Correspondence to Dr Jun Zhang; [email protected]
STRENGTHS AND LIMITATIONS OF THIS STUDY
Esketamine will be administered via the epidural route.
The intraoperative and postoperative use of esketamine may extend the drug exposure.
Key confounding factors, including postoperative pain, depression, anxiety and surgery start time, will be meticulously recorded.
If required, subgroup analyses will be employed to reduce potential confounding biases.
Given that this is a single-centre trial, additional validation in other institutions is essential.
Introduction
General anaesthesia has been shown to impair postoperative sleep pattern.1 The incidence of postoperative sleep disturbance (PSD) has been reported to vary between 44% and 71%.2 3 PSD is associated with an increased risk of more serious postoperative pain and cardiac arrest.4 5 Additionally, postoperative sleep quality (PSQ) has been linked to postoperative recovery.6 Previous studies have identified risk factors for PSD as including male gender, anxiety, depression, light exposure and moderate to severe pain.7 The use of earplugs and eye masks did not significantly improve PSQ in patients undergoing major abdominal surgeries.8 Furthermore, the reported compliance rate for using earplugs and eye masks was a mere 60%. These results suggested that reduced light and noise exposure offered only limited benefits in improving PSQ. Prior studies have reported that invasive interventions, including stellate ganglion block and transcutaneous electrical acupoint stimulation, can improve PSQ.9 10 However, a high complication rate has been associated with stellate ganglion block.11 Additionally, the requirement for additional equipment in transcutaneous electrical acupoint stimulation limits its widespread use. Recently, there has been an increased focus among researchers on pharmacological intervention to improve PSQ.12
Regarding pharmaceutical interventions, dexmedetomidine, esketamine and tramadol have been used to improve PSQ.13 14 Recent studies have reported that intravenous esketamine could improve PSQ in patients receiving gynaecological laparoscopy and scoliosis correction surgery.3 15 Researchers have hypothesised that esketamine could improve PSQ due to its analgesic and antidepressant properties. Ketamine is non-inferior to electroconvulsive therapy in the treatment of nonpsychotic treatment-resistant major depression.16 The use of esketamine intraoperatively, as opposed to postoperatively, might yield a relatively short-term effect in improving PSQ. In the study by Qiu et al,3 the follow-up period extended only over 3 days. Previous studies have documented the use of intraoperative and postoperative epidural administration of esketamine for analgesia and opioid-sparing.17 18 However, to the best of our knowledge, the impact of perioperative epidural administration of esketamine on improving PSQ has yet to be thoroughly investigated.
To address this research gap, we have designed a randomised, double-blind, parallel-group controlled trial to explore the effect of epidural esketamine on PSQ in patients undergoing laparoscopic and robotic lower abdominal surgeries. Our hypothesis posits that epidural esketamine may improve PSQ, particularly in patients tending towards depression.
Methods and analysis
Study design and patients
The study protocol adheres to the guidelines of Standard Protocol Items: Recommendations for Interventional Trials. This is a single-centre, randomised, double-blind, parallel-group controlled clinical trial. The study is set to be conducted at Shanghai Cancer Centre in China. The study flow diagram is presented in figure 1. Details regarding patient enrolment, study intervention and outcome assessment are provided in online supplemental material 1.
Enlarge this image.Figure 1. The flow diagram of the study. Poor sleep quality is defined as the Pittsburgh Sleep Quality Index score >5. HAD, Hospital Anxiety and Depression Scale; PACU, postanaesthesia care unit; NRS-s, Numeric Rating Scale of Sleep.
Inclusion criteria
Inclusion criteria are as follows: (1) An American Society of Anesthesiologists score of I–III. (2) Participants aged between 18 and 75 years. (3) Patients scheduled for robot-assisted or laparoscopic lower abdominal surgery, including surgeries for colon cancer, rectal cancer, colorectal cancer and prostate cancer.
Exclusion criteria
Exclusion criteria are as follows: (1) Patients incapable of reading or signing informed consent. (2) Individuals with poorly controlled hypertension (blood pressure >160/100 mm Hg). (3) Patients with blood coagulation dysfunction. (4) Patients with an allergy to ropivacaine. (5) Individuals with a history of glaucoma or ocular hypertension. (6) Patients diagnosed with or suspected of having schizophrenia. (7) Long-term user of sleeping pills. (8) Patients with severe coronary heart disease, recent myocardial infarction (within at least 6 months) or chest pain following light activity. (9) Individuals with known or suspected sleep apnoea.
Randomisation and blinding
Enrolled patients will be randomly allocated to either the intervention group or the control group in a 1:1 ratio. Randomisation will be conducted by an independent researcher (YZ) using SPSS software. The results of the randomisation will be securely sealed in opaque envelopes. An anaesthetist (GZ), not involved in the management of anaesthesia, will open the envelope 1 hour prior to the surgery. The independent anaesthetist (GZ) will then prepare the epidural medication in accordance with the allocated group. Anaesthetists managing the anaesthesia will remain blinded to the group allocation. After surgery, the follow-up visit will be conducted by a researcher (HY) who will also be blinded to the group allocation.
Study intervention
Regarding the intraoperative intervention, for the esketamine group, 0.2 mg/kg of esketamine will be combined with a specified amount of ropivacaine, subsequently diluted in 0.9% saline. Initially, ropivacaine (4 mg) and esketamine (20 mg) will be prepared and diluted in 0.9% saline to create a 20 mL mixture. The volume of the mixture to be used will be determined as (weight (kg)×0.2) mL, with the remaining mixture being discarded. Consequently, the final injection composition will consist of 0.2% ropivacaine combined with 1 mg/mL esketamine. For the control group, the epidural injection will consist of 0.2% ropivacaine, also diluted in 0.9% saline. The volume of the injection for both groups will be determined as (weight (kg)×0.2) mL.
Regarding the postoperative intervention, the analgesic regimen for the esketamine group will include: esketamine 25 mg, sufentanil 100 µg and ropivacaine 300 mg. For the control group, the analgesic regimen will comprise sufentanil 100 µg and ropivacaine 300 mg. Sufentanil is not replaced with esketamine in the formula due to concerns that opioid-free analgesia might lead to a relatively poor analgesic effect, as indicated in a previous study.18 The total volume for the patient-controlled analgesia pump will be set at 200 mL for both groups. The background infusion rate is set at 4 mL/hour, and the bonus dose is established at 4 mL. The locking time for the bonus dose will be fixed at 15 min. If a patient presses the bonus button during the locking time, the request will be recorded as an additional compression, but no bonus analgesics will be administered, defining this as a failed compression.
Perioperative management
The Pittsburgh Sleep Quality Index (PSQI) and the Hospital Anxiety and Depression Scale (HAD) assessments will be conducted 1 day prior to surgery. On the day of surgery, the sleep quality from the preceding night will be evaluated using the Numeric Rating Scale of Sleep (NRS-s, on a scale of 0–10, 0=worst possible sleep, 10=best possible sleep).
All patients will undergo routine monitoring in the operating room. An epidural puncture will be executed through T10–T11 or T11–T12 intervertebral spaces, with the epidural catheter being inserted to a depth of 4 cm. An initial test dose of 3 mL of 1% lidocaine will be administered. The allocated epidural injection (8–9 mL of specified drug, as detailed in the study intervention) will be administered in two stages prior to the commencement of surgery (once before and once after the induction of anaesthesia). Prior to the induction of anaesthesia, the level of epidural block will be assessed using wet cotton balls. Subsequent injections of 4–5 mL will be administered at 45 min intervals. Based on our institutional experience, with surgical durations typically lasting at least 90 min (often exceeding 2 hours), the prepared mixture is expected to be utilised entirely during the surgery. Should the surgery extend beyond the anticipated duration and additional epidural analgesia is required, further administration of 0.2% ropivacaine will be employed in both groups.
General anaesthesia induction will involve etomidate, propofol, sufentanil (at a dosage of 0.35 µg/kg) and rocuronium. Anaesthesia maintenance will use propofol (targeting a plasma concentration of 1 µg/mL), sevoflurane (at 0.7 MAC) and remifentanil (at a rate of 0.05 µg/kg×min). Rocuronium will be administered at 45 min intervals or as needed. The anaesthetist will cease the administration of inhaled anaesthetic 15 min before the end of the surgery. Granisetron (3 mg) will be administered as a prophylactic measure against postoperative nausea and vomiting.
A postoperative analgesia device will be implemented at the conclusion of the surgery. Patients will be transferred to the postanaesthesia care unit (PACU) following the surgery. Arterial blood gas analyses will be conducted on all patients before they depart from PACU. Patients will be discharged from the PACU once their Steward score >5. Sufentanil will be provided as rescue analgesia in the PACU for patient with a pain score >3.
The postoperative analgesia device will be discontinued between 10:00–12:00 hours on the second day after surgery (D2). Regarding rescue analgesia measures, oxycodone (2–3 mg) will be administered by the research team for patients with a pain score >4.
Primary and secondary outcomes
The primary outcome measure for the trial is the incidence of poor sleep quality on the third day after surgery (D3). Poor sleep quality is evaluated using the PSQI. Based on previous studies, good sleep quality is defined by a PSQI score ≤5 and poor sleep quality by a PSQI score >5.19 20
The secondary outcomes include (1) NRS-s assessments conducted on D1, D2, D3 and D5 and (2) Postoperative pain, encompassing both rest and movement pain. This will be assessed using a Numerical Rating Scale (NRS) on D0 (in PACU), and D1, D2, D3 and D5. Assessment for pain and sleep quality will occur between 10:00 and 12:00 hours and (3) The Depression and Anxiety score. Depression and anxiety scores will be evaluated on D3 using the HAD; (4) The numbers of analgesic pump compressions and failed compressions, both of which will be recorded and (5) The duration of stay in the PACU.
Safety outcomes
Safety outcomes encompass delirium, fidgeting, hallucinations, dizziness and nightmares. These events will be evaluated both in the PACU and during the follow-up period. If necessary, dexmedetomidine (at a dosage of 0.3 /kg) will be administered intravenously through a microinjection pump in the PACU. In the event of severe psychiatric symptoms during the follow-up period, the use of an analgesic pump will be discontinued. All adverse events and corresponding interventions will be meticulously documented in the case report forms (CRFs).
Data collection and monitoring
The anaesthetist will gather the demographic data (including age, sex and body mass index) along with perioperative data (such as surgical types and surgical duration). All follow-up data will be compiled by a researcher blinded to the group allocation. Analyses will be conducted based on intention-to-treat data. All collected data will be meticulously recorded in the CRFs. The CRFs will be securely stored in a locked cabinet under the supervision of the principal investigator until the enrolment is completed. A designated researcher will be responsible for entering these data into the electronic database.
The decision not to establish a data monitoring committee was based on two considerations: (1) Epidural esketamine usage in previous studies did not result in severe adverse events. Consequently, the associated risk of complications is considered relatively low. (2) This trial does not involve a large sample size. Moreover, the study will undergo continuous review by the ethics committee. During this trial, any serious adverse events related to ketamine (including severe disturbance of consciousness, convulsions and temporary blindness) must be reported immediately to the principal investigator (JZ). On such occurrences, the perioperative care team will administer timely treatment to safeguard patient safety. Furthermore, any serious adverse events will be reported to the Ethics Committee of Shanghai Cancer Centre within 24 hours. The ethics committee board will then deliberate and decide whether the study should continue, undergo modifications or be discontinued.
Sample size calculation
Sample size calculation was performed using the PASS software (V.2021, USA). According to previous studies, the incidence of poor sleep quality ranged between 65% and 70%.2 7 Consequently, for this study, the incidence of poor sleep quality was set at 65%. It was hypothesised that epidural esketamine could lower the incidence of poor sleep quality to 35%, based on a previous study indicating intravenous esketamine reduced the incidence of PSD by nearly half.3 The trial will ensure equal numbers of patients in both groups. The chosen test statistic was the two-sized Z test. The significant level for the test was set at 0.05, with a power of 90%. A minimal sample size of 54 was determined for each group. Taking potential drop-out into account, the sample size determined in the original protocol remains compelling. Ultimately, the plan is to enrol a total of 128 patients, allocating 64 patients to each group.
Statistical analysis
Data normality will be assessed using the Shapiro-Wilk normality test. For normally distributed data, means±SD will be used, while for non-distributed data, median (IQRs) will be employed. The independent sample t-test or the Mann-Whitney test will be applied to continuous data, depending on its distribution. Categorical data will be analysed using the χ2 test. Analyses will be conducted on an intention-to-treat basis. A significant level of 0.05 will be maintained for all analyses. All statistical analyses will be executed using SPSS software (V.26, USA).
Subgroup analyses will be conducted based on: (1) Preoperative HAD scores, categorised as either >7 or ≤7 for depression or anxiety scores. (2) Pain management effectiveness, with postoperative NRS score ≤3 classified as good pain control and score >3 or the use of rescue analgesia within the first two postoperative days (D1 and D2) indicating poor pain control.
Patients and public involvement
Patients and the public will not be involved in the design, enrolment, conduct and report of the study.
Ethics and dissemination
Ethical approval for this study has been obtained from the Ethics Committee of the Shanghai Cancer Center (2309281-9). The study protocol is registered with the Chinese Clinical Trial Registry (ChiCTR2300076862). All participating patients are to provide written informed consent 1 day prior to surgery. The manuscript shall be authored by our research team. Study results are to be disseminated through publication in a peer-reviewed journal.
Discussion
In this trial, the PSQI and NRS-s will be employed to assess PSQ. The PSQI is a prevalent tool for sleep dysfunction in clinical samples and has been extensively used in previous studies to assess PSQ.6 21 22 Our plan is to use the PSQI just once during the follow-up period, as an excessive number of questions might lead to invalid responses. The NRS-s is convenient and straightforward to use, having also been applied in previous study.15 However, a limitation of the NRS-s is its omission of some crucial information, such as sleep efficiency, sleep duration, sleep disturbances and the use of sleep medications. Therefore, employing both the PSQI and NRS-s may guarantee the reliability and completeness of data in this study.
A previous study has identified that multiple factors can influence PSQ.7 These main confounding factors include anxiety, depression and moderate to severe postoperative pain. In our study, the HAD and NRS will be used to identify these confounding factors. Furthermore, the time from onset to operation may also influence PSQ.23 Epidural analgesia will be employed for postoperative pain control, and the commencement time of surgery will be recorded. A prior meta-analysis has indicated that ketamine may ameliorate postoperative depression.24 However, in the study by Qiu et al,3 no significant differences were observed in depression scores between the two groups during the follow-up period. Therefore, this trial aims to explore whether depression symptoms are alleviated in patients within the esketamine group who experience improved sleep quality.
Another strength of this study’s design and methodology is its approach to statistical analysis. Given that PSD can stem from numerous factors, controlling potential confounding factors is imperative. In this trial, subgroup analyses will be employed to manage these potential confounding factors, thereby potentially reducing confounding bias.
A limitation of this study is its single-centre trial design. The study’s findings ought to be verified in other institutions. Another constraint of the study design is the exclusion of intravenous esketamine. An intravenous esketamine group was not established due to concerns regarding various types of postoperative analgesia. Given that postoperative pain is a crucial confounding factor, diverse forms of postoperative analgesia could amplify confounding bias. The third limitation concerns the variable duration of postoperative analgesia among patients. The analgesia pump is removed at a specific time point to mitigate bias in nocturnal pain scoring.
In conclusion, this randomised controlled trial aims to investigate the impact of epidural esketamine on PSQ following minimally invasive lower abdominal surgery. The outcomes of the trial are expected to furnish evidence regarding the association between epidural esketamine and the enhancement of PSQ.
We appreciated Anni Chen for the language polishing.
Ethics statements
Patient consent for publication
Not applicable.
YY and YZ contributed equally.
Contributors YY and YZ contributed equally to this work and are co-first authors. YY and JZ contributed to the conception and design of the study. YY and YZ will contribute to the enrolment and data collection. ZY will conduct the randomisation. GZ will conduct the allocation. HY will perform the follow-up. YY will write the manuscript. JZ will contribute to the critical revision of the manuscript. All authors have reviewed this protocol and agreed on the publication.
Funding This study was supported by the Medical Guidance Supporting Project of the Shanghai Municipal Science and Technology Committee (No.22Y11904200).
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.
1 Song Y, Liu Y, Yuan Y, et al. Effects of general versus subarachnoid anaesthesia on circadian melatonin rhythm and postoperative delirium in elderly patients undergoing hip fracture surgery: a prospective cohort clinical trial. EBioMedicine 2021; 70: 103490. doi:10.1016/j.ebiom.2021.103490
2 Yang S, Zhang Q, Xu Y, et al. Development and validation of nomogram prediction model for postoperative sleep disturbance in patients undergoing non-cardiac surgery: a prospective cohort study. Nat Sci Sleep 2021; 13: 1473–83. doi:10.2147/NSS.S319339
3 Qiu D, Wang X-M, Yang J-J, et al. Effect of intraoperative Esketamine infusion on postoperative sleep disturbance after gynecological laparoscopy: a randomized clinical trial. JAMA Netw Open 2022; 5: e2244514. doi:10.1001/jamanetworkopen.2022.44514
4 Chouchou F, Khoury S, Chauny J-M, et al. Postoperative sleep disruptions: a potential catalyst of acute pain. Sleep Med Rev 2014; 18: 273–82. doi:10.1016/j.smrv.2013.07.002
5 Miner SES, Pahal D, Nichols L, et al. Sleep disruption is associated with increased ventricular ectopy and cardiac arrest in hospitalized adults. Sleep 2016; 39: 927–35. doi:10.5665/sleep.5656
6 Niu Z, Gao X, Shi Z, et al. Effect of total intravenous anesthesia or inhalation anesthesia on postoperative quality of recovery in patients undergoing total laparoscopic hysterectomy: a randomized controlled trial. J Clin Anesth 2021; 73: 110374. doi:10.1016/j.jclinane.2021.110374
7 Seid Tegegne S, Fenta Alemnew E. Postoperative poor sleep quality and its associated factors among adult patients: a multicenter cross-sectional study. Ann Med Surg (Lond) 2022; 74: 103273. doi:10.1016/j.amsu.2022.103273
8 Leong RW, Davies LJ, Fook-Chong S, et al. Effect of the use of earplugs and eye masks on the quality of sleep after major abdominal surgery: a randomised controlled trial. Anaesthesia 2021; 76: 1482–91. doi:10.1111/anae.15468
9 Wang J, Lu F-F, Ge M-M, et al. Transcutaneous electrical acupoint stimulation improves postoperative sleep quality in patients undergoing laparoscopic gastrointestinal tumor surgery: a prospective, randomized controlled trial. Pain Ther 2023; 12: 707–22. doi:10.1007/s40122-023-00493-2
10 Yang R-Z, Li Y-Z, Liang M, et al. Stellate ganglion block improves postoperative sleep quality and analgesia in patients with breast cancer: a randomized controlled trial. Pain Ther 2023; 12: 491–503. doi:10.1007/s40122-022-00473-y
11 Goel V, Patwardhan AM, Ibrahim M, et al. Complications associated with Stellate ganglion nerve block: a systematic review. Reg Anesth Pain Med 2019. doi:10.1136/rapm-2018-100127 [ Epub ahead of print 16 Apr 2019 ].
12 Yang D, Yang L, Li Q, et al. Pharmacotherapy for improving postoperative sleep quality: a protocol for a systematic review and network meta-analysis. BMJ Open 2023; 13: e069724. doi:10.1136/bmjopen-2022-069724
13 Fu M, Chen S, Xu R, et al. Effects of intravenous analgesia using tramadol on postoperative depression state and sleep quality in women undergoing abdominal endoscopic surgery: a randomized controlled trial. Drug Des Devel Ther 2022; 16: 1289–300. doi:10.2147/DDDT.S357773
14 Huang X, Lin D, Sun Y, et al. Effect of dexmedetomidine on postoperative sleep quality: a systematic review. DDDT 2021; Volume 15: 2161–70. doi:10.2147/DDDT.S304162
15 Zhang Y, Cui F, Ma J-H, et al. Mini-dose esketamine-dexmedetomidine combination to supplement analgesia for patients after Scoliosis correction surgery: a double-blind randomised trial. Br J Anaesth 2023; 131: 385–96. doi:10.1016/j.bja.2023.05.001
16 Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med 2023; 388: 2315–25. doi:10.1056/NEJMoa2302399
17 Prabhakar P, Mariappan R, Moorthy RK, et al. Adding ketamine to epidural morphine does not prolong postoperative analgesia after lumbar laminectomy or discectomy. J Neurosurg Anesthesiol 2023. doi:10.1097/ANA.0000000000000914 [ Epub ahead of print 29 Mar 2023 ].
18 Yan H, Chen W, Chen Y, et al. Opioid-free versus opioid-based anesthesia on postoperative pain after thoracoscopic surgery: the use of intravenous and epidural esketamine. Anesth Analg 2023; 137: 399–408. doi:10.1213/ANE.0000000000006547
19 Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Research 1989; 28: 193–213. doi:10.1016/0165-1781(89)90047-4
20 Chen HC, Hsu NW, Chou P. Subgrouping poor sleep quality in community-dwelling older adults with latent class analysis - the Yilan study, Taiwan. Sci Rep 2020; 10: 5432. doi:10.1038/s41598-020-62374-4
21 Mollayeva T, Thurairajah P, Burton K, et al. The Pittsburgh sleep quality index as a screening tool for sleep dysfunction in clinical and non-clinical samples: a systematic review and meta-analysis. Sleep Med Rev 2016; 25: 52–73. doi:10.1016/j.smrv.2015.01.009
22 Lei M, Zhang P, Liu Y, et al. Propofol and Sufentanil may affect the patients' sleep quality independently of the surgical stress response: a prospective Nonrandomized controlled trial in 1033 patients' undergone diagnostic upper gastrointestinal Endoscopy. BMC Anesthesiol 2017; 17: 53. doi:10.1186/s12871-017-0341-3
23 Yang R, Xu X-X, Liu H, et al. The impact of morning surgery or afternoon surgery on postoperative sleep quality and melatonin levels of elderly patients: a prospective, randomized study. Nat Sci Sleep 2022; 14: 1677–86. doi:10.2147/NSS.S377209
24 Guo J, Qiu D, Gu H-W, et al. Efficacy and safety of perioperative application of ketamine on postoperative depression: a meta-analysis of randomized controlled studies. Mol Psychiatry 2023; 28: 2266–76. doi:10.1038/s41380-023-01945-z
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Details
; Zhang, Yunkui 1 ; Zhou, Guoxia 1 ; Yang, Zaixian 1 ; Han, Yan 1 ; Zhang, Jun 1
1 Department of Anaesthesiology, Shanghai Cancer Centre, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China