Topical Vitamin C and N-Acetylcysteine for Reducing Symptoms After Lugol Chromoendoscopy: A Multicenter Randomized Controlled Trial

Background: Lugol chromoendoscopy improves detection of esophageal squamous neoplasia but can cause short-term retrosternal and pharyngeal discomfort. We evaluated topical vitamin C solution (VCS) and N-acetylcysteine (NAC) after Lugol staining. Methods: In this multicenter, randomized, double-blind, saline-controlled trial, 748 participants were allocated 1:1:1 to 0.9% normal saline (NS), 2% VCS, or 10% NAC after Lugol chromoendoscopy. The co-primary outcomes were overall post-procedure symptoms at 15 and 30 minutes. The main efficacy analysis was complete-case and included 681 participants; extreme-case analyses evaluated the effect of missing outcomes. Results: At 15 minutes, symptoms occurred in 44.34% of the NS group, 8.80% of the VCS group, and 9.43% of the NAC group. Relative risks versus NS were 0.198 (95% CI 0.126–0.312) for VCS and 0.213 (95% CI 0.140–0.322) for NAC. At 30 minutes, the corresponding incidences were 31.67%, 4.17%, and 4.10%, with relative risks of 0.132 (95% CI 0.067–0.257) and 0.129 (95% CI 0.068–0.245). Conclusions were unchanged in extreme-case sensitivity analyses. VAS category distributions favored both active-treatment groups. Median time to onset of decolorization was 11 seconds with NS and 2 seconds with each active solution; median time to complete decolorization was >180, 6, and 12 seconds, respectively. Conclusions: Topical VCS and NAC each reduced short-term symptoms after Lugol chromoendoscopy compared with NS and promoted rapid mucosal decolorization. The direct comparison between VCS and NAC was exploratory and does not establish equivalence or non-inferiority.