Clinical trial NCT06859892: Dexmedetomidine-Esketamine Combination and Sleep Disturbances After Major Noncardiac Surgery
Official title: Effect of Dexmedetomidine-esketamine Combination on Sleep Disturbances After Major Noncardiac Surgery: a Single-center, Randomised, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Adults
Major Noncardiac Surgery
Dexmedetomidine
Esketamine
Postoperative Sleep Disturbances
Keywords: adults
major noncardiac surgery
dexmedetomidine
esketamine
postoperative sleep disturbances
Lead sponsor: Peking University First Hospital
Sponsor class: OTHER
First posted: 2025-03-05
Enrollment: 476
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Sleep disturbances are common early after major surgery, and are associated with delayed recovery. A previous study showed that dexmedetomidine-esketamine combination as a supplement to patient-controlled intravenous analgesia improved postoperative analgesia and subjective sleep quality in patients after scoliosis correction surgery. The purpose of this trial is to test the hypothesis that dexmedetomidine-esketamine combination used as a supplement during general anesthesia and postoperative intravenous analgesia may reduce sleep disturbances in adult after major noncardiac surgery.

Detailed description: Sleep disturbances after surgery is usually manifested as sleep deprivation, altered circadian rhythm, and disturbed sleep structure. The reported incidence of sleep disturbances was 31.4% after gynecologic surgery, 31.9% after urologic surgery, and 35.9% after spine surgery. The occurrence of sleep disturbances is associated with worse perioperative outcomes, including aggravated pain intensity, increased delirium, higher risk of cardiovascular events, and delayed hospital discharge.

Dexmedetomidine is a high-specific alpha 2-adrenergic agonist with anxiolytic, sedative, and analgesic effects. When used during general anesthesia and for postoperative analgesia, dexmedetomidine is associated with improved analgesia and sleep quality. The effect of dexmedetomidine is dose-dependent. However, even commonly used dosage increases bradycardia and hypotension.

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine with a higher affinity for NMDA receptors and is approximately twice as potent as racemic ketamine in analgesia. When used during general anesthesia and for postoperative analgesia, esketamine improves analgesia and reduces opioid consumption, but psychiatric symptoms may occur.

The sedative effect of dexmedetomidine is helpful to relieve psychiatric side effects of ketamine/esketamine. A previous study showed that dexmedetomidine-esketamine combination as a supplement to patient-controlled intravenous analgesia improved postoperative analgesia and subjective sleep quality in patients after scoliosis correction surgery.

This trial is designed to test the hypothesis that dexmedetomidine-esketamine combination used as a supplement during general anesthesia and postoperative intravenous analgesia may reduce sleep disturbances in adult after major noncardiac surgery.

Eligibility criteria: Inclusion Criteria:

1. Aged ≥18 years.
2. Scheduled for major noncardiac surgery (≥60 minutes) under general anesthesia with an expected end of surgery no later than 18:00 pm.
3. Required patient-controlled intravenous analgesia after surgery.

Exclusion Criteria:

1. Emergency surgery, transurethral surgery, organ transplantation.
2. Pregnant or lactating women.
3. Patients who need hypnotics for sleep disturbance or antidepressants for depression prior to surgery.
4. History of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis.
5. Inability to communicate due to coma, severe dementia, or speech disorders, endured hypoxic encephalopathy or traumatic brain injury, or after neurosurgery.
6. Comorbid with hyperthyroidism and pheochromocytoma.
7. Preoperative left ventricular ejection fraction \<30%, sick sinus syndrome, severe sinus bradycardia (heart rate \<50 beats/min), atrioventricular block of degree II or higher without pacemaker implantation, or systolic blood pressure below 90 mmHg despite use of vasopressors.
8. Diagnosed as sleep apnea, or judged to be at high risk of moderate-to-severe sleep apnea as assessed by STOP-Bang.
9. Severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction (on dialysis), or ASA classification ≥IV.
10. Hypersensitive to dexmedetomidine and/or esketamine.
11. Other conditions that are deemed unsuitable for study participation.

Primary outcomes:
measure: Incidence of sleep disturbances within 3 days after surgery
timeFrame: Up to 3 days after surgery
Secondary outcomes:
measure: Quality of recovery at 24 hours after surgery
timeFrame: At 24 hours after surgery
measure: Subjective sleep quality in the first 3 nights after surgery.
timeFrame: Up to 3 days after surgery.
measure: Pain intensity both at rest and with movement during the first 3 postoperative days
timeFrame: Up to 3 days after surgery
measure: Anxiety and depression on the third day after surgery
timeFrame: On the third day after surgery
measure: Subjective sleep quality on the 30th day after surgery
timeFrame: On the 30th day after surgery
Other outcomes:
measure: Time to extubation after surgery
timeFrame: On the day of surgery
measure: Incidence of emergence agitation after surgery
timeFrame: Up to 2 hours after extubation
measure: Cumulative opioid consumption within 48 hours after surgery
timeFrame: Within 48 hours after surgery
measure: Proportion of patients requiring rescue analgesia within 48 hours after surgery
timeFrame: Within 48 hours after surgery
measure: Length of hospital stay after surgery
timeFrame: Up to 30 days after surgery.
measure: Agitation and sedation levels during the first 3 postoperative days
timeFrame: Up to 3 days after surgery
measure: Incidence of postoperative complications
timeFrame: Up to 30 days after surgery
measure: All-cause 30-day mortality
timeFrame: Up to 30 days after surgery
Locations:
city: Beijing
country: China
facility: Peking University First Hospital
Study officials:
affiliation: Dong-Xin Wang, MD, PhD, Peking University First Hospital
name: Dong-Xin Wang
role: STUDY_CHAIR
References:
citation: Allen RW, Burney CP, Davis A, Henkin J, Kelly J, Judd BG, Ivatury SJ. Deep Sleep and Beeps: Sleep Quality Improvement Project in General Surgery Patients. J Am Coll Surg. 2021 Jun;232(6):882-888. doi: 10.1016/j.jamcollsurg.2021.02.010. Epub 2021 Mar 3.
citation: Myles PS, Shulman MA, Reilly J, Kasza J, Romero L. Measurement of quality of recovery after surgery using the 15-item quality of recovery scale: a systematic review and meta-analysis. Br J Anaesth. 2022 Jun;128(6):1029-1039. doi: 10.1016/j.bja.2022.03.009. Epub 2022 Apr 14.
citation: Kjolhede P, Langstrom P, Nilsson P, Wodlin NB, Nilsson L. The impact of quality of sleep on recovery from fast-track abdominal hysterectomy. J Clin Sleep Med. 2012 Aug 15;8(4):395-402. doi: 10.5664/jcsm.2032.
citation: Gulam S, Xyrichis A, Lee GA. Still too noisy - An audit of sleep quality in trauma and orthopaedic patients. Int Emerg Nurs. 2020 Mar;49:100812. doi: 10.1016/j.ienj.2019.100812. Epub 2020 Jan 30.
citation: Ruiz FS, Andersen ML, Guindalini C, Araujo LP, Lopes JD, Tufik S. Sleep influences the immune response and the rejection process alters sleep pattern: Evidence from a skin allograft model in mice. Brain Behav Immun. 2017 Mar;61:274-288. doi: 10.1016/j.bbi.2016.12.027. Epub 2017 Jan 7.
citation: Chouchou F, Khoury S, Chauny JM, Denis R, Lavigne GJ. Postoperative sleep disruptions: a potential catalyst of acute pain? Sleep Med Rev. 2014 Jun;18(3):273-82. doi: 10.1016/j.smrv.2013.07.002. Epub 2013 Sep 24.
citation: Fernandes NM, Nield LE, Popel N, Cantor WJ, Plante S, Goldman L, Prabhakar M, Manlhiot C, McCrindle BW, Miner SE. Symptoms of disturbed sleep predict major adverse cardiac events after percutaneous coronary intervention. Can J Cardiol. 2014 Jan;30(1):118-24. doi: 10.1016/j.cjca.2013.07.009. Epub 2013 Oct 16.
citation: Lu Y, Li YW, Wang L, Lydic R, Baghdoyan HA, Shi XY, Zhang H. Promoting sleep and circadian health may prevent postoperative delirium: A systematic review and meta-analysis of randomized clinical trials. Sleep Med Rev. 2019 Dec;48:101207. doi: 10.1016/j.smrv.2019.08.001. Epub 2019 Aug 22.
citation: Wang X, Hua D, Tang X, Li S, Sun R, Xie Z, Zhou Z, Zhao Y, Wang J, Li S, Luo A. The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders. Nat Sci Sleep. 2021 Aug 6;13:1395-1410. doi: 10.2147/NSS.S320745. eCollection 2021.
citation: Meewisse AJG, Gribnau A, Thiessen SE, Stenvers DJ, Hermanides J, van Zuylen ML. Effect of time of day on outcomes in elective surgery: a systematic review. Anaesthesia. 2024 Dec;79(12):1325-1334. doi: 10.1111/anae.16395. Epub 2024 Aug 7.
citation: Song B, Li Y, Teng X, Li X, Yang Y, Zhu J. Comparison of Morning and Evening Operation Under General Anesthesia on Intraoperative Anesthetic Requirement, Postoperative Sleep Quality, and Pain: A Randomized Controlled Trial. Nat Sci Sleep. 2020 Jul 16;12:467-475. doi: 10.2147/NSS.S257896. eCollection 2020.
citation: Luo M, Song B, Zhu J. Sleep Disturbances After General Anesthesia: Current Perspectives. Front Neurol. 2020 Jul 8;11:629. doi: 10.3389/fneur.2020.00629. eCollection 2020.
citation: Chung F, Liao P, Elsaid H, Shapiro CM, Kang W. Factors associated with postoperative exacerbation of sleep-disordered breathing. Anesthesiology. 2014 Feb;120(2):299-311. doi: 10.1097/ALN.0000000000000041.
citation: Duan G, Wang K, Peng T, Wu Z, Li H. The Effects of Intraoperative Dexmedetomidine Use and Its Different Dose on Postoperative Sleep Disturbance in Patients Who Have Undergone Non-Cardiac Major Surgery: A Real-World Cohort Study. Nat Sci Sleep. 2020 Mar 12;12:209-219. doi: 10.2147/NSS.S239706. eCollection 2020.
citation: Su X, Wang DX. Improve postoperative sleep: what can we do? Curr Opin Anaesthesiol. 2018 Feb;31(1):83-88. doi: 10.1097/ACO.0000000000000538.
citation: Krenk L, Jennum P, Kehlet H. Sleep disturbances after fast-track hip and knee arthroplasty. Br J Anaesth. 2012 Nov;109(5):769-75. doi: 10.1093/bja/aes252. Epub 2012 Jul 24.
citation: Gogenur I, Wildschiotz G, Rosenberg J. Circadian distribution of sleep phases after major abdominal surgery. Br J Anaesth. 2008 Jan;100(1):45-9. doi: 10.1093/bja/aem340. Epub 2007 Nov 23.