This single center randomized controlled clinical trial was conducted at the First Affiliated Hospital of Soochow University between March 2023 and August 2023. This study was approved by the Istitutional Research Ethics Committee of the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. The trial was registered in the Chinese Clinical Trial Registry (No. Chi CTR2200063821). Each patient was given written informed consent in accordance with the principles of the Helsinki Declaration. CONSORT guidelines are adhered to by this study.

A total of 220 patients were screened during the study conducted at the First Affiliated Hospital of Soochow University. This study included 200 participants who were scheduled for elective surgery. ASA I-II patients from both sexes and aged 18–70 years were included. The exclusion criteria included BMI ≥ 30 kg/m2, patients with severe liver and kidney dysfunction, history of chronic cough, bronchial asthma, chronic obstructive pulmonary disease, acute upper respiratory tract infection, recently used bronchodilators, steroid hormones, or angiotensin converting enzyme inhibitors, and patients who were allergic to the study drug, or had a history of mental illness.

Eligible participants were randomized 1:1 to group K, which received esketamine, and group C, which received normal saline, using computer-generated random numbers. In sealed opaque envelopes, the randomization results were stored prior to medication preparation. Opaque envelopes that were sealed held patient group information. The patients and anesthesiologists who measured the severity of cough were blinded for the group assignment. In a 20-ml syringe, the pretreatment drugs were prepared by an anesthetic nurse who was not involved in inducing anesthesia. Intention-to-treat analysis was applied in this investigation. The data was analyzed based on the original groups to which they were assigned at the end of the study.

Routine monitoring, which included non-invasive blood pressure (NBP), electrocardiogram (ECG), and pulse oxygen saturation (SPO2) was completed upon arrival in the operating room without premedication being administered. The patients were given oxygen and the study drug before anesthesia was administered. Before sufentanil induction, group K pretreated with 0.15 mg/kg esketamine for 5 s, while group C pretreated with the same volume of normal saline. After pretreatment drug administration, sufentanil was used to induce anesthesia over 5 s, and patients were monitored for episodes of cough 1 min after the injection of sufentanil. The severity of the cough was classified as mild (1–2 times), moderate (3–5 times), and severe (> 5 times) depending on the number of coughs observed [11]. The primary outcomes were the incidence and severity of the cough 1 min after sufentanil injection. The secondary outcomes included hemodynamic changes at different time points and side effects of sufentanil during general anesthesia induction. Before esketamine or normal saline administration (T0), MAP and HR need to be recorded, followed by 1 min after the administration (T1) and one minute after sufentanil injection (T2). Propofol 2 mg/kg and rocuronium 0.8 mg/kg were used to finish anesthesia induction, followed by orotracheal intubation. 1–2 Mac of sevoflurane with 40% oxygen and 60% air was used to maintain anesthesia for all patients and monitored for at least 30 min after surgery in the PACU. Side effects of sufentanil including apnea, muscle rigidity, bradycardia, or nausea were also recorded during the investigation.

The PASS 11 program (PASS, Kaysville, UT, USA) was used to estimate the sample size. With pretreatment with esketamine, the incidence of cough evoked by 0.4 μg/kg sufentanil in our pilot trial was reduced to 8%. The sample size was determined to be 91 patients per group at a power of 80% and a two-tailed α error of 5%. We recruited 100 patients for each group in order to account for potential 10% dropout rates.

Statistical analysis was conducted using SPSS 22.0 software (IBM Corp, Armonk, NY, USA). Normal distribution of the data was confirmed using Kolmogorov–Smirnov test. The mean ± standard deviation is used to express quantitative data with a normal distribution, and an independent-samples T test was used to compare the differences between two groups. The chi-square test was used to analyze categorical variables that were expressed as percentages. Analysis of variance with repeated measures design was used to compare continuous variables at various time periods. It was considered statistically significant when P < 0.05.