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Yamano H-o, Matsushita H-o, Yoshikawa K, et al. BMJ Open Gastro 2016;3:e000101. doi:10.1136/bmjgast-2016-000101 1
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regimen is a burden to patients because of the long inammatory bowel disease; (6) resected digestive tract
cleansing time and large dose volume. Low-volume regi- (except appendectomy); (7) possibility of gastrointes-
mens which were introduced to reduce the volume that tinal obstruction, perforation or disorders of gastric
patients must drink are now more frequently used; one emptying; (8) toxic megacolon; (9) chronic constipation
of these low-volume regimens is polyethylene (defection <3 times a week); (10) history of hypersensi-
glycol-ascorbic acid solution (PEG-Asc; Moviprep).110 tivity to PEG or any other ingredient in the products
For example, 2 L of PEG-Asc can be taken either divided used in this study; (11) pregnancy or breast feeding; or
as 1 L on the evening before and 1 L on the morning of (12) diagnosis of advanced colorectal cancer.
the procedure (split dosing), or taken as 2 L on the day
of the procedure (same-day dosing). It is also recom- Study design
mended that patients drink a further 1 L of clear liquid This was an observer-blinded, prospective, randomised
to prevent the feelings of thirst and dehydration.11 study. Patients were randomised to receive one of the
PEG-Asc contains higher amounts of PEG (1.7-fold) following three cleansing regimens using a computer-
compared with PEG-ES and sodium sulfate (1.3-fold), generated random number list:
NaCl, KCl, and ascorbic acid and sodium ascorbate. PEG, The PEG-Asc-S regimen involved intake of 1.5 L
sodium sulfate and excess ascorbic acid are not absorb- of hypertonic PEG-Asc (Moviprep, Ajinomoto
able from the gastrointestinal tract,1214 and exert an Pharmaceutical Co) with one-split dosing (1 L of
osmotic action in the colon that causes increased laxative PEG-Asc+0.5 L of water, then 0.5 L of PEG-Asc
effects. While the extent of dehydration using hypertonic +0.25 L of water).
PEG-Asc has not yet been claried, it has been suggested The PEG-Asc-M regimen involved intake of 1.5 L of
that isotonic PEG-ES causes little uid exchange across PEG-Asc with four-split dosing (ve lots of (0.3 L of
the colonic mucosal membrane.15 A recent MRI study PEG-Asc+0.15 L of water)).
demonstrated that the intake of PEG-Asc causes disten- The PEG-ES regimen involved intake of 2.25 L of iso-
tion of the ascending and transverse colons, stimulating tonic PEG-ES solution (Ajinomoto Pharmaceutical Co)
colonic motility and resulting in defecation; this prevents with no-split dosing.
the total colon volume increasing beyond an average of A detailed description of the composition of PEG-Asc
1.2 L.16 Hence, an intake volume of <2 L of PEG-Asc on and PEG-ES is given in the online supplementary table S1.
the day of colonoscopy would be an attractive regimen if As shown in gure 1, the total volume which the
it were still efcacious. patient is required to drink was 2.25 L for all three regi-
In the present study, we explored the effects of lower mens. Dosing was performed in our hospital under the
volume PEG-Asc same-day regimens using either a four- guidance of endoscopy-specic nurses, and colonoscopy
split dose or a one-split dose on efcacy and safety was performed on the same day by qualied colonosco-
including dehydration. We used isotonic PEG-ES solu- pists with at least 4 years of experience who were blinded
tion with no-split dose as a control. to the cleansing regimens. On the day before colonos-
copy, patients did not eat a prepacked low-residue diet,
and were instead instructed to have an ordinary supper
MATERIALS AND METHODS but without seaweed, mushrooms or fruits such as kiwi-
This study was conducted in Akita Red Cross Hospital, fruit that contain seeds that are not easily digested.
Akita, Japan from December 2013 to July 2014. The Patients were also recommended to have plenty of water
study protocol was approved by the Institutional Review or tea but not to have laxatives. On the day of colonos-
Board of this hospital, and the study was performed in copy, patients were instructed not to have breakfast.
accordance with the Declaration of Helsinki and Good To compare the dehydration effects between regi-
Clinical Guidelines. Written informed consent was mens, haematocrit (Ht), red blood cell values and
obtained from all patients. This study was registered with haemoglobin were measured just before dosing (base-
the University Hospital Medical Information Network line), at the end of dosing and at the end of colonos-
(UMIN) Clinical Trials Registry System http://www. copy. Biochemical tests were also performed just before
umin.ac.jp/ctr/index.htm (UMIN000013103). the start of dosing (baseline), at the end of dosing and
at the end of colonoscopy. The percentage changes in
Patients Ht, haemoglobin, Na, etc, from baseline to the end of
Eligible patients were those who required a total colon- dosing and from baseline to the end of colonoscopy
oscopy to the caecum, and were older than 20 years. were dened as 100(DB)/B and 100(CB)/B, respect-
Patients were excluded if they had: (1) severe chronic ively, where B is the value at baseline, D is the value at
renal failure (creatinine >1.5 mg/dL); (2) severe con- the end of dosing and C is the value at the end of
gestive heart failure (New York Heart Association class colonoscopy.
III or IV); (3) history of percutaneous coronary interven-
tion or coronary artery bypass grafting for the treatment Assessment of bowel cleansing
of myocardial infraction in the past 3 months; (4) blood The efcacy of bowel cleansing was evaluated based on
electrolyte abnormalities; (5) chronic active video-stored images of procedures by an independent
2 Yamano H-o, Matsushita H-o, Yoshikawa K, et al. BMJ Open Gastro 2016;3:e000101. doi:10.1136/bmjgast-2016-000101
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outside committee blinded to the treatment allocations. model was used for the differences in laboratory test
The degree of bowel cleansing was rated for each of the values between baseline and at the end of dosing, and
following segments: caecum/ascending colon, transverse between baseline and at the end of colonoscopy in the
colon, descending colon, sigmoid colon and the same group. The mixed-effects model was used for the
rectum.1 17 The overall quality of cleansing was deter- differences between groups at the end of dosing and at
mined based on the assessment of the individual seg- the end of colonoscopy. The criterion for statistical dif-
ments as excellent (clean in all segments), good ference was p<0.05.
(removable residue in one or more segments), poor
(non-removable solid stool in one or more segments) or
missing (image data were accidentally not recorded or RESULTS
were of poor quality). Excellent and good are successful Study disposition is shown in gure 2. A total of 310
grades. Unsuccessful grades of C ( poor) and D (bad) in patients were randomised to the PEG-Asc-S group
the Hareeld Cleansing Scale were combined as poor in (n=107), the PEG-Asc-M group (n=99) or the PEG-ES
the present study.1 17 group (n=104). After randomisation, two patients in the
PEG-Asc-S group withdrew their consent, two patients in
Statistics the PEG-ES group had a major protocol deviation, and
This study was designed to demonstrate that PEG-Asc three patients in the PEG-Asc-S group and two patients
given as a one-split dose and as a four-split dose was at in the PEG-ES group discontinued dosing because of
least as safe as PEG-ES in terms of the proportion of Ht nausea due to stomach fullness. One patient in the
in the normal range. Previously, 94% of participants who PEG-Asc-M group had nausea but completed dosing.
received PEG-ES showed Ht in the normal range at the Therefore, a nal total of 301 patients were analysed
end of dosing (unpublished results of the phase III (102 in the PEG-Asc-S group, 99 in the PEG-Asc-M
Japanese clinical trial of PEG-Asc, provided by group and 100 in the PEG-ES group).
Ajinomoto Pharmaceutical Co, Tokyo. A non-inferiority Table 1 shows the demographic characteristics and
design was therefore used, with non-inferiority dened reasons for colonoscopy. These characteristics and
as occurring if the lower limit of the two-sided 95% CI reasons were not signicantly different between the
for the difference in occurrence rates of normal Ht three groups.
between the treatment groups was <10%. A sample size
of 93 participants per group was estimated to be Efficacy
required, with a two-sided signicance level of =0.05, The time necessary for the completion of dosing is
equivalent limit of non-inferiority of 0.10, and a power shown in gure 3. The time for bowel preparation in
of 80%. the PEG-Asc-S group (3.330.48 hours, n=102) was sig-
The differences in demographic properties and nicantly longer than in the PEG-Asc-M group (3.00
reason for colonoscopy between the three groups were 0.53 hours, n=99) and the PEG-ES group (3.05
analysed using Cochran-Mantel-Haenszel tests or analysis 0.56 hours, n=100; p<0.001 for both comparisons).
of variance (ANOVA). The difference in the efcacy dis- There was no signicant difference in bowel prepar-
tribution (excellent, good, poor or missing) between ation time between the PEG-Asc-M and the PEG-ES
two bowel preparations was evaluated using the groups.
Wilcoxon rank-sum test (two samples). The difference The distribution of overall cleansing evaluation as
in time necessary for bowel preparation between differ- excellent, good, poor or missing in each group is shown
ent groups was assessed using ANOVA. The mixed-effects in table 2. The distribution did not signicantly differ
Yamano H-o, Matsushita H-o, Yoshikawa K, et al. BMJ Open Gastro 2016;3:e000101. doi:10.1136/bmjgast-2016-000101 3
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Figure 2 Flow diagram showing randomisation of patients into treatment groups. PEG-Asc, polyethylene glycol-ascorbic acid
solution; PEG-ES, polyethylene glycol-electrolyte solution.
between any two of the groups; however, there was a ten- Dehydration parametersHt, haemoglobin and red
dency for there to be more excellent ratings in the blood cells
PEG-Asc-S (76%) and PEG-Asc-M (75%) groups than in Table 3 shows the Ht values at baseline, at the end of
the PEG-ES group (65%). Bowel preparation was suc- dosing and at the end of colonoscopy. Ht in all three
cessful (the combined ratings of excellent+good) for regimens was signicantly increased at the end of dosing
96%, 94% and 95% of patients in the Modi-S, Modi-M compared with baseline ( p<0.001 for all three compari-
and PEG-ES groups, respectively. sons), indicating occurrence of physiological dehydra-
The number of polyps/adenomas per person (mean tion during the cleansing.
SD, range) in the PEG-Asc-S, PEG-Asc-M and PEG-ES The percentage changes in Ht from baseline to the
groups were 2.972.92 (015), 3.323.51 (019) and end of dosing were 3.533.32%, 4.113.07% and 1.31
3.533.27 (017). There was no signicant difference 3.01% in the PEG-Asc-S, PEG-Asc-M and PEG-ES
between any two groups. groups, respectively (gure 4). The extent of these
4 Yamano H-o, Matsushita H-o, Yoshikawa K, et al. BMJ Open Gastro 2016;3:e000101. doi:10.1136/bmjgast-2016-000101
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Yamano H-o, Matsushita H-o, Yoshikawa K, et al. BMJ Open Gastro 2016;3:e000101. doi:10.1136/bmjgast-2016-000101 5
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online supplementary table S4). These percentage changes Although there was a tendency for more excellent
were negative in all three groups. Percentage changes in ratings in the PEG-Asc-S (76%) and PEG-Asc-M (75%)
blood urea nitrogen from baseline to the end of dosing in groups than in the PEG-ES group (65%), the distribu-
the PEG-Asc-S and PEG-Asc-M groups were signicantly tions of overall cleansing evaluation of excellent, good
smaller than that in the PEG-ES group when compared in and poor between three regimens were not signicantly
absolute values (p<0.001 and p<0.05, respectively). different. Compliance was considered to be good
because patients did not have to eat a prepacked low-
DISCUSSION residue diet, take laxative medicines or take a part or
In the present study, three lower volume bowel cleansing full dose of the cleansing regimen on the day before col-
regimens were explored; 1.5 L of PEG-Asc+0.75 L of onoscopy. Fasting on the morning of the colonoscopy
water with one-split dosing (PEG-Asc-S) or four-split was very important. Guidance for patients to follow the
dosing (PEG-Asc-M), and 2.25 L of PEG-ES with no-split exact intake schedule may be another important aspect
dosing (PEG-ES). The success rates of bowel preparation that resulted in the very high success rates using these
with these three regimens were more than 94%. lower volume regimens.
6 Yamano H-o, Matsushita H-o, Yoshikawa K, et al. BMJ Open Gastro 2016;3:e000101. doi:10.1136/bmjgast-2016-000101
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Figure 4 Percentage changes in levels of haematocrit, red blood cells and haemoglobin from baseline to the end of dosing
(left) and from baseline to the end of colonoscopy (right). Baseline is the value measured before dosing. Significances of
percentage changes in red blood cells and haemoglobin between the PEG-Asc-S and PEG-ES groups, and that between the
PEG-Asc-M and PEG-ES groups were the same as those of haematocrit (not shown here; detailed description given in the
online supplementary tables S2 and S3). ***p<0.001. PEG-Asc, polyethylene glycol-ascorbic acid solution; PEG-ES,
polyethylene glycol-electrolyte solution.
Yamano H-o, Matsushita H-o, Yoshikawa K, et al. BMJ Open Gastro 2016;3:e000101. doi:10.1136/bmjgast-2016-000101 7
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However, even isotonic PEG-ES has physiological dehy- Pharmaceutical Co, Tokyo, Japan, to Digestive Disease Center, Akita Red
dration effects during cleansing. Cross Hospital, Akita, Japan.
The Ht changes from baseline to the end of colonos- Competing interests HY received grant support for this study from
copy in the PEG-Asc-S, PEG-Asc-M and PEG-ES groups Ajinomoto Pharmaceutical Co and lecturing fees from Eisai Co, Takeda
Pharmaceutical Co, Ajinomoto Pharmaceutical Co, KYORIN Pharmaceutical Co,
(0.65%, 0.54% and 2.47%, respectively) indicate
DAIICHI SANKYO Co, AstraZeneca K. K., ZERIA Pharmaceutical Co, Otsuka
that rehydration occurred during colonoscopy. As Pharmaceutical Co, Olympus medical science sales Co and Olympus Co.
patients did not have breakfast on the day of colonos-
Patient consent Obtained.
copy, the Ht value at baseline would reect a slightly
dehydrated state. The value of 2.47% in the PEG-ES Ethics approval Institutional Review Board at Akita Red Cross Hospital, Akita,
Japan.
group would reect the non-dehydrated state at the end
of colonoscopy. In other word, patients in the PEG-Asc-S Provenance and peer review Not commissioned; externally peer reviewed.
and PEG-Asc-M groups at the end of colonoscopy were Data sharing statement The authors included an online supplementary file
2% more dehydrated than those in the PEG-ES group. with additional data.
This suggests that patients treated with PEG-Asc should Open Access This is an Open Access article distributed in accordance with
intake additional water after colonoscopy to cope with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
the physiological dehydration. which permits others to distribute, remix, adapt, build upon this work non-
The percentage changes (in absolute values) of blood commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
urea nitrogen from baseline to the end of dosing in the creativecommons.org/licenses/by-nc/4.0/
PEG-ES group were signicantly greater than that in the
PEG-Asc-S and PEG-Asc-M groups, and the difference
between the PEG-Asc-S and PEG-Asc-M groups was not REFERENCES
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