Abstract
Purpose
Respiratory management remains a major challenge during painless endoscopy in overweight or obese patients because of altered body fat distribution and reduced pulmonary reserve. This study evaluated whether ciprofol could reduce respiratory adverse events compared with propofol during painless gastroscopy in this population.
Methods
In this single-center, prospective, single-blind randomized controlled trial, 106 overweight or obese patients undergoing painless gastroscopy were randomly assigned (1:1) to receive either propofol (2 mg/kg) or ciprofol (0.4 mg/kg) following intravenous alfentanil (5 μg/kg). The primary outcome was the overall incidence of respiratory adverse events from anesthesia induction to completion of endoscopy, including hypoxemia (SpO2 <90% for >15 s), respiratory depression (respiratory rate <8 breaths/min for >30 s), and apnea (absence of chest wall movement for >20 s).
Results
A total of 106 patients completed the study (53 per group). The incidence of respiratory adverse events was significantly lower in the ciprofol group than in the propofol group (33.96% vs. 66.04%, P=0.001). The lowest intraoperative SpO2 was significantly higher in the ciprofol group (93.50% vs. 89.00%, P=0.044). Compared with ciprofol, propofol was associated with higher incidences of hypotension (22.64% vs. 7.55%, P=0.030) and injection pain (18.87% vs. 0%, P=0.001). No significant differences were observed in other adverse events, including nausea and vomiting.
Conclusion
In overweight or obese patients undergoing painless gastroscopy, ciprofol at 0.4 mg/kg significantly reduced respiratory adverse events, improved oxygenation, and decreased injection pain compared with propofol. These findings suggest that ciprofol may be a preferable anesthetic option for painless endoscopy in this population.
Clinical Trial Registration
ChiCTR2600117367.
Keywords: ciprofol, overweight patients, painless endoscopy, respiratory adverse events
Introduction
Gastrointestinal endoscopy, including gastroscopy and colonoscopy, is currently one of the most used and reliable minimally invasive procedures for the diagnosis and treatment of gastrointestinal diseases such as gastroesophageal reflux disease, gastritis, and intestinal polyps.1 It allows direct visualization of gastrointestinal mucosal lesions while enabling biopsy and therapeutic interventions, thereby significantly improving diagnostic and therapeutic efficiency. However, conventional unsedated gastrointestinal endoscopy often causes discomfort, including throat pain, nausea, vomiting, abdominal distension, anxiety, and fear due to mechanical stimulation of the pharyngeal and gastrointestinal mucosa. Some patients may even refuse or discontinue the procedure because of intolerance to these symptoms, negatively affecting both procedural success and patient experience. With advances in anesthetic techniques and the increasing emphasis on comfort-oriented medical care, painless gastrointestinal endoscopy has become widely adopted. Intravenous sedation or anesthesia significantly improves patient comfort, reduces stress responses, facilitates endoscopic manipulation, and decreases procedure-related adverse reactions, making it the preferred approach for gastrointestinal endoscopy in current clinical practice.2
Obesity is a chronic metabolic disease characterized by excessive fat accumulation and is associated with genetic, environmental, and lifestyle factors.3 It is not only an important risk factor for cardiovascular disease, diabetes mellitus, and metabolic syndrome4–8 but is also closely associated with gastrointestinal disorders. Previous studies have demonstrated that obesity is an independent risk factor for gastroesophageal reflux disease (GERD).9 Excessive fat accumulation increases intra-abdominal pressure and impairs lower esophageal sphincter function, thereby increasing the risk of gastroesophageal reflux. Obesity is also a major risk factor for severe GERD-related complications, including Barrett’s esophagus and esophageal adenocarcinoma.10 As gastrointestinal endoscopy remains the standard diagnostic and therapeutic modality for gastrointestinal diseases, its application in obese populations continues to increase, making overweight and obese patients an important high-risk population during painless endoscopic procedures.
Body mass index (BMI) is widely used for the quantitative assessment of overweight and obesity and is calculated as weight (kg) divided by height squared (m2). The World Health Organization (WHO) defines overweight as a BMI of 25.0–29.9 kg/m2 and obesity as a BMI ≥30.0 kg/m2.11 However, accumulating evidence suggests that Asian populations have different body fat distribution and metabolic characteristics compared with Western populations, resulting in increased cardiometabolic risk at lower BMI levels. Therefore, stricter BMI cutoffs have been recommended for Asian populations12. According to Chinese criteria, BMI ≥24 kg/m2 is defined as overweight and BMI ≥28 kg/m2 as obesity.13 Accordingly, the present study included patients with BMI ≥24 kg/m2 to ensure clinical relevance for Asian populations.
Anesthetic management during painless gastrointestinal endoscopy is particularly challenging in overweight and obese patients because of altered respiratory physiology. Excessive thoracic and abdominal fat accumulation reduces lung compliance and functional residual capacity. Previous studies have shown that every 5 kg/m2 increase in BMI is associated with a 5–15% reduction in functional residual capacity.14,15 In addition, fat deposition around the pharynx and upper airway increases the risk of airway obstruction, hypoventilation, and difficult airway management. Obstructive sleep apnea (OSA) is highly prevalent in obese individuals, with reported incidences ranging from 40% to 90%.16 During sedation or sleep, decreased upper airway muscle tone further predisposes these patients to recurrent apnea or hypoventilation, resulting in hypoxemia and hypercapnia.17 Previous studies have identified obesity as an independent risk factor for sedation-related complications.18 Obese patients undergoing endoscopic sedation have significantly higher risks of hypoxemia and airway intervention requirements compared with non-obese patients.18,19 Wang et al further demonstrated that obese patients receiving propofol combined with low-dose sufentanil for gastrointestinal endoscopy had a hypoxemia incidence as high as 21.2%, significantly greater than that observed in normal-weight populations.20
Propofol is currently the most commonly used intravenous anesthetic agent for painless gastrointestinal endoscopy because of its rapid onset, short half-life, rapid recovery, and low incidence of postoperative nausea and vomiting.21–23 However, propofol has a narrow therapeutic window, and higher doses are required to maintain adequate sedation, which is associated with increased risks of respiratory depression, hypotension, and injection pain.24,25 To reduce propofol dosage, it is commonly combined with low-dose opioids, which provide synergistic sedation and analgesia while minimizing propofol-related adverse effects.26 Nevertheless, increasing propofol doses may still aggravate respiratory and circulatory depression in overweight or obese patients.
Ciprofol is a novel intravenous anesthetic developed in China and is structurally derived from propofol. Phase I clinical studies demonstrated that ciprofol provides rapid induction and recovery with dose-dependent sedative effects. Doses ≥0.4 mg/kg achieved 100% successful deep sedation/anesthesia for gastrointestinal endoscopy while requiring significantly lower doses than propofol because of its approximately fourfold greater pharmacologic potency. A multicenter, randomized, non-inferiority Phase III trial further demonstrated that 0.4 mg/kg ciprofol achieved a 100% procedural success rate during gastrointestinal endoscopy.27 Although recovery time was slightly longer than with propofol, ciprofol was associated with lower incidences of respiratory adverse events, including respiratory depression, apnea, hypoxemia, and injection pain.28,29
Alfentanil was selected as the adjunct opioid because of its rapid onset, short duration of action, and favorable pharmacokinetic profile. By administering the same alfentanil regimen in both groups, potential confounding effects related to opioid use were minimized, allowing a more direct assessment of the respiratory safety profiles of ciprofol and propofol.
Based on the above findings, ciprofol may offer potential advantages in both sedative efficacy and respiratory safety. Therefore, this study aimed to investigate whether ciprofol could reduce the incidence of respiratory adverse events compared with propofol in overweight or obese patients undergoing painless gastrointestinal endoscopy, thereby providing evidence for safer and more effective anesthetic management strategies in this high-risk population.
Methods
The study protocol has been prepared using the SPIRIT 2013 Statement guidelines and in full concordance with the Declaration of Helsinki. And the patient cohort analyzed in this study is independent from the cohorts reported in our previous publications.
Inclusion and Exclusion Criteria
This study recruited overweight patients undergoing painless gastroscopy. Patients who met the following criteria were enrolled: 1) Aged between 18 and 65 years, regardless of gender; 2) Body mass index (BMI) ≥ 24 kg/m2 (in accordance with the Asian BMI classification standards); 3) Scheduled for gastroscopy diagnosis or treatment in our hospital; 4) American Society of Anesthesiologists (ASA) physical status classification of Grade I or II; 5) Fully understood the study protocol, voluntarily participated in the study, and signed the informed consent form personally or by their legal relatives.
Patients with any of the following conditions were excluded: 1) Requiring complex endoscopic procedures; 2) A history of allergy or hypersensitivity to soy, egg products, opioids, or any other anesthetics; 3) A history of drug or alcohol abuse within the past 3 months; 4) Severe cardiovascular diseases, including uncontrolled hypertension (systolic blood pressure ≥ 170 mmHg, diastolic blood pressure ≥ 105 mmHg without antihypertensive medication), severe arrhythmia, heart failure, Adams-Stokes syndrome, unstable angina pectoris, myocardial infarction within 6 months, third-degree atrioventricular block, or QTcF interval ≥ 450 ms; 5) Severe respiratory diseases, including respiratory insufficiency, chronic obstructive pulmonary disease (COPD), bronchospasm requiring treatment within 3 months, acute respiratory tract infection with obvious fever, wheezing, nasal rales, cough, or other symptoms within 1 week; 6) Cerebrovascular diseases, including brain injury, convulsion, increased intracranial pressure, or cerebral aneurysm; 7) Mental illnesses, including schizophrenia, mania, etc.; 8) Severe gastrointestinal diseases, including gastric retention or persistent bleeding; 9) Pregnancy or lactation period; 10) Participation in any other clinical trials within 30 days; 11) Inability to communicate effectively with researchers.
Randomization and Blinding
Patients were randomly assigned in a 1:1 ratio to either the propofol group or the ciprofol group using a computer-generated randomization sequence. Group allocation was concealed in sequentially numbered opaque envelopes and opened immediately before anesthesia induction by an independent anesthesiologist who was not involved in postoperative data collection or statistical analysis. Due to differences in the dosing regimens of the two study drugs, the anesthesiologist responsible for drug administration could not be blinded to group allocation. However, outcome assessment, data collection, and statistical analyses were performed by independent investigators who remained blinded throughout the study.
Study Interventions Process
All clinical procedures were performed by a single attending anesthesiologist, with an independent researcher responsible for continuous data recording throughout the study. The recorded data included patients’ basic demographic information, vital signs on admission to the endoscopy room, and all adverse events occurring during the gastroscopy procedure.
A standardized preprocedural protocol was strictly implemented for all patients: fasting for at least 6 hours and water deprivation for 4 hours before the procedure, with the establishment of a peripheral venous access. An oral anti-foaming agent was administered before gastroscopy initiation. Upon admission, routine monitoring of electrocardiogram (ECG), peripheral oxygen saturation (SpO2), and non-invasive blood pressure was started, with the blood pressure cuff uniformly applied to the left upper arm; all patients were positioned in the left lateral decubitus position for the procedure. Nasal cannula oxygenation at a flow rate of 3–4 L/min was initiated 1 minute before anesthetic induction in accordance with routine clinical practice at our institution. Considering the short preparation time before painless gastroscopy and the need to maintain procedural efficiency in the endoscopy unit, a 1-minute preoxygenation period was adopted uniformly for all participants.
Drug administration was performed by the attending anesthesiologist via slow and uniform intravenous injection (injection time ≥ 30seconds). Patients in both groups first received an analgesic dose of alfentanil (5 μg/kg), followed by the study anesthetic: propofol at a dose of 2 mg/kg in the propofol group and ciprofol at a dose of 0.4 mg/kg in the ciprofol group. The Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale was used to evaluate the sedation level 1 minute after the completion of the initial drug dose. Gastroscopy insertion was initiated if the MOAA/S score was ≤ 1. Additional bolus doses of the corresponding anesthetic were permitted if the MOAA/S score remained ≥ 2 at 2 minutes after the initial dose or if the initial gastroscopy insertion attempt failed.
Vital signs were continuously monitored and recorded during the entire gastroscopy procedure. Immediate respiratory intervention measures, including the jaw thrust maneuver and mask oxygenation, were initiated if the SpO2 dropped below 90% and failed to recover for 15 consecutive seconds. After the completion of gastroscopy, all patients were transferred to the post-anesthesia care unit (PACU) for continuous monitoring and recovery, only after their vital signs were confirmed to be stable.
Primary and Secondary Outcomes
The primary outcome was the incidence of respiratory adverse events, defined as the occurrence of at least one of the following events during the procedure: respiratory depression (respiratory rate < 8 breaths/min lasting > 30s), hypoxemia (SpO2 < 90% lasting > 15s), or apnea (absence of thoracic movement lasting > 20s). Each patient was counted once only for the composite endpoint, regardless of the number of component events experienced.
Definitions of respiratory adverse events were based on previous endoscopy sedation studies and current clinical monitoring standards.
Secondary outcome indicators included time to sedation onset, incidence of injection pain, requirement for respiratory intervention (such as jaw thrust or mask ventilation), changes in hemodynamic indicators, incidence of adverse reactions (eg, nausea, vomiting, abdominal pain), recovery time, and duration of gastroscopy procedure.
Definitions of key indicators were as follows: Time to sedation onset was defined as the time from the initiation of drug injection to the achievement of a Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score ≤ 1. The duration of gastroscopy refers to the time from insertion to withdrawal. Patient recovery time was the interval from the completion of drug administration to eye opening. Both patient and endoscopist satisfaction were evaluated using a 10-point scale, where 0 indicated complete dissatisfaction, and 10 indicated complete satisfaction.
Sample Size Calculation
The Sample size was estimated using PASS 25.0 software based on the difference in respiratory adverse events between the experimental and control groups. According to our preliminary pilot study, the incidence of respiratory adverse events was 28.7% for ciprofol and 60.0% for propofol. With a two-sided α of 0.05, a statistical power of 0.90, and an estimated dropout rate of 10%, the final sample size was determined to be 106 cases, with 53 cases assigned to the propofol group and 53 cases to the ciprofol group.
Statistical Analysis
Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 9.0 (GraphPad Software, San Diego, CA, USA). All statistical tests were two-sided, and P < 0.05 was considered statistically significant.
Continuous variables were assessed for normality using the Shapiro–Wilk test and expressed as mean ± standard deviation (SD) for normally distributed data or median (interquartile range [IQR]) for non-normally distributed data. Homogeneity of variance was evaluated using Levene’s test before parametric analyses.
Baseline characteristics were summarized descriptively to assess clinical comparability between groups and were not subjected to formal hypothesis testing. Categorical variables were compared using the chi-square test or Fisher’s exact test when expected cell counts were less than 5.
Repeated physiological measurements, including mean arterial pressure (MAP), were analyzed using repeated-measures analysis of variance (ANOVA). Mauchly’s test was used to assess sphericity assumptions, and the Greenhouse–Geisser correction was applied when sphericity assumptions were violated. Post-hoc multiple comparisons were performed using Bonferroni correction.
The subgroup analyses were exploratory and were performed to evaluate the consistency of treatment effects across predefined clinical characteristics. No formal adjustment for multiplicity was performed for secondary or subgroup analyses; therefore, these findings should be interpreted cautiously.
All randomized patients who completed the study procedures were included in the final intention-to-treat analysis. No missing primary outcome data were observed. Also, no missing data occurred for repeated measurements of SpO2, respiratory rate, or MAP.
Secondary outcomes and subgroup analyses were considered exploratory.
Results
In this study, a total of 106 eligible overweight or obese patients underwent painless gastroscopy and were included in the final analysis. The figure (Figure 1) below illustrates the flowchart of participant screening and inclusion process in the study.
Figure 1.
CONSORT flow diagram of patient enrollment, randomization, follow-up, and analysis. All randomized patients completed the study and were included in the final analysis. No missing primary outcome data were observed.
Patient General Characteristics
A total of 106 patients were randomized and completed the study. All enrolled patients were classified as ASA physical status I or II. The number of overweight (BMI 24.0–27.9 kg/m2) and obese (BMI ≥ 28.0 kg/m2) patients was additionally summarized in Table 1. Baseline demographic and clinical characteristics were generally balanced between the two groups (Table 1). Patient age, sex distribution, body mass index, ASA classification, smoking history, alcohol consumption history, comorbidities, and procedure duration appeared comparable across treatment groups.
Table 1.
Baseline Characteristics of the Participants
| Characteristic | Propofol (n=53) | Ciprofol (n=53) | t/ χ2/Z | P |
|---|---|---|---|---|
| BMI (kg/m2) | 25.61(24.88,27.98) | 26.04(25.25,27.73) | 0.739 | 0.460 |
| Overweight (n, %) | 40(75.47) | 41(77.36) | 0.052 | 0.819 |
| Obese (n, %) | 13(24.53) | 12(22.64) | ||
| ASA I | 30(56.60) | 24(45.28) | 1.359 | 0.244 |
| ASA II | 23(43.40) | 29(54.72) | ||
| Age (Years) | 48.5 ± 8.6 | 50.8 ± 7.9 | 1.425 | 0.157 |
| Female (n, %) | 13(24.53) | 12(22.64) | 0.052 | 0.819 |
| Male (n, %) | 40(75.47) | 41(77.36) | ||
| Smoke (n, %) | 9(16.98) | 14(26.42) | 1.388 | 0.239 |
| Drink (n, %) | 17(32.08) | 17(32.08) | <0.001 | 1.000 |
| Hypertension (n, %) | 14(26.42) | 23(43.40) | 3.363 | 0.067 |
| Diabetes (n, %) | 4(7.55) | 3(5.66) | <0.001 | 1.000 |
| Snore (n, %) | 29(54.72) | 32(60.38) | 0.348 | 0.556 |
| Gastroscopy procedure duration(s) | 192.00(164.50,309.00) | 201.00(160.00,258.50) | 0.025 | 0.980 |
Primary Outcomes
The incidence of respiratory adverse events during painless gastroscopy was analyzed between the two groups (Table 2). The results demonstrated that the overall incidence of respiratory adverse events was significantly lower in the ciprofol group than in the propofol group. Specifically, respiratory adverse events occurred in 35 patients in the propofol group compared with 18 patients in the ciprofol group (66.04% vs 33.96%, P=0.001).
Table 2.
Comparison of Respiratory Adverse Events Between the Two Groups
| Propofol (n=53) |
Ciprofol (n=53) |
Estimated Effect (95% CI) |
χ2 | P | |
|---|---|---|---|---|---|
| Respiratory adverse events (n, %) | 35(66.04) | 18(33.96) | RR:1.94 (1.28 to 2.97) | 10.906 | 0.001 |
| Hypoxemia (n, %) | 30(56.60) | 15(28.30) | RR:2.00 (1.23 to 3.26) | 8.689 | 0.003 |
| Apnea (n, %) | 6(11.32) | 2(3.77) | RR:3.00 (0.63 to 14.20) | 1.217 | 0.270 |
| Respiratory depression (n, %) | 7(13.21) | 3(5.66) | RR:2.33 (0.64 to 8.54) | 1.767 | 0.184 |
| Experienced multiple respiratory adverse events (n, %) | 7(13.21) | 2(3.77) | RR:3.50 (0.76 to 16.08) | 1.943 | 0.163 |
To further clarify differences among specific types of respiratory adverse events, subgroup analyses were performed. Hypoxemia was the most common respiratory adverse event and showed the most pronounced intergroup difference. The incidence of hypoxemia was 56.60% (30/53) in the propofol group and 28.30% (15/53) in the ciprofol group, with a statistically significant difference between groups (56.60% vs 28.30%, P=0.003).
In contrast, no statistically significant differences were observed between groups in the incidence of apnea or respiratory depression. The incidence of apnea was 11.32% in the propofol group and 3.77% in the ciprofol group, while the incidence of respiratory depression was 13.21% and 5.66%, respectively (both P>0.05). These findings suggest that the two anesthetic regimens showed comparable effects in preventing apnea and respiratory depression in the present study.
Secondary Outcomes
To further evaluate the effects of ciprofol and propofol on respiratory function in overweight or obese patients during anesthesia, peripheral oxygen saturation (SpO2) and respiratory rate (RR) were dynamically monitored and analyzed throughout the procedure. SpO2 levels were compared between the two groups at four predefined time points: upon admission to the endoscopy room (T0), after anesthetic induction (T1), 2 minutes after induction (T2), and before discharge from the recovery room (T3). No statistically significant differences in SpO2 were observed between the propofol group and the ciprofol group at any time point (Figure 2A). In addition, comparisons of SpO2 changes between adjacent monitoring time points also revealed no significant intergroup differences (Figure 2B), suggesting that both anesthetic regimens produced comparable dynamic fluctuations in oxygen saturation.
Figure 2.
Vital signs were recorded at patient admission to the endoscopy room (T0), after anesthetic induction (T1), 2 minutes after induction (T2), and before discharge from the recovery room (T3). (A) Peripheral oxygen saturation (SpO2) levels in the propofol group and ciprofol group at the four time points showed no statistically significant differences (P > 0.05). (B) Changes in SpO2 differences between adjacent time points were not significantly different between the two groups (P > 0.05). (C) Comparison of the minimum SpO2 values between the propofol group and the ciprofol group demonstrated a statistically significant difference (*P < 0.05). (D) The differences between baseline SpO2 at admission and minimum SpO2 were compared between the two groups, with no statistically significant difference observed (P > 0.05). (E) Respiratory rate (RR) was recorded at the four time points in both groups. A statistically significant difference was observed at T3 (before discharge from the recovery room) (***P < 0.001). (F) Changes in respiratory rate differences between adjacent monitoring time points were compared between the propofol group and the ciprofol group, with no statistically significant difference observed (P > 0.05).
However, analysis of the minimum SpO2 during the entire anesthetic period demonstrated that the median minimum SpO2 was significantly lower in the propofol group than in the ciprofol group (89.0% vs 93.5%, P=0.044; Figure 2C). Furthermore, the difference between baseline SpO2 and minimum SpO2 was analyzed to assess the extent of oxygen desaturation. No statistically significant difference was observed between the two groups (P=0.057; Figure 2D), indicating a comparable magnitude of SpO2 decline during the procedure.
Respiratory rate was also analyzed at the same four monitoring time points. No significant differences were observed between groups at T0, T1, or T2. However, at T3, RR was significantly higher in the propofol group than in the ciprofol group (16.28 vs 13.57 breaths/min; mean difference, 2.72; 95% CI, 0.96–4.48; P=0.001; Figure 2E), suggesting a faster recovery of respiratory rhythm in the propofol group before discharge from the recovery room. Comparisons of RR changes between adjacent monitoring time points showed no statistically significant differences between groups (Figure 2F).
Repeated-measures analysis of variance (ANOVA) was performed to compare mean arterial pressure (MAP) between the two groups across four time points (Figure 3). The results showed that MAP levels in both groups exhibited a significant decreasing trend over time, with statistically significant differences in MAP across time points (F = 127.713, P < 0.001) (Supplementary Table S2). However, no statistically significant interaction was observed between MAP levels and time in the two groups (F = 0.996, P = 0.395), indicating that the propofol and ciprofol groups showed consistent MAP change trends across the four time points, with no significant intergroup difference in the trend. Further analyses regarding mean arterial pressure (MAP) are presented in Supplementary Table S1, with no statistically significant differences identified between the two groups.
Figure 3.
Repeated measurements of mean arterial pressure (MAP).
To comprehensively evaluate the clinical performance of the two intravenous anesthetic regimens in overweight or obese patients undergoing painless gastroscopy, additional analyses were performed on sedation onset time, duration of hypoxemia, and recovery time (Figure 4).
Figure 4.
Results of Other Secondary Outcome Measures. (A) Comparison of the time to sedation onset and duration of hypoxemia between the two groups showed no statistically significant differences (all P > 0.05). (B) Comparison of the recovery time between the two groups demonstrated a statistically significant difference (P = 0.025). *:P≤0.05.
No statistically significant differences were observed between the propofol group and the ciprofol group in terms of sedation onset time or duration of hypoxemia (P>0.05). The sedation onset time was 58.10±8.29 s in the propofol group and 59.40±11.42 s in the ciprofol group (P=0.507), indicating that both anesthetic regimens rapidly achieved the sedation depth required for gastroscopy and provided comparable efficacy in facilitating the procedure. Similarly, the duration of hypoxemia did not differ significantly between the two groups (54.27±35.58 s vs 49.29±43.85 s, P=0.684), suggesting similar effectiveness in limiting hypoxemia duration and promoting recovery of oxygenation.
However, a significant difference was observed in recovery time (P=0.025). Patients in the ciprofol group had a significantly longer recovery time compared with those in the propofol group (9.20±2.97 min vs 7.84±2.69 min).
Statistical analysis was also performed on the safety-related adverse events during anesthesia and endoscopic examination in both groups (Table 3). The results showed that the incidence of injection pain was 18.87% in the propofol group, while no injection pain occurred in the ciprofol group throughout the study, and the difference in incidence between the two groups was statistically significant (P = 0.001). The incidence of hypotension in the propofol group was 22.64%, significantly higher than 7.55% in the ciprofol group (P = 0.030). However, the incidence of bradycardia in the ciprofol group was 22.64%, significantly higher than 5.66% in the propofol group, and this difference was also statistically significant (P = 0.012).
Table 3.
Comparison of Adverse Events Between the Two Groups
| Adverse Event (AE) | Propofol (n=53) |
Ciprofol (n=53) |
Estimated Effect (95% CI) |
χ2 | P |
|---|---|---|---|---|---|
| Hypotension (n, %) | 12(22.64) | 4(7.55) | RR:3.00 (1.03 to 8.71) | 4.711 | 0.030 |
| Injection pain (n, %) | 10(18.87) | 0(0.0) | – | 11.042 | 0.001 |
| Bradycardia (n, %) | 3(5.66) | 12(22.64) | RR:0.25 (0.08 to 0.84) | 6.290 | 0.012 |
| Patient movement (n, %) | 1(1.89) | 1(1.89) | RR:1.00 (0.05 to 15.57) | <0.001 | 1.000 |
Notes: No relative risk (RR) could be calculated for injection pain, given that the incidence of injection pain was zero in the ciprofol group.
In addition, no tachycardia occurred in either group during the entire endoscopic examination. After the completion of endoscopy, no postoperative adverse events such as nausea, vomiting, coughing, or abdominal pain were observed in either group.
To further quantitatively evaluate the effects of ciprofol and propofol on oxygenation during anesthesia, the present study systematically analyzed the corrective interventions required for oxygenation abnormalities throughout anesthetic induction, maintenance, and the endoscopic procedure (Table 4). Statistical analysis showed no significant differences between the propofol and ciprofol groups in the frequency of any individual oxygenation intervention (all P>0.05), suggesting that the need for specific corrective measures was generally comparable between the two anesthetic regimens.
Table 4.
Comparison of Airway Interventions Between the Two Groups
| Propofol (n=53) |
Ciprofol (n=53) |
Estimated Effect (95% CI) |
χ2 | P | |
|---|---|---|---|---|---|
| Required intervention (at least one item) | 27(50.94) | 14(26.42) | RR:1.93 (1.15 to 3.25) | 6.722 | 0.010 |
| Jaw thrust | 15(28.30) | 9(16.98) | RR:1.67 (0.80 to 3.47) | 1.939 | 0.164 |
| Mask oxygenation | 9(16.98) | 4(7.55) | RR:2.25 (0.74 to 6.86) | 2.192 | 0.139 |
| Nasopharyngeal airway | 3(5.66) | 1(1.89) | RR:3.00 (0.32 to 27.93) | 0.260 | 0.610 |
Specifically, jaw-thrust maneuvers, which were performed to relieve upper airway obstruction and improve ventilation, were required in 15 patients (28.30%) in the propofol group and 9 patients (16.98%) in the ciprofol group. Mask oxygen supplementation, used for rapid correction of hypoxemia and improvement of oxygen saturation, was administered in 9 patients (16.98%) in the propofol group and 4 patients (7.55%) in the ciprofol group. Nasopharyngeal airway placement, used to maintain upper airway patency and adequate ventilation, was required in 3 patients (5.66%) in the propofol group and 1 patient (1.89%) in the ciprofol group.
Further analysis of the overall need for oxygenation interventions demonstrated that 27 patients (50.94%) in the propofol group required at least one corrective intervention, compared with 14 patients (26.42%) in the ciprofol group. This difference was statistically significant (P=0.01), indicating that patients receiving ciprofol experienced fewer oxygenation abnormalities requiring clinical intervention during anesthesia and endoscopic examination compared with those receiving propofol.
Exploratory subgroup analyses (Figure 5) were performed according to age, sex, hypertension, diabetes mellitus, smoking history, and alcohol consumption history.
Figure 5.
Exploratory Subgroup Analysis.
No statistically significant interactions were detected between treatment assignment and subgroup variables. Given that these subgroup analyses were exploratory in nature and the study was not originally powered to detect between-subgroup differences, these findings should be interpreted with caution.
Discussion
This study focused on the critical clinical issue of anesthetic safety during painless gastroscopy in overweight or obese patients. Given the increased risk of anesthesia-related respiratory complications in this special population, we conducted a randomized controlled trial to systematically compare the clinical efficacy and safety of ciprofol combined with alfentanil versus propofol combined with alfentanil in patients with BMI ≥24 kg/m2. The results demonstrated that a regimen of ciprofol 0.4 mg/kg combined with alfentanil 5 μg/kg significantly reduced the overall incidence of respiratory adverse events during anesthesia and endoscopic examination compared with the propofol-based regimen. In addition, ciprofol showed advantages in reducing injection pain and improving hemodynamic stability, providing reliable clinical evidence for individualized anesthetic management in overweight or obese patients undergoing painless endoscopy.
The most important finding of the present study was that the incidence of respiratory adverse events was significantly lower in the ciprofol group than in the propofol group (33.96% vs 66.04%), with the most prominent difference observed in the incidence of hypoxemia. These findings are highly consistent with the multicenter phase III trial conducted by Li et al27 In that study, involving 289 patients undergoing gastrointestinal endoscopy, ciprofol 0.4 mg/kg significantly reduced the incidence of respiratory complications compared with propofol at an equivalent sedative dose, further supporting the reliability and reproducibility of our results. However, it should be noted that previous studies by Zhang et al30 and Eberl et al31 reported substantially lower hypoxemia rates with propofol combined with alfentanil (14.1% and 13.25%, respectively) than those observed in the present study (56.60%). This discrepancy is likely attributable to differences in study populations, as our study specifically enrolled overweight or obese patients. Due to excessive thoracoabdominal fat accumulation, upper airway narrowing, and reduced pulmonary reserve, overweight or obese patients inherently have a substantially higher baseline risk of respiratory depression and hypoxemia during sedation than individuals with normal body weight.
Interestingly, no statistically significant differences were observed between the two groups in the incidence of apnea (11.32% vs 3.77%) or respiratory depression (13.21% vs 5.66%). This finding may be related to the synergistic effects of alfentanil. As a short-acting μ-opioid receptor agonist, alfentanil provides potent analgesia with rapid onset and metabolism, thereby reducing procedural discomfort and decreasing the required dose of intravenous anesthetics.32 However, alfentanil itself exerts mild respiratory depressant effects,33 which may partially offset the respiratory protective advantage of ciprofol over propofol. Although the alfentanil dose used in this study (5 μg/kg) is commonly applied in clinical painless gastroscopy, our findings suggest that it may still influence respiratory rhythm to some extent. These observations may provide a potential direction for optimizing opioid-anesthetic combinations to.
The results regarding oxygenation interventions further support the respiratory safety advantages of ciprofol. Although no statistically significant differences were observed between groups in the use of individual oxygenation interventions, including jaw thrust, mask oxygen supplementation, or nasopharyngeal airway placement (all P>0.05), the overall rate of patients requiring at least one oxygenation intervention was significantly lower in the ciprofol group than in the propofol group (26.42% vs 50.94%). These findings suggest that ciprofol causes less respiratory suppression and better preserves spontaneous respiratory regulation and oxygenation stability in overweight or obese patients, thereby reducing the overall need for airway and oxygenation interventions during sedation.
Hemodynamic stability is another major concern in overweight or obese patients because of their elevated cardiovascular risk.34,35 In the present study, MAP decreased significantly over time in both groups, consistent with the dose-dependent vasodilatory and myocardial depressive effects of intravenous anesthetics.36 However, the magnitude of MAP reduction during the induction and early maintenance phases appeared smaller in the ciprofol group, suggesting a milder suppressive effect on blood pressure. Although these intergroup differences did not reach statistical significance, the observed trend was consistent with previous findings reported by Zhang et al30 and supports the potential hemodynamic advantages of ciprofol. Experimental studies have further demonstrated that ciprofol may exert cardioprotective effects through upregulation of hypoxia-inducible factor-1α (HIF-1α) and inhibition of ferroptosis in cardiomyocytes, thereby attenuating myocardial ischemia-reperfusion injury.37 Such effects may be particularly important in overweight or obese patients, who often exhibit impaired vascular compliance and reduced cardiovascular reserve.38 Therefore, the relatively stable hemodynamic profile associated with ciprofol may provide additional safety benefits in this high-risk population.
Both the ciprofol group (0.4 mg/kg induction) and the propofol group (2 mg/kg induction) achieved a 100% success rate for painless gastroscopy, indicating that low-dose ciprofol provided sedative efficacy comparable to standard-dose propofol and was sufficient to ensure procedural completion. These findings are consistent with the phase IIb trial conducted by Teng et al,1 further confirming the clinical efficacy and reliability of ciprofol for procedural sedation. Pharmacologic studies have shown that ciprofol has approximately 4–5 times greater affinity for the γ-aminobutyric acid A (GABAA) receptor than propofol,39,40 which may explain why lower doses of ciprofol can achieve anesthetic effects comparable to those of propofol.
Regarding adverse events, ciprofol demonstrated two notable clinical advantages over propofol. First, the incidence of injection pain was significantly lower in the ciprofol group (0% vs 18.87%, P=0.001). Previous studies suggest that the greater hydrophobicity and lower plasma concentration of ciprofol reduce vascular endothelial irritation, thereby decreasing injection pain.41,42 Interestingly, the injection pain rate observed in the propofol group in this study was substantially lower than that reported in previous studies of propofol alone,43–45 possibly because alfentanil was administered before propofol, thereby attenuating injection pain. Second, the incidence of hypotension was significantly lower in the ciprofol group than in the propofol group (7.55% vs 22.64%, P=0.030), consistent with previous findings by Li et al46 and further supporting the superior hemodynamic stability of ciprofol.
In the present study, the incidence of bradycardia was higher in the ciprofol group. The underlying mechanism remains unclear. Ciprofol is a propofol analogue that exerts sedative and hypnotic effects mainly through GABA-A receptors, and modulation of central autonomic activity may partly contribute to heart rate changes. In addition, gastrointestinal endoscopy itself may induce vagal reflexes, and concomitant alfentanil administration may further enhance vagal predominance or attenuate sympathetic responses. Therefore, the increased incidence of bradycardia observed in the ciprofol group may reflect the combined effects of ciprofol-related autonomic modulation, opioid coadministration, procedural vagal stimulation, and individual patient susceptibility. Notably, all bradycardia episodes in this study were transient and did not require pharmacological intervention. Further studies are needed to clarify the mechanism and clinical significance of ciprofol-associated bradycardia.
In addition, recovery time was significantly longer in the ciprofol group than in the propofol group (9.20±2.97 min vs 7.84±2.69 min, P=0.025), consistent with previous findings reported by Chen et al47 This difference may be explained by the pharmacokinetic characteristics of ciprofol, which has a longer elimination half-life (t1/2β = 1.58–2.47 h)48 than propofol (0.5–1.0 h).49 The relatively slower clearance of ciprofol from the central nervous system may contribute to delayed recovery despite comparable sedation depth.
No postoperative nausea or vomiting was observed in either group. Similar findings were reported by Chen et al,50 who observed no nausea or vomiting in patients receiving ciprofol. This favorable outcome may also be related to the use of alfentanil, which has been associated with lower rates of postoperative nausea and vomiting compared with equipotent doses of fentanyl or sufentanil.51 Collectively, these findings further support the safety and tolerability of both anesthetic regimens during the recovery period.
Limitations
Despite these meaningful findings, this study has several limitations. First, the sample size was relatively small (106 patients), and the study was conducted at a single center, which may limit the generalizability of the findings and introduce potential selection bias. Therefore, larger multicenter studies are warranted to validate the robustness and external applicability of our results. Second, end-tidal carbon dioxide (PETCO2) was not monitored during anesthesia, precluding a comprehensive assessment of ventilatory function. Given that PETCO2 monitoring facilitates the early detection of hypoventilation, particularly in overweight or obese patients with reduced respiratory reserve, its absence represents an important limitation. Third, all patients received only 1 minute of preoxygenation before anesthesia induction, which reflected routine clinical practice at our institution. However, longer preoxygenation durations may further increase oxygen reserves and potentially reduce the incidence of hypoxemia, especially in high-risk populations such as overweight and obese patients. Future studies should investigate the optimal preoxygenation strategy in this setting. Also, this study only focused on short-term effects during anesthesia and the recovery period, without tracking patients’ recovery quality within 24 hours after surgery (eg, postoperative drowsiness, cognitive dysfunction), so long-term safety data remain to be supplemented. Finally, multiple secondary and subgroup analyses were performed without formal adjustment for multiplicity; therefore, these findings should be considered exploratory and interpreted with caution.
Future Research
Based on the study’s findings and limitations, future research can further explore the following aspects: 1) Developing individualized dose adjustment strategies for ciprofol, incorporating factors such as patients’ BMI, ASA classification, and snoring history to formulate precise medication regimens; 2) Optimizing the combined dose of alfentanil to minimize the synergistic effect of respiratory depression while maintaining adequate analgesic efficacy; 3) Adopting multimodal monitoring (eg, PETCO2, bispectral index BIS) to enhance the accuracy of anesthetic management; 4) Conducting long-term follow-up studies to comprehensively evaluate the impact of ciprofol on patients’ postoperative recovery quality.
Conclusion
In overweight or obese patients (BMI ≥24 kg/m2) undergoing painless gastroscopy, a sedation regimen of ciprofol (0.4 mg/kg) combined with alfentanil (5 μg/kg) significantly reduced the incidence of respiratory adverse events, particularly hypoxemia, compared with propofol, while maintaining a high procedural success rate. Ciprofol was also associated with a lower incidence of injection pain and hypotension, suggesting potential advantages in the anesthetic management of this patient population. These findings support ciprofol as a safe and effective alternative to propofol for painless endoscopy in overweight or obese patients. However, the increased incidence of bradycardia and prolonged recovery time observed with ciprofol should be considered when selecting anesthetic regimens, and further large-scale studies are warranted to confirm its clinical benefits and safety profile.
Funding Statement
This research was supported by Medical and Health Science Program of Zhejiang Province (2025HY0551) and the Beijing Kangmeng Charity Foundation (Grant No. S186).
Data Sharing Statement
Deidentified individual participant data underlying the results reported in this article, including demographic characteristics, outcome data, and adverse event data, will be made available upon reasonable request to the corresponding authors. Data will be available beginning 6 months after publication and ending 2 years after publication.
Ethics Approval and Consent to Participate
Ethics Committee in Clinical Research of the First Affiliated Hospital of Wenzhou Medical University in December 2024 (No.157/2024, received 12/14/2024).
Ethics Committee in Clinical Research of the First Affiliated Hospital of Wenzhou Medical University in December 2025 (No.605/2025, received 01/16/2026).
The study protocol received initial approval from the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University in December 2024. During the recruitment period, modifications to the inclusion criteria were required because of slower-than-expected enrollment. The amended protocol was reviewed and approved by the same Ethics Committee before implementation. All participants were enrolled only after the corresponding ethics approvals had been obtained. Written informed consent was obtained from all participants before study participation.
Disclosure
The authors report no conflicts of interest in this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Deidentified individual participant data underlying the results reported in this article, including demographic characteristics, outcome data, and adverse event data, will be made available upon reasonable request to the corresponding authors. Data will be available beginning 6 months after publication and ending 2 years after publication.