Effect of esketamine on postoperative sleep disturbance in patients undergoing spinal surgery: a study protocol for a randomised, double-blinded, placebo-controlled clinical trial
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* Minyu Jian
* Yiwei Chen
* Shuo Wang
* Yang Zhou
* Haiyang Liu
* Fa Liang
* Ruquan Han
* Huiwen Wang

## Abstract

**Introduction** Postoperative sleep disturbance (PSD) is a common complication after spinal surgery that can be related to postsurgical pain, perioperative anxiety and depression. Recent studies have shown that esketamine may improve sleep disturbance after surgery; however, it remains unclear whether intraoperative infusion of esketamine can improve the postoperative sleep quality of patients undergoing spinal surgery.

**Methods and analysis** This is a protocol for a randomised, double-blinded, placebo-controlled clinical trial to evaluate the effect of esketamine on PSD in patients undergoing spinal surgery. Patients aged 18–65 years who plan to undergo selective spinal surgery will be randomly allocated to the esketamine group or control group at a ratio of 1:1. Esketamine or saline will be infused at the same speed of 0.3 mg/kg/hour during the surgery by the anaesthesiologists in charge, who are blinded to the randomisation. The primary outcome of the study is the incidence of PSD during the first 3 days after surgery. The secondary outcomes include objective sleep quality, numeric rating scale scores, dosage of analgesics and Hospital Anxiety and Depression Scale scores.

**Ethics and dissemination** The study was approved by the Ethical Committee of Beijing Tiantan Hospital, Capital Medical University (KY2024-013-02),Beijing, China. The study was registered on ClinicalTrials.gov on 4 June 2024 (NCT 06451627). Our study might guide perioperative anaesthesia management plans and improve PSD in patients undergoing spinal surgery. The findings of the study will be published in peer-reviewed journals and will be presented at national or international conferences.

**Trial registration number** [NCT06451627](http://bmjopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06451627&atom=%2Fbmjopen%2F15%2F3%2Fe090089.atom).

*   Anaesthesia in neurology
*   Anaesthesia in orthopaedics
*   Sleep medicine

### STRENGTHS AND LIMITATIONS OF THIS STUDY

*   This study is a randomised controlled trial to evaluate the effect and safety of esketamine on postoperative sleep disturbance (PSD) of patients undergoing spinal surgery.

*   Participants and evaluators will be blinded to the type of drug administered until the final statistical analyses are completed.

*   This study will use both self-reported sleep information and objective sleep information measured by a smart wristwatch to measure the sleep quality.

*   This study does not include the efficacy and safety of esketamine nasal spray or oral administration for PSD.

## Introduction

Postoperative sleep disturbance (PSD), which can result in sleep fragmentation, deprivation and a reduction in slow-wave sleep (SWS) and rapid eye movement (REM) sleep, is one of the most common complications after major surgery, and its incidence varies from 30 to 80%.1 The incidence of PSD after spinal surgery is approximately 61.4%.2 Previous investigations have reported that continued PSD can cause chronic pain or increased pain sensitivity, heightened stress levels, delirium, gastrointestinal dysfunction, increased risk of cardiovascular events and decreased immune responses.3 Therefore, sleep promotion is one of the most important ways to help surgical patients recover by reducing delirium, pain, fatigue and cognitive dysfunction.

PSD is associated with factors such as the type of anaesthesia, postoperative pain, the ward environment and psychological factors such as preoperative anxiety or depression.4 Currently, clinical treatments considered to improve PSD include enhanced analgesia and non-pharmacological5 and pharmacological interventions6 (such as melatonin). Inadequate pain control, which remains a main problem for postoperative management, can impact patients’ sleep and rehabilitation to a large extent.7 ,8 Opioids are commonly used for postoperative analgesia after spinal surgery; however, they do not improve but rather worsen postoperative sleep by decreasing the duration of REM sleep and non-rapid eye movement stage 3 sleep and increasing the apnoea-hypopnoea index.9 Therefore, it is necessary to consider other analgesics and administer multimodal analgesia.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is the only intravenous anaesthetic drug that has both sedative and analgesic effects. Esketamine is a right-handed monomer of ketamine that retains all the advantages of ketamine and has a stronger affinity for NMDA receptors. A meta-analysis10 showed that esketamine can assist in analgesia and decrease the intensity of pain within 24 hours after surgery, as well as reduce the total dosage of opioid analgesics. In addition, previous studies reported that subanaesthetic doses (0.2 mg/kg and 0.4 mg/kg, intravenously) of esketamine have a rapid and powerful therapeutic effect on patients with treatment-resistant depression.11 Recently, there has been increasing interest in its ability to improve sleep disturbance because of its anti-inflammatory, powerful analgesic and antidepressant effects.12 In addition, esketamine may affect circadian genes to regulate sleep-wake and circadian systems.13 Duncan *et al* reported that ketamine may act on clock-related molecules and brain-derived neurotrophic factor levels, leading to alterations in the circadian rhythm of the central clock, increasing total sleep, REM sleep, and SWS and improving sleep quality in patients with treatment-resistant depression.14 Initial studies have shown that intraoperative and postoperative infusion of esketamine can improve PSD15 in patients after gynaecological laparoscopy. However, only a few high-quality clinical studies have confirmed the effect of esketamine on PSD in surgical patients.

Since research on the effect of esketamine on PSD in patients undergoing major spinal surgery is scarce and objective measures of sleep are lacking,15 this randomised, double-blinded, placebo-controlled clinical trial will be conducted. The primary outcome is the incidence of PSD, defined as an Athens Insomnia Scale (AIS) score of 6 points or higher during the first 3 days after surgery. Objective monitoring of postoperative sleep will also be performed as a secondary outcome.

## Methods/design

### Study design

This study is a prospective, single-centre, randomised, double-blinded, placebo-controlled clinical trial that will be carried out at Beijing Tiantan Hospital, Capital Medical University, Beijing, China. The trial was approved by the Institutional Review Board of Beijing Tiantan Hospital (KY2024-013-02) and registered at ClinicalTrials.gov (NCT 06451627) on 4 June 2024. All participants or their legal representatives will sign informed consent (see online supplemental material) after screening and before randomisation.

### Supplementary data

[[bmjopen-2024-090089supp001.pdf]](pending:yes) 

The study is recruiting participants. The study started on June 10th 2024, and the anticipated completion date is December 28th 2025.

### Participant recruitment

#### Inclusion criteria

1.  Aged 18–65 years.

2.  American Society of Anesthesiologists (ASA) physical status classification of I–III.

3.  Patients scheduled to undergo elective spinal surgery under general anaesthesia.

4.  Signed informed consent.

#### Exclusion criteria

1.  Body mass index ≥35 kg/m2.

2.  Severe lesions of important organs.

3.  The estimated duration of surgery is more than 4 hours.

4.  Patients who were retained for tracheal intubation or admitted to the intensive care unit postoperatively.

5.  History of adverse reactions or contraindications to ketamine or esketamine.

6.  Patients with cognitive dysfunction or communication disorders.

7.  Patients who refused to participate in this study.

### Randomisation and blinding

All patients scheduled for spinal surgery will be screened 2 days before surgery for eligibility. They will be informed about the aims, procedures, benefits, possible risks of study and how to react if risks occur. Written informed consent will be obtained during preoperative evaluation by an anaesthesiologist. Subsequently, each patient will be randomly allocated to either the esketamine group or the control group at a 1:1 ratio using a variable block randomisation method. All study-related investigators will be blinded to the randomisation results.

Dispensing and labelling of the study drugs will be performed by an independent nurse. Esketamine (Hengrui Induction, Jiangsu, China) will be diluted to a concentration of 1 mg/mL with normal saline. Both esketamine and normal saline will be kept in syringes (50 mL) with the same appearance and labelled with ‘the trial drugs, randomisation code’. The trial drug will be given to the participants at a speed of 0.3 mL/kg/hour during the surgery. The labelled syringes will be distributed to the attending anaesthesiologists responsible for anaesthetic management after induction. The anaesthesiologists, assessors and patients will be blinded to the type of drug administered until the final statistical analyses are completed. The administered drug will be unmasked during medical treatment when severe adverse events related to esketamine occur, with the agreement of the primary investigator.

### Anaesthesia management

The baseline characteristics will be collected before administering anaesthesia, including date of birth, gender, height, weight, allergy history, medical history, diagnosis, type of surgery, preoperative sleep quality by Pittsburgh Sleep Quality Index (PSQI) and ASA physical status.

Standard ASA parameters, including blood pressure, ECG, pulse oxygen saturation, body temperature and end-tidal carbon dioxide partial pressure, will be monitored perioperatively. Anaesthesia induction will be conducted with 1–2 mg/kg propofol or 0.3 mg/kg etomidate, 0.2–0.4 µg/kg sufentanil and 0.6 mg/kg rocuronium or 0.1–0.15 mg/kg cisatracurium. Total intravenous anaesthesia with propofol, remifentanil and the ‘trial drug’ will be implemented for anaesthesia maintenance based on the bispectral index (BIS) and will be maintained between 40 and 60. The surgeon will perform wound infiltration with 20 mL of 0.5% ropivacaine after the last suture.

Patient-controlled analgesia devices will be applied after surgery by using sufentanil (2 µg/kg) and ondansetron (16 mg) in a total volume of 100 mL to maintain Numeric Rating Scale (NRS) scores ≤3. The device is programmed to administer a background dose of 2 mL/hour, as well as a bolus dose of 0.5 mL with a lockout interval of 15 min for 48 hours. Other analgesics could be used for rescue therapy for severe pain (NRS score >3) during the postoperative period and should be recorded.

### Outcomes

The primary outcome of the study is the incidence of PSD during the first 3 days after surgery, which will be evaluated using the AIS on the mornings (08:00–10:00) of postoperative days (PODs) 1–3, and a score of 6 or higher is defined as PSD.

The secondary outcomes included the following:

1.  Objective sleeping quality will be assessed with a wristwatch (Huawei Watch GT3 Pro, Huawei Technologies Co, Shenzhen, China) on the first and third nights after surgery. The wristwatch connects to a mobile app via Bluetooth and generates a sleep report that covers total sleep time, light sleep time, deep sleep time, the number of awakenings and so on.

2.  Postoperative pain assessment: postoperative pain at rest and during movement will be evaluated on the mornings (08:00–10:00) of PODs 1–3 using an 11-point NRS (0 indicating no pain and 10 indicating the worst pain imaginable). The analgesic consumption and supplemental analgesic use within 72 hours will also be recorded.

3.  Postoperative anxiety and depression assessment: postoperative anxiety and depression scores will be measured using the Hospital Anxiety and Depression Scale on the mornings (08:00–10:00) of PODs 1 and 3, and a score of 8 points or higher indicated depression or anxiety.

Safety outcomes will include all drug-related adverse events, including bradycardia, hypotension, tachycardia, hypertension, arrhythmia, nystagmus, hypersalivation, euphoria, emergence agitation, hallucinations, dreaminess and nightmares during surgery or before discharge. Patients will be followed up for 3 consecutive days (08:00–10:00).

### Data management

All paper versions of the original materials, including the protocol, case report forms and informed consent forms, will be photographed and saved in an encrypted database. All electronic data will be stored in the electronic medical records of Beijing Tiantan Hospital. All procedures for evaluating endpoints will be filmed and saved.

### Sample size calculation

The PASS V.15 software (NCSS, LLC, USA) was used to calculate the sample size based on the primary endpoint. According to the previous study,15 the incidence of PSD after surgery is approximately 44%, and we hypothesised that the incidence of PSD will decrease to 22% after esketamine infusion. Taking this into account, the sample size in each group should be 78 to achieve a power of 80% at a two-tailed significance level of 0.05, with a drop-out rate of 10%.

### Statistical analysis

The statistical analysis will be performed by an independent statistician using SPSS V.25.0 (Somers, NY, USA). The data will be analysed on a per protocol basis. Descriptive statistics of all variables describing the characteristics of the patients enrolled in the study and those excluded from the study will be analysed. All measurement data will be analysed for a normal distribution and homogeneity of variance. Normally distributed data will be presented as means±SDs. Non-normally distributed data will be presented as medians. Categorical variables will be summarised as per cent and numbers of patients.

The primary endpoint of the incidence of PSD during the first 3 days will be analysed using the χ2 test or Fisher’s exact test. The secondary outcomes will be analysed using t-tests, Mann-Whitney U tests and χ2 or Fisher’s exact tests, as appropriate. A logistic regression model will be used to assess the potential risk factors associated with PSD. A two-sided p value <0.05 will be considered to indicate statistical significance. No interim analysis will be performed, and the study will be terminated after enrolment of the last patient.

### Reporting of adverse events

All adverse events associated with this trial will be recorded in detail and closely monitored until resolution or stabilisation or until it has been shown that study treatment is not the cause of the event. The principal investigator will be responsible for reporting all adverse events. Once adverse events occur, they should be immediately reported to the ethics committee within 24 hours and informed to the principal investigator to determine the severity of the adverse events.

### Patient and public involvement

Patients and the public will not be involved in the trial design. Participants will have access to the findings of the study on request.

### Ethics and dissemination

Approval for the study was provided by the Ethical Committee of Beijing Tiantan Hospital, Capital Medical University (KY2024-013-02). The study was registered on ClinicalTrials.gov on 4 June 2024. The findings of the study will be published in peer-reviewed journals and will be presented at national or international conferences.

## Discussion

This study explored the efficacy and safety of intraoperative esketamine infusion on PSD in patients undergoing elective spinal surgery with general anaesthesia. Participants will receive either esketamine or saline infusion at a speed of 0.3 mg/kg/hour during the surgery. Moreover, propofol and remifentanil were implemented for anaesthesia maintenance based on the BIS, and the BIS was maintained between 40 and 60. Both subjective and objective sleep measures will be assessed after surgery. The adverse events will also be observed and reported.

Pain is a main cause of PSD in surgical patients and can prolong sleep latency and reduce total sleep time.7 However, it is extremely difficult to manage postoperative pain in patients undergoing orthopaedic surgery, especially spinal surgery. Opioids, commonly used clinical analgesics, have many adverse effects, including respiratory depression, nausea, vomiting and postoperative hyperalgesia, and can also cause PSD characterised by a reduced duration of SWS, REM suppression and increased duration of arousal.16 Therefore, multimodal analgesia can better control postoperative pain through nerve blockade and the use of non-opioid medications such as esketamine. Esketamine infusion can relieve postoperative pain in a dose-dependent manner within 24 hours, and a higher dose of esketamine can prolong analgesic time and increase sleep quality.17 

A meta-analysis18 showed that a subanaesthetic dose of ketamine (0.1–0.5 mg/kg) can decrease pain intensity and opioid consumption within 48 hours after spinal surgery, but it may cause adverse central nervous system (CNS) events such as hallucination, confusion, disorientation, nightmares and drowsiness, which can affect the sleep experience. The incidence of CNS adverse events was 13.7%.18 Qiu *et al* 15 reported that intraoperative infusion of esketamine (0.3 mg/kg/hour) has a prophylactic effect on PSD in surgical patients, and 1 patient reported having nightmares. Therefore, particular attention will still be paid to the side effects of esketamine, especially CNS adverse events.

Both objective and subjective measures can assess sleep quality. However, it is worth noting that self-reported perceived sleep can differ from objective findings, including those from actigraphy and polysomnography (PSG), in normal sleepers and insomnia patients.19 20 Therefore, a comprehensive assessment of sleep often requires a combination of subjective and objective measures. Previous studies on the prophylactic effects of esketamine on PSD in surgical patients lacked objective sleep indicators.15 Although PSG is the gold standard for objective sleep monitoring, it is impractical for use in the clinical environment, especially for patients after spinal surgery. Alternative devices, such as actigraphy devices, can assess general sleep quality and have been validated in several populations.16 Therefore, a smart wristwatch (Huawei Watch GT3 Pro, Huawei Technologies Co, Shenzhen, China) was chosen to monitor objective sleep. Both self-reported subjective measures, including the AIS/PSQI and objective measures, including total sleep time, light sleep time, deep sleep time and the number of awakenings, will be used for outcomes in our study.

Our study also has several limitations. First, intravenous, nasal spray or oral administration of esketamine alone or in combination has been reported to improve sleep disturbance in depressive patients,21 but this study will only administer esketamine intravenously, and the efficacy and safety of esketamine nasal spray or oral administration for PSD in spinal surgery should be explored in the future. Second, the authors focused only on the effects of esketamine on perioperative sleep disturbance and did not explore its long-term effects on sleep. Third, the study is a single-centre trial, and multicentre trials are needed in the future to verify the effects of esketamine infusion on PSD after other major surgeries. Supplement use of esketamine and dexmedetomidine in patient-controlled sufentanil analgesia has been shown to improve the analgesia and subjective sleep quality after scoliosis correction surgery. Further studies should be performed to investigate whether the postoperative use of esketamine will improve the sleep quality of these patients.

In summary, this is a double-blinded randomised controlled trial focusing on the effect of esketamine on the subjective and objective sleep quality of patients undergoing spinal surgery.

## Data availability statement

Data are available upon reasonable request.

## Ethics statements

### Patient consent for publication

Consent obtained from parent(s)/guardian(s).

## Footnotes

*   MJ and YC are joint first authors.

*   MJ and YC contributed equally.

*   Contributors HW and MJ conceived the primary idea of the study. All authors contributed to the writing of the protocol. HW and YC drafted this paper in close cooperation with MJ. The study will be executed by HW, YC, SW, YZ, HL, FL, RH and MJ. Data analysis will be performed by YC and MJ. All authors have read and approved the final manuscript. HW is responsible for the overall content as guarantor.

*   Funding This study is supported by funding from the Beijing Municipal Medical Administration Youth Talent Plan (QML20230509).

*   Competing interests None declared.

*   Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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