Mini-dose Dexmedetomidine-Esketamine Infusion and Perioperative Sleep Quality

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.

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥65 years and \<90 years;
* Scheduled to undergo unilateral knee or hip arthroplasty.

Exclusion Criteria:

* Refuse to participate;
* Hypnotic therapy for sleep disorders within 3 months;
* Preoperative history of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis;
* 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 (Child-Pugh class C), renal dysfunction (required preoperative dialysis), or expected survival ≤24 hours;
* Receiving treatment with dexmedetomidine, clonidine, or esketamine;
* Allergy to dexmedetomidine or esketamine.