Does the timing of bowel preparation change the outcome of bowel cleansing?

Bowel preparation is one of the most important quality indicators of colonoscopy, and it has been reported that adenoma detection and the incidence of postcolonoscopy colorectal cancer vary with the degree of bowel cleansing.¹ Previously, the standard bowel preparation for colonoscopy was a large dose of laxatives taken the day before the examination. Subsequently, it was proven that a portion of the laxative taken on the same day of the examination resulted in better bowel cleansing, better patient acceptability, and improved adenoma detection rate. This led to the recommendation of a split dose in current European Society of Gastrointestinal Endoscopy and the American Society for Gastrointestinal Endoscopy bowel prep guidelines.^{2, 3}

In European countries and North America, performing colonoscopy in the morning has been established as a normal endoscopic procedure, starting with the initial day before and high-volume medications, and then moving to a split dose the day before and the same day of the colonoscopy. On the other hand, in Japan and other Asian countries, colonoscopy was mainly performed in the afternoon because upper gastrointestinal endoscopy for gastric cancer screening was widely performed. Since the development of bowel preparation methods, the full dose of laxatives was mainly administered on the morning of the day of colonoscopy because of the time available. Therefore, European guidelines recommend the same day, full-dose bowel preparation for afternoon colonoscopy. A meta-analysis of randomized controlled trials (RCTs) comparing a split-dose and nonsplit-dose regimen showed that the bowel cleansing was best within 3 h from the last dose to the examination, slightly worse at 4–5 h than at 3 h, and worst at >5 h.⁴ These results were common regardless of the split-dose and nonsplit-dose regimen and the type of laxative. The longer the time between the end of laxative administration and the start of the examination has been shown to decrease the degree of bowel cleansing because of small bowel secretions and segment fecal material in the small bowel. European Society of Gastrointestinal Endoscopy guidelines recommend that laxative administration be completed within 5 h of the start of the examination.² On the other hand, the American Society for Gastrointestinal Endoscopy guideline recommends that laxatives be administered between 3 and 8 h before the start of the examination, on the same day as the second regimen of a split dose. However, only observational studies have investigated the timing of laxative administration and the start of examination, and there is a lack of evidence from RCTs. In actual practice, there was a wide range in the recommended administration time, and a more reliable and appropriate time was required. In addition, it was necessary to consider the risk of vomiting or aspiration of laxatives remaining in the stomach, and it was also necessary to clarify that the dose should be finished 2 h before the examination.²

In this issue of Digestive Endoscopy, Hye Min Kim et al.⁵ performed the world's first RCT focusing on the time between laxative ingestion and the start of the examination. Patients with planned outpatient elective colonoscopy aged 40–75 years were enrolled and randomly assigned to the early group (completed 2–4 h before the examination) or the late group (completed 4–8 h before the examination). The primary end-point was the percentage of successful bowel cleansing (the Boston bowel preparation scale [BBPS] ≥6, each segment ≥2) and the percentage of perfect bowel preparation (BBPS 9 points).⁶ The study was set up as a noninferiority design with a 5% noninferiority margin to demonstrate noninferiority of the early group to the late group; patients in the early group were instructed to complete the dose 3 h before the examination and patients in the late group were instructed to complete the dose 6 h before the examination. Secondary end-points were patient acceptability, safety, and endoscopic results such as adenoma detection rate. A total of 524 patients were assigned to the study, and per-protocol analysis was conducted in the early (255 patients) and late (249 patients) groups. The primary end-point of successful bowel cleansing was 97.6% in the early group and 95.2% in the late group, with a rate difference of 2.5% (−0.8% to 5.7%), proving noninferiority (P_{fornoninferiority} < 0.001). The highest BBPS score was significantly higher in the early group (56.5%) and in the late group (39.8%). The sleep disturbance was significantly lower in the early group, but overall satisfaction was similar between the two groups. On the other hand, nausea, vomiting, and bloating were not different between the two groups, and aspiration was absent in both groups.

Based on the results of this study, the early group tended to have a better bowel cleansing and it was proven noninferior; the early group had less sleep disturbance. The results of this study support the results of a previous meta-analysis and will be reconfirmed in the RCT.⁴ However, the failure to prove superiority may be due to the use of high-volume polyethylene glycol (PEG) in both groups. The large volume of laxatives may have made it difficult to detect differences in timing. Sleep disturbance, which had been mentioned as a disadvantage of the split-dose regimen, was less frequent in the early group, suggesting that the early group may be a solution to the weakness of the split-dose regimen. However, there was no difference in overall patient satisfaction between the early and late groups. As a possible factor, I imagine that 4 L of PEG, regardless of timing, is powerful enough to reduce patient acceptability. Low-volume regimens such as PEG + ascorbate,⁷ magnesium citrate plus picosulphate,⁸ and oral sulfate solution⁹ are currently available and have proven to be noninferior to high-volume PEG in terms of cleanliness.² These low-volume regimens have also proven to be more acceptable than high-volume PEG; similar studies using low-volume regimens may yield different results. It is also important that aspiration, a concern of anesthesiologists, did not occur in the early group, which is important in terms of sleep disturbance and patient acceptability. The results were acceptable from a clinical practice viewpoint. Another result of this study is that the same day administration method is used for the afternoon examination. Therefore, the early group's start timing can be applied to the use of the same day method. In the case of the afternoon examination, there is a possibility that the patient will be instructed to start administration just as soon as possible because there is plenty of time in the morning. Based on the results of this study, I believe that it would be appropriate to instruct the patient to start oral administration retroactively from the time of the start of the examination.

Future clinical questions include: When is the optimal timing of administration in the low-volume regimen that will become the mainstream in the future? How many hours before the start of the examination should the patient start and finish taking the medication?

Author K.H. received honoraria for lectures from Nippon Chemiphar Co., EA Pharma Co., Ltd, and Fuji Pharma Co., Ltd.

K.H. received research funds from Nippon Chemiphar Co.