Simethicone with or without N-acetylcysteine as premedication in esophagogastroduodenoscopy: a systematic review and meta-analysis

Caroline Tanadia, Fegita Beatrix Pajalaa, Yehuda Tri Nugroho Supranotob, Kevin Tandartoc, Maureen Miracle Stellaa, Randy Adiwinatad, Paulus Simadibratad, Marcellus Simadibratae

Atma Jaya Catholic University of Indonesia; Indonesian Institute of Bioinformatics, Malang; Columbia Asia Hospital, Semarang; MRCCC Siloam Hospital Semanggi, Jakarta; Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia

aSchool of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia (Caroline Tanadi, Fegita Beatrix Pajala, Maureen Miracle Stella); bBioinformatics Research Center, Indonesian Institute of Bioinformatics (INBIO-INDONESIA), Malang (Yehuda Tri Nugroho Supranoto); cIntensive Care Unit, Columbia Asia Hospital, Semarang (Kevin Tandarto); dGastrointestinal Cancer Center, MRCCC Siloam Hospital Semanggi, Jakarta (Randy Adiwinata Paulus Simadibrata); eDivision of Gastroenterology, Pancreatobiliary and Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta (Marcellus Simadibrata), Indonesia

Correspondence to: Caroline Tanadi, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia, e-mail: carolinetanadi1@gmail.com
Received 6 June 2024; accepted 6 November 2024; published online 12 December 2024
DOI: https://doi.org/10.20524/aog.2024.0930
© 2025 Hellenic Society of Gastroenterology

Abstract

Background The impairment of gastrointestinal mucosa visibility during esophagogastroduodenoscopy (EGD), due to the presence of foam and bubbles, may lead to reduced quality in the EGD results. The combination of simethicone, a defoaming agent, along with N-acetylcysteine (NAC), which has mucolytic properties, has been proposed to improve the visibility of the mucosa. This study aimed to evaluate the effectiveness of pre-procedural administration of simethicone and N-acetylcysteine in improving mucosal visibility, procedure time and mucosal cleansing volume needed during EGD.

Methods We conducted a comprehensive literature search from inception to November 23, 2023, in PubMed, CENTRAL, ProQuest, SAGE, and JSTOR. We included randomized clinical trials that investigated the effects of simethicone with or without NAC as premedication in EGD. For the quantitative analysis, standardized mean difference (SMD) was used to assess continuous outcomes and risk ratio for dichotomous outcomes. The Cochrane risk of bias 2 tool was used to evaluate the risk of bias.

Results This meta-analysis comprised a total of 20 studies and found that simethicone with or without NAC improved mucosal visibility compared with control (SMD -1.27, 95% confidence interval [CI] -1.74 to -0.81, P<0.001). The combination of simethicone and NAC was significantly better than simethicone alone (SMD -0.68, 95%CI -1.08 to -0.28, P=0.001). Simethicone with or without NAC also shortened the procedure time compared to control (MD -1.40, 95%CI -2.67 to -0.12, P=0.03). The risk of bias was low with a moderate grade of certainty.

Conclusion The administration of simethicone with or without NAC may improve EGD quality.

Keywords Simethicone, N-acetylcysteine, premedication, esophagogastroduodenoscopy, meta-analysis

Ann Gastroenterol 2025; 38 (1): 28-40

Introduction

Esophagogastroduodenoscopy (EGD) is a diagnostic technique that allows visualization of the oropharynx, esophagus, stomach and proximal duodenum [1]. This procedure is extremely important in discovering multiple pathologies found in the upper gastrointestinal tract. Unfortunately, foam and bubbles may build up along the gastrointestinal tract and obscure its mucosa. This can lead to longer endoscopic duration, lower patient tolerance, and a decline in diagnostic accuracy [2].

Simethicone, an oral agent made of the combination of silica gel and dimethylpolysiloxane, has the ability to eliminate air bubbles. It is biologically inert and not absorbed by the digestive tract. This agent has been proposed as a premedication that could be useful in eliminating foams and bubbles [3]. N-acetylcysteine (NAC), a mucolytic and antioxidant agent, has also been proposed as a premedication to reduce mucus covering the gastrointestinal mucosa. NAC works by altering the viscoelastic characteristics of gastric mucin, thus eliminating excess mucus in the gastrointestinal tract [4].

The use of defoaming agents such as simethicone, with or without NAC, for improving the viability of gastrointestinal mucosa has already been reported by several studies. However, very few studies provided systematically updated evidence of these agents. The purpose of this study was to conduct a systematic assessment of the current body of evidence on the efficacy of simethicone and NAC prior to EGD in enhancing mucosal visibility.

Materials and methods

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline 2020 (Supplementary Table 1). The protocol for this study has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023486128.

Literature search

A literature search investigating the efficacy of simethicone alone vs. simethicone with NAC as a premedication in gastroscopy was conducted from inception to November 23, 2023, in CENTRAL, PubMed, ProQuest, SAGE and JSTOR. The following search strategy was used during the literature search: ((((((“Simethicone”[Mesh]) OR “dimethicone” [Supplementary Concept]) OR (Simethicone)) OR (Simethicone)) OR (Dimethicone)) OR ((((((“Acetylcysteine”[Mesh]) OR (Acetylcysteine)) OR (N-acetylcysteine)) OR (N-acetyl-L-cysteine)) OR (NAC)) OR (NALC))) AND (((((((((“Gastroscopy”[Mesh]) OR (Gastroscopy)) OR (Oesophagogastroduodenoscopy)) OR (Oesophago-gastro-duodenoscopy)) OR (Esophagogastroduodenoscopy)) OR (Esophago-gastro-duodenoscopy)) OR (OGD)) OR (EGD)) OR (Upper endoscopy)).

Study selection

The inclusion criteria for this study were: (1) investigated the effects of simethicone with/without NAC as premedication in gastroscopy; (2) was a human study; (3) was a randomised clinical trial (RCT); (4) was written in English; (5) full text was available. The exclusion criteria were as follows: (1) non-RCT study, case report, case series, review, in vivo or in vitro study, letter to editor; (2) lack of suitable data; (3) unclear methodology.

Data extraction

Two reviewers independently extracted the data from the included papers. Any disagreements were settled via discussion with a third reviewer. The data extracted in this study were: first author name, country, publication year, population (number of patients, age, sex, race), type of intervention, control, outcome, and adverse events.

Statistical analysis

For continuous variables, standardized mean difference (SMD) was used if the measuring tools varied, whereas mean difference (MD) was used if the measuring tools were the same for all studies. For dichotomous variables, risk ratio (RR) was used. All effect measures used a confidence interval (CI) of 95%. RR <1 indicates a result that favors the intervention group (simethicone with/without acetylcysteine). Heterogeneity was evaluated using I2 and the χ2 test. A random-effect model was used if there was substantial heterogeneity (I2>50% or P<0.1), whereas if there was no substantial heterogeneity (I2<50% and P>0.1) a fixed-effect model was applied. If more than 10 studies were included, publication bias was investigated using a funnel plot [5]. All statistical analyses were conducted using RevMan 5.4.

Quality assessment

The Cochrane risk of bias 2 (RoB 2) tool was used to assess the risk of bias of each included study. The RoB 2 tool contains 5 domains: (1) bias in the randomization process; (2) deviation from intended intervention; (3) missing outcome data; (4) measurement of outcome; (5) selection bias. If there is an overall low risk of bias, then there is a low risk of bias across all domains. Meanwhile, if there are some concerns about numerous domains or a high risk of bias for at least 1 domain, then the overall risk of bias is high [5]. This process was completed independently by 2 reviewers and any disagreements were handled via discussion with a third reviewer.

Certainty of evidence

The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) scale. GRADE contains 5 domains: (1) risk of bias; (2) indirectness; (3) inconsistency; (4) imprecision; (5) publication bias [6]. Risk of bias was evaluated using the Cochrane RoB 2 tool [5]. A study that had RR=1, MD=0 or SMD=0 was deemed imprecise [7]. Studies with substantial heterogeneity (I2>50%) were deemed inconsistent. Each outcome can be graded as having a high, moderate, low or very low level of certainty. A high level of certainty means that we are very confident that the true effect lies close to the estimate of effect, whereas a very low level of certainty means that we have very little confidence that the true effect lies close to the estimate of effect [6]. This process was also completed by 2 independent reviewers, with any disagreements handled via discussion with a third reviewer.

Results

After conducting a search through Pubmed, CENTRAL, ProQuest, SAGE and JSTOR, and removing duplicates, we identified 1140 articles. From the articles retrieved, we selected a total of 20 RCTs. The PRISMA flow diagram for the selection process is shown in Fig. 1.

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Figure 1 PRISMA flow diagram

The studies included ranged from the year 1992-2023, and originated from Asia, Europe, the Middle East, and Chile. A total of 20 RCTs with 8893 participants were included in this review [8-27]. Four of these 20 studies were excluded from the meta-analysis as they lacked appropriate data for quantitative analysis [11,16,19,22]. Eighteen studies investigated the efficacy of simethicone with or without NAC vs. controls [8,10-12,14-27], 7 studies simethicone with NAC against simethicone alone [9,12,13,16,18,20,25], and 2 studies simethicone with NAC against NAC alone [12,25]. The dosage for simethicone ranged from 20 mg to 400 mg, while the NAC dosage ranged from 300-1000 mg. All premedications were given as a single dose 15-30 min before EGD. The characteristics of each included study are summarized in Table 1.

Table 1 Characteristics of included studies

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Mucosal visibility

For mucosal visibility, a total of 16 studies were identified [9,12,13,15-27]. Nine of 10 studies reported better mucosal visibility during EGD in those given simethicone compared to control [12,16,17,19-21,24-26]. Only Monrroy et al [18] reported no significant difference between groups in mucosal visibility. Similarly, 11 studies that investigated the efficacy of simethicone with or without NAC against controls also reported significantly better mucosal visibility in the simethicone with or without NAC group [12,15-17,19-22,24-26]. Meanwhile, 2 studies reported that simethicone with or without NAC did not significantly improve mucosal visibility compared with controls [23,27]. When compared to the control group, Monrroy et al [18] found that simethicone with NAC improved mucosal visibility significantly, but not simethicone alone.

Seven studies compared the efficacy of simethicone with NAC against simethicone alone [9,12,13,16,18,20,25]. Four studies reported significantly better mucosal visibility in the simethicone with NAC group when compared to the simethicone alone group [9,18,20,25]. In contrast, 2 studies reported no significant difference in mucosal visibility between the simethicone with NAC group and the simethicone alone group [12,16]. Chang et al [13] found that the group receiving simethicone with NAC had significantly better mucosal visibility when compared to 5 mL simethicone syrup (containing 100 mg simethicone), but not to 100 mg simethicone in 100 mL water. Only 2 studies were identified that compared the efficacy of simethicone with NAC against NAC alone. Both studies had a similar conclusion: that the use of simethicone with NAC resulted in better mucosal visibility compared to NAC alone [12,25].

We performed a meta-analysis comparing the mucosal visibility in simethicone with or without NAC with control and confirmed that the simethicone with or without NAC group produced significantly better mucosal visibility (SMD -1.27, 95%CI -1.74 to -0.81, P<0.001; Fig. 2). In addition, we found that the combination of simethicone with NAC resulted in significantly better mucosal visibility compared to simethicone alone (SMD -0.68, 95%CI -1.08 to -0.28, P=0.001; Fig. 3). A meta-analysis to compare the mucosal visibility between the groups simethicone with NAC and NAC alone could not be performed because the number of studies was too small.

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Figure 2 Mucosal visibility in simethicone with or without NAC vs. controls [12,15,17,18,20,21,23-27]. The mucosal visibility in the simethicone with or without NAC group is significantly better than in the control group (SMD -1.27, 95%CI -1.74 to -0.81, P<0.001). A random-effect model was used given the presence of significant heterogeneity (I2=94%, P<0.001). Each green box represents the result of 1 study, with the horizontal line representing the 95%CI. The diamond at the bottom represents the pooled effect of the studies

CI, confidence interval; NAC, N-acetylcysteine; SMD, standardized mean difference

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Figure 3 Mucosal visibility in simethicone with NAC vs. simethicone [9,12,13,18,20,25]. The mucosal visibility in the simethicone with NAC group is significantly better than in the simethicone alone group (SMD -0.68, 95%CI -1.08 to -0.28, P=0.001). A random-effect model was used due to the presence of significant heterogeneity (I2=92%, P<0.001). Each green box represents the result of 1 study, with the horizontal line representing the 95%CI. The diamond at the bottom represents the pooled effect of the studies

CI, confidence interval; NAC, N-acetylcysteine; SMD, standardized mean difference

Procedure time

A total of 13 studies investigated the procedure time [8,10,11,14,15,17,18,20,23-27]. Four out of 9 studies reported significantly shorter procedure times in the simethicone group compared to control [8,11,17,25], whereas the other 5 studies did not find any significant difference between groups [10,18,20,24,26]. Similarly, most of the studies that investigated the procedure time in a simethicone with or without NAC group and a control group reported no significant difference in the procedure time [10,14,15,18,23,24,26,27]. Only 4 studies reported shorter procedure times in the simethicone ± NAC group when compared to control [8,11,17,25]. Mahawongkajit et al [20] only found significantly shorter procedure time in the simethicone with NAC group, but not in the simethicone alone group, when compared to control. When comparing the procedure times for simethicone with NAC vs. simethicone alone, all 4 studies found no significant difference between the groups [13,18,20,25]. Only 1 study compared the procedure times for simethicone with NAC vs. NAC alone, and found the procedure time to be similar in both groups [25].

Our meta-analysis suggests that using simethicone with or without NAC might be beneficial in reducing procedure time when compared to control (MD -1.40, 95%CI -2.67 to -0.12, P=0.03; Fig. 4). On the other hand, the combination of simethicone with NAC was not better than simethicone alone in reducing the procedure time (MD -0.00, 95%CI -0.17 to -0.17, P=0.99; Supplementary Fig. 1). A meta-analysis comparing simethicone with NAC against NAC alone could not be performed because the number of studies was too small.

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Figure 4 Procedure duration in simethicone with or without NAC vs. controls [8,10,14,15,17,18,20,23-27]. The procedure duration in the simethicone with or without NAC group is significantly shorter than in the control group (MD -1.40, 95%CI -2.67 to -0.12, P=0.03). A random-effect model was used due to the presence of significant heterogeneity (I2=98%, P<0.001). Each green box represents the result of 1 study, with the horizontal line representing the 95%CI. The diamond at the bottom represents the pooled effect of the studies

CI, confidence interval; MD, mean difference; NAC, N-acetylcysteine

Cleansing volume

Six studies examined the effect of various premedications on the amount of cleansing volume required during EGD [14,15,17,18,20,26]. All 3 studies reported a significantly smaller amount of cleansing volume needed during EGD in the simethicone group compared to control [17,20,26]. This finding was also reported for the simethicone with or without NAC group compared with controls [14,15,17,18,20,26]. Similarly, the amount of volume cleansing used was significantly lower in the simethicone with NAC group compared to the simethicone alone group [20]. Only Krishnamurthy et al [25] compared the amount of volume cleansing between simethicone with NAC and NAC alone. This study found that the combination of simethicone with NAC resulted in a smaller amount of cleansing volume compared to NAC alone.

In our meta-analysis, we found that the amount of cleansing volume was significantly smaller in the simethicone with or without NAC group when compared to control (MD -29.12, 95%CI -50.60 to -7.64], P=0.008; Fig. 5). A meta-analysis comparing the cleansing volume between the simethicone with NAC group and the simethicone alone group was not conducted given the lack of suitable data. We could not perform a meta-analysis comparing the simethicone with NAC group against the NAC alone group because of the small number of studies.

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Figure 5 Cleansing volume used in simethicone with or without NAC vs. controls [14,15,17,20,26]. The amount of mucosal cleansing volume used in the simethicone with or without NAC group is significantly lower than in the control group (MD -29.12, 95%CI -50.60 to -7.64, P=0.008). A random-effect model was used due to the presence of significant heterogeneity (I2=91%, P<0.001). Each green box represents the result of 1 study, with the horizontal line representing the 95%CI. The diamond at the bottom represents the pooled effect of the studies

CI, confidence interval; MD, mean difference; NAC, N-acetylcysteine

Lesion detection

A total of 5 studies investigated the efficacy of the premedication on lesion detection rate [13,16,18,19,26]. Four of 5 studies found no difference in the lesion detection rate between the simethicone group compared to control, and also no difference between the simethicone with or without NAC group and controls [13,16,19,26]. On the other hand, Monrroy et al [18] reported a significantly higher lesion detection rate in the intervention group compared with controls. Both studies that compared the lesion detection rate between simethicone with NAC against simethicone alone concluded no significant difference [9,16] No study compared the lesion detection rate between simethicone with NAC against NAC alone.

Our meta-analysis showed that simethicone with or without NAC did not improve the lesion detection rate when compared to control (RR 1.21, 95%CI 1.07-1.36, P=0.002; Supplementary Fig. 2). In fact, the lesion detection rate was higher in the control group. Similarly, the lesion detection rate did not differ between the simethicone with NAC group and the simethicone alone group (RR 1.00, 95%CI 0.88-1.12, P=0.94; Supplementary Fig. 3).

Side-effects

A total of 13 studies evaluated the safety of simethicone and/or NAC. In general, adverse events were rare in all groups [8,10-12,14-16,18,20,21,24,25,27]. Some of the adverse events reported were nausea (n=10), vomiting (n=10), abdominal pain (n=7), flatulence (n=6), and laryngospasm (n=1) in the control group. In the simethicone group, the reported adverse events were nausea (n=12), vomiting (n=6), abdominal pain (n=2), flatulence (n=2), and regurgitation (n=1). However, there was no statistical difference between the 2 groups [10,16,24]. No studies investigated the safety of simethicone with NAC against NAC alone.

Our meta-analysis validated the safety of simethicone with or without NAC. The simethicone with or without NAC group had considerably fewer adverse events than the control group (RR 0.60, 95%CI 0.38-0.94, P=0.03; Supplementary Fig. 4). As there were zero events in both the simethicone with NAC and simethicone alone group, a meta-analysis was not possible.

Risk of bias

There was an overall moderate risk of bias in the studies included in this review. Among the 20 RCTs assessed, 9 articles [12,13,15-18,20,23,24] were considered at a low risk of bias and 11 articles [8-11,14,19,21,22,25-27] had some concerns about bias. Patients in all included studies were adequately divided into groups using simple randomization procedures. Allocation concealment was achieved using sealed opaque envelopes in 12 studies [8,11-13,15-18,20,23-25], but details about allocation concealment were not provided in 8 studies [9,10,14,21,22,25-27]. Physicians who performed endoscopies were blinded in all included studies and no incomplete outcome data were reported except in 1 study [11]. No selective reporting was found in any of the studies, and no other potential source of bias was present. The risk of bias for each study can be viewed in Supplementary Table 2.

Publication bias

For analyses that had at least 10 studies, we performed a funnel plot to detect the presence of publication bias. We constructed funnel plots for mucosal visibility (Supplementary Fig. 5) and procedure time (Supplementary Fig. 6) in the group simethicone with or without NAC against control. Both funnel plots showed asymmetry, especially the funnel plot for procedure time. This indicated that there could be publishing bias in our study and suggests that newer studies should be performed in order to overcome this bias.

Certainty of evidence

As shown in Supplementary Table 3, the certainty of evidence ranged from moderate to high. The estimated outcomes of procedure duration (simethicone with NAC vs. simethicone group), lesion detection and adverse events showed a high quality of evidence, whereas mucosal visibility, procedure duration (simethicone with or without NAC vs. control group) and cleansing volume showed a moderate quality of evidence. More specifically, we downgraded the quality of the body of evidence by 1 level in view of the significant heterogeneity (I2>50%). Overall, the certainty of evidence in all included studies was rated moderate.

Discussion

The presence of foam and mucus may impair mucosal visibility and hide lesions during EGD. Thus, a defoaming agent, such as simethicone, and a mucolytic agent, such as NAC, have been proposed to address this issue [25]. This review aimed to determine the efficacy and safety of premedications used for EGD, namely simethicone and NAC.

Three prior meta-analyses have investigated the effectiveness of simethicone with or without NAC. Both Chen et al [28] and Sajid et al [29] reported improved visibility in the simethicone with or without NAC group. However, these 2 meta-analyses only focused on comparing the efficacy of simethicone with or without NAC vs. controls. Furthermore, these 2 studies only focused on a single outcome, namely mucosal visibility. The meta-analysis by Li et al [30] was more comprehensive, and investigated multiple outcomes, including mucosal visibility, procedure time, lesion detection and side-effects. However, this meta-analysis included only 10 studies that compared simethicone with or without NAC against control, and only 3 studies that compared simethicone with NAC against simethicone alone. Hence, the results of this study, especially for the comparison of simethicone with NAC against simethicone alone, might not be valid in view of the small number of studies. In contrast, our review found a total of 20 RCTs, with 6 studies comparing the efficacy of simethicone with NAC against simethicone alone. Furthermore, apart from investigating the mucosal visibility, procedure time, lesion detection and side-effects, we also evaluated the cleansing volume required during EGD. This outcome had not been investigated before, and may provide more comprehensive information regarding the efficacy of simethicone and/or NAC.

In line with previous findings, our review also concluded that the use of simethicone with or without NAC improved mucosal visibility and shortened procedure time compared with controls [28-30]. In line with the findings of Li et al [30], we also did not find a higher lesion detection rate in the simethicone with or without NAC group compared to control. Notably, our review found that the combination of simethicone with NAC improved visibility significantly better than simethicone alone. This result differed from the study by Li et al [30], in which simethicone with NAC was not better than simethicone alone in improving visibility. The difference in this finding might be due to the larger number of studies included in our review. Furthermore, our review also found that the use of simethicone with or without NAC significantly reduced the amount of cleansing volume required during EGD. This further strengthened the conclusion that simethicone with or without NAC may be beneficial in improving the quality of EGD. Similar to previous findings, our review also found that simethicone and/or NAC have a good safety profile [30].

Some of the limitations of our study include the heterogeneity in the data, such as the dosage for simethicone and NAC, as well as the different measuring tools used for evaluating mucosal visibility. Although our study had an overall low risk of bias, we found a possibility for publication bias, as proven by the presence of asymmetry in the funnel plot. We could not perform a meta-analysis to evaluate the efficacy of simethicone with NAC against NAC alone, or a comparison of simethicone with NAC against simethicone alone, in relation to cleansing volume because of the small number of studies.

In conclusion, this review found that the use of simethicone, either alone or in combination with NAC, can help improve mucosal visibility, shorten procedure time, and reduce the amount of cleansing volume required during EGD. The combination of simethicone with NAC achieved better mucosal visibility when compared to simethicone alone. Simethicone and/or NAC have a satisfactory safety profile, as the use of simethicone with or without NAC did not cause more adverse events when compared to control, supporting its use for premedication in EGD. The studies evaluated in this review showed a low risk of bias, with a moderate grade of certainty. However, our review detected the possibility of publication bias and thus we recommend that more studies be performed regarding simethicone with/without NAC as premedication for EGD.

Summary Box

What is already known:

  • Simethicone with or without N-acetylcysteine (NAC) is superior to control in improving mucosal visibility, but not superior to simethicone alone

  • Simethicone with or without NAC is superior to control as regards procedure time, but not superior to simethicone alone

  • Simethicone with or without NAC is not superior to control in improving lesion detection rate

What the new findings are:

  • Simethicone with NAC is superior to simethicone alone in improving mucosal visibility

  • Simethicone with or without NAC is superior to control in reducing the amount of cleansing volume needed during EGD

  • The use of simethicone with or without NAC as premedication for esophagogastroduodenoscopy (EGD) resulted in few or no adverse events

Acknowledgment

We would like to acknowledge the Gastrointestinal Cancer Center, MRCCC Siloam Hospital Semanggi, for all its support in conducting this research.

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Notes

Conflict of Interest: None