Introduction
Endoscopic submucosal dissection (ESD) is a recently developed technique for gastrointestinal
neoplasms with no risk of lymph node metastasis. ESD has a high en bloc resection
rate and is minimally invasive. ESD is indicated for large superficial colorectal
tumors and is now widely performed [1]
[2]
[3].
However, bleeding after colorectal ESD remains a major complication and needs to be
prevented.
Shioji et al. reported that prophylactic clip closure of the mucosal defect caused
by removal of a polyp (mean size 7.8 mm) does not decrease delayed bleeding after
endoscopic mucosal resection (EMR) [4]. However, Liaquat et al. reported that prophylactic clip closure after EMR of large
(≥ 2 cm) colorectal lesions did reduce the risk of delayed bleeding [5].
In comparison with EMR, ESD creates larger mucosal defects, and the rate of delayed
bleeding associated with ESD is higher than that with EMR.
Recently, Fujihara et al. [6] reported that prophylactic closure of large mucosal defects after colorectal ESD
reduced peritoneal inflammatory reactions and abdominal symptoms, but there is no
consensus about the effect of prophylactic clip closure for prevention of delayed
bleeding after colorectal ESD.
Delayed bleeding requires emergency endoscopic procedures and/or blood transfusions
and rarely requires surgery. This results in longer hospitalization.
The aim of this study was to determine whether prophylactic clip closure reduces the
risk of delayed bleeding after colorectal ESD.
Patients and methods
Consecutive patients who underwent colorectal ESD at Itami City Hospital from January
2012 to May 2017 were analyzed retrospectively. All ESD procedures were performed
by a single experienced endoscopist (H. O.) who had performed approximately 200 upper
gastrointestinal ESDs and 30 colorectal ESDs.
Inclusion and exclusion criteria
The choice of ESD was determined by each colonoscopist based on the Japan Gastroenterological
Endoscopy Society guidelines [2]
[7]
[8].
Lesions that could not be resected or required surgery because of an intraoperative
perforation were excluded from this study. Lesions in the anal canal or ileocecal
valve were excluded because it was difficult to achieve prophylactic clip closure.
Lesions with a resected specimen diameter greater than 5 cm or with a mucosal defect
that could not be closed with a clip were also excluded.
Premedication before colorectal ESD
Patients were given a low-fiber diet on the day before ESD and prescribed 24 mg of
sennoside (Pursennid; Novartis Pharma, Tokyo, Japan) the night before ESD. On the
morning of ESD, 68 g of magnesium citrate (Magcorol P; Horii Pharmaceutical, Osaka,
Japan) dissolved in 1.8 L of water was used to cleanse the bowel. An intravenous injection
was administered immediately before the procedure, consisting of 10 mg scopolamine
butyl bromide (Buscopan; Nippon Boehringer Ingelheim, Tokyo, Japan) or 0.5 mg of glucagon
(Glucagon G Novo; Eisai Ltd, Tokyo, Japan), 17.5 mg of pethidine hydrochloride (Takeda
Pharma, Osaka, Japan), and 2 – 3 mg of midazolam (Dormicum; Astellas Pharma, Tokyo,
Japan).
Colorectal ESD procedures
The colorectal ESD procedures were performed with a CO2 inflation system using a standard
colonoscope (PCF-Q260AZI, Q260AI, or HQ290I; Olympus, Tokyo, Japan) for lesions located
in the cecum and ascending, transverse, and descending colons and a gastroscope (GIF-H260Z
and GIF-Q260J; Olympus) for lesions located in the rectum and sigmoid colon. Before
the procedure, a disposable attachment (F-050/040/020; Top Corp., Tokyo, Japan) was
mounted onto the tip of the endoscope. The VIO 300 D (ERBE Elektromedizin, Tübingen
Germany) was used as a high-frequency electrosurgical unit; 10 % glycerin (Glyceol;
Chugai Pharmaceutical Co., Tokyo, Japan) and hyaluronate solutions (MucoUp; Johnson
& Johnson K.K., Tokyo, Japan) were used for injection. We principally used the FlushKnife,
FlushKnife BT (Fujifilm Medical, Tokyo, Japan), or DualKnife J (Olympus). If necessary,
we used other endo-knives such as the SB Knife Jr (Sumitomo Bakelite, Tokyo, Japan)
and the ITknife nano (Olympus). The electric currents used for the circumferential
incision and submucosal dissection were the endcut mode and coagulation mode, respectively.
After the lesion was resected, we performed preventive coagulation of visible vessels
in the resection area with hemostatic forceps such as Coagrasper (Olympus) or Tighturn
(Zeon Medical, Tokyo, Japan). However, when we closed a mucosal defect, we rarely
performed preventive coagulation. The degree of submucosal fibrosis was classified
into 3 types (F0 – 2), as described previously [9].
Clip closure technique
After the lesion was resected, a large mucosal defect remained. In patients enrolled
in 2012 – 2013, the defects were not closed, but in patients enrolled from 2014, the
defects were usually closed endoscopically. To close the mucosal defect, we used a
normal clip closure technique, but if the mucosal defect was too large to be closed
by normal clip closure, we used Otake’s clip closure technique, as described previously
[10].
Initially, a small incision was made around the mucosal defect with the FlushKnife,
FlushKnife BT, or DualKnife J. The number of incisions depended on the size of the
mucosal defect. The incision provided a better grip for the clip, which could be lifted
easily across the defect without slipping. This makes it easier to reduce the size
of the defect and place additional clips if necessary.
We use the EZ clip (HX-610-090L; Olympus) or ZEOCLIP (ZP-CH; Zeon Medical) for closure.
Schedule after ESD
Blood tests and X-ray examination were performed on the day after ESD; if delayed
bleeding occurred, the blood test was repeated. Some patients (n = 15) underwent X-ray
examination 3 – 7 d after ESD for other causes such as abdominal pain. After the colorectal
ESD procedure, the fasting period was 2 d, and the hospitalization period was 8 d.
Measured outcomes
We mainly aimed to identify whether prophylactic clip closure reduced the rate of
delayed bleeding following colorectal ESD. Delayed bleeding was defined as clinical
evidence of bleeding that required endoscopic hemostasis or a decrease in the hemoglobin
level of > 2 g/dL after ESD. Lesions in which the mucosal defect was not closed were
included in the non-closure group, and lesions in which the mucosal defect was closed
were included in the closure group.
Ethics
The study protocol was approved by the ethics committee of Itami City Hospital and
was performed in accordance with the Declaration of Helsinki.
Statistical analysis
Continuous and categorical variables are shown as means ± standard deviations, ranges,
and proportions. Background and clinical outcomes were compared using the chi-square
test, Fisher’s exact test, or Student’s t-test, as appropriate. A value of P < 0.05 was considered statistically significant. Statistical analysis was performed
using JMP software (version 11.2.0; SAS Institute Inc., Cary, NC).
Results
Between January 2012 and May 2017, a total of 195 lesions in 186 patients were treated
with colorectal ESD. A total of 39 lesions were excluded from the analysis because
they could not be resected, needed surgery because of intraoperative perforation,
were located in the anal canal or ileocecal valve, were greater than 5 cm in diameter,
or had a mucosal defect that could not be closed ([Fig. 1]). Of 156 lesions, 61 that were not closed and 95 that were closed with clips were
included. Background and clinical outcomes of all patients are divided into 2 periods
at the beginning of prophylactic clip closure ( [Table 1]). Regarding the macroscopic features, the prevalence of nongranular-type laterally
spreading tumor (LST-NG) was higher in the second period than in the first period.
The sizes of the resected specimens and tumors were larger in the second period than
in the first period. The prevalence of carcinoma was higher in the second period than
in the first period.
Table 1
Background and clinical outcomes of patients by period.
|
1st period
(n = 73)
|
2nd period
(n = 122)
|
P value
|
|
Age (years)
|
69.6 ± 9.6
|
70.6 ± 9.5
|
0.48
|
|
Sex (male/female)
|
45/28
|
81/41
|
0.50
|
|
Use of antithrombotic drugs (anticoagulants/antiplatelet drugs)
|
7 (2/6)
|
23 (8/17)
|
0.08
|
|
Tumor location (colon/rectum)
|
49/24
|
95/27
|
0.13
|
|
Macroscopic features (LST-G/LST-NG/protruded)
|
34/24/15
|
54/62/6
|
0.001
|
|
Resected specimen size (mm)
|
30.5 ± 13.7
|
37.2 ± 15.2
|
0.003
|
|
Tumor size (mm)
|
23.3 ± 13.3
|
28.0 ± 13.9
|
0.02
|
|
Fibrosis (F0/F1/F2)*
|
50/21/2
|
70/45/7
|
0.26
|
|
2nd device (SB knife Jr/IT knife nano/other)
|
14/2/1
|
24/3/5
|
0.75
|
|
Histology (adenoma/carcinoma)
|
51/22
|
45/77
|
< 0.001
|
|
Procedure time (min)
|
73.7 ± 6.1
|
82.2 ± 4.7
|
0.27
|
|
Adverse events
|
|
|
|
|
|
5
|
3
|
0.13
|
|
|
1
|
6
|
0.20
|
|
En bloc resection rate, n (%)
|
69 (94.5)
|
120 (98.3)
|
0.20
|
LST-G: granular-type laterally spreading tumor; LST-NG: nongranular-type laterally
spreading tumor. Data are presented as the mean ± standard deviation. The P values represent the results of analysis of variance with the chi-square test, Fisher’s
exact test, or Student’s t-test. * The degree of submucosal fibrosis was classified
into 3 types (F0 – 2), as described previously [9].
Fig. 1 Flow diagram.
[Table 2] shows the differences in background and clinical outcomes between the closure and
non-closure groups. Age, sex, tumor location, use of antithrombotic drugs, macroscopic
features, the resected specimen size, tumor size, fibrosis, and procedure time were
not significantly different between the 2 groups. The rate of carcinoma was higher
in the closure group than in the non-closure group. The usage rate of hemostatic forceps
was lower in the closure group than in the non-closure group.
Table 2
Background and clinical outcomes in the closure group vs. non-closure group.
|
Closure group
(n = 95)
|
Non-closure group
(n = 61)
|
P value
|
|
Age (years)
|
70.3 ± 9.4
|
70.1 ± 8.5
|
0.90
|
|
Sex (male/female)
|
62/33
|
42/19
|
0.73
|
|
Tumor location (colon/rectum)
|
78/17
|
44/17
|
0.23
|
|
Use of antithrombotic drugs (anticoagulants/antiplatelet drugs)
|
19 (16/5)
|
8 (6/3)
|
0.29
|
|
Macroscopic features (LST-G/LST-NG/protruded)
|
39/50/6
|
26/24/11
|
0.05
|
|
Resected specimen size (mm)
|
32.2 ± 8.1
|
30.1 ± 11.7
|
0.42
|
|
Tumor size (mm)
|
23.5 ± 7.0
|
22.2 ± 9.0
|
0.32
|
|
Fibrosis (F0/F1/F2)*
|
60/32/3
|
38/19/4
|
0.60
|
|
Histology (adenoma/carcinoma)
|
41/54
|
43/18
|
0.001
|
|
Procedure time (min)
|
64.3 ± 33.9
|
72.8 ± 46.7
|
0.19
|
|
Use of hemostatic forceps
|
64
|
59
|
< 0.001
|
|
Closure time (min)
|
10.4 ± 4.6
|
–
|
|
|
Delayed bleeding
|
0/95
|
5/56
|
0.008
|
LST-G: granular-type laterally spreading tumor; LST-NG: nongranular-type laterally
spreading tumor. Data are presented as a mean ± standard deviation. The P values represent the results of analysis of variance with chi-square test, Fisher’s
exact test, or Student’s t-test. * The degree of submucosal fibrosis was classified
into 3 types (F0 – 2), as described previously [9].
The rate of delayed bleeding was 5/61 (8.2 %) in the non-closure group; delayed bleeding
did not occur in the closure group (P = 0.008). Lesions that could not be closed had no delayed bleeding, and the result
was the same when we included 8 lesions that could not be closed in the closure group. The
median size of the resected tumors in 5 bleeding lesions was 35 mm (range 18 – 47 mm).
[Table 3] shows the differences in clinical outcomes between the normal clip closure group
(group N) and the clip closure group using Otake’s technique (group O). The closure
procedure time was longer in group O (11.1 min) than in group N (8.3 min). The number
of clips was not different between the groups. The size of the resected specimen was
larger in group O than in group N.
Table 3
Clinical outcome of normal clip closure and clip closure using Otake’s technique.
|
Normal clip closure (n = 23)
|
Clip closure using Otake’s technique (n = 72)
|
P value
|
|
Closure procedure time (min)
|
8.3 ± 5.8
|
11.1 ± 4.0
|
0.01
|
|
Number of clips (range)
|
4.73 ± 1.63 (3 – 8)
|
4.51 ± 1.52 (2 – 9)
|
0.54
|
|
Resected specimen size (mm)
|
29.0 ± 7.7
|
34.3 ± 10.2
|
0.03
|
Data are presented as a mean ± standard deviation. The P values represent the results of analysis of variance with Student’s t-test
[Table 4] shows the characteristics of patients who could not be closed with a clip. The sizes
of the resected specimens and tumors were 51.4 ± 9.9 mm and 39.4 ± 5.5 mm, respectively,
which were larger than those of the closure group.
Table 4
Characteristics of patients with lesions that could not be closed with a clip.
|
Patient number
|
Sex
|
Age (years)
|
Location
|
Macroscopic features
|
Resected specimen size (mm)
|
Tumor size (mm)
|
Procedure time (min)
|
Fibrosis (F0/F1/F2)*
|
Histology (adenoma/carcinoma)
|
|
1
|
M
|
78
|
Transverse colon
|
LST-NG
|
45
|
30
|
120
|
F1
|
Carcinoma
|
|
2
|
M
|
62
|
Transverse colon
|
LST-NG
|
52
|
45
|
270
|
F2
|
Carcinoma
|
|
3
|
M
|
75
|
Cecum
|
LST-NG
|
60
|
44
|
310
|
F1
|
Carcinoma
|
|
4
|
F
|
56
|
Rectum
|
LST-NG
|
40
|
38
|
98
|
F1
|
Carcinoma
|
|
5
|
F
|
74
|
Sigmoid colon
|
LST-G
|
48
|
36
|
88
|
F1
|
Carcinoma
|
|
6
|
M
|
75
|
Rectum
|
LST-G
|
45
|
35
|
69
|
F0
|
Adenoma
|
|
7
|
F
|
41
|
Sigmoid colon
|
LST-G
|
50
|
42
|
81
|
F0
|
Carcinoma
|
|
8
|
M
|
79
|
Transverse colon
|
LST-G
|
71
|
45
|
135
|
F0
|
Carcinoma
|
F: female; M: male; LST-G: granular-type laterally spreading tumor; LST-NG: nongranular-type
laterally spreading tumor. * The degree of submucosal fibrosis was classified into
3 types (F0 – 2), as described previously [9].
[Fig. 2 a] shows the day that delayed bleeding occurred. Delayed bleeding occurred within 7 d
and mostly occurred within 2 d. [Fig. 2 b] shows the residual clip rate in patients who underwent X-ray examination in the
closure group. Among 15 lesions, the residual clip rates on day 3, 5, and 6 were 100 %,
80 %, and 93 %, respectively.
Fig 2 a The timing of delayed bleeding. Delayed bleeding occurred within 7 d and mostly within
2 d. b Correlation between the residual clip rate and days after ESD in patients who underwent
X-ray examination in the closure group. The residual clip rate on days 3 – 6 was high.
Adverse events associated with clipping, such as perforation, did not occur.
Discussion
In the present study, we have shown that prophylactic clip closure significantly decreases
the risk of delayed bleeding after colorectal ESD. This is the first study to demonstrate
the clinical efficacy of prophylactic clip closure for prevention of delayed bleeding
after colorectal ESD.
In reports with a large number of cases (> 100), the rate of delayed bleeding in colorectal
ESD ranges between 1.5 % and 4.4 % [1]
[3]
[11]
[12]. High rates (7.9 % and 11.9 %) are found in reports of a small number of cases (< 100)
[13]
[14]. As reported by Odagiri et al., the rate of delayed bleeding may be affected by
the number of cases [12]. The delayed bleeding rate is higher than that of EMR for small colorectal lesions
[4].
A meta-analysis showed that the delayed bleeding rate in gastric ESD was 4.53 % [15], and it is still a major complication. In gastric ESD, post-ESD preventive coagulation
therapy of visible vessels in the ulcer with hemostatic forceps may reduce delayed
bleeding [16].
However, in colorectal ESD, preventive coagulation may lead to excessive coagulation
of the muscularis propria [17], which may increase the risk of delayed perforation, because the muscularis propria
of the colon is much thinner than that of the stomach [18].
Recently, Liaquat et al. reported that prophylactic clip closure reduced the risk
of delayed bleeding after EMR of large (≥ 2 cm) colorectal lesions [5].
On the basis of these reports, we thought that prophylactic clip closure would be
more effective and securer than preventive coagulation to decrease the risk of delayed
bleeding after colorectal ESD. In the present study, by achieving prophylactic clip
closure of the mucosal defect, the need for hemostatic forceps was reduced in the
closure group, and the usage rate of hemostatic forceps was lower in the closure group
than in the non-closure group.
Several methods have been reported on the closure of mucosal defect after colorectal
ESD [6]
[10]
[19]
[20]
[21]
[22]
[23]. As it is simple and easy, we have chosen Otake’s method to close large mucosal
defects that would be difficult to close using conventional clipping.
Our results showed that the mean procedure time for closure was 10.4 min, which is
similar to the procedure time described in previous studies [10]; we think the procedure time for closure is acceptable. From January 2014, we could
not close 8 of 103 mucosal defects. Five bleeding mucosal defects in the non-closure
group were within the range that might be closed if we had tried. Lesions that could
not be closed with a clip had a larger resected specimen and tumor size and a longer
procedure time. There were 12 lesions greater than 5 cm. Among the 8 lesions greater
than 5 cm in the second period, there were only 2 for which we could close the mucosal
defect; among the remaining 6, we could not close 2 and did not try to close the other
4. Additionally, delayed bleeding was found in 3 excluded lesions; 2 of them were
in the second period. These 3 lesions were larger than 5 cm and located in the anal
canal and ileocecal valve. To reduce delayed bleeding, we think it is desirable that
all post-ESD mucosal defects be closed prophylactically if possible. If prophylactic
clip closure fails or is predicted to fail in advance – for example, in cases with
lesions larger than 5 cm – another clipping technique [22]
[23] or a shielding method using polyglycolic acid sheets with fibrin glue [24]
[25] might be an option to decrease delayed bleeding.
In the present study, delayed bleeding occurred mostly within 2 d, and most of the
clips used for prophylactic clip closure remained for 3 – 6 d. This residual clip
rate is similar to that in a previous report [26]. As it has been reported that healing of a large mucosal defect was accelerated
by closure [26]
[27], we believe that accelerated wound healing with prophylactic clip closure contributes
to decreased risk of delayed bleeding.
In the present study, delayed perforation did not occur, and we did not evaluate the
efficacy of prophylactic clip closure for protection from delayed perforation.
When closing a mucosal defect, the probability of local recurrence is a matter of
concern. In lesions where an en bloc resection was performed using ESD, the recurrence
rate is extremely low [28], and local recurrence should not be a concern because we achieved en bloc resection
in all lesions in the closure group.
In the analysis of the treatment period, the rate of LST-NG was higher and size of
the resected specimens and tumors larger in the second period than in the first period.
We think these factors caused the rate of carcinoma to be higher in the second period
than in the first period and different between the closure and non-closure groups.
This indicates that ESD was performed for more difficult lesions in the second period
than in the first period. However, these factors have not been reported as predictors
of delayed bleeding [29].
Some limitations of the present study must be considered. First, this was a retrospective,
single-institution study. Second, the lesions that received prophylactic clip closure
were treated recently, so the learning curve with colorectal ESD cannot be ignored.
It has been reported that colorectal ESD can be safely performed by endoscopists who
have an experience of ≥ 30 cases [30]. The endoscopist in this study had sufficient experience, having performed approximately
200 upper gastrointestinal ESDs and 30 colorectal ESDs. To exclude the effect of the
learning curve, a prospective study is needed.
In conclusion, we demonstrated that prophylactic clip closure might reduce the risk
of delayed bleeding after colorectal ESD. In the future, a multicenter prospective
study will be needed to confirm the effectiveness of prophylactic clip closure.
