As well as its application as a diagnostic imaging test for patients with abdominal pain, AUS is also used for screening for metastasis in patients who have undergone resection for cancer6–8, hepatocellular carcinoma in patients with viral hepatitis9, pancreatic cancer in patients at high risk due to family history, obesity, and type 2 diabetes10, among others. AUS is simple to perform, involves no ionizing radiation, and is less costly than CT and MRI. EGD is used as a diagnostic tool for patients with symptoms of acid-peptic disease and also in screening for Helicobacter pylori-related gastric cancer11, 12 and for follow-up after endoscopic resection of esophageal cancer13 and gastric cancer6, 14. Both AUS and EGD are used in medical check-ups for asymptomatic patients with no basal disease. Patients who require both AUS and EGD prefer to schedule these procedures for the same day because they both need preparation of nil per os. Because bowel gas deteriorates the image quality of AUS, it is common to perform AUS prior to EGD, and both must be completed within a limited period in the morning with efficient setup. This one-way order of AUS prior to EGD limits the availability of examination appointments and reduces the efficiency of examination. In Japan, the government introduced endoscopic screening for gastric cancer as a national program in 2016. It has been reported that the program was difficult to introduce immediately because of insufficient medical resources15. Increasing examination efficiency will become even more important in the future. In addition to endoscopy, there is concern that materials such as oral radiocontrast can deteriorate the image quality of AUS performed subsequently, and previous studies have investigated whether such materials affect the image quality of AUS from the perspective of a time-saving strategy in the emergent situation16, 17.
Room air, which is widely used for GI luminal distension in EGD, has the advantages of universal availability and low cost. However, room air is poorly absorbed by the GI tract, resulting in post-procedure pain related to distension. As CO2 is rapidly absorbed by the GI mucosa, there is increased interest in its use as an insufflation agent for endoscopic procedures. Many studies have shown the usefulness of CO2 in endoscopic procedures that are relatively lengthy, including colonoscopy, EGD with colonoscopy, endoscopic retrograde cholangiopancreatography (ERCP), balloon endoscopy, and endoscopic procedures such as endoscopic submucosal dissection (ESD)2.
We hypothesized that the use of CO2 for insufflation in EGD would not deteriorate the image quality of subsequent AUS. To prove this hypothesis, we designed a non-inferiority test and demonstrated a negligible difference in the means of image quality of all 16 organs between pre- and post-EGD AUS, as well as a non-inferiority of post-EGD AUS. However, in the non-inferiority test, the two-sided 95% CI of post-EGD AUS did not cross the 0-outcome difference, which indicates a statistically significant difference from the pre-EGD AUS. This puzzling phenomenon might have resulted from having a sample size that was too large, or/and having too generous a non-inferiority margin5. An adequate sample size for this study had been calculated as around 26, but for statistical study of all 16 organs in 30 cases, a significantly larger number of 480 samples was used. Regarding the non-inferiority margin, we set this at the point of –0.40, which is the same as a depiction rate of –10%, because we had considered a larger difference as clinically relevant. Furthermore, in the AUS studies after administration of oral radiocontrast, a one-point score difference in the five-point Likert scale was selected16, 17. Because the present –0.40-point margin of a four-point Likert scale is quite small compared with these reports, it is hard to say that our margin is too generous. Furthermore, because there is a possibility that the sample size was not adequate, we re-calculated the sample size using actual data obtained in the present study. Using a standard deviation (SD) of 0.69, which was calculated from the square root of the means of the sample variances of pre- and post-EGD AUS, the difference of means of 0.08, a power of 90%, and a 1-sided α-level of 0.025, resulted in a sample size of 18 subjects. The number of 26 subjects that we had estimated before the study is not much different from this re-calculated sample size. Ultimately, the fact that the effect size was 0.172 also supports our hypothesis.
Regarding each organ, even if all of the means of image quality score for post-EGD AUS for each organ were slightly less than those for pre-EGD AUS, 14/16 organs were demonstrated to be non-inferior. The two organs that were not demonstrated to be non-inferior were the celiac artery and superior mesenteric artery. It is not clear why the AUS image quality deteriorated after EGD in these two arteries. Because they are located close to each other, observation of the site at which these arteries branch seems to be poor even if CO2 insufflation is used. If the non-inferiority margin of –0.60, which is same as a depiction rate of –15%, was acceptable rather than –0.40, all organs would be non-inferior.
We had expected that as CO2 would extrude the bowel gas downstream and be absorbed rapidly, the AUS image quality after EGD with CO2 insufflation would improve for some organs, such as the pancreas body and tail, where the quality is easily deteriorated by the presence of bowel gas in front of them. However, the mean image quality was reduced for all organs. Nakagawara et al.4 reported that using CO2 insufflation instead of air improved the image quality of AUS at 60 min after EGD in some patients. They used a three-point Likert scale of better, unchanged, and worse for evaluation of image quality of AUS after EGD, compared with that of AUS images before EGD as control. They reported that image quality for the pancreas head and body, pancreas tail, and extrahepatic bile duct were judged better in 26.1% (6/23 cases), 26.1% (6/23 cases), and 43.5% (10/23 cases), respectively, for AUS after EGD. When the method for evaluating the depiction rate in our study was changed to that of difference in image quality, of better/unchanged/worse, we found 11/6/13 (better by 36.7%), 8/9/13 (26.7%), 12/7/11 (40%), and 12/8/10 (40%) cases in the pancreas head, body, tail, and common bile duct, respectively. In the present study, image quality also improved in some patients post-EGD AUS (Figure 4), but for other patients the quality worsened, so it is misleading to state that CO2 insufflation improves AUS image quality even if this does occur in some patients. We concluded that CO2 insufflation in EGD does not improve image quality in AUS that is performed following EGD.
Nakagawara et al.4 also reported that image quality post-EGD AUS depended on the duration of the period after EGD. They showed that the deterioration in quality at <15 min after EGD had recovered by 30 min or later. In the present study, because EGD was performed under planned moderate sedation, post-EGD AUS was performed 53–110 min after recovery from sedation. In the case of EGD performed without sedation, the shortest possible time between the end of EGD and AUS would be approximately 30 min.
Several limitations of the present study must be acknowledged. First, as the subjects were examinees for medical check-ups and enrolled in this study at our single institution, selection bias may have affected the results, particularly with regard to the subject characteristics. Second, in the absence of published data, the margin of non-inferiority was selected because we considered a larger difference to be clinically relevant. This margin size may have affected interpretation of the results. Third, because we demonstrated only the non-inferiority of the depiction rate, there is a possibility that EGD using CO2 insufflation may affect the image characteristics of certain diseases in the subsequent AUS examination.
In conclusion, the use of CO2 for insufflation in EGD does not cause much deterioration in the image quality of AUS performed subsequently. Therefore, it is permissible to perform EGD prior to AUS, which is expected to improve the efficiency of examination setup.