Comparing Left Colon Mucus Production by Water Versus Saline Infusion During Water Exchange Colonoscopy: a Prospective Randomized Controlled Trial
Phase: NA
Conditions: Colon Mucous, Colonoscopy
Sponsor: Evergreen General Hospital, Taiwan

Date: 02/01/2021 
 
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Title: Comparing left colon mucus production by water versus saline infusion 
during water exchange colonoscopy: a prospective randomized controlled trial 
 
Background 
  Water exchange (WE) colonoscopy is a standardized technique developed 
to achieve gasless colonoscope insertion. WE maximizes colon cleanliness 
and improve the adenoma detection rate (ADR).1-3 The American Society for 
Gastrointestinal Endoscopy has recommended using sterile water during 
gastrointestinal endoscopy and this form the basis of standard protocol at most 
endoscopy units.4 However, increased mucus production in the left colon is 
anecdotally observed during withdrawal of water-aided colonoscopy.5  
In a recent pilot study, El Rahyel et al. reported normal saline infusion 
significantly reduced left colon mucus production compared to sterile water 
during water-aided colonoscopy.6 This finding is promising for future WE 
practice. However, in that pilot study, the insertion method was not WE, the 
patients were not randomized, and the effect of saline infusion on serum 
electrolyte was not examined. Therefore, the provocative finding warrants 
validation.  
The primary aims of this study are to compare the left colon mucus scores 
between colonoscopy using carbon dioxide (CO2) insufflation and WE, and in 
those patients undergoing WE, the scores between groups using warm water 
versus warm mixed saline/water infusions during insertion. We hypothesize 
that the mucus scores would be lower when saline is used during WE 
insertion.  
 
Methods 
  This will be a prospective, randomized, controlled trial comparing left colon 
mucus scores between CO2 insufflation, WE insertion with water (WE water 
group), WE insertion with 1:1 mixed normal saline/water (WE 50% saline 
group), and WE insertion with 1:3 mixed normal saline/water (WE 25% saline 
group). The mucus score will be graded during withdrawal by blinded 
colonoscopists and research assistant. It will be conducted at Evergreen 
General Hospital in Taoyuan, Taiwan. Consecutive patients will be enrolled 

Date: 02/01/2021 
 
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from March 2021 to July 2022. A written informed consent will be obtained 
from all participating patients. The study has obtained approval from 
Institutional Review Boards and has been registered with ClinicalTrials.gov 
(NCT04769739). 
 
Participants 
  Consecutive patients aged 20-75 years old undergoing colonoscopy for 
screening, surveillance, and positive fecal immunochemical test will be 
considered for enrollment. The exclusion criteria will include familial 
adenomatous polyposis and hereditary non-polyposis colorectal cancer 
syndrome, active inflammatory bowel disease, previous colonic resection, 
gastrointestinal bleeding, therapeutic colonoscopy (e.g., hemostasis, removal 
of large polyp), evidence of colonic obstruction based on pre-colonoscopy 
clinical evaluation, American Society of Anesthesiology classification of 
physical status grade 3 or higher, allergy to fentanyl or midazolam, mental 
retardation, pregnancy, and refusal to provide a written informed consent.  
 
Randomization 
  Patients will be randomized in a 1:1:1:1 ratio to undergo CO2 insufflation and 
WE insertions with either water infusion, 50% saline infusion, or 25% saline 
infusion. Randomization will be carried out by a computer-generated random 
sequence. Individual random sequences will be placed in an opaque envelope 
kept by an independent research assistant not directly involved in this study, 
which will be opened immediately before the procedure. 
 
Bowel Preparation and Sedation 
Patients will be instructed to eat low-residual foods for two days before 
colonoscopy. Oral and written instructions on the split-dose bowel preparation 
of 3 L polyethylene glycol will be provided. Colonoscopy will be performed with 
moderate sedation using intravenous fentanyl plus midazolam.  
 
Colonoscopy Procedures 
Colonoscopies will be performed by two board-certified colonoscopists who 

Date: 02/01/2021 
 
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have experience in WE (Chi-Liang Cheng, Yen-Lin Kuo). The colonoscopist is 
blinded as to whether water or mixed saline/water is being used. Standard 
colonoscopes (CF-Q260AL/I, CF-HQ290L/I; Olympus Medical Systems Corp., 
Tokyo, Japan) will be used.  
Antispasmodic medication will be administered during colonoscopy 
examination if indicated. All infused fluids will be warmed to approximately 
32-33 °C. CO2 insufflation will be used for CO2 group and during the 
withdrawal phase of the WE group. Colonoscopy will begin with the patients in 
the left lateral position. In the WE group, the air pump will be turned off before 
starting the procedure. During the insertion phase, air and residual water or 
feces in the rectum will be aspirated, and then the colon will be irrigated with 
warm fluid using a flushing pump (Olympus AFU-100; Olympus Corp.). There 
will be no restriction placed on the overall volume of fluid infused to achieve 
adequate cleansing. WE entails the infusion of fluid to open the lumen and 
suction of infused fluid sequentially. Air pockets, when encountered, will be 
aspirated. When the cecum is reached and after most of the fluid is suctioned 
to collapse the cecal lumen, CO2 will be opened. Cecal intubation will be 
defined as the passage of the scope tip beyond the ileocecal valve with 
visualization of the medial wall between the ileocecal valve and the appendix 
orifice. 
Polyp search and resection will be performed during the withdrawal phase in 
all groups. Insertion polypectomy will not be performed. All proximal colon 
(defined as the colon segment proximal to the descending colon) polyps will be 
removed irrespective of their size and appearance. All diminutive polyps with 
hyperplastic appearance (based on narrow band imaging) in the rectosigmoid 
colon will be documented by photography and left alone. Polyp size will be 
determined by comparison with an opened biopsy forceps or a snare. 
In all groups, the following information will be recorded: bowel preparation 
quality using the Boston Bowel Preparation Scale score; the total amount of 
sedative medications; the length of colonoscopy reaching cecum; the amount 
of fluid infused and suctioned during insertion and withdrawal phases; the 
insertion time; the withdrawal time; the need of abdominal compression and/or 
position change to assist colonoscopy insertion; and the overall polyp number, 

Date: 02/01/2021 
 
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size, histology and location. 
 
Mucus scores 
During the withdrawal phase of the colonoscopy, the blinded colonoscopist 
and another blinded research assistant will grade the amount of mucus 
produced in the left colon (descending colon, sigmoid colon, rectum) 
independently. No validated scoring system for the mucus production in the 
colon is available. We use a 5-point Colon Mucus Scale (CMS) (0-4 points), 
modified from the original colon mucus study by El Rahyel et al.,6 to quantitate 
the amount of mucus production in left colon: score 0: no visible mucus; score 
1: minimal amounts of clear mucus in thin streaks or strands; score 2: mild 
opaque mucus in thin strands; score 3: moderate opaque mucus in thicker 
clumps covering one side of surface; score 4: more opaque mucus in thicker 
clumps covering more views of lumen (Figure 1). Prior to beginning scoring, 
the colonoscopists and study assistant will review 10 videos and discuss their 
scores. After they have reached consensus on the 10 cases, scoring will be 
performed independently.  
 
Outcomes 
The primary outcomes are the left colon mucus scores using CMS between 
colonoscopy using CO2 insufflation and WE, and, in those patients undergoing 
WE, the scores between groups using water versus 50% saline versus 25% 
saline. Secondary outcomes include procedure times (insertion and withdrawal 
times) and acute serum electrolyte abnormality in the WE saline groups. 
Patients assigned to the WE saline groups will receive measurements of the 
serum sodium, potassium, and chloride, which will be performed 20 minutes 
before and 60 minutes after the colonoscopy.  
 
Sample size estimation 
We performed an observational study focusing on left colon mucus 
production using CMS scoring system by unblinded colonoscopist and 
compared either full strength normal saline (normal saline group), 1:1 mixed 
normal saline/water (50% saline group), or 1:3 mixed normal saline/water 

Date: 02/01/2021 
 
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(25% saline group) during WE insertion in patients undergoing routine 
colonoscopies in December 2020. We compared these findings with the 
reference WE water group which was video recorded during our previous 
randomized controlled trial comparing right colon adenoma miss rate using 
WE and CO2 insufflation.7 The results showed that fluid containing saline 
significantly reduced the mucus production compared to water alone (Table 1). 
The sample size estimation is based on the assumption that WE 50% saline 
infusion will reduce left colon mucus score compared to WE water infusion. 
Mucus score reduction to ≤ 1 is considered clinically significant. According to 
our preliminary data, we estimate the proportion of subjects with CMS score ≤ 
1 to be 50% in the WE water group. The sample size needed to show the 
proportion of subjects with CMS score ≤ 1 that can be increased to 80% by WE 
50% saline infusion at a 5% alpha error level with 90% power will be 68 
patients per group. To account for dropouts, incomplete procedures, and 
inadequate preparation, an additional 10% will be enrolled. Therefore, a total 
of 300 patients (75 patients in each group) will be enrolled.  
 
Statistical analysis 
Categorical variables will be presented as numbers (percentages), whereas 
continuous variables will be expressed as the means ± standard deviations. 
Overall P values for categorical and continuous parameters will be obtained by 
Fisher’s exact test and Kruskal-Wallis test, respectively. Pairwise comparisons 
among all groups were performed when the overall group effect was significant. 
Agreement between the blinded raters will be tested with Fleiss kappa. For 
mucus production quantity, the 2-category scale (minimal [score 0-1] vs. 
moderate [score 2-4]) will be examined. Potential risk factors for mucus 
production include female sex, lower body mass index, prior abdominal or 
pelvic surgery, poor bowel preparation, water as the infused solution, larger 
volume of infusion, and longer insertion time. Univariate and multivariate 
logistic regression analyses will be used to assess which of the demographic 
and procedural data are independent predictors of moderate mucus production. 
Factors with a P value < 0.1 on univariate analysis will be further entered in the 
multivariate logistic regression analysis. The odds ratio with 95% confidence 

Date: 02/01/2021 
 
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interval will be used to describe the influence of various factors on mucus 
production. All statistical analyses will be performed by using SAS version 9.3 
or later (SAS Institute Inc., Cary, NC, USA). The criterion for statistical 
significance will be a P value <0.05. 
 
References 
1. Jia H, Pan Y, Guo X, et al. Water exchange method significantly improves 
adenoma detection rate: a multicenter randomized controlled trial. Am J 
Gastroenterol 2017; 112: 568-576. 
2. Cadoni S, Falt P, Rondonotti E, et al. Water exchange for screening 
colonoscopy 
increases 
adenoma 
detection 
rate: 
a 
multicenter, 
double-blinded, randomized controlled trial. Endoscopy 2017; 49: 456-467. 
3. Hsieh YH, Tseng CW, Hu CT, et al. Prospective multicenter randomized 
controlled trial comparing adenoma detection rate in colonoscopy using 
water exchange, water immersion, and air insufflation. Gastrointest Endosc 
2017; 86: 192-201. 
4. ASGE Quality Assurance in Endoscopy Committee. Calderwood AH, Day 
LW, Muthusamy VR, et al. ASGE guideline for infection control during GI 
endoscopy. Gastrointest Endosc 2018; 87: 1167-1179. 
5. Anderson JC, Kahi CJ, Sullivan A, et al. Comparing adenoma and polyp 
miss rates for total underwater colonoscopy versus standard CO2: a 
randomized controlled trial using a tandem colonoscopy approach. 
Gastrointest Endosc 2019; 89: 591-598. 
6. El Rahyel A, McWhinney CD, Parsa N, et al. Room temperature water 
infusion during colonoscopy insertion induces rectosigmoid colon mucus 
production. Endoscopy 2020; 52: 1118-1121. 
7. Cheng CL, Kuo YL, Hsieh YH, et al. Comparison of right colon adenoma 
miss rates between water exchange and carbon dioxide insufflation: a 
prospective 
randomized 
controlled 
trial. 
J 
Clin 
Gastroenterol 
2021;55:869-875. 
 
 
 

Date: 02/01/2021 
 
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Figure 1. Left Colon Mucus Scale (CMS) scores 
Score 1                             Score 2 
   
 
 
Score 3                             Score 4 
   
 
 
 
 
 
 
 
 
 
 
 
 

Date: 02/01/2021 
 
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Table 1. Left colon CMS score* by unblinded endoscopists during WE 
colonoscopy 
Variable 
WE/normal 
saline 
(n=17) 
WE/50% 
saline 
(n=17) 
WE/25% 
saline 
(n=17) 
WE/ 
water 
(n=17) 
P-value 
CMS score, mean 
(SD) 
0.35  
(0.49) 
0.94  
(0.66) 
1.06  
(0.83) 
1.88 
(0.78) 
<0.0001 
Patients with CMS 
score ≤1, n (%) 
17  
(100) 
14  
(82) 
13  
(77) 
4  
(24) 
<0.0001 
*Colon Mucus Scale (CMS) score: No mucus (score 0); Minimal amounts of 
clear mucus in thin streaks or strands (score 1); Mild opaque mucus in thin 
strands (score 2); Moderate opaque mucus in thicker clumps covering one 
side of the surface (score 3); More opaque mucus in thicker clumps covering 
more views of the lumen (score 4).