Nocturnal Mini-dose Dexmedetomidine-Esketamine Infusion and Perioperative Sleep Quality
Study Details
Study Description
Brief Summary
Sleep disturbances are prevalent in older patients with osteoarthrosis or fracture who are 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. Esketamine is a N-methyl-D-aspartic acid receptor antagonist and has been used as an anesthetic and analgesic. Recent studies showed that low-dose esketamine has anti-depressive and sleep-promoting effects. The investigators suppose that mini-dose dexmedetomidine-esketamine combined infusion at night can improve perioperative sleep quality in patients scheduled for knee or hip replacement surgery.
Condition or Disease | Intervention/Treatment | Phase |
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N/A |
Detailed 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 a significant circadian rhythm, 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 system 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.
Esketamine is a N-methyl-D-aspartic acid receptor antagonist and has been used as an anesthetic and analgesic. Recent studies showed that low-dose esketamine has anti-depressive and sleep-promoting effects.
We suppose that, for older patients with osteoarthrosis or fracture who are scheduled for knee or hip replacement surgery, nighttime infusion of mini-dose dexmedetomidine-esketamine combination starting from the preoperative night and continuing in the postoperative period may improve sleep quality and postoperative recovery.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Dexmedetomidine-esketamine combination Dexmedetomidine-esketamine combination will be infused at a rate of 0.01 ml/kg/h (dexmedetomidine 0.02 μg/kg/h and esketamine 5 μg/kg/h) during the night before surgery, the night of surgery, and the first 2 nights after surgery (from 8:00 pm-8:00 am). |
Drug: Dexmedetomidine
Dexmedetomidine will be infused at a rate of 0.01 ml/ kg/h (0.02 μg/kg/h) during the night before surgery, the night of surgery, and the first 2 nights after surgery (from 8:00 pm-8:00 am).
Drug: Esketamine
Esketamine will be infused at a rate of 0.01 ml/ kg/h (5 μg/kg/h) during the night before surgery, the night of surgery, and the first 2 nights after surgery (from 8:00 pm-8:00 am).
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Placebo Comparator: Normal saline Placebo (normal saline) will be infused at a rate of 0.01 ml/kg/h during the night before surgery, the night of surgery, and the first 2 nights after surgery (from 8:00 pm-8:00 am). |
Drug: Normal saline
Normal saline will be infused at a rate of 0.01 ml/ kg/h during the night before surgery, the night of surgery, and the first 2 nights after surgery (from 8:00 pm-8:00 am).
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Outcome Measures
Primary Outcome Measures
- Subjective sleep quality in the night of surgery. [The night on the day of surgery.]
Subjective sleep quality will be assessed in the next morning (between 8:00 am to 10:00 am) with 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 (score ranges from 0 to 100, with higher scores representing better sleep). The mean score of the five items represents the overall RCSQ score.
- 3-year event-free survival. [Up to 3 years after surgery.]
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.
Secondary Outcome Measures
- Subjective sleep quality during the perioperative period. [From the night before surgery until the fifth night after surgery.]
Subjective sleep quality will be assessed daily in the next morning (between 8:00 am to 10:00 am) using the Richards-Campbell Sleep Questionnaire (RCSQ).
- Total sleep time per night during the perioperative period. [From the night before surgery until the fifth night after surgery.]
Objective sleep quality will be monitored with the SOMNOtouch NIBP (Somnomedics GmbH, Randersacker, Germany) from 8:00 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.
- Sleep efficiency per night during the perioperative period. [From the night before surgery until the fifth night after surgery.]
Objective sleep quality will be monitored with SOMNOtouch NIBP (Somnomedics GmbH, Randersacker, Germany) from 8:00 pm to 8:00 am from the night before surgery until the fifth night after surgery. Sleep efficiency is defined as the ratio of total sleep time/time in bed.
- Sleep onset latency per night during the perioperative period. [From the night before surgery until the fifth night after surgery.]
Objective sleep quality will be monitored with SOMNOtouch NIBP (Somnomedics GmbH, Randersacker, Germany) from 8:00 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.
- Wake after sleep onset per night during the perioperative period. [From the night before surgery until the fifth night after surgery.]
Objective sleep quality will be monitored with SOMNOtouch NIBP (Somnomedics GmbH, Randersacker, Germany) from 8:00 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.
- Intensity of pain during the first 5 postoperative days. [Up to 5 days after surgery.]
Intensity of pain will be assessed twice after surgery with the Numeric Rating Scale (an 11- point scale where 0 indicates no pain and 10 the worst pain).
- The incidence of delirium within 5 days after surgery. [Up to 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).
- Use of supplemental analgesics [Up to 5 days after surgery.]
Include opioids and non-opioid analgesics.
- Subjective sleep quality (Pittsburgh Sleep Quality Index) at 3 months after surgery. [At the end of the 3rd month 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.
- Cognitive function at 3 months after surgery. [At the end of the 3rd month after surgery.]
Cognitive function is assessed with the modified Telephone Interview for Cognitive Status.
- 3-year overall survival. [Up to 3 years after surgery.]
Overall survival is defined as the time interval from surgery to all-cause death.
- Quality of life every year within 3 years after surgery. [Up to 3 years after surgery.]
Quality of life will be assessed at the end of each year after surgery, with short form 36 questionnaire.
- Cognitive function within 3 years after surgery. [Up to 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.
Other Outcome Measures
- Cerebrospinal fluid and blood proteomics examination (selected patients). [During anesthesia.]
Cerebrospinal fluid and blood sample will be collected. Deep proteome analysis will be performed to detect protein biomarkers including amyloid-beta, total tau, and phosphorylated tau.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥65 years and <90 years;
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Scheduled to undergo unilateral knee or hip arthroplasty.
Exclusion Criteria:
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Refuse to participate;
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Hypnotic therapy for sleep disorders within 3 months;
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Preoperative history of schizophrenia, epilepsy, Parkinson's disease, myasthenia gravis, or delirium;
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Diagnosed as obstructive sleep apnea, or at high risk of moderate to severe obstructive sleep apnea according to the Stop-Bang questionnaire;
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Inability to communicate in the preoperative period because of coma, profound dementia, or language barrier;
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Sick sinus syndrome, severe sinus bradycardia (heart rate <50 beats/min), or atrioventricular block above grade II without pacemaker implanted;
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Severe hepatic dysfunction (Child-Pugh class C), renal dysfunction (required preoperative dialysis), or expected survival ≤24 hours;
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Receiving treatment with dexmedetomidine, clonidine, or esketamine;
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Allergy to dexmedetomidine or esketamine.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Beijing Hospital | Beijing | Beijing | China | 100005 |
2 | Peking University First Hospital | Beijing | Beijing | China | 100034 |
Sponsors and Collaborators
- Peking University First Hospital
- Beijing Hospital
Investigators
- Principal Investigator: Dong-Xin Wang, MD,PhD, Peking University First Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
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