This single-center, prospective, randomized, controlled trial was conducted from November 2021 to July 2022 at Qilu Hospital of Shandong University in Jinan, China. Ethical approval was granted by the Medical Ethics Committee (Chairperson Professor Tian Hui) of Qilu Hospital, Shandong University ((Ke) Lun Audit 2021 (186)) on 15/07/2021. The study was registered on 23/10/2021 (https://www.chictr.org.cn). We designed and reported this study using CONSORT statements. We obtained written, informed consent from the patient, his or her next of kin, or a legal representative.

Inclusion criteria: (1) American Society of Anesthesiologists classification (ASA) class I or II; (2) age 18–65 years; (3) 28 kg/m2 ≤ BMI < 40 kg/m2; (4) undergoing sedation for EGD and/or colonoscopy procedures, (5) informed consent from the patient or family. Exclusion criteria: (1) nasal bleeding, nasal mucosal injury, space-occupying lesions in the nasal cavity; (2) diagnosed heart disease (heart failure, angina pectoris, heart attack, arrhythmia); (3) diagnosed lung disease (asthma, bronchitis, COPD, pulmonary maculopathy, pulmonary embolism, lung cancer); (4) those with previous hypotension (systolic blood pressure ≤ 90 mmHg), bradycardia (heart rate < 50 beats/min), or hypoxemia (SaO2 < 90%); (5) presence of underlying disease requiring oxygen; (6) emergency surgery; (7) multiple trauma; (8) upper respiratory tract infection; (9) allergy to sedative drugs such as propofol or devices such as tape, and (10) disagreement to participate in this study. Post-inclusion exclusion criteria: (1) failure to complete endoscopy by sedation; (2) serious adverse events during the experiment forcing the patient to discontinue endoscopy; and (3) noncompliance with the protocol requirements.

Patients were randomly divided into a capnography group or a standard group in a 1:1 ratio using a random sequence of numbers generated through computerized randomization software. In the capnography group, the capnographic data of the patients were available for additional noninvasive assessment of ventilation. The capnographic data of patients assigned to the standard monitoring group were not visible because the carbon dioxide sampling port of the nasal cannula was kept closed; therefore, only the integrated pulse oximetric readout of the monitor was visible.

Investigators randomly assigned patients to the study groups by opening pre-generated, sequentially numbered, opaque, sealed envelopes. The patients, endoscopy unit staff, and endoscopists were blinded to the study arm assignments. Both groups used nasal cannulae with carbon dioxide collection devices in identical packaging and shapes that were connected to capnography devices. A subject could be unblinded in the event of a severe adverse event requiring hospitalization or prolonged hospitalization (disability, affecting the ability to work; life-threatening or death; causing congenital malformations) or another emergency. The sponsor, study director, and clinical monitor were notified before unblinding.

Routine heart rate monitoring, blood pressure monitoring, and electrocardiography were performed on all patients. For the assessment of SpO2, the integrated pulse oximeter of the capnography device was used. A nasal cannula (Capnostream 20; Medtronic, Inc.) with an oral sampling port to accommodate mouth breathers provided 2 L/min oxygen and continuously sampled the CO2 content of both inspired and expired patient gas. The sampling line was connected to a portable bedside monitor (Capnostream 20; Medtronic, Inc.) that displayed a time-based capnogram, PETCO2 (mmHg), the derived respiratory rate, and SpO2 by integrated pulse oximetry (Nellcor, Covidien, Boulder, CO, USA).

The patient was placed in the lateral position and pre-oxygenated by deep breathing with 2 L min− 1 oxygen. 5 or 7.5 µg of intravenous sufentanil (sufentanil citrate injection, 50 ug 1 mL− 1ampule− 1; Yichang Humanwell Pharmaceutical Co, Ltd, Yichang, China) was administered during the induction of anesthesia in both groups. After 3 min, sedation was induced by a 1.5 mg/kg intravenous injection of propofol (propofol injection long-chain triglyceride, 200 mg /20 Ml/ampule, Fresenius Kabi Deutschland, Bad Homburg, Germany), administered by hand at a rate of 0.5 ml/s. Sedation depth was evaluated according to the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score [19] (Table S2 in Supplementary Appendix). According to our routine practice, deep sedation to a MOAA/S score of 0/1 was performed first to ensure the successful insertion of the endoscope tube and to decrease adverse responses to the insertion of the endoscope tube into the upper airway. During endoscopy, moderate sedation with a MOAA/S score of 2/3 was maintained with additional propofol (20–30 mg).

In the event of inadequate alveolar ventilation during sedation, the investigators administered the following five interventions sequentially until all respiratory-related parameters returned to normal, recording the means of the last intervention: a: increasing oxygen flow (5 L/min); b: a chin lift or jaw thrust maneuver; c: placement of the nasopharyngeal airway and a chin lift; d: mask positive-pressure ventilation, and e: ventilator-assisted ventilation with tube insertion. The division of labor among participants was fixed throughout the experiment, and the gastroenterologist performed the endoscopy.

After endoscopy completion, patients who can provide meaningful verbal responses and have stable vital signs were withdrawn from monitoring and transferred to the recovery room. Discharge was allowed when a post-anesthesia discharge scoring system (PADSS) (Table S3 in Supplementary Appendix) score of > 9 was met. When fully recovered, patient satisfaction of sedation was assessed through a numeric analog scale (Table S4 in Supplementary Appendix) before patients were discharged. Endoscopists were asked to rate their satisfaction of sedation on a numeric analog scale (1, min – 10, max) at the end of the procedure.

Adverse events were any instances where adverse symptoms and abnormal signs occurred after the application of the intervention, whether or not they were causally related to the trial. Any adverse events, including those provided voluntarily by the subject or identified through investigator inquiries and monitoring, were actively managed and closely followed until they resolved or stabilized. Adverse events of anesthesia sedation, including PONV, hypotension, bradycardia, and premature ventricular contractions occurred, were treated with ondansetron hydrochloride, atropine, noradrenaline, and lidocaine, respectively. (Table S5 in Supplementary Appendix)

Inadequate alveolar ventilation during sedation included altered ventilation, apnoea, or decreased oxygen saturation. The capnographic criterion for apnoea was the absence of exhaled CO2; altered respiration was defined as a reduction in end-tidal CO2 by more than half from the baseline value; decreased oxygen saturation was defined as SpO2 < 90%, ≥ 10s.

The primary outcome was the incidence of hypoxia during sedation, defined as a decrease in SpO2 to ≤ 90%, ≥ 10s. The period of sedation was defined as the period from the start of the first medication administration until the discontinuation of electronic monitoring after the completion of the procedure.

The secondary outcomes included (i) incidence of subclinical respiratory depression (90% ≤ SpO2 < 95%) and severe hypoxia (SpO2 ≤ 85%); (ii) interventions; (iii) minimum SpO2 during operation; iv) patient and endoscopist satisfaction, v) adverse events of anesthesia sedation.

The sample size was calculated using PASS software (version 11.0, NCSS, LLC, Kaysville, UT, United States). The Two Independent Proportions procedure was used. Test results indicate a 32% incidence of hypoxia in mildly obese patients under sedation procedure; thus, 32% of patients in the capnography group were expected to develop hypoxia. P1 and P2 were calculated based on the assumption that capnography would achieve a reduction in the incidence of hypoxia from 32 to 15%. Given an α = 0.05 and a power of 80%, it was estimated that 108 patients per group would be required for the study. Assuming a dropout rate of 5%, a total of 228 patients would be needed.

A blinded statistician performed statistical analysis using SPSS (version 25.0). Data are summarized as mean ± SD/median (IQR) for continuous data and as frequencies/percentages for categorical data. The standardized mean difference (SMD) was defined as the difference between the mean value of a covariate in one group and the corresponding mean value of a covariate in the other group, divided by the pooled standard deviation. When assessing the balance between groups, an SMD < 0.1 indicated a better balance and was considered as a small difference between the two groups. The incidence of hypoxia for the primary outcome was analyzed using Fisher’s exact test for categorical variables. Secondary outcomes were also analyzed with the use of Fisher’s exact test for categorical variables as well as Student’s t-test for continuous variables with a composite normal distribution. Statistical significance was set at P < 0.05.