preoperation			1.05	0.79		3.59	0.31	
	AES (n=108)	24 (23–26)			4 (2–6)			
	ANS (n=108)	24 (22–26)			4 (3–6)			
	MES (n=108)	24 (23–26)			4 (3–6)			
	MNS (n=108)	24 (22–25)			5 (3–7)			
Postoperative day 1			5.46	0.14		0.59	0.90	
	AES (n=106)	18 (15–21)			8 (6–10)			
	ANS (n=108)	18 (15–20)			8 (6–10)			
	MES (n=107)	16 (14–20)			8 (7–10)			
	MNS (n=105)	18 (14–20)			8 (7–10)			
Postoperative day 3			7.61	0.06		0.83	0.84	
	AES (n=106)	20 (18–22)			7 (6–9)			
	ANS (n=108)	20 (18–22)			8 (6–10)			
	MES (n=107)	19 (18–21)			8 (6–10)			
	MNS (n=105)	20 (18–22)			8 (6–9)			
Postoperative day 7			9.44	0.02		2.33	0.51	
	AES (n=106)	22 (20–24)			7 (5–9)			
	ANS (n=108)	22 (20–24)			7 (5–9)			
	MES (n=107)	21 (19–23)			7 (6–9)			
	MNS (n=105)	21 (19–23)			7 (5–9)			
AES, afternoon operation with esketmine intervention; ANS, afternoon operation with normal saline intervention; HAD, Hospital Anxiety and Depression; MES, morning operation with esketmine intervention; MMSE, Mini-Mental State Examination; MNS, morning operation with normal saline intervention.

Data presented as median (IQR) were compared using Kruskal–Wallis test.

Both esketamine administration and operation time failed to significantly affect MMSE and HAD score, but follow up time point, preoperative plasma CRP (C reactive protein) concentration and age significantly impacted MMSE score (Tables 4 and 5). What is more, an interaction between operation time and follow up time point was found when assessing MMSE on postoperative days 7 [B=0.147, OR (95% CI) 1.158 (1.037–1.293); P=0.009]. Female had a lower postoperative HAD score than male [B=−0.125, OR (95% CI) 0.882 (0.783–0.994); P=0.039]. And patients with preoperative hypnagogue administration also had a lower postoperative HAD score than without [B=−0.408, OR (95% CI) 0.665 (0.566–0.781); P<0.001].

Table 4 The GEE analysis of MMSE score.

Parameter	B	SE	P	OR (95% CI)	
Intercept	1.416	0.146	<0.001	4.123 (3.097–5.488)	
Esketamine vs normal saline	−0.001	0.058	0.984	0.999 (0.891–1.120)	
Afternoon operation vs morning operation	0.001	0.057	0.982	1.001 (0.896–1.119)	
Follow up time point	
 Postoperative day 7	−0.756	0.054	<0.001	0.470 (0.422–0.522)	
 Postoperative day 3	−1.122	0.066	<0.001	0.326 (0.286–0.370)	
 Postoperative day 1	−1.839	0.072	<0.001	0.159 (0.138–0.183)	
 Preoperation	0			1	
Grading of surgical complexity	
 1	0.185	0.085	0.031	1.203 (1.017–1.422)	
 2	0.137	0.064	0.033	1.147 (1.011–1.301)	
 3	0.048	0.069	0.486	1.049 (0.917–1.201)	
 4	0			1	
Years of education	
 ≤5 years	−1.172	0.105	<0.001	0.310 (0.252–0.381)	
 6–8 years	−0.886	0.100	<0.001	0.412 (0.339–0.501)	
 9–11 years	−0.522	0.096	<0.001	0.593 (0.491–0.716)	
 12–15 years	0.099	0.104	0.340	1.104 (0.901–1.354)	
 >15 years	0			1	
Age	−0.138	0.020	<0.001	0.871 (0.838–0.906)	
C reactive protein mg/l	−0.091	0.033	0.006	0.913 (0.856–0.974)	
Operation time * Follow up time point	
 Afternoon operation*Postoperative day 7	0.147	0.056	0.009	1.158 (1.037–1.293)	
 Afternoon operation*Postoperative day 3	0.137	0.072	0.056	1.147 (0.996–1.321)	
 Afternoon operation*Postoperative day 1	0.152	0.082	0.063	1.164 (0.992–1.366)	
 Afternoon operation*Preoperation	0			1	
GEE, generalized estimating equation; MMSE, mini-mental state examination.

Table 5 The GEE analysis of HAD score.

Parameter	B	SE	P	OR (95% CI)	
Intercept	−0.524	0.187	0.005	0.592 (0.410–0.855)	
Esketamine vs normal saline	−0.054	0.093	0.562	0.947 (0.789–1.137)	
Afternoon operation vs morning operation	−0.047	0.094	0.614	0.954 (0.794–1.146)	
Follow up time point	
 Postoperative day 7	0.858	0.105	<0.001	2.359 (1.920–2.900)	
 Postoperative day 3	0.944	0.093	<0.001	2.571 (2.141–3.087)	
 Postoperative day 1	1.155	0.095	<0.001	3.174 (2.633–3.826)	
 Preoperation	0			1	
Sex female vs male	−0.125	0.061	0.039	0.882 (0.783–0.994)	
Hypnagogue	−0.408	0.082	<0.001	0.665 (0.566–0.781)	
Age	−0.065	0.028	0.020	0.937 (0.887–0.990)	
C reactive protein mg/l	0.088	0.037	0.018	1.092 (1.015–1.175)	
GEE, generalized estimating equation; HAD, hospital anxiety and depression.

There was no significant difference in NRS score among groups during follow up (Table 6). Follow up time points, type of surgery and grading of surgical complexity significantly impacted the score of NRS (Table 7). In contrast with longer anesthesia duration [B=0.093, OR (95% CI) 1.097 (1.019–1.182); P=0.014], longer working years of anesthesiologist [B=−0.190, OR (95% CI) 0.83 (0.791–0.871); P<0.001] and more sufentanyl consumption [B=−0.060, OR (95% CI) 0.946 (0.901–0.993); P=0.024] significantly decreased postoperative NRS score. We did not find the interaction between operation time * esketamine, operation time * visit time and esketamine * visit time among these outcomes.

Table 6 The NRS score during follow up.

Follow up time point	AES (n=106)	ANS (n=108)	MES (n=107)	MNS (n=105)	Z	P	
Admit to PACU	2 (1–2)	2 (1–3)	2 (1–2)	2 (1–2)	2.06	0.56	
Discharge from PACU	1 (1–2)	1 (0–2)	1 (1–2)	1 (0–2)	5.54	0.14	
Return to ward	3 (2–4)	3 (2–4)	3 (2–4)	3 (2–4)	1.05	0.79	
Postoperative day 1	2 (1–3)	2 (1–3)	2 (1–3)	2 (1–3)	0.27	0.97	
Postoperative day 2	2 (1–3)	3 (1–4)	2 (1–3)	2 (1–3)	7.62	0.06	
Postoperative day 3	1 (1–2)	1 (1–2)	1 (1–2)	1 (1–2)	2.77	0.43	
Postoperative day 7	0 (0–2)	0 (0–1)	0 (0–2)	0 (0–2)	0.12	0.99	
AES, afternoon operation with esketmine intervention; ANS, afternoon operation with normal saline intervention; MES, morning operation with esketmine intervention; MNS, morning operation with normal saline intervention; NRS, numerical rating scale; PACU, post anesthesia recovery room.

Data presented as median (IQR) were compared using Kruskal–Wallis test.

Table 7 The GEE analysis of NRS score.

Parameter	B	SE	P	OR (95% CI)	
Intercept	−0.100	0.079	0.191	0.901 (0.771–1.053)	
Esketamine vs normal saline	−0.010	0.082	0.919	0.992 (0.844–1.165)	
Afternoon operation vs morning operation	0.041	0.078	0.597	1.042 (0.895–1.213)	
Follow up time point	
 Admit to PACU	−0.620	0.076	<0.001	0.538 (0.464–0.625)	
 Discharge from PACU	−0.140	0.075	0.069	0.873 (0.754–1.011)	
 Return to ward	0.535	0.11	<0.001	1.708 (1.378–2.117)	
 Postoperative day 1	0.268	0.099	0.006	1.308 (1.078–1.586)	
 Postoperative day 2	0.963	0.079	<0.001	2.620 (2.245–3.058)	
 Postoperative day 3	−0.310	0.074	<0.001	0.737 (0.637–0.852)	
 Postoperative day 7	0			1	
Type of surgery	
 Breast/Vascular	−0.290	0.134	0.034	0.752 (0.578–0.978)	
 Ears/Nose/Throat/ Ophthalmology	0.101	0.130	0.440	1.106 (0.857–1.427)	
 Gastrointestinal/Gynecology	0.138	0.107	0.193	1.149 (0.932–1.415)	
 Hepatobiliary/Pancreatic	0.265	0.128	0.038	1.304 (1.015–1.674)	
 Neurosurgical	0.230	0.108	0.032	1.259 (1.019–1.555)	
 Orthopedic/Spine	0.040	0.112	0.719	1.041 (0.836–1.296)	
 Thoracic	0.116	0.117	0.321	1.123 (0.893–1.414)	
 Urologic	0			1	
Sex female vs male	0.100	0.048	0.039	1.105 (1.005–1.215)	
Grading of surgical complexity	
 1	−0.240	0.096	0.011	0.784 (0.649–0.947)	
 2	−0.170	0.078	0.028	0.842 (0.723–0.982)	
 3	−0.060	0.075	0.418	0.941 (0.812–1.090)	
 4	0			1	
Working years of anesthesiologist	−0.190	0.025	<0.001	0.830 (0.791–0.871)	
Anesthesia duration, min	0.093	0.038	0.014	1.097 (1.019–1.182)	
Sufentanyl mcg/kg/h	−0.060	0.025	0.024	0.946 (0.901–0.993)	
GEE, generalized estimating equation; NRS, numerical rating scale; PACU, post anesthesia recovery room.

There were no significant differences in the consumption of remifentanil, sevoflurane and liquid, intraoperative blood loss, and anesthesia duration across groups. And no interaction between operation time * esketamine was found. We also did not find the interaction between operation time and esketamine. However, both afternoon operation and esketamine intervention decreased the consumption of propofol (H=7.70, P=0.01, H=4.72, P=0.03, respectively) and the length of stay in PACU (H=6.64, P=0.01, H=5.79 P=0.02, respectively) significantly. Besides, esketamine but not operation time significantly decreased the consumption of sufentanyl (H=5.31, P=0.02) (Table 8). Esketamine also significantly decreased the incidence of intraoperative hypotension (P<0.01) and emergence agitation (P=0.01) (Table 9). We did not observe any unintended effects or harms in each group related to the trail procedure.

Table 8 The effects of operation time and esketamine intervention on anesthesia management.

	AES	ANS	MES	MNS	Time effect	Agent effect	Time*Agent	
	(n=106)	(n=108)	(n=107)	(n=105)	H	P	H	P	H	P	
Anesthesia administration	
 Propofol, mg/kg/h	2.51 (1.90–3.12)	2.47 (1.87–3.61)	2.62 (1.94–3.45)	2.91 (2.18–3.83)	7.70	0.01	4.72	0.03	1.31	0.25	
 Sufentanil, μg/kg/h	0.32 (0.25–0.38)	0.33 (0.25–0.41)	0.31 (0.24–0.39)	0.35 (0.27–0.43)	1.35	0.25	5.31	0.02	0.77	0.38	
 Remifentanil, μg/kg/h	2.87 (1.50–4.88)	2.75 (1.43–3.97)	2.41 (1.56–4.37)	2.76 (1.55–4.78)	0.01	0.92	0.04	0.84	0.6	0.44	
 Sevoflurane, ml/h	8.39 (6.95–10.8)	7.68 (6.33–9.81)	8.52 (7.00–9.80)	8.66 (7.08–10.1)	1.42	0.23	2.2	0.14	2.56	0.11	
 Liquid, ml	950 (600–1250)	850 (600–1150)	850 (600–1100)	850 (600–1200)	1.03	0.31	0.33	0.57	1.38	0.24	
 Blood loss, ml	115 (40–300)	110 (40–210)	90 (40–185)	85 (35–260)	1.97	0.16	0.4	0.53	0.66	0.42	
Anesthesia duration, min	131 (102–170)	135 (100–176)	131 (98–162)	137 (102–175)	0.06	0.81	0.14	0.71	0.30	0.58	
Length of stay in PACU, min	45 (35–55)	40 (30–50)	50 (40–55)	45 (40–50)	6.64	0.01	5.79	0.02	0.11	0.74	
Postoperative analgesia					χ 2	P					
 PCEA	16 (15.1%)	14 (13.0%)	18 (16.8%)	17 (16.2%)	10.98	0.09					
 PCIA	61 (57.5%)	59 (54.6%)	41 (38.3%)	47 (44.8%)							
AES, afternoon operation with esketmine intervention; ANS, afternoon operation with normal saline intervention; MES, morning operation with esketmine intervention; MNS, morning operation with normal saline intervention; PACU, post anesthesia recovery room; PCEA, patient controlled epidural analgesia; PCIA, patient controlled intravenous analgesia.

Data presented as median (IQR) were compared using Scheirer–Ray–Har test. Data presented as number (proportion) were compared using χ 2 test.

Table 9 The effects of operation time and esketamine intervention on perioperative adverse events.

	Afternoon operation	Morning operation				
	Esketamine (n=106)	Normal saline (n=108)	Esketamine (n=107)	Normal saline (n=105)	χ 2	P	OR (95% CI)	
Intraoperation	
 Injection pain	24 (22.6%)	17 (15.7%)	19 (17.8%)	16 (15.2%)	1.60	0.21	0.73 (0.44–1.20)	
 Cough	4 (3.8%)	5 (4.6%)	6 (5.6%)	4 (3.8%)	0.06	0.81	0.90 (0.36–2.25)	
 Hypotension	45 (42.5%)	65 (60.2%)	50 (46.7%)	68 (64.8%)	13.63	<0.01	2.07 (1.40–3.04)	
 Hypertension	13 (12.3%)	5 (4.6%)	4 (3.7%)	6 (5.7%)	1.38	0.24	0.63 (0.29–1.37)	
 SpO2 < 95%	41 (38.7%)	48 (44.4%)	47 (43.9%)	48 (45.7%)	0.61	0.43	1.17 (0.79–1.71)	
PACU	
 Hypotension	9 (8.5%)	10 (9.3%)	6 (5.6%)	8 (7.6%)	0.30	0.59	1.22 (0.60–2.49)	
 Hypertension	15 (14.2%)	10 (9.3%)	15 (14.0%)	15 (14.3%)	0.52	0.47	0.81 (0.46–1.43)	
 SpO2 < 95%	23 (21.7%)	25 (23.1%)	20 (18.7%)	22 (21.0%)	0.23	0.64	1.12 (0.70–1.78)	
 EA	18 (17.0%)	28 (25.9%)	19 (17.8%)	31 (29.5%)	6.51	0.01	1.82 (1.15–2.90)	
 Nausea	24 (22.6%)	27 (25.0%)	29 (27.1%)	21 (20.0%)	0.32	0.57	0.88 (0.56–1.37)	
 Vomiting	10 (9.4%)	7 (6.5%)	8 (7.5%)	8 (7.6%)	0.30	0.59	0.82 (0.40–1.68)	
 Dizziness	21 (19.8%)	18 (16.7%)	33 (30.8%)	24 (22.9%)	1.94	0.16	0.72 (0.46–1.14)	
Postoperation	
 Nausea	35 (33.0%)	38 (35.2%)	36 (33.6%)	26 (24.8%)	0.53	0.47	0.86 (0.57–1.29)	
 Vomiting	16 (15.1%)	14 (13.0%)	10 (9.3%)	10 (9.5%)	0.09	0.76	0.91 (0.51–1.65)	
 Pruritus	13 (12.3%)	13 (12.0%)	15 (14.0%)	24 (22.9%)	1.47	0.23	1.39 (0.82–2.37)	
 Dizziness	42 (39.6%)	40 (37.0%)	34 (31.8%)	46 (43.8%)	1.00	0.32	1.22 (0.83–1.81)	
EA, Emergence agitation; PACU, post anesthesia recovery room.

Data presented as number (proportion) were compared using Cochran–Mantel–Haenszel test.

Discussion

The present study showed a clinically significant morning versus afternoon variation in the incidence of POD, with patients undergoing elective noncardiac surgery in the afternoon displaying a lower POD incidence than those operated in the morning. We designed an anesthetic procedure with little variation to increase homogeneity and employed a continuous ABP monitoring system to reduce the risk of brain hypoperfusion, as well as BIS monition to avoid inappropriate anesthetic depth19. Unexpectedly, a relative higher incidence of POD in the morning at 1 day postoperatively, which might be credited to the timing of assessments. In addition, intravenous analgesics on postoperative day 1 might confound the hypoactive delirium with sedation. Previous study found that POD was detected more often in the morning than evening20. And, it has been recommended that the screening for POD should be conducted at least once per day (preferably two or three times per day) for at least 3 days, starting in the PACU on the day of surgery or at latest on postoperative day 121. More attention should be paid to optimize the interval and duration of POD assessments to raise the reliability of conclusion in further study.

Several theories have been proposed to explain POD, broadly consisting of direct central nervous system insults (such as oxidative stress injury induced by hypoxia) and aberrant stress responses (such as neuroinflammation induced by systemic inflammation)22. Elderly population is characterized by neurodegeneration which is linked with the reciprocal influence among neuroinflammation, oxidative stress, and circadian rhythm deterioration. Previous study has elucidated a strong diurnal variation in immune function and redox homeostasis23,24. And, the early active phase seems display a higher susceptibility to insults than the late active phase25–28. Besides, circadian genes in memory-relevant brain regions (like the hippocampus, retrosplenial cortex, prefrontal cortex, and amygdala) participate in memory formation, retention, and recall29–31. Notably, significant changes in circadian gene expression with aging has been confirmed in human prefrontal cortex32. These findings suggest that circadian genes could regulate the vulnerability of brain to perioperative insults via participating in the potential mechanisms of POD and exert rhythmically control over cognition. Current literature supported the effectiveness of melatonin (a marker of circadian rhythm with hypnotic, anxiolytic, and anti-inflammatory actions) in POD prevention33. The strategies targeted at circadian health would be a useful way to prevent POD.

NMDA-dependent synaptic plasticity (including intercellular signaling, membrane excitability, neuronal morphology, intracellular signaling, and epigenetic modifications) has been well established in the memory-related neuron29. Interestingly, the surface expression of NMDAR on mouse CA1 pyramidal cells varies with circadian rhythmicity and NMDAR activation is reduced during the dark phase34. Moreover, MK801(a NMDAR antagonist) could reduce infarct volumes during the inactive but not active phase and significantly reduce primary mouse cortical neurons death induced by oxygen-glucose deprivation in ‘inactive phase’35. These findings verified the influence of circadian rhythm on the neuroprotectants of NMDAR antagonists.

Several studies have explored the neuroprotection of esketamine in subjects with treatment-resistant depression36. However, a single low-dose ketamine (0.5 mg/kg) injection before surgical incision failed to decrease the incidences of POD and other adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding) in patients older than 60 years undergoing major cardiac and noncardiac surgery under GA in the first three postoperative days37. Recent meta-analysis also indicated that there were no significant differences in the incidences of POD and postoperative neurocognitive disorders (POND), as well as psychological adverse effects, level of pain, length of stay in hospital, and mortality, in adult patients received perioperative ketamine administration compared to placebo. Subgroup analyses showed similar results according to surgical setting, ketamine dose, mode of administration, combination or not with other drug(s), and assessment timing or definition of cognitive disorders38. Unexpectedly, present study also failed to provide evidences of esketamine in postoperative neurocognitive protection in elderly patients undergoing elective noncardiac surgery. The opposite circadian cycles in nocturnal rodents versus diurnal humans may contribute to this failure in translational studies on the neuroprotectants of esketamine. In terms of POD prevention, further studies should focus on the mechanism referred to the crosstalk between clock gene and NMDAR.

Increasing evidence suggested that esketamine administration at a low-dose of loading with or without continuous infusion provided stable hemodynamics10, decreased pain score11,12, and antidepressant effect11. However, 0.2 mg/kg esketamine pretreatment decreased the incidence of intraoperative hypotension and emergence agitation but failed to decrease the postoperative pain and HAD scores in present study. These findings suggested that esketamine might be an available strategy in elderly patients with high risk of hypotension.

Present study predefined the potential covariates as adjusted factors for analysis and determined the afternoon was probably a better time to undergo elective noncardiac surgery than the morning in elderly patients. Importantly, perioperative neurocognition protection concerns not only elective surgery, but also emergence surgery. Although consideration of the time of surgery is an option, this is not possible for emergence surgery because of the unpredictable time. Indeed, the surgery time is not the only parameter responsible for the risk of POD in elderly patients. The development of POD is a combination of patient vulnerability and perioperative insults39. Given that patients undergo morning surgeries in clinical practice, the consequences and applications of identifying the neuroprotective potential of modulation of circadian rhythm and NMDA receptor activity are more important than the time of surgery. In view of official permits, it should be prudent to extend off-label use although esketamine decreased the risk of intraoperative hypotension and emergence agitation in present study. Besides, biological samples were not collected resulted that the possible mechanism on the diurnal variation of POD could not be determined, which was another limitation of present study.

In conclusion, consideration of the timing of surgery might lead to improved outcome, with afternoon surgery providing postoperative neurocognitive protection. Although, a single-center design allowed us to avoid many confounding factors resulting from heterogeneous perioperative patient management, present findings should be cautiously generalized to other populations and healthcare settings before validating in a multicenter trial with large sample size.

Ethical approval

Ethical approval for this study (No. WDRY2021-K124) was provided by the Institutional Review Board at Renmin Hospital of Wuhan University, Wuhan, China on 18 August 2021.

Consent

Written informed consent were obtained from the subjects or legal surrogates.

Source of funding

This work was supported by the National Natural Science Foundation of China (81801085) and Chen Xiao-Ping Foundation for the Development for Science and Technology of Hubei Province (CXPJJH12000005-07-28). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author contribution

Q.M. and Z.X.: have contributed equally to this work and share senior authorship; Y.Z. and R.C.: are co–first authors and contributed equally to this work. All authors contributed to the manuscript and approved the final version. Z.X.: concept and design; Q.M. and Y.Z.: obtained funding; Y.Z. and R.C.: drafting manuscript and statistical analysis; R.C., S.T., T.S., Y.Y., R.S., K.W., Z.Z., and X.L.: acquisition, analysis, or interpretation of data; Q.M.: critical revision of the manuscript for important intellectual content.

Conflicts of interest disclosure

The authors declare that they have no financial conflict of interest with regard to the content of this report.

Research registration unique identifying number (UIN)

Chinese Clinical Trial Registry Identifier: ChiCTR2100051179.

Guarantor

Qingtao Meng and Zhongyuan Xia had full access to all the data in the study and takes responsibility for the integrity of the data, the accuracy of the data analysis, and the decision to submit for publication.

Data availability statement

Data available: Yes.

Data types: Deidentified participant data.

How to access data: Request for data must be sent to an individual. Qingtao Meng; mengqingtao2018@126.com.

When available: Beginning date: 01-01-2027.

Document types: None.

Who can access the data: Researchers whose proposed use of the data has been approved.

Types of analyses: For a specified purpose.

Mechanisms of data availability: With a signed data access agreement.

Any additional restrictions: None.

Provenance and peer review

None.

Supplementary Material

Acknowledgement

Assistance with the study: The authors would like to thank Prof Yang Wu and Fan Zhang for important intellectual suggestions. The authors also would like to thank Qin Zhou, Zhen Qiu, Qingwen Li, and Yuanmei Guo for their kind assistance.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/international-journal-of-surgery.

Published online 28 May 2024
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