Comparison of laxatives used in CT colonography with full bowel preparation

Purpose. Our study aimed to identify an optimal full-cleanse bowel preparation scheme for patients undergoing CT colonography.Material and methods. The final sample included 118 patients: 81 females (68.6%), with the median age being 75 years (IQR 675-80 years). For bowel preparation 39 (33.1%) patients used PM/Ca, 36 (30.5%) – 2 L PEG + Asc, 19 (16.1%) – 3 L PEG, 24 (20.3%) – 4 L PEG. Otherwise, the preparation did not differ in all four groups. Visual assessment of residual stool, residual fluid, and distension degree was performed using a 4-point Likert scale. The patient’s subjective tolerance assessment was executed according to the survey results using a 5-point Likert scale.Results. There were no statistically significant differences in quality of bowel preparation in all four groups. Mean value of the total residual stool score in groups was 46.2 ± 2.87 for PM/Ca; 46.9 ± 2.34 for 2 L PEG + Asc; 46.5 ± 1.98 for 3 L PEG; 45.9 ± 3.18 for 4 L PEG (p > 0.05). The median of the total residual fluid score in groups was 36 (33–38) for PM/Ca; 36.5 (34–39) for 2 L PEG + Asc; 37 (36–39) for 3 L PEG; 36 (34–40) for 4 L PEG (p > 0.05). Mean value of the total distention degree score in groups was 43 ± 4.34 for PM/Ca; 44.6 ± 3.13 for 2 L PEG + Asc; 44.2 ± 3.98 for 3 L PEG; 43.5 ± 4.9 for 4 L PEG (p > 0.05). There was a statistically significant difference in the patient tolerance total score, depending on the laxative (p = 0.001). The total preparation score was significantly lower for PM/Ca when compared with 2 L PEG + Asc. (p = 0.021), 3 L PEG (p = 0.001), and 4 L PEG (p = 0.043).Conclusion. Use of PM/Ca in CTC preparation lowers the burden of full cleanse exam preparation and can be recommended as a safe laxative choice, including senior age patients. 


Introduction
Colorectal cancer (CRC) is the second leading cause of cancer-related death and takes the third place of incidence among all human cancers in the world [1]. CRC screening, followed by polypectomy, decreases the risk of morbidity and mortality by 53% [2]. Computed-tomographic colonography (CTC) is a recommended radiological examination of choice for the diagnosis of colorectal neoplasia [3] and a method for CRC screening in the intermediate-risk group [4].
One of CTC's primary advantages compared with optical colonoscopy (OC) is the higher patient compliance [5][6][7]. Nevertheless, according to previous research, CTC requires a special bowel preparation, which is the most burdensome part of the whole procedure for patients [8,9].
CTC preparation includes following a special diet, cathartics, and fecal tagging (FT) [10,11]. CTC requires the same diet as in OC preparation and means excluding fiber-rich products [12]. Iodine and barium contrast agents are used for tagging in OC [11]. Fecal tagging increases CTC's sensitivity and specificity and is mandatory for CTC preparation [10,13].
The laxatives used for CTC preparation can be classified as "wet" and "dry", the former being based on polyethylene glycol (PEG), the latter being saline cathartics such as sodium picosulfate, magnesium citrate, and sodium phosphate [14].
All cathartic preparation schemes can be divided into full cleanse and limited bowel preparation [15]. Limited preparation schemes are less burdensome for patients and have a higher compliance rate [16,17]. But using these schemes can decrease specificity [18]. Moreover, same-day colonoscopy for polypectomy with no need for a second cleansing can be performed only when using a full-preparation scheme [3].
Besides, currently, good results in full bowel cleansing have been achieved with low volume laxative prescription, such as 2 L PEG combined with ascorbic acid (PEG + Asc) [19,20] and a combined laxative (sodium picosulfate, magnesium oxide, citric acid (PM/Ca) [21].
We have used 4 variations of the full cathartic bowel cleaning as a standard scheme in our institution: 4 L PEG, 3 L PEG, 2 L PEG + Asc, and a combined laxative (PM/Ca).
To our knowledge, by the time of writing this article, there had been no research comparing those preparation schemes as well as no published data of using PM/Ca for CTC.
The purpose of this study was to identify an optimal full-cleanse bowel preparation scheme for patients undergoing CTC on an out-patient basis.

Purpose
To identify an optimal full-cleanse bowel preparation scheme for patients undergoing CTC on an outpatient basis.

Study design
The local ethics committee has approved our retrospective research. As mentioned above, we used 4 full bowel prep schemes in our institution, namely 4 L PEG, 3 L PEG, 2 L PEG + Asc, and a combined laxative (PM/Ca). The rest of the preparation was the same in all schemes and is described below.
Our study includes patients who have undergone CTC from August 2017 to March 2020 for CRC screening purposes. Inclusion criteria were: preparation using one of the studied laxatives, RF tagging, and a filled post-test questionnaire.
Exclusion criteria were: patients having symptoms suspicious for CRC, clinically diagnosed familial adeno matous polyposis, familial nonpolyposis CRC, inflammatory bowel disease, surgically treated CRC, previous allergic reaction to one of the preparation agents or iodine-containing contrast agent, and hyoscine butylbromide (Fig. 1).

Bowel preparation
Participants were prepared with a diet, laxative, and residue fecal tagging. A low-residue diet was recommended 3 days before the study, meaning excluding fiber-rich products (including fruits, vegetables, wholewheat bread, cereal, etc.). Clear liquids intake and no solid food all day were recommended on the day before the examination.
One of 4 studied laxatives was prescribed for bowel preparation the day before the examination: 4 L PEG, 3 L PEG, 2 L PEG + Asc, and PM/Ca as instructed (Table 1).
A water solution of iohexol with 350 mg of iodine per mL (50 ml mixed with 500 ml of water) was used 329 didn't fill in a questionnaire for residue stool tagging. The solution was ingested in two steps (at 5 PM and before sleep).

Bowel distension and scan parameters
All the patients have undergone CTC between 9 AM and 11 AM. An hour before the exam, a spasmolytic was prescribed: 10 mg of hyoscine butylbromide.
Room air was administered to achieve colonic disten tion. The rate of distension was controlled with regard to patient discomfort and scout radiographs. No intravenous contrast medium was injected. Both supine and prone position scans were obtained. In case of inadequate distension in those positions additional decubitus scans were added.
The studies were performed on two CT scanners: GE Lightspeed 16 and GE Lightspeed VCT 64, GE Healthcare, Waukesha, WI, USA) using the low-dose scan protocol: 120 kV (140 kV for obese patients), effec tive tube current of 50-75 mAs with Z-plane current modulation, detector collimation 64 × 0.625 mm, 0.6 s. tube rotation time, 1.375 pitch, 1.25 mm slice thickness images reconstruction.

Assessment of bowel preparation and CTC data interpretation
The scan data was interpreted by radiologists with 2 to 10 years of experience in CT abdominal imaging (Advantage Workstation 4.5 GE Healthcare, Waukesha, WI, USA) using dedicated CTC interpretation software (ColonVicar).
Evaluation of bowel preparation was accomplished using 2D multiplanar reconstructions with a wide (2000 HU width, 0 HU center) and narrow (400 HU, 40 HU center) window width.
We have used the following categories for bowel preparation evaluation: presence and volume of re-sidual stool, presence, and volume of residual fluid, adequacy of distension. Additionally, we have evaluated the fecal tagging density in Hounsfield units, as well as having done the subjective bowel preparation evaluation.
We have used a modified, former suggested scheme in the assessment of residual stool, fluid, and adequacy of distension [22,23] following a 4-point Likert scale, where 1 point corresponded to the maximum volume of residual stool, full-filling of colon lumen with residual fluid and no colon distension, whereas 4 points corresponded to no residual stool and fluid and maximal colon distension respectively (Fig. 2).
Every colonic segment has been assessed with these parameters in both supine and prone positions: caecum, ascending, transverse, descending, sigmoid, and rectum. Next, a total score of preparation quality was calculated for every patient. The maximum score of 48 points corresponded to excellent preparation, a minimum score of 12 points -to inadequate preparation. A 1-point mark for every parameter corresponded to the least adequate preparation.
The criteria of image quality were presented on a special training in order to provide maximum objectivity and repeatability of assessment. The training consisted of five representative cases for each parameter.

Patient tolerability of bowel preparation assessment
All the patients who have undergone CTC were suggested to fill a questionnaire in 3 to 7 days after the examination. Such an interval had been chosen to minimize the influence of the examination itself on the answers related to the preparation burden. The questionnaire included questions concerning the exam Contents of the 1st pack are mixed with 150 ml of water. This solution must be ingested between 4 PM and 6 PM with no less than 5 glasses (250 ml) of water or clear liquid taken after. The 2 nd pack's contents must be diluted the same way and ingested before sleep ( Contents of one pack should be dissolved in 1 liter of water before ingestion. 4 L of this solution must be taken in the evening before the day of the examination preparation and the examination and was composed according to the recommended bowel preparation tolerability questionnaire [24]. Preparation burden was assessed following the next parameters: subjective burden as a whole, abdominal pain, nausea and vomiting, headache and dizziness, bloating, sleep disturbances, and stool frequency. All of the parameters were assessed using a five-point Likert scale with 1 point corresponding to the least burden and 5 point -maximum burden. Next, the points of personal tolerability were summarized for every patient. A minimum possible sum of tolerability points of 9 corresponded to the least burdensome preparation, a maximum possible of 45 -to the most burdensome preparation. Likewise, the subjective burden of exam preparation was assessed.

Volum of residual fluids
Score 1 Score 2 Score 3 Score 4

Statistical analysis
The necessary sample size was calculated using Lehr's formula (with study power set to 80%). Comparison of demographic data and common patients' characteristics in groups was made with Kruskal-Wallis nonparametric criterion after the differing from normal distribution has been confirmed and using Pearson's χ criterion for categorical data.
Fisher's F-criterion was used as a method of comparison for the total score of distension ratio and residue stool points, and the Kruskal-Wallis nonparametric criterion with post-hoc tests was used for summarizing points of residue fluid and preparation burden.
Welch F-criterion and Games-Howell post-hoc test were used to determine the difference in subjective preparation burden evaluation after the normality of distribution has been confirmed. P-value <0.05 were considered statistically significant. All statistical analyses were performed using Jamovi statistical software (version 1.2.27).
In the PM/Ca preparation group, large polyps and CRC were found in two cases (5.1%), a diverticular disease in 16 cases (41%). In the 2 L PEG + Asc group, large polyps and CRC also were found in two cases (5.9%), whereas diverticular disease in 14 cases (38.9%). Among the patients prescribed 3 L PEG for preparation, large polyps and CRR were found in one case (9.6%), and diverticular disease in 11 cases (57.9%). Finally, in the 4 L PEG preparation group, large polyps and CRC were found in 3 cases, a diverticular disease in 8 (34.8%). No data on following colonoscopy was gathered as it exceeded this study's bounds.
77 patients had undergone colonoscopy sometime before the exam. No statistically significant difference for this rate has been found as well (р>0.05). In the PM/Ca preparation group 26 patients have undergone colonoscopy before (66.7%), in the 2 L PEG + Asc group -26 patients (72.2%); in 3 L PEG preparation group -19 patients (47.4%), in 4 L PEG preparation group -16 patients (66.7%).
No adverse events occurred during the preparation and the CTC exam.

Preparation quality
No statistically significant difference in preparation quality after using any of the prescribed laxatives was found during the evaluation. In particular, there was no difference in the evaluation of residual stool: the mean value of residual stool total score was 46.2 ± 2.87 for PM/Ca group; 46.9 ± 2.34 for 2 L PEG + Asc group; 46.5 ± 1.98 for 3 L PEG group; 45.9 ± 3.18 for 4 L PEG group (р > 0.05). (Fig.3). Also, there was no statistical difference in the volume of residual fluid and bowel distension. The median of residual fluid total score was 36 (33-38) for PM/Ca group; 36.5 (34-39) for 2 L PEG + Asc group; 37 (36-39) for 3 L PEG group; 36 (34-40) for 4 L PEG group (р > 0.05). The mean value of bowel distension total score was 43 ± 4.34 for PM/Ca group; 44.6 ± 3.13 for 2 L PEG + Asc group; 44.2 ± 3.98 for 3 L PEG group; 43.5 ± 4.9 for 4 L PEG group (р > 0.05) ( Table 3).     Statistically different values of tagged residual fluid density were obtained in patients depending on the laxative used for preparation (p < 0.005). A pairwise comparison of groups showed that residual fluid density is lower after using 4 L PEG than after using PM/Ca (p = 0.012). In other groups, the differences in residual fluid density were statistically insignificant (p > 0.05).

Preparation tolerance
A statistically significant difference was found in the total preparation tolerance score of the participants depending on the laxative used for preparation (p=0.001). The total preparation tolerance score was significantly lower when using PM/Ca in comparison with 2 L PEG + Asc (p = 0.021), 3L PEG (p = 0.001) and 4 L PEG (p = 0.043) (Fig. 4). In one case, the preparation using PM/Ca (2.6%) was named as the most burdensome, in 5 cases when using 2 L PEG + Asc (13.9%), in 6 cases when using 3 L PEG (31.6%), and in 5 cases when using 4 L PEG (20.8%). The difference in subjective burden tolerance was statistically significant between the studied laxatives (p < 0.001). A pair-wise comparison of groups showed that subjective preparation tolerance was significantly higher when using PM/Ca than using 2 L PEG + Asc (p = 0.016) ( Table 4).

Discussion
In our study, the best score was received for patients using the combined saline laxative preparation (PM/Ca) when compared to other laxatives (2 L PEG + Asc, 3 L PEG, and 4 L PEG). According to our findings, this study is the first one evaluating the use of PM/Ca in CTC and comparing the data of four bowel preparation schemes.
In our study, we have compared four laxatives used for CTC preparation with full colon preparation, two of those representing classic preparation schemes (3 L PEG and 4 L PEG), one laxative with lessened volume based on macrogol (2 L PEG + Asc) and one combined osmotic laxative (PM/Ca). Other than the laxative used, the preparation scheme was identical for every group.
In all variations, the preparation quality was equally high: total residue stool, fluid, and distension score were in the range between 36 and 47 points out of 48 possible in all preparation schemes, and there was no statistical difference between groups. Bowel preparation quality corresponded to a fully cleansed colon that allowed performing a colonoscopy on the same day (Fig. 5).
Previous studies have shown a better tolerance of PM/Ca than PEG-based laxatives in bowel preparation [21,25,26]. Our study confirms this data: PM/Ca had the highest tolerability in CTC bowel preparation. Besides, the tolerability was higher as in comparison with classic preparation schemes (3 L PEG and 4 L PEG, (p = 0.001, p = 0.043, respectively) so in the scheme with lesser laxative volume (2 L PEG + Asc) (p = 0.021).
Along with that, our study showed that type of laxative used for preparation influences the density of a tagged residual fluid.
Despite that the mean tagging density exceeded the recommended 500 HU in all preparation schemes, the density had a statistically significant lower value when using PM/Ca than when using 4 L PEG (р = 0.012).
Residual liquid density was also higher when using 3 L PEG and 2 L PEG + Asc than PM/Ca, but no statistically significant differences were found. This fact has to be considered during PM/Ca preparation, and possibly the scheme of residual stool tagging has to be optimized. One possible solution is to change the twotime ingestion of a contrast agent to a single ingestion; the other is to increase the amount of contrast agent, though the latter will increase the cost of preparation. The supposed advantage of a single contrast agent ingestion over the two-time ingestion needs to be confirmed in further experiments.
In our study, no statistically significant differences were found between the preparation with 2 L PEG + Asc and 3 L PEG and 4 L PEG, as opposed to previously published studies [19,20].
This fact may be connected to the sample size, but it also can indirectly confirm a better tolerance of PM/Ca.
The study done by Gweon TG and contributing authors have proven the safety of PM/Ca in regards to electrolyte imbalance and hemodynamic markers during the preparation for colonoscopy [21]. In our study, 31 (79.5%) patients of the PM/Ca group belonged to the 65+ age group. No adverse events occurred , indicating the safety of using this laxative in the senior age group.
Our study has several limitations, the first being its retrospective nature. Next is a relatively small size of samples. We had not conducted the sensitivity and specificity analysis for polyps and CRC findings. Still, our study's bowel preparation scheme was the same as the one published before [13], which could guarantee the same diagnostic precision.

Conclusion
Using PM/Ca in CTC preparation lowers the burden of exam preparation with a full colon cleanse. It can be recommended as a safe laxative choice, including senior age patients. A less burdensome preparation is a significant achievement, increasing the CRC screening coverage among patients.