Nocturnal Low-dose Dexmedetomidine Infusion and Perioperative Sleep Quality

Dexmedetomidine Clinical Trial

Official title:

Effect of Nocturnal Low-dose Dexmedetomidine Infusion on Sleep Quality in Older Patients Undergoing Knee or Hip Replacement Surgery: A Multicenter Randomized Controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05246007
• Other study ID #: 2021-639
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 2022
• Est. completion date: December 2026

Study information

• Verified date: April 2022
• Source: Peking University First Hospital
• Contact: Dong-Xin Wang, MD, PhD
• Phone: 86 10 83572784
• Email: wangdongxin[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Sleep disturbances are prevalent in older patients with osteoarthrosis or fracture scheduled for knee or hip replacement surgery. The occurrence of sleep disturbances is associated with worse outcomes including increased risk of delirium and cardiac events, and worsened functional recovery. Dexmedetomidine is a highly selective α2-adrenergic agonist with sedative, anxiolytic, and analgesic properties. It exerts sedative effects via activating the endogenous sleep pathways and produces a state like non-rapid eye movement sleep, which is different from opioid- and benzodiazepine-induced sedation. Night-time infusion of low-dose dexmedetomidine may improve sleep quality. However, evidence in this aspect is limited.

Description:

Sleep is a naturally recurring state characterized by lowered consciousness, reduced sensory and voluntary activity, and inhibited interaction with surroundings. Normal sleep has a particular structure and significant circadian rhythms; and is vital for both physical and mental health. Evidence shows that the restorative effect of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products like β-amyloid or tau protein via the glymphatic pathway in the neurological system.

Sleep disturbances frequently occur in elderly patients with chronic pain and complicated comorbidity. A meta-analysis shows that in adults, total sleep time, sleep efficiency, percentage of slow-wave sleep, and percentage of rapid eye movement (REM) sleep significantly decrease, while sleep latency, percentage of stage 1 non-REM sleep, percentage of stage 2 non-REM sleep, and wake after sleep onset significantly increase with ageing. Coexisting disease such as asthma and obstructive sleep apnea are also associated with poorer sleep quality, as manifested by increased stage 1 and 2 non-REM sleep, and decreased REM sleep. Furthermore, pain and sleep disturbances are closely correlated, and sleep disturbances frequently accompany pain from osteoarthritis (OA) or fracture in elderly patients who are scheduled for knee or hip arthroplasty.

Sleep disturbances are common after major surgery owing to preoperative comorbidity, residual anesthetic effects, surgical trauma, postoperative pain, use of analgesics, and hospital environment. Patients may report shortened total sleep time, increased number of arousals/awakenings, lowered subjective sleep quality, and sometimes nightmares. Polysomnographic monitoring reveals sleep deprivation, sleep fragmentation, altered sleep architecture (increased light sleep, decreased or disappeared deep and rapid eye movement sleep), and disordered circadian rhythm. Considering the importance of normal sleep for human health, it is not surprising that sleep disturbances may produce harmful effects on patients' recovery. Indeed, emerging evidence suggests that sleep disturbances are associated with increased sensitivity to pain, higher inflammation, more delirium, more cardiovascular events, and prolonged hospital stay.

Dexmedetomidine, an α2 adrenoceptor agonist with both sedative and analgesic properties, has increasingly been used. Unlike other sedative agents, dexmedetomidine exerts its sedative effects through an endogenous sleep-promoting pathway and preserves sleep architecture to some degree. In a recent study of mechanically ventilated ICU patients, nighttime infusion of a sedative dose of dexmedetomidine (median infusion rate 0.6 μg/kg/h [interquartile range, 0.4 to 0.7]) helped preserve the circadian of sleep and improved the sleep architecture by increasing sleep efficiency and stage 2 non-REM sleep. In our previous study of non-mechanically ventilated ICU patients, nighttime infusion of low-dose of dexmedetomidine (0.1 μg/kg/h) improved the sleep architecture by increasing sleep efficiency and stage 2 non-REM sleep. Our subsequent large randomized controlled trial showed that low-dose night-time infusion of dexmedetomidine improved sleep and decreased the incidence of delirium; furthermore, it improved 2-year survival and 3-year quality of life after surgery.

We suppose that, for older patients with osteoarthrosis or fracture who are scheduled for knee or hip replacement surgery, nighttime infusion of low-dose dexmedetomidine starting from the preoperative night and continuing in the postoperative period may improve sleep quality and postoperative recovery.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 432
• Est. completion date: December 2026
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years to 90 Years

Eligibility

Inclusion Criteria:

• Age =65 years and <90 years;

• Scheduled to undergo unilateral knee or hip arthroplasty under spinal or combined spinal-epidural anesthesia.

Exclusion Criteria:

• Refuse to participate;

• Hypnotic therapy for sleep disorders within 3 months;

• Presence of contraindications to intrathecal anesthesia;

• Preoperative history of schizophrenia, epilepsy, Parkinson's disease, myasthenia gravis, or delirium;

• Diagnosed as obstructive sleep apnea, or at high risk of moderate to severe obstructive sleep apnea according to the STOP-Bang questionnaire;

• Inability to communicate in the preoperative period because of coma, profound dementia, or language barrier;

• Sick sinus syndrome, severe sinus bradycardia (heart rate <50 beats/min), or atrioventricular block above grade II without pacemaker implanted;

• Severe hepatic dysfunction (Childe Pugh class C); renal dysfunction (required preoperative dialysis), or expected survival =24 hours;

• Receiving treatment with dexmedetomidine or clonidine;

• Allergy to dexmedetomidine.

Related Conditions & MeSH terms

• Dexmedetomidine
• Hip Replacement Surgery
• Knee Replacement Surgery
• Old Age
• Sleep Quality

Intervention

Drug:
• Dexmedetomidine
Dexmedetomidine will be infused at a rate of 0.02 ml/kg/h (0.025 µg/kg/h) during the night before surgery, the night of surgery, and the first 2 nights after surgery (from 9:00 pm-6:00 am).
• Normal Saline
Placebo (normal saline) will be infused at a rate of 0.02 ml/kg/h during the night before surgery, the night of surgery, and the first 2 nights after surgery (from 9:00 pm-6:00 am).

Locations

Country	Name	City	State
China	Beijing Hospital	Beijing	Beijing
China	Peking University First Hospital	Beijing	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Peking University First Hospital	Beijing Hospital

Country where clinical trial is conducted

China, 

References & Publications (12)

Alexopoulou C, Kondili E, Diamantaki E, Psarologakis C, Kokkini S, Bolaki M, Georgopoulos D. Effects of dexmedetomidine on sleep quality in critically ill patients: a pilot study. Anesthesiology. 2014 Oct;121(4):801-7. doi: 10.1097/ALN.0000000000000361. — View Citation

Er MS, Altinel EC, Altinel L, Erten RA, Eroglu M. An assessment of sleep quality in patients undergoing total knee arthroplasty before and after surgery. Acta Orthop Traumatol Turc. 2014;48(1):50-4. doi: 10.3944/AOTT.2014.3163. — View Citation

Fatah RMN, Abdulrahman BB. A sleep disturbance after total knee arthroplasty. J Family Med Prim Care. 2020 Jan 28;9(1):119-124. doi: 10.4103/jfmpc.jfmpc_595_19. eCollection 2020 Jan. — View Citation

Li HJ, Li CJ, Wei XN, Hu J, Mu DL, Wang DX. Dexmedetomidine in combination with morphine improves postoperative analgesia and sleep quality in elderly patients after open abdominal surgery: A pilot randomized control trial. PLoS One. 2018 Aug 14;13(8):e0202008. doi: 10.1371/journal.pone.0202008. eCollection 2018. — View Citation

Lintzeris N, Moodley R, Campbell G, Larance B, Bruno R, Nielsen S, Degenhardt L. Sleep Quality Among People Living With Chronic Noncancer Pain: Findings From the Pain and Opioids IN Treatment (POINT) Cohort. Clin J Pain. 2016 May;32(5):380-7. — View Citation

Onen SH, Onen F, Courpron P, Dubray C. How pain and analgesics disturb sleep. Clin J Pain. 2005 Sep-Oct;21(5):422-31. Review. — View Citation

Sasaki E, Tsuda E, Yamamoto Y, Maeda S, Inoue R, Chiba D, Okubo N, Takahashi I, Nakaji S, Ishibashi Y. Nocturnal knee pain increases with the severity of knee osteoarthritis, disturbing patient sleep quality. Arthritis Care Res (Hoboken). 2014 Jul;66(7):1027-32. doi: 10.1002/acr.22258. — View Citation

Siegel JM. Sleep viewed as a state of adaptive inactivity. Nat Rev Neurosci. 2009 Oct;10(10):747-53. doi: 10.1038/nrn2697. Epub 2009 Aug 5. Review. — View Citation

Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, Ma D. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 Oct 15;388(10054):1893-1902. doi: 10.1016/S0140-6736(16)30580-3. Epub 2016 Aug 16. — View Citation

Wu XH, Cui F, Zhang C, Meng ZT, Wang DX, Ma J, Wang GF, Zhu SN, Ma D. Low-dose Dexmedetomidine Improves Sleep Quality Pattern in Elderly Patients after Noncardiac Surgery in the Intensive Care Unit: A Pilot Randomized Controlled Trial. Anesthesiology. 2016 Nov;125(5):979-991. — View Citation

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224. — View Citation

Zhang DF, Su X, Meng ZT, Li HL, Wang DX, Xue-Ying Li, Maze M, Ma D. Impact of Dexmedetomidine on Long-term Outcomes After Noncardiac Surgery in Elderly: 3-Year Follow-up of a Randomized Controlled Trial. Ann Surg. 2019 Aug;270(2):356-363. doi: 10.1097/SLA.0000000000002801. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cerebrospinal fluid proteomics examination (selected patients).	Cerebrospinal fluid (1 ml) will be collected during spinal anesthesia. Deep proteome analysis will be performed to detect protein biomarkers including amyloid-beta, total tau, and phosphorylated tau.	During anesthesia.
Primary	Subjective sleep quality (overall RCSQ score) during the night of surgery.	Subjective sleep quality will be assessed in the morning (between 8:00 am to 10:00 am) using the Richards-Campbell Sleep Questionnaire (RCSQ). The RCSQ is a self-reported measure that evaluated perception of nighttime sleep in five items, including sleep depth, sleep latency, number of awakenings, returning to sleep, and overall sleep quality. Each item was assessed with a 100-millimeter visual analog scale (VAS; score ranges from 0 to 100, with higher scores representing better sleep). The mean score of the five items represents the overall RCSQ score. The RCSQ also included a sixth item, not included in the overall score, that evaluated perceived nighttime noise (score ranges from 0 to 100, where 0="very noisy" and 100="very quiet").	During the night of surgery.
Secondary	Subjective sleep quality (overall RCSQ score) during the perioperative period.	Subjective sleep quality will be assessed daily in the morning (between 8:00 am to 10:00 am) using the Richards-Campbell Sleep Questionnaire (RCSQ).	From the night before surgery until the fifth night after surgery.
Secondary	Total sleep time per night during the perioperative period.	Objective sleep quality will be monitored with an actigraphy from 6:00 pm to 8:00 am from the night before surgery until the fifth night after surgery. Total sleep time is defined as the sum in time scored as asleep.	From the night before surgery until the fifth night after surgery.
Secondary	Sleep efficiency per night during the perioperative period.	Objective sleep quality will be monitored with an actigraphy from 6:00 pm to 8:00 am from the night before surgery until the fifth night after surgery. Sleep efficiency is defined as 100*total sleep time/time in bed.	From the night before surgery until the fifth night after surgery.
Secondary	Sleep onset latency per night during the perioperative period.	Objective sleep quality will be monitored with an actigraphy from 6:00 pm to 8:00 am from the night before surgery until the fifth night after surgery. Sleep onset latency is defined as time difference between time to bed and sleep start.	From the night before surgery until the fifth night after surgery.
Secondary	Wake after sleep onset per night during the perioperative period.	Objective sleep quality will be monitored with an actigraphy from 6:00 pm to 8:00 am from the night before surgery until the fifth night after surgery. Wake after sleep onset is defined as the total time scored as awake between sleep start and sleep end.	From the night before surgery until the fifth night after surgery.
Secondary	Intensity of pain during the first 3 postoperative days.	Intensity of pain will be assessed at 6, 12, 24, 48, and 72 hours after surgery with the Numeric Rating Scale (an 11-point scale where 0 indicates no pain and 10 the worst pain)	Up to 3 days after surgery.
Secondary	The incidence of delirium within 5 days after surgery.	Delirium is assessed twice daily (8:00-10:00 am and 6:00-8:00 pm) with the 3-minute diagnostic interview for Confusion Assessment Method-defined delirium (3D-CAM).	Up to 5 days after surgery.
Secondary	The joint range of motion after surgery.	Range of motion is assessed between 8:00 am to 10:00 am at 1, 3, and 5 days after surgery.	Up to 5 days after surgery.
Secondary	Length of stay in hospital after surgery.	Length of stay in hospital after surgery.	Up to 30 days after surgery.
Secondary	Incidence of non-delirium complications within 30 days.	Non-delirium complications are defined as newly occurred medical events other than delirium that are deemed harmful and required therapeutic intervention, i.e., grade II or higher on the Clavien-Dindo classification.	Up to 30 days after surgery.
Secondary	Subjective sleep quality (Pittsburgh Sleep Quality Index) at 30 days after surgery.	Subjective sleep quality at 30 days after surgery will be assessed with the Pittsburgh Sleep Quality Index. This is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score.	On the 30th day after surgery.
Secondary	Cognitive function at 3 months after surgery.	Cognitive function is assessed with the modified Telephone Interview for Cognitive Status.	At the end of the 3rd month after surgery.
Secondary	Quality of life at 3 months after surgery.	Quality of life is assessed with short form 36 questionnaire.	At the end of the 3rd month after surgery.
Secondary	3-year overall survival.	Overall survival is defined as the time interval from surgery to all-cause death.	Up to 3 years after surgery.
Secondary	3-year event-free survival.	Event-free survival is defined as the time interval from surgery to the earliest date of new serious disease (require hospitalization) or all-cause death.	Up to 3 years after surgery.
Secondary	Cognitive function within 3 years after surgery.	Cognitive function will be assessed at the end of each year after surgery, with the modified Telephone Interview for Cognitive Status.	Up to 3 years after surgery.
Secondary	Quality of life every year within 3 years after surgery.	Quality of life will be assessed at the end of each year after surgery, with short form 36 questionnaire.	Up to 3 years after surgery.