The combination of simethicone and N-acetylcysteine in lidocaine ice popsicle compared with lidocaine ice popsicle alone in patients undergoing unsedated esophagogastroduodenoscopy: A prospective double-blind randomized controlled trial

BACKGROUND: Optimal mucosal visualization is essential for high-quality esophagogastroduodenoscopy (EGD), particularly for the detection of subtle upper gastrointestinal lesions. Oral simethicone and N-acetylcysteine (NAC) are commonly used to improve mucosal cleanliness, whereas lidocaine ice popsicles provide effective topical pharyngeal anesthesia for unsedated EGD. We evaluated whether incorporating simethicone and NAC into a lidocaine ice popsicle could improve mucosal visibility while maintaining patient comfort. METHODS: This single-center, prospective, double-blind, randomized controlled trial enrolled 374 adults undergoing unsedated diagnostic EGD between December 2024 and June 2025. Participants were randomized (1:1) to receive either a lidocaine ice popsicle containing simethicone (100 mg) and NAC (600 mg) or a conventional lidocaine ice popsicle. The primary outcome was mucosal visibility assessed using a modified Total Visibility Score (TVS). Secondary outcomes included procedure time, water volume required for mucosal cleansing, additional simethicone use, endoscopist satisfaction, ease of esophageal instrumentation, gag reflex, patient satisfaction, discomfort, pain, and adverse events. Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). RESULTS: All 374 randomized participants (187 per group) completed the study and were analyzed according to their assigned groups. Baseline characteristics were descriptively similar between groups. The intervention group had a significantly lower TVS than the control group (6.19 ± 0.51 vs. 10.39 ± 2.22; mean difference, -4.20; 95% CI, -4.53 to -3.88; P < 0.001), indicating better mucosal visibility. Exploratory segment-specific analyses showed lower visibility scores in all six gastrointestinal segments. The intervention group also had higher endoscopist satisfaction, shorter procedure time (10.87 ± 1.44 vs. 12.75 ± 0.96 min; P < 0.001), lower water requirements for mucosal cleansing, and less frequent use of additional diluted simethicone during EGD (12.8% vs. 96.8%; P < 0.001). Exploratory analyses showed statistically significant differences in gag reflex and pain scores, although the absolute differences were small. Patient satisfaction, discomfort, and ease of esophageal instrumentation did not differ significantly between groups. No adverse events were observed during the defined observation period. CONCLUSIONS: The combined formulation of simethicone and N-acetylcysteine incorporated into a lidocaine ice popsicle improved mucosal visibility compared with a lidocaine ice popsicle alone during unsedated EGD and was associated with improved procedural efficiency. This integrated formulation may provide a practical approach to pre-endoscopic preparation by combining topical anesthesia with mucosal cleansing. Further multicenter studies are warranted to confirm its effectiveness, generalizability, and safety with longer follow-up. TRIAL REGISTRATION: Thai Clinical Trials Registry TCTR20240606004.