Introduction

Cognitive impairment following anesthesia and surgery is a common complication in elderly individuals, mainly manifested falls in memory, attention, information processing, and cognitive flexibility.1 In 2018, new recommendations for the nomenclature of cognitive change associated with anesthesia and surgery recommended perioperative neurocognitive disorders (PND) as an overarching term for cognitive decline identified in the perioperative period, including acute postoperative delirium (POD), delayed neurocognitive recovery (within the 30 days recovery period, dNCR), and postoperative neurocognitive dysfunction (from expected recovery 30 days to 12 months, POCD).2,3 Previous studies have shown that patients aged 65 and above who underwent non-cardiac surgery had a 26% prevalence of POCD 1 week after surgery which decreased to 10% 3 months postoperatively.4 PND is associated with delayed recovery, prolonged hospital stays, additional healthcare expenditures, and even increased probability for 1-year postoperative mortality.5 However, up to date, limited treatment options for PND are available and the exact mechanism remains unclear.

Several studies have suggested that neuro-inflammation induced by surgery and anesthesia is a major contributor to the development of POCD.6,7 It is well known that aseptic surgical trauma causes inflammation at the surgical site, which is amplified via peripheral pro-inflammatory cytokines, and this leads to disruption of the blood–brain barrier (BBB), allowing pro-inflammatory cytokines to enter the central nervous system (CNS) and activate microglia. Once activated, microglia continue to up-regulate the expression of pro-inflammatory cytokines, thus amplifying neuro-inflammation could lead to neuronal apoptosis and contribute to the development of POCD.8,9

Ketamine, formerly referred to as a “dissociative anesthetic”, has reemerged as a useful anesthetic/analgesic agent. The unique properties of ketamine and its large versatility make it suitable to be used in anesthesia, procedural sedation, and pain management.10,11 As a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, the binding of ketamine to NMDA receptors leads to decreased frequency and duration of Ca2+ channel opening and thus inhibits glutaminergic transmission. This mechanism has proven to be neuro-protective in several neurological conditions.12 A meta-analysis has demonstrated that ketamine administration could reduce IL-6 production in patients undergoing surgery,13 which was the major pro-inflammatory cytokine and used as a biomarker of the inflammatory reaction. Furthermore, a bolus of 0.5 mg/kg ketamine at induction of anesthesia improved recent verbal and nonverbal memories and executive functions 1 week after surgery in patients undergoing cardiac procedures.14 Inflammatory regulatory properties of ketamine are increasingly the focus of attention.

Esketamine is the S-enantiomer of ketamine which displays an approximately fourfold greater affinity for the glutamate NMDA receptor15 and has been FDA-approved in the United States in 2019 for treating depression that has failed to respond to trials of two or more antidepressants. A majority of esketamine studies focused on the treatment of resistant depression.16–18 Recent years have witnessed a growing interest and enthusiasm of anesthesiologists for the application of esketamine in gastrointestinal endoscopy,19 endoscopic retrograde cholangiopancreatography,20 abortion surgery,21 etc. Intravenous esketamine as an adjunct to general anesthesia has demonstrated its clinical superiority to ketamine in double analgesic potencies, spared opioid requirements, improved recovery, and few adverse effects.22 Furthermore, recent studies have shown that sub-anesthetic doses of esketamine could maintain the stability of hemodynamics during anesthesia induction23 and reduce postoperative pain in the PACU in the elderly, without affecting postoperative nausea and vomiting, and postoperative agitation.24 However, there are currently rare data on the impact of sub-anesthetic doses of esketamine on postoperative cognitive function in elderly patients.

Here, we investigated the effect of the sub-anesthetic doses of esketamine on postoperative cognitive function in elderly patients undergoing gastrointestinal surgery and also explored the potential mechanisms of PND.

Methods Ethical Considerations

The randomized, prospective, controlled, double-blind study was approved by the Ethics Committee of Affiliated Yixing Hospital of Jiangsu University (approval number: LS2022K080-1) and performed consistent with the principles of the Helsinki Declaration on Human Experimentation. This trial was registered at the Chinese Clinical Trial Registry http://www.chictr.org.cn/showproj.aspx?proj=169798 (ChiCTR2200062421). All participants provided written informed consent.

Study Design and Participants

Patients aged 65 and above who received gastrointestinal surgery under general anesthesia, MMSE scores >24,25,26 right-handed, and ASA I–III were included in the study from August 11 to November 10, 2022. Exclusion criteria were as follows: 1) history of neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease)27,28; 2) intracranial hypertension; 3) severe uncontrolled hypertension; 4) communication disorders; 5) glaucoma; 6) serious postoperative complications and admitted to the ICU; 7) reoperation; and 8) loss of follow-up. As repeated neuropsychological testing could produce a practice effect and result in misinterpretation of outcomes,29 15 age- and sex-matched volunteers were recruited from the friends and family members of patients in the trial group using the same exclusion criteria.

Randomization and Blind

A computer random number sequence was generated by an independent statistician before the initiation of the study. The allocations were printed and placed in separate sealed envelopes, and the patients were randomly divided into 2 groups in a 1:1 ratio: the esketamine group (group S) was intravenously instilled with 0.15mg/kg esketamine (Drug batch number: 211222BL; 2mL/50mg, Jiangsu Hengrui Pharmaceutical, Co Lianyungang, China) 5min before the beginning of the surgery, while the control group (group C) was administered the same volume of normal saline similarly.

Anesthesia Protocol

Anesthesia protocols were standardized, and no anticholinergic agents were used as premedication. All patients received standard monitoring on admission to the operating theatre, including oxygen saturation (SpO2), ECG, noninvasive blood pressure, invasive arterial blood pressure, and the Bispectral Index (BIS).30

Anesthesia induction was performed by sequential administration of midazolam [(0.04 mg/kg), 1mL/5mg, Jiangsu Enhua Pharmaceutical Co, Xuzhou, China], sufentanil [(0.3µg/kg), 1mL/µg, Yichang Renfu Pharmaceutical Co, Yichang, China], propofol [(1–2 mg/kg), 20mL/0.2g, Sichuan Guorui Pharmaceutical Co, Leshan, China] and cisatracurium [(0.15 mg/kg, 5mL/10mg, Jiangsu Hengrui Pharmaceutical Co, Lianyungang, China)]. All patients were intubated 3 minutes afterward and then mechanically ventilated with 100% oxygen, VT 8–10mL/kg, frequency 10–14/min, keeping an end-tidal CO2 of 30–40 mmHg during the surgery procedure. Sufentanil 0.1µg/kg was administrated before the skin incision. The anesthesia was maintained with a continuous intravenous infusion of propofol 4–12 mg/kg/h and remifentanil 15-40 μg/kg/h (1mg, Jiangsu Enhua Pharmaceutical Co, Xuzhou, China), with intermittent injections of cisatracurium to maintain muscle relaxation and concentration titration to maintain hemodynamic stability and adequate depth of anesthesia (BIS values 40–60). Ketorolac 30mg (1mL/30mg, sdnewtimes pharmaceutical Co, Xinyi, China) was given intravenously 5 minutes before sewing and the intravenous administration of anesthetics was stopped 5min before the end of the operation. Reversal of residual neuromuscular blockade was done with a mixture of neostigmine [(0.02 mg/kg), 1mL/0.5mg, Henan Runhong Pharmaceutical Co, Zhengzhou, China] and atropine[(0.01 mg/kg), 1mL/0.5mg, Tianjin Jinyao Pharmaceutical Co, Tianjin, China] and the patient was extubated. Patients were subsequently transferred to the ward after 15min monitoring without a continuous postoperative analgesia program proposed by the anesthesiologist. Rescue analgesia was provided with ketorolac 30mg IV injection whenever the patient complained of a Visual Analogue Scale. (VAS) score equal to or more than 4, and the maximum total daily was not allowed to exceed 120mg.

Demographic data were self-reported by participants, and other medical data were obtained from hospital medical records.

Neuropsychological Testing and Diagnosis of PND

All patients received a standard battery of neuropsychological tests before surgery, at 7 days and 3 months after surgery, while the health volunteers underwent testing in a corresponding time interval. According to a 1995 consensus statement (CS)31 and recommendations from the International Study on Postoperative Cognitive Dysfunction, this series of neuropsychological tests was chosen (ISPOCD).4,32 It consisted of the Trail Making Test (Part A), the RAVLT Memory Test, the Verbal Fluency Test, the Finger Tapping Test, the Digit Symbol subtest of the Wechsler Adult Intelligence Scale (Chinese version), the Digit Span (forward and backward) subtest of the Wechsler Memory Scale (Chinese version), the Grooved Pegboard Test, and the Block Test 9 tests. The neuropsychological testing battery used here was designed to measure short- and intermediate-term memory, attention and concentration, executive function, and psychomotor skills. All neuropsychological tests were conducted by an independent experienced psychiatrist blinded to the trial.

According to the International Study of PND definition,4 PND was diagnosed by calculating the “Z-score”. In each test, the Z value was obtained by subtracting the mean change in healthy controls from the difference between the postoperative score and the preoperative baseline score and then dividing it by the standard deviation of the health volunteers’ change score. The cognitive decline was defined as those with a Z-score ≤−1.96 on at least 2 different tests.

Plasma Samples

There has been a good supply of evidence confirming that patients who develop POCD show increases in serum and cerebrospinal fluid (CSF) pro-inflammatory cytokines,33,34 particularly interleukin 6 (IL-6) and S100β.35,36 Therefore, we investigated whether esketamine could alleviate postoperative cognitive deficits by detecting the levels of S100β and IL-6 in serum.

The plasma samples were collected to detect the levels of S100β and IL-6 before surgery and 1 day after the surgery. A peripheral blood sample of 5 mL was taken and put into EDTA anticoagulant tubes. The samples were immediately centrifuged at 3000×g for 10 min at 4 °C and stored at −80°C for subsequent analysis. Serum IL-6 and S100β were measured by using commercially available ELISA kits (Boster Biological Technology Co, Wuhan, China, and Signalway Antibody Co, Nanjing, China), according to the manufacturer’s instructions.

Statistical Analysis Sample Size Calculation

PASS 15.0 software was used to calculate the sample size. According to previous reports, the incidence of POCD in geriatric patients with gastrointestinal tumors is 40%.37 The pilot study showed that esketamine administration could reduce the incidence of PND by 30%. Given a power of 85% and a significance level of 5%, the sample size was determined to be 66, with 33 subjects in each arm using a 1:1 ratio for the groups. We added 20% for missing data or attritions, so a final sample size of 84 patients (42 patients per group) was recruited.

Data Analysis

We used IBM SPSS version 25 (IBM SPSS, Armonk, NY) for all analyses. Continuous variables were presented as a mean or median (interquartile range) and processed with Student’s t-test. Categorical variables were presented as the number of patients and processed with the Chi-squared test or Fisher’s exact probability test. The levels of plasma S-100β and IL-6 were analyzed by one-way repeated measures ANOVA. P<0.05 was considered statistically significant.

Result Enrolled Patients

A study flow diagram is shown in Figure 1. A total of 84 patients were scheduled to undergo gastrointestinal surgery under general anesthesia and 15 volunteers were recruited for this study. Seventeen patients were excluded due to Parkinson’s (n=1), low education (n=3), poorly controlled hypertension (n=1), admission to the ICU after surgery (n=1), refusal to participate in the study (n=7), serious complications after surgery (n=1), and missing follow-up at 3 months after surgery (n=3). Ultimately, 67 patients were included in the analysis, 34 in group C and 33 in group S. The demographic data of surgical patients and healthy volunteers were comparable (Table 1).

Table 1 Baseline Characteristics of Surgical Patients and Volunteers

Figure 1 Enrollment flowchart.

Demographic, Clinical, and Surgical Characteristics

Demographic and clinical and surgical variables were similar between group C and group S (P>0.05), except for the higher dose of remifentanil (P=0.003), an increased postoperative VAS scores (P=0.032), an elevated ketorolac consumption (P=0.043) in group C (Table 2).

Table 2 Demographic, Clinical, and Surgical Characteristics in Both Groups

Cognitive Outcomes

Table 3 summarizes the neuropsychological test results. According to the above diagnostic criteria, 5 patients in group S (18.75%) and 13 patients in group C (38.24%) were diagnosed with dNCR at 7 days after surgery, while 2 patients in group S (6.06%) and 5 patients in group C (14.71%) were diagnosed with POCD at 3 months after surgery. The incidence of dNCR at 7 days after surgery was lower in group S, compared with patients in group C (P<0.05); however, the incidence of POCD 3 months after surgery was similar in both groups (P>0.05) (Table 4).

Table 3 Neuropsychological Test Results

Table 4 Incidence of PND in Both Groups

Patient scores on the different tasks are presented in Table 5. Compared with Group S, patients in group C performed worse primarily in the delayed memory panel of the RAVLT memory test (P<0.05), the Grooved Pegboard Test (P<0.05), and the Finger Tapping Test (P<0.05) 7 days after surgery (Table 5).

Table 5 Performance in Neuropsychological Test

Serum IL-6 and S100B Levels

The plasma levels of S-100β and IL-6 presented similar varying trends in both groups increasing significantly (Figures 2 and 3, P<0.05) at 1-day post-surgery compared to preoperative, and plasma levels at 1 day after surgery in the S group were dramatically lower than those of the C group (Figures 2 and 3, P<0.05).

Figure 2 Plasma IL-6 concentrations (pg/mL) at different time points.*P<0.05.

Figure 3 Plasma S100β concentrations (pg/mL) at different time points. *P<0.05.

Discussion

A systematic review and meta-analysis including six RCTs have suggested that ketamine intraoperative administration may offer some protection towards POCD; however, the grade quality of evidence was very low.38 The effect of ketamine on postoperative cognitive function remains controversial,39,40 confusing the research on esketamine. In the present study, we found that the esketamine group performed better than the control group on the delayed memory panel of the RAVLT memory test, grooved pegboard test, and finger tapping test at 7 days postoperatively. The observed results indicated that a single dose of 0.15mg/kg esketamine could reduce the incidence of dNCR 7 days following surgery and improve early postoperative cognitive function in elderly patients undergoing gastrointestinal surgery but without any impact on long-term neuro-cognitive prognosis. Our result was consistent with the study by Tu et al41 and highlighted the neuroprotective property of esketamine.

To date, there is no defined dose range of sub-anesthetic dose esketamine available. It has been documented that the sub-anesthetic dose of ketamine is in the range between 0.3 and 0.5mg/kg.42 As esketamine has twofold higher potency compared with racemic ketamine,19 it is generally accepted that the range of sub-anesthetic dose of esketamine is 0.15–0.25 mg/kg. A sub-anesthetic dose of 0.2mg/kg esketamine was applied in a majority of research.43 However, it has also been reported that patients exhibited post-operative mental symptoms even at a sub-anesthetic dose of 0.25mg/kg esketamine.44 Considering subjects of this study were elderly who underwent gastrointestinal surgeries, we selected the smaller dose of 0.15mg/kg of esketamine.

A previous study39 compared the effect of esketamine to remifentanil on the neurocognitive outcome after open-heart surgery in 106 patients has concluded that esketamine offers no greater neuroprotection. Considering the anti-inflammatory45 and neuroprotective46 effects of remifentanil used in the control group, we do not think the neuro-protective effect of esketamine could be ignored.

Our study also found that the plasma level of IL-6 and S100β protein in group S was significantly lower than that in group C, confirming the anti-inflammatory and neuroprotective properties of esketamine. IL-6 increases after surgery and is positively correlated with the severity of surgical trauma, thereby regarded as an inflammatory biomarker presenting surgery-related injury.47 S100β is a class of calcium-binding proteins found mainly in central glial cells such as astrocytes and microglia. When central neurons and the BBB are damaged, S100β release and increase its level in the peripheral blood.48 Therefore, an increase in peripheral S100β is considered a specific marker of brain injury.49 We speculated that esketamine administration might inhibit the release of surgery-induced peripheral inflammatory cytokines and then suppress neuro-inflammation in CNS and neuronal apoptosis. Esketamine has been demonstrated to be effective in suppressing neuro-inflammation in rodent models,50,51 which supported our perspective to some extent.

Early-stage research in cardiac surgery under extracorporeal circulation has shown that the administration of a single IV low dose of ketamine (0.25 mg/kg) at induction of anesthesia steadily reduced the production of IL-6 until the seventh postoperative day, a long time after ketamine has disappeared from patients’ blood.52 Likewise, we proposed that esketamine might also have a similar mode of action; thus, a single dose of esketamine could improve cognitive decline 7 days after surgery but not 3 months post-operatively.

Aside from the neuroprotective activity mentioned above, this study presented the advantage of sub-anesthetic doses of esketamine as an adjuvant of general anesthesia. Esketamine exerted less opioid consumption and relatively mild adverse responses. We did not find a delayed recovery time in group S, which seemed inconsistent with the study by Zhang et al24 0.2mg/kg esketamine used in their study, higher than 0.15 mg/kg in the present study, might explain the difference in recovery following surgery.

This study has some limitations. First, the relatively small number of patients we recruited provides evidence for the effect of esketamine on reducing the incidence of PND in patients undergoing gastrointestinal surgery, but further studies would require some multicenter, large-sample clinical trials to validate it. Second, we only examined the changes in serum inflammatory factor levels in patients 1 day before and after surgery and did not examine their long-term postoperative levels, which is not sufficient to reflect the dynamic changes in serum inflammatory factors. Finally, the concentration of S100β and IL-6 in the cerebrospinal fluid may be more appropriate for assessing central neuro-inflammation. However, ethical issues limit the collection of cerebrospinal fluid in the current study.

Conclusions

In summary, the administration of subanesthetic doses of esketamine before the initiation of surgery could attenuate early postoperative cognitive impairment. The underlying mechanism might be related to the anti-neuro-inflammatory and neuroprotective effects of esketamine.

Data Sharing Statement

An unauthorized version of the Chinese MMSE was used by the study team without permission. The MMSE is a copyrighted instrument and may not be used or reproduced in whole or in part, in any form or language, or by any means without written permission of PAR (www.parinc.com). The datasets generated during and/or analyzed during the current study are not publicly available due to the privacy policy but are available from the corresponding authors on reasonable requests.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the General Program of Health Commission of Wuxi (grant number, MS201934), the Double hundred top talent project of Wuxi (grant number, HB2020109), and the General Program of Health Commission of Jiangsu (grant number, M2021069).

Disclosure

The authors declare that they have no competing interests in this work.

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