Nocturnal Low-dose Dexmedetomidine Infusion and Perioperative Sleep Quality

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Old Age, Knee Replacement Surgery, Hip Replacement Surgery, Dexmedetomidine, Sleep Quality

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Normal Saline


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine group<br>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). | Drug: Dexmedetomidine<br>* 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).<br>* Other names: Dexmedetomidine for infusion;|
| Placebo Comparator: Placebo group<br>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). | Drug: Normal Saline<br>* 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).<br>* Other names: Normal Saline for infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| Length of stay in hospital after surgery. | Length of stay in hospital after surgery. | Up to 30 days after surgery. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 3-year overall survival. | Overall survival is defined as the time interval from surgery to all-cause death. | Up to 3 years after surgery. | 
| 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. | 
| 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. | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Old Age, Knee replacement surgery, Hip replacement surgery, Dexmedetomidine, Sleep quality