Acceptability, Safety, and Feasibility of Transnasal and Peroral Ultrathin Endoscopy Using GAGLESS Mouthpieces: A Prospective Randomized Trial

Abstract

Background/Aim

Esophagogastroduodenoscopy (EGD) is an effective screening method for early detection of gastric cancer. The GAGLESS mouthpiece has a structure that widens the pharyngeal cavity and suppresses the pharyngeal reflex. This study aimed to investigate the acceptability, safety, and feasibility of transnasal and peroral ultrathin endoscopy using GAGLESS mouthpieces (Clinical Trial Number: UMIN000036922).

Patients and Methods

This study was a multicenter, prospective, randomized, open-label trial performed using a questionnaire. The study included 101 consecutive patients who visited the participating medical institutions between June 2019 and March 2022 (median age=47 years, range=24-87 years; all male). Patients aged ≥20 years at the time of consent acquisition who were the first to undergo EGD were included in the study. The primary endpoint was the degree of distress during EGD, as determined using a visual analog scale (VAS).

Results

The VAS score during endoscopic passage through the pharynx was significantly better in the transnasal endoscopy group than in the oral endoscopy group (2.420 vs. 4.092, p=0.001). There was no significant difference in the VAS scores between the two groups during anesthesia or throughout the examination. Compared with nasal endoscopy, oral endoscopy with a GAGLESS mouthpiece did not reduce the VAS score but did significantly improve gastric visibility.

Conclusion

For patients in whom there was difficulty in inserting a nasal endoscope, using a GAGLESS mouthpiece rather than a conventional mouthpiece may be more useful in reducing pain.

Worldwide, approximately 1.1 million new cases and 770,000 deaths due to gastric cancer were recorded in 2020 (1). However, gastric cancer can be cured when detected early. Gastric cancer screening is an effective method for early detection. Gastric cancer screening modalities include esophagogastroduodenoscopy (EGD) and upper gastrointestinal imaging. The widespread use of EGD screening is essential considering the oversight rate associated with upper gastrointestinal imaging (2), and its effectiveness has been demonstrated in recent years (3,4). The pharyngeal reflex, which occurs in response to the endoscope passing through the pharynx, is a problem associated with EGD use. When a conventional mouthpiece is fixed on the front teeth, the back of the tongue is raised, and the pharynx through which the endoscope passes is narrowed, making it difficult to insert the endoscope, thus increasing the pain during the examination. In contrast, a GAGLESS mouthpiece (INABA RUBBER, Tottori, Japan) (Figure 1A) has a structure that engages the back teeth; this widens the pharyngeal cavity and suppresses the pharyngeal reflex (Figure 1B) (5). A previous study reported that using a GAGLESS mouthpiece resulted in better visual analog scale (VAS) scores during EGD than when using conventional mouthpieces; furthermore, systolic blood pressure was less in the GAGLESS group, and diastolic blood pressure was lower in this group (6). To date, there have been no studies comparing the VAS of transnasal and peroral ultrathin endoscopy with a small-diameter endoscope using GAGLESS mouthpieces.

Figure 1. GAGLESS mouthpiece. A: An image showing the mouthpiece. B: The GAGLESS mouthpiece is structured so as to engage the back teeth; this widens the pharyngeal cavity and suppresses the pharyngeal reflex.

The Irisawa Medical Clinic launched a prospective randomized trial to assess the acceptability, safety, and feasibility of transnasal and peroral ultrathin endoscopy using GAGLESS mouthpieces in June 2019 (clinical trial number: UMIN000036922).

Nasal insertion is less painful than oral insertion with small-diameter endoscopes (7). Therefore, this study aimed to examine the acceptability, safety, and feasibility of oral endoscopy with a small-diameter endoscope using a GAGLESS mouthpiece.

Patients and Methods

Equipment. The endoscopes used in this study were EG-L580NW (Fujifilm Corp., Tokyo, Japan), GIF-XP290N (Olympus Medical Systems Co. Ltd., Tokyo, Japan), GIF-PQ260 (Olympus Medical Systems Co. Ltd.) and GIF-1200N (Olympus Medical Systems Co. Ltd.). The distal end and the insertion tube diameters of each endoscope were 5.8 mm and 5.9 mm for EG-L580NW, 5.4 mm and 5.8 mm for GIF-XP290N, 7.9 mm and 7.7 mm for GIF-PQ260, and 5.4 mm and 5.8 mm for GIF-1200N, respectively. During this study, the endoscope used was chosen by each participating institution, and the mouthpiece used was the GAGLESS mouthpiece. The height, width, and caliber of the GAGLESS mouthpiece was 22 mm, 65 mm, and 15 mm, respectively.

Salivary amylase levels were measured using a salivary amylase monitor (NIPRO Co., Osaka, Japan).

Study design and ethics approval. This study was a multicenter, prospective, randomized, open-label trial and questionnaire survey. It included men aged ≥20 years during consent acquisition who were the first to undergo EGD. Only the oral endoscopy group received a GAGLESS mouthpiece. None of the patients received sedation. All the procedures were performed by nine endoscopists. Vital signs and salivary amylase levels, which are useful for determining stress during EGD (8), were measured before and after EGD. After EGD, we determined the VAS scores to assess the degree of pain during anesthesia (pharyngeal or nasal), during the passage of the endoscope through the pyriform sinus, and during the entire period of examination. Patients were asked about their experiences (whether they would prefer the same test or another insertion route the next time). The endoscopists were asked the following: if the procedure was successful; if the test was completed; if a dye-endoscopy/biopsy was performed; if oxygen inhalation was required; the final diagnosis; ease of the procedure; and if the esophagus, stomach, or duodenum were visible. Visibility and ease of insertion into the pyriform sinus were confirmed. The study complied with the ethical guidelines of the 1964 Declaration of Helsinki.

Endpoints. The primary endpoint was the degree of distress during EGD, which was determined using VAS. The secondary endpoints were the examination time, degree of success of the procedure, ease of endoscopic insertion, comparison of blood pressure, SpO₂, pulse rate, salivary amylase levels before and after EGD, endoscopic diagnosis, adverse events (according to endoscopic insertion), patient data (past endoscopy history, pretreatment pain level, pain level while the endoscope passed through the pharynx, and regarding the next EGD), and the endoscopist’s evaluations (ease of insertion into the pharynx, visibility of the esophagus, visibility of the stomach, visibility of the duodenum, and ease of the entire procedure), which were evaluated on a scale of 1 to 10, with lower scores representing better results.

Statistical analyses. We considered the mean difference between the two comparative groups to be 1.0, and the common standard deviation to be 1.6, based on a pilot study on nasal endoscopy (7). To achieve 80% statistical power with a two-sided significance level of 5%, we required a minimum of 41 participants per group. Considering some uncertainty for the baseline scenario and dropouts, we set the target sample size to 50 participants per group.

Random allocation was performed using permutated block randomization stratified by centers, and a random number table was created using SAS Ver. 9.4 (SAS Institute Inc., Cary, NC, USA). This clinical trial was an open-label trial; however, the block sizes were known only to the statistician (H.N.) who created the allocation table.

Statistical analyses were performed for the full analysis set, which consisted of participants who started at least part of the investigational treatments. The primary endpoint, the VAS score, was compared between the two groups using Welch’s t-test. For the analyses of secondary endpoints, Welch’s t-test was performed for continuous variables and the chi-square or Fisher’s exact test was performed for the categorical variables. All statistical tests were two-sided with a significance level of 5% and were performed using SAS Ver. 9.4.

Data collection. The Institutional Review Board of Yasugi Municipal Hospital (protocol code: 2019-2, date of approval: May 27, 2019) approved this study, involving 101 consecutive patients who visited the participating medical institutions between June 2019 and March 2022 [median age=47 (range=24-87) years; all male]. All study participants provided informed consent prior to the procedure. The study sample included patients with gastroesophageal reflux disease (n=15; 15%) and chronic gastritis (n=42; 42%). A total of 28 patients presented with no abnormalities (Table I). None of the patients met the exclusion criteria. No antispasmodic agents were used in any of the patients. Two patients in the transnasal endoscopy group were unable to undergo endoscopy via the nasal route, and the examination was completed after switching to the oral route (Figure 2).

Table I. Patient characteristics.

GERD: Gastroesophageal reflux disease.

Figure 2. Flowchart depicting the study design and patient selection criteria.

Results

The procedure was unsuccessful in two patients in the transnasal group as the nasal cavity was narrow, and the endoscope could not be inserted.

GF-PQ260, which had a larger distal end and insertion tube diameter, was significantly more commonly used in the oral group than the transnasal endoscopy group (p=0.003). The gastric visibility was significantly better in the oral than the other group (p=0.047) (Table II). The pulse rate after examination was significantly higher in the oral than the transnasal endoscopy group (p=0.028) (Table II). Patients in the transnasal endoscopy group were significantly older than those in the other group (p=0.016) (Table III).

Table II. Characteristics and evaluation items of patients.

EGD: Esophagogastroduodenoscopy; GERD: gastroesophageal reflux disease; N.A.: not applicable; VAS: visual analog scale – lower values are better. *Responses: 1: I am satisfied and want to receive it the same way next time. 2: I am generally satisfied and want to receive it the same way next time. 3: I neither agree nor disagree; 4: It was painful; thus, I want to receive it another way next time.

Table III. Characteristics and evaluation items of patients.

DBP: Diastolic blood pressure; SBP: systolic blood pressure; SpO₂: percutaneous oxygen saturation. Data are the mean±standard deviation.

The mean VAS score during endoscopic passage through the pharynx was significantly better in the transnasal than in the oral endoscopy group (2.420 vs. 4.092, p=0.001). There was no significant difference between the two groups in terms of VAS scores during anesthesia and throughout the examination (Table IV).

Table IV. Characteristics and evaluation items of patients.

CI: Confidence interval. Data are the mean±standard deviation. Pretreatment indicates during anesthesia.

Discussion

In this study, we expected the distress indices, including the VAS score, during narrow-diameter endoscopy to be significantly better in the transoral endoscopy group using the GAGLESS mouthpiece than in the transnasal endoscopy group. However, the VAS score during pharyngeal passage and the pulse rate after examination were significantly better in the transnasal endoscopy group. This was because the VAS values in the transnasal endoscopy group were better than those previously reported (7). Patient age was significantly higher in the transnasal endoscopy group, and many scopes with larger distal ends and insertion tube diameters were used in the transoral endoscopy group. The VAS scores of the transnasal endoscopy group in this study were better than those reported in a previous study published in 2013 (7). The outer diameters of the tip and flexible part of the endoscope have been reduced, which may have led to the reduced pain observed in this study. The 2013 study reported that the pain level experienced during transnasal endoscopy was significantly higher in younger than older people. In this study, patients in the transnasal endoscopy group were significantly older and significantly larger number of scopes with larger distal ends and insertion tube diameters were used in them compared to the oral endoscopy group. Because the allocation was random, a specific factor may have been biased and within the range of random error. Multivariate analysis was performed to assess the possible confounding factors of age, gastric visibility, type of endoscope, and VAS scores; no factor was found to be significantly associated with the VAS score.

The items examined in this study were the acceptability, safety, and feasibility of oral endoscopy using a GAGLESS mouthpiece. VAS scores throughout the examination and adverse events were not significantly different between the two groups. Visibility of the stomach was significantly better in the oral than the transnasal endoscopy group. Hence, oral endoscopy using a GAGLESS mouthpiece could be considered acceptable and feasible. In this study, two patients in the transnasal endoscopy group were unable to undergo transnasal endoscopy due to narrow nasal cavities. Considering that there are cases in which it is difficult to insert a transnasal endoscope, the GAGLESS mouthpiece may contribute to pain relief during oral endoscopy. It might also have been helpful in the past when oral endoscopy was performed in cases in which it was difficult to insert a transnasal endoscope. In the future, it will be important to use the latest small-diameter endoscopes and verify the VAS score as a non-inferiority test of transnasal endoscopy compared with oral endoscopy with use of GAGLESS mouthpieces.

There is a concern in Western countries regarding the feasibility of upper gastrointestinal endoscopy with ultrathin endoscopes for gastric cancer screening due to their limited image resolution and field of view (9). In Japan, with regards to the endoscope type used when performing gastric cancer screening, according to Kobayashi et al., no difference in gastric cancer detection rate and early cancer detection rate between normal-diameter and small-diameter endoscopes was reported; however, none of the studies published in English have reported this (10).

The use of sedation and CO₂ insufflation in oral endoscopy is becoming widespread in Japan, and the frequency of their use in upper gastrointestinal endoscopy is increasing (11,12). These methods are effective; however, each has its challenges. Challenges associated with sedation include: i) Oversedation, and this should be avoided in patients with renal and heart diseases, who are at particularly increased risk; ii) difficulty in communicating the findings of the procedure to the patients on the day of the examination; and iii) inability of patients to drive after the examination. Recently, the use of midazolam and propofol for sedation during EGD has become widespread. Flumazenil is used as an antagonist of midazolam but propofol has no antagonist; therefore, sedation using propofol should be performed only by experienced anesthesiologists (13). The issues with CO₂ insufflation include high cost and induction of CO₂ narcosis in patients (14).

Because gastric cancer is the third leading cause of cancer-related mortality worldwide (1), endoscopic gastric cancer screening was initiated in Japan in 2014 (14). However, considering its cost-effectiveness, widespread application of endoscopic screening is desirable to establish a new medical examination provision system that conducts examinations at appropriate screening intervals according to the individual’s background (15). We also emphasize improving the feasibility of oral EGD, particularly during health checkups. Gastric cancer screening using EGD is essential to improve the prognosis of patients with gastric cancer. Due to its widespread use, pain reduction during EGD is important. Improving pain relief during EGD by combining the pain-relief methods implemented at each facility is essential.

Study limitations. Firstly, the reason for better visualization of the stomach with an oral endoscope than with a nasal endoscope remains undetermined. GIF-PQ260 is a scope with a thick distal end and insertion tube diameter and is commonly used for oral endoscopy. It was the oldest scope used in this clinical study and has the poorest resolution. Since this evaluation was based on the personal opinions of endoscopists, the possibility of bias cannot be ruled out. Therefore, future studies should clearly define the endoscope to be used and an appropriate scoring system.

Secondly, the sample size in this study was small and the methodology was flawed in that the patient age was significantly higher in the transnasal than that in the oral endoscopy group; furthermore, many scopes with large distal end and insertion tube diameters were used in the transoral endoscopy group. Future studies should be performed with larger sample sizes; moreover, the VAS scores for oral endoscopy using small-diameter endoscopes should be statistically re-examined, and the endoscopes to be used should be standardized.

Conclusion

VAS scores encountered in oral endoscopy with GAGLESS mouthpieces were not reduced compared to those in nasal endoscopy. However, the use of a GAGLESS mouthpiece significantly improved gastric visibility. Further studies using clear definitions and scoring system are warranted. When faced with difficulty in inserting a nasal endoscope, using a GAGLESS mouthpiece rather than a conventional mouthpiece may be more useful in reducing the pain experienced by patients.

Conflicts of Interest

H.I. is Deputy Editor-in-Chief of Digestive Endoscopy. All other Authors declare no conflict of interests pertaining to the content of this article.

Authors’ Contributions

Conceptualization and study design: K.M., A.I., K.M., M.F., and H.I.; data collection and sample management: K.M., A.I., N.U., H.W., Y.I., H.K., Y.S., Y.A., and R.A.; data analysis and interpretation: K.M., H.N., K.F., M.U., and H.I. All authors critically revised the article. All the Authors have read and agreed to the published version of the article.

Acknowledgements

The Authors thank Editage (www.editage.jp) for English language editing.