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Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an invasive procedure that required deep sedation to suppress coughing and body movements. Deep sedation, on the other hand, has been shown to cause respiratory and circulatory depression, especially when the airway is shared with the endoscopist. Esketamine is a novel sedative and analgesic with little respiratory inhibition that appears to be an appropriate adjuvant in propofol sedation for EBUS-TBNA. We compared the efficacy and safety of esketamine combined with propofol target-controlled infusion (TCI) and propofol TCI for deep sedation in EBUS-TBNA., Methods: The study included 135 patients with ASA II-III undergoing EBUS-TBNA. They were randomly divided into two groups (group E and group P). Both groups received midazolam (0.01-0.03 mg/kg) and oxycodone (0.07-0.08 mg/kg). Then, patients in group E received 0.3 mg/kg esketamine, propofol TCI, and 0.2 mg·kg -1 ·h -1 esketamine for sedative maintenance. Patients in group P received only propofol TCI. The primary outcome was the dose of 1% lidocaine administrated by the endoscopist and the times of lidocaine sprays. Secondary outcome indicators were cough score, propofol dosage, patient satisfaction, endoscopist satisfaction, the incidence of sedation-related adverse effects and side effects, and recovery time., Results: Patients in group E were given significantly less lidocaine (4.36 ml/h (2.67-6.00) vs 6.00 ml/h (4.36-7.20), P < 0.001) and less spraying frequency (2.18 times/h (1.33-3.00) vs 3.00 times/h (2.18-3.60), P < 0.001) than group P. There was a statistically significant difference in cough score between the two groups (group E 2 (0-4) vs group P 3 (2-4), P =0.03). Also, mean arterial pressure (MAP) was higher in group E in the 30 th  min (T5, 84.10 ± 12.91 mmHg versus 79.04 ± 10.01 mmHg, P =0.012) and 40 th  min (T6, 87.72 ± 15.55 mmHg versus 82.14 ± 10.51 mmHg, P =0.026). There were no significant differences between the two groups in terms of sedation-related adverse events and side effects, recovery time, endoscopist satisfaction, and patient satisfaction., Conclusions: In patients with ASA II-III, esketamine as an adjuvant in combination with propofol TCI deep sedation for EBUS-TBNA can improve the sedation effect, reduce coughing reaction during the procedure, and obtain more stable blood pressure. No reduction in the occurrence of sedation-related side effects was observed. This trial is registered with ChiCTR2200061124., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Sichen Cui et al.)