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Human ethics and consent and trail registration

The trial was performed and reported accordance with the CONSORT guidelines for interventional trials at the Hangzhou First People’s Hospital, School of Medicine, Westlake University, following approval by the Ethics Committee (2020YLSD003- 01).We provided written forms to all the participants involved in the research which illustrated the research purpose, process, the risks and benefits, and obtained their individual or guardian participants written informed consent from July 2021 to December 2021. And the trail was registered at the Chinese clinical trial registry (2021/06/19,ChiCTR2100047459).

Patients inclusion and exclusion criteria

The inclusion criteria were as follows: (1) patients aged 60 ~ 80 years old with an American Society of Anesthesiologists (ASA) class I or II; (2)Geriatric patients with respiratory diseases undergoing elective FB treatment (routine bronchoscopy and some simple FB treatments including transbronchial needle aspiration biopsy, transbronchial brushing, and bronchoalveolar lavage); (3)body mass index < 30 kg/m2. The exclusion criteria were as follows: (1)operation time > 30 min; (2)neuropsychiatric diseases and taking related medications; (3) target organ damage such as liver, kidney, heart and brain; (4)allergies to anesthetic drugs; (5)cannot cooperate with doctors; (6)uncontrolled hypertension, heart disease, diabetes and other diseases.

Randomization and grouping

A total of 105 elderly patients who underwent bronchofiberoscopy were enrolled in this study. By using a list of numbers generated by the QuickCalcs (GraphpadPrism 7),the patients were randomly assigned to three groups (n = 35 each).

Grouping: Group A (remimazolam + fentanyl + local anesthesia): intravenous injection of remimazolam 0.2 mg/kg and fentanyl 0.5 µg/kg for sedation,10 ml 2% lidocaine spraying pharynx and tracheal mucosa for local anesthesia; Group B (midazolam + fentanyl + local anesthesia): intravenous injection of midazolam 0.075 mg/kg and fentanyl 0.5 µg/kg for sedation, 10 ml 2% lidocaine spraying pharynx and tracheal mucosa for local anesthesia; and an additional dose with fentanyl 25 µg every 5 to 10 min for the either group if necessary; Group C (local anesthesia): 10 ml 2% lidocaine spraying pharynx and tracheal mucosa for local anesthesia.

Experimental protocols

The patients were instructed to fast before the operation. Electrocardiogram (ECG), heart rate (HR), saturation of pulse oximetry (SpO₂),non-invasive blood pressure (NBP), respiratory rate(RR), end-tidal carbon dioxide (PetCO₂) and bispectral index (BIS) were monitored in the operating room with the patient in supine position. Group A was inducted by intravenous injections of remimazolam 0.2 mg/kg and fentanyl 0.5 µg/kg for sedation/analgesia. Group B was inducted by intravenous injections of midazolam 0.075 mg/kg and fentanyl 0.5 µg/kg for sedation/analgesia. Group C was performed by spraying 2% lidocaine on the surface of tracheal mucosa without any other special treatment.

The endoscopic operation process was performed by an experienced respiratory physician. Each patient in Gruop A, Group B and Group C was assisted with local anesthesia by spraying 10 ml 2% lidocaine when the fiberoptic bronchoscope first entered the glottis, carina, and left and right bronchus, and then fiberoptic bronchoscopy was performed.

When the Modified Observer’s Alertness/Sedation (MOAA/S) score was ≤ 3, bronchoscopy was started. If a persistent cough occurs during the operation and body movement affects the operator’s operation, 25 µg of fentanyl can be administered every 5 to 10 min until a maximum of 200 µg is achieved. It was designated a treatment failure if the degree of sedation was still insufficient for the operation. Every patient was sent to the post-anesthesia care unit (PACU) after operation. Patients can exit PACU until regained consciousness and completed command actions, recovered orientation ability, and raised the head while supine for more than 10 s.

Measurement of endpoints

Primary endpoints

The vital signs including HR, BP, MAP, SpO2,RR, PetCO2, BIS were recorded at four times. T₀: the time patient was awake while breathing room air pre-anesthesia, T₁: the post-anesthesia induction state under nasal cannula oxygen inhalation (oxygen flow rate 3–5 L/min), T₂: the time when the bronchoscopy was inserted into the glottis, T₃: the postoperative at the time of completion, T₄: when the patient wakes up.

The rate of adverse events was recorded. Including intraoperative coughing, hypoxemia, and other adverse events (including blood pressure fluctuation > 20% before anesthesia, bradycardia or tachycardia, arrhythmia, larynx or bronchospasm, etc.).

Record the MOAA/S scores of groups A and B at each time point from T₁ to T₄: 5 points – Responds readily to name spoken in normal tone; 4 points – Lethargic response to name spoken in normal tone; 3 points – Responds only after name is called loudly and/or repeatedly; 2 points – Responds only after mild prodding or shaking; 1 point – Responds only after painful trapezius squeeze; 0 point – Does not respond to painful trapezius squeeze.

Secondary endpoints

Record the onset time of the drugs, operation time (the time from the beginning of insertion of the bronchoscopy to the completion of the insertion), and recovery time (have command action, recovery of orientation ability, time to raise the head in supine position >10 s). Assessment of surgeon satisfaction (excellent: the opening of the glottis is excellent; good: the opening of the glottis is good, the mirror placement is smooth, and the patient’s cooperation is good; poor: the opening of the glottis is not opening properly, there is obvious body movement or coughing, which leads to mirror withdrawal affecting the operator’s operation), patients satisfaction (satisfactory: there was no discomfort during the bronchoscopy; moderate satisfactory: there was mild discomfort during the bronchoscopy and willing to accept a re-examination; unsatisfactory: patient felt extremely uncomfortable during the bronchoscopy and was unwilling to go through it again).

Statistical analysis

The sample size for calculating the difference in recovery time between the two groups was determined using G-power (version 3.1.9.2, α = 0.05, power = 0.8) depending on our preliminary study results (intervention group: mean = 2.26, SD = 2.08; control group: mean = 4.25, SD = 3). A total of 28 patients were required per group, and considering an expulsion rate of 0.2, the sample size was increased to 35 patients per group.

All variables were expressed as numbers, mean (SD) or median (interquartile range). Statistical analysis was performed using the SPSS25.0 Software and the measurement data was normally distributed using the Shapiro-Wilk test. The normally distributed measurement data were expressed as mean ± standard deviation (X ± s), and the comparison between groups was analyzed by one-way ANOVA, and the Bonferroni multiple comparison test was performed, and the Welch test was used for heterogeneity of variance. Non-normally distributed continuous variables were expressed as medians (interquartile ranges), and analyzed using nonparametric tests (Kruskal-Wallis H test). Counting data were compared using chi-square test or Fisher test, and Bonferroni correction test was used. Bilateral P < 0.05 was considered statistically significant.