Mini-dose Dexmedetomidine-Esketamine Supplemented Analgesia in Patients at High-risk of OSA

Patients with obstructive sleep apnea (OSA) are at increased risk of developing sleep disturbances after surgery. Dexmedetomidine is a highly selective α2-adrenergic agonist with sedative, analgesic, and anxiolytic effects. Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine and twice as potent as racemic ketamine for analgesia. A recent trial showed that mini-dose esketamine-dexmedetomidine in combination with opioids improved analgesia and subjective sleep quality after scoliosis correction surgery. This trial is designed to test the hypothesis that mini-dose dexmedetomidine-esketamine supplemented analgesia may improve postoperative sleep quality in patients at high-risk of OSA.

Obstructive sleep apnea (OSA) is characterized by repetitive narrowing or obstruction of the upper airway during sleep, resulting in recurrent hypoxemia and hypercapnia and disordered sleep. During the postoperative period, the residual effects of anesthetics, sedatives, analgesics, and muscle relaxants suppress the activation of airway muscles; surgical stress, pain, and environmental interference further deteriorate sleep quality. All these factors aggravate the pathophysiological changes in OSA patients and may lead to worse perioperative outcomes, including increased respiratory and cardiac events, intensive care unit (ICU) admission and delirium, as well as prolonged length of hospital stay.

Opioids are commonly used for postoperative analgesia. Patients with OSA have significantly increased sensitivity to the side effects of opioids, such as central respiratory depression (reduced central respiratory drive) and peripheral respiratory depression (airway collapse). Opioids themselves can also cause sleep disturbances, as manifested by sleep fragmentation, decreased rapid-eye-movement sleep, and frequent nightmares. On the other hand, sleep deprivations can also lead to increased pain sensitivity and thus opioid consumption. Therefore, it is important to explore better postoperative analgesia to improve postoperative sleep quality of patients at high-risk of OSA.

Dexmedetomidine is a highly selective α2-adrenergic agonist with sedative, analgesic, and anxiolytic effects. It produces sedation by activating the endogenous sleep-promoting pathway and produces a state resembling nonrapid eye movement sleep. Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. When given in sub-anaesthetic doses, ketamine produces analgesic and anti-hyperalgesic effects and is recommended as a component of multimodal analgesia. Esketamine is the S-enantiomer of racemic ketamine and approximately twice as potent as racemic ketamine for analgesia.

A recent trial showed that mini-dose esketamine-dexmedetomidine in combination with opioids improved analgesia and subjective sleep quality after scoliosis correction surgery. This trial is designed to test the hypothesis that mini-dose dexmedetomidine-esketamine supplemented analgesia may improve sleep quality in patients at high-risk of OSA after thoracic or abdominal surgery.

Eligibility Criteria:
Inclusion criteria:

1. Aged ≥18 years but ≤80 years;
2. Preoperative diagnosis of OSA, or judged to be at moderate-to-high risk of OSA according to the STOP-Bang Questionnaire;
3. Scheduled to undergo thoracoscopic or laparoscopic surgery under general anesthesia, with an expected surgical duration of ≥1 hours, and required patient-controlled intravenous analgesia (PCIA) after surgery.

Exclusion criteria:

1. Diagnosed as central sleep apnea syndrome;
2. Previous history of schizophrenia, epilepsy, Parkinson disease, or myasthenia gravis.
3. History of schizophrenia, or having antipsychotic drugs (including antidepressants or anxiolytics);
4. Inability to communicate in the preoperative period because of coma, profound dementia, or deafness;
5. History of drug or alcohol dependence, or sedative or hypnotic therapy within 1 month before surgery;
6. Contraindications to ketamine (such as hyperthyroidism, pheochromocytoma, or glaucoma);
7. Sick sinus syndrome, severe sinus bradycardia (\<50 beats per minute), or second-degree or above atrioventricular block without pacemaker;
8. Contraindications to high-flow nasal cannula therapy (such as mediastinal emphysema, shock or hypotension, cerebrospinal fluid leakage, nasosinusitis, otitis media, or deviation of nasal septum);
9. Severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction (requirement of renal replacement therapy), severe heart dysfunction (preoperative New York Heart Association functional classification ≥3 or left ventricular ejection fraction \<30%), or ASA classification IV or above;
10. Expected intensive care unit (ICU) admission with tracheal intubation after surgery;
11. Other conditions that are considered unsuitable for study participation.