Complications of Gastric Endoscopic Submucosal Dissection

Review

Complications of Gastric Endoscopic Submucosal Dissection

Ichiro Oda, Haruhisa Suzuki, Satoru Nonaka and Shigetaka Yoshinaga

Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan

Endoscopic resection is now a widely accepted treatment forearly gastric cancer, having a negligible risk of lymph-nodemetastasis. Endoscopic submucosal dissection (ESD) is a rela-tively new endoscopic resection method developed in the mid-1990s that facilitates en-bloc resection even in patients with largeor ulcerative lesions difficult to resect using conventional endo-scopic mucosal resection (EMR). However, compared to EMR,ESD requires a longer procedure time and a higher level of tech-nical expertise, in addition to having a slightly greater risk ofcomplications. Endoscopists must be aware of not only therisk factors for, and incidence of, complications, but alsohow to effectively treat such complications. Perforation and

bleeding are the major complications associated with gastricESD. The perforation and delayed bleeding rates have beenreported to range from 1.2% to 5.2% and 0% to 15.6%, respectively,and can usually be managed with appropriate endoscopic treat-ment. Immediate bleeding during gastric ESD is quite commonand controlling such bleeding, which is primarily achieved bycarrying out electrocautery, plays a critical role in the successfulcompletion of ESD.

Key words: bleeding, complication, early gastric cancer,endoscopic submucosal dissection, perforation

INTRODUCTION

ENDOSCOPIC RESECTION IS now widely accepted asa less invasive method for local resection of early gastric

cancer (EGC), having a negligible risk of lymph-nodemetastasis.1–3 The appropriate endoscopic resection techniqueshould be safe, effective and suitable for a variety of clinicalsituations. However, endoscopic resection is associated withvarious complication risks, most importantly, bleeding andperforation.

Recently, the number of patients who undergo endoscopicresection instead of surgery has been increasing in Japanbecause the indications for such a procedure have beenexpanded and the various techniques have improved, rangingfrom conventional endoscopic mucosal resection (EMR) toendoscopic submucosal dissection (ESD).4–6 Therefore, asmore endoscopic resections are being carried out, successfulmanagement of complications has become even more impor-tant, so endoscopists must be aware of not only the riskfactors for, and incidence of, complications, but also how toeffectively treat such complications. In the present review,we describe gastric ESD-related complications and themethods for managing them successfully.

INCIDENCE OF COMPLICATIONS

WE DETERMINED THE incidence of complicationsfrom 28 articles published in English involving

studies with at least 300 ESD cases for EGC in each(Table 1).7–34

PerforationMost perforations occur during ESD and the risk of perfo-ration reportedly ranges from 1.2% to 5.2% for gastric ESD(Table 1). In terms of delayed perforation occurring aftercompletion of gastric ESD, one study reported that suchperforations occurred in six (0.5%) of 1159 consecutivepatients with 1329 EGC who underwent ESD (Table 1).24

Another report indicated two cases (0.43%) of delayed per-foration occurring after completion of ESD for 468 gastricnon-invasive neoplasia including not only EGC, but alsogastric adenomas.35 There are also several case reports ofdelayed perforation after ESD for EGC.36–38

Gastric perforations have been analyzed according tolesion location, size and ulcer finding.7 The rate of gastricperforation in both the upper and middle thirds of thestomach is higher than in the lower third of the stomachprobably because the gastric wall in the former two locationsis thinner than in the latter. Another likely reason for theincreased risk of complications in the upper and middlethirds of the stomach is the fact that ESD is carried out inthose locations using the retroflex position of the endoscope

Corresponding: Ichiro Oda, Endoscopy Division, National CancerCenter Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.Email: [email protected] 27 June 2012; accepted 1 August 2012.

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Digestive Endoscopy 2013; 25 (Suppl. 1): 71–78 doi: 10.1111/j.1443-1661.2012.01376.x

© 2013 The AuthorsDigestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society

71

Tab

le1

Inci

den

ceof

gast

ric

end

osco

pic

sub

muc

osal

dis

sect

ion

com

plic

atio

ns

Aut

hor

Year

No.

lesi

ons

Del

ayed

ble

edin

g%

(n)

Perf

orat

ion

%(n

)D

elay

edp

erfo

ratio

n%

(n)

Sten

osis

%(n

)P

neum

onia

%(n

)R

efer

ence

Od

aet

al.

2005

1033

5.7%

(59)

3.4%

(35)

––

–7

Min

amie

tal

.20

0618

94–

4.8%

(91)

––

–8

Od

aet

al.

2006

303

0%(0

)3.

6%(1

1)–

––

9

Jung

etal

.20

0755

27.

6%(4

2)2.

7%(1

5)–

––

10

Take

naka

etal

.20

0830

60.

7%(2

)5.

2%(1

6)–

––

11

Ono

etal

.20

0831

48.

3%(2

6)4.

5%(1

4)–

––

12

Tsun

ada

etal

.20

0853

2–

––

0.9%

(5)

–13

Taki

zaw

aet

al.

2008

1083

5.8%

(63)

––

––

14

Hot

eya

etal

.20

0957

24.

9%(2

8)3.

5%(2

0)–

––

15

Isom

oto

etal

.20

0958

91.

7%(1

0)4.

2%(2

5)–

––

16

Chu

nget

al.

2009

1000

15.6

%(1

56)

1.2%

(12)

––

–17

Cod

aet

al.

2009

2011

––

–0.

7%(1

5)–

18

Hot

taet

al.

2010

703

0.3%

(2)

4.1%

(29)

––

–19

Man

nen

etal

.20

1047

88.

9%(3

9)3.

9%(1

7)–

––

20

Got

oet

al.

2010

454

5.7%

(26)

––

––

21

Tsuj

iet

al.

2010

398

5.8%

(23)

––

––

22

Jeon

etal

.20

1017

11–

2.3%

(39)

––

–23

Han

aoka

etal

.20

1013

29–

–0.

5%(6

)–

–24

Isom

oto

etal

.20

1071

3–

––

–0.

8%(6

)25

Iizuk

aet

al.

2010

308

––

–1.

9%(6

)–

26

Ahn

etal

.20

1183

35.

3%(4

4)1.

7%(1

4)–

––

27

Aka

saka

etal

.20

1111

883.

1%(3

7)4.

1%(4

9)–

–1.

6%(1

9)28

Lee

etal

.20

1180

64.

2%(3

4)3.

5%(2

8)–

––

29

Hig

ashi

yam

aet

al.

2011

924

3.0%

(28)

––

––

30

Oka

da

etal

.20

1164

74.

3%(2

8)–

––

–31

Sugi

mot

oet

al.

2012

485

3.7%

(18)

3.9%

(19)

––

–32

Got

oet

al.

2012

1814

5.5%

(100

)–

––

–33

Toyo

kaw

aet

al.

2012

1123

5.0%

(56)

2.4%

(27)

––

–34

72 I Oda et al. Digestive Endoscopy 2013; 25 (Suppl. 1): 71–78


compared to direct endoscopic observation of lesions in thelower third of the stomach. The rate of gastric perforationalso increases for larger size lesions and lesions with ulcerfindings.

BleedingCases of bleeding complications can be subdivided intoimmediate (intraoperative) bleeding occurring during theprocedure and delayed bleeding taking place after the pro-cedure with respect to the time of onset. Immediate bleed-ing is infrequent with EMR techniques, but is quitecommon with ESD. Management of immediate bleedingplays a critical role in the successful completion of ESD. Itis difficult to measure precisely the volume of bleedingduring EMR and ESD, so significant immediate bleedingwas defined in a previous study as the diminution of�2 g/dL in hemoglobin (Hb) comparing pre-procedure andnext-day levels.7 Evidence of significant immediate bleed-ing was found in 63 of 945 patients (7%) in that particularstudy.7 The rates of significant immediate bleeding in theupper and middle thirds of the stomach are higher than inthe lower third of the stomach because of the larger diam-eter of the submucosal arteries in the upper and middlethirds of the stomach.39

Delayed bleeding after ESD has been reported to rangefrom 0% to 15.6% (Table 1). This wide variation is partlydue to differences in the definition of delayed bleeding asused in the reported studies. For example, the definition ofdelayed bleeding can vary from a clinical symptom of bleed-ing such as hematemesis and melena to bleeding requiring ablood transfusion or even bleeding necessitating endoscopictreatment. Delayed bleeding usually occurs within 24 h post-ESD and has been reported to relate to lesion location, size,patient age and procedure time.7,31,34 The first of those studiesindicated delayed bleeding occurred more frequently afterESD for lesions in the lower and middle thirds of thestomach compared to the upper third of the stomach.7 Thereasons for this remain unclear, but antral peristaltic activityand the alkaline effect of bile juice reflux may contribute tosome extent. It is also speculated that this increase in the riskof delayed bleeding for lesions in the lower third of thestomach could be due to the fact that immediate bleeding insuch cases is less common; therefore, the need for intraop-erative hemostatic treatment is less than for lesions locatedin the upper third of the stomach. The second study reportedthat resected specimens �40 mm in size was the only sig-nificant factor associated with delayed bleeding after ESD.31

The third study indicated that patient age �80 years andlengthier procedure time were associated with a significantlyhigher risk of delayed bleeding after ESD.34 In relation to

antiplatelet drugs, the possible influence on delayed bleedingof such drugs is controversial.40,41

Other complicationsThe risk of stenosis has been reported to range from 0.7% to1.9% in all gastric ESD cases (Table 1). In particular, endo-scopists should be careful of stenosis occurring after ESDfor lesions located near the cardia and pylorus. Stenosis wasfound in 17% of cardiac ESD cases and in 7% of the casesinvolving lesions located near the pylorus. Circumferentialextent of a mucosal defect > 3/4 and longitudinal extent>5 cm were each significantly related to the occurrence ofpost-ESD stenosis in both cardiac and pyloric resections.18

Gastric ESD is usually carried out under deep sedationwithout tracheal intubation so there is a slight risk of aspi-ration pneumonia. The risk of such pneumonia has beenreported to range from 0.8% to 1.6% for gastric ESD(Table 1) and there have been at least two case reports onfatal instances of pneumonia.42,43

There have also been several case reports on air embolism,which is uncommon, but a potentially fatal complicationassociated with gastric ESD.44,45 In order to minimize suchfatal complications, some institutions have started to useCO2 insufflation as an added safety measure.46

In addition, there is one report about deep vein thrombosis(DVT) after gastric ESD that indicated ESD proceduresinvolved a moderate risk of thromboembolism. D-dimerlevels the day after ESD, in particular, may be associatedwith DVT in ESD patients.47

MANAGEMENT OF COMPLICATIONS

Perforation

Prevention

POSSIBLE MECHANISMS FOR perforations inducedby ESD are unanticipated injury of the muscularis

propria caused by insufficient submucosal injection or mis-calculation as to the gastric wall curve. In order to avoidperforation, adequate space in the submucosal layer betweenthe muscularis propria and mucosal layer is essential; there-fore, a sufficient amount of submucosal injection solution isnecessary. In order to lift the mucosa for the longer proce-dure period required by ESD, the effectiveness of sodiumhyaluronate (MucoUp; Johnson & Johnson Corp., Tokyo,Japan), Glyceol (Chugai Pharmaceutical Co., Tokyo, Japan),or a combination of sodium hyaluronate and Glyceol havepreviously been reported for submucosal injection.48–51 Theuse of an injection solution mixed with indigocarmine dyefor submucosal injection is effective in better recognizing thecurvature of the gastric wall curve by distinguishing thewhite muscularis propria from the blue submucosal layer.

Digestive Endoscopy 2013; 25 (Suppl. 1): 71–78 Gastric ESD complications 73


The use of a transparent attachment to the scope is alsouseful in recognizing the gastric wall curve by lifting themucosal layer with the attachment.

Endoscopic closureIn the past, gastric perforations during endoscopic resectionsof early cancers invariably led to emergency surgery whichresulted in all the advantages of endoscopic resection beinglost.8 Endoscopic clips were originally developed for hemo-static purposes.52 Closure of a perforation using such clipsafter snare excision of a gastric leiomyoma was first reportedby Binmoeller et al. in 1993.53 In 2006, endoscopic closurewith endoscopic clips for endoscopic resection-relatedgastric perforations was reported to be effective in a series ofconsecutive cases.8 In that study, 115 (98.3%) of 117 patientswith gastric perforations were successfully treated con-servatively using endoscopic clips for closure of theirperforations.

Two methods of endoscopic closure have been reported,including the ‘single-closure method’ and the ‘omental-patch method’ using endoclips with a right-angle hook (HX-610-090, HX-610-090 L; Olympus Medical Systems Corp.,Tokyo, Japan).8 The single-closure method is carried out totreat small defects, and starts from the edge of the perfora-tion rather than the center (Fig. 1). Perforations during ESDare usually smaller and linear compared to those resultingfrom EMR generally allowing for the single-closure methodto be used effectively in sealing such perforations. Theomental-patch method is carried out on relatively largerdefects by suctioning either the greater omentum or the

lesser omentum into the stomach lumen and then clippingthe omentum as a patch to the edges of the perforation.

Peritoneal tapVital signs including blood pressure, oxygen saturation andelectrocardiogram readings must be continuously monitoredduring these endoscopic treatment procedures. Patientswith a large perforation can experience a large amount ofair entering the abdominal cavity leading to abdominalcompartment syndrome. In order to prevent severe abdomi-nal compartment syndrome when a gastric perforationoccurs, frequent abdominal palpation is recommended tocheck the degree of abdominal fullness with air. If severeabdominal fullness is noted, decompression of the pneumo-peritoneum must be carried out with a puncture needle.8

Recently, CO2 insufflation has increasingly been used insteadof air insufflation to minimize such pneumoperitoneumcaused by a gastric perforation.46

Bleeding

Hemostasis for immediate bleedingElectrocautery is used for hemostasis of immediate bleedingduring ESD because endoscopic clips interfere with the sub-sequent resection procedure.39,54 Electrocautery is usuallycarried out using different devices depending on the degree ofbleeding. Minor oozing can be controlled by electrocauteryusing a cutting device such as the IT knife 2, Hook knife,Dual knife (KD-611 L, KD-620LR, KD-650 L; OlympusMedical Systems Corp.), SAFEKnifeV or FlushKnife BT(DK2518DV, DK2618JB; Fujifilm Corp., Tokyo, Japan)

A B

Figure 1 (a) Small perforation 5 mm in size occurring during gastric endoscopic submucosal dissection (ESD). (b) Perforation closedsuccessfully with the ‘single-closure method’ using endoscopic clips.



(Fig. 2). It is also necessary to pre-coagulate to prevent bleed-ing using a cutting device when vessels are found during theprocedure. Electrocautery using hemostatic forceps such asthe Coagrasper (FD-410LR; Olympus Medical SystemsCorp.) or hot biopsy forceps (Radial Jaw; Boston ScientificJapan Corp., Tokyo, Japan) is suitable for arterial bleeding(Fig. 3). The critical step in achieving good hemostasis isidentification of the exact bleeding point using water flushing.Endoscopes equipped with water-jet systems (GIF-Q260J;Olympus Medical Systems Corp.; EG-450RD5; FujifilmCorp., Tokyo, Japan) have recently become available for usein precisely determining the bleeding point.

Hemostasis for delayed bleeding

All endoscopic treatment modalities can also be used indi-vidually or in combination for hemostasis of delayed bleed-ing after endoscopic resection. Different modalities areapplied according to the period of delayed bleeding. In theearly days of delayed bleeding, the artificial ulcer floor isstill soft with less granulation tissue so endoscopic clipsor electrocautery using hemostatic forceps can be appliedto control this complication. In the later days of delayedbleeding, the artificial ulcer floor hardens with granu-lation tissue so the injection method is preferable. In our

BA

Figure 2 (a) Example of minor oozing bleeding during gastric endoscopic submucosal dissection (ESD). (b) Minor oozing bleedingcontrolled by electrocautery using a cutting device.

BA

Figure 3 (a) Example of arterial bleeding during gastric endoscopic submucosal dissection (ESD). (b) Arterial bleeding managed byelectrocautery using hemostatic forceps.



previously published case series, 76% of patients ex-perienced delayed bleeding within 24 h after ESD and theremaining 24% between 2 and 15 days following theprocedure.7

In an effort to prevent delayed bleeding, it has beenreported that prophylactic post-ESD coagulation of visiblevessels in the resection area is useful regardless of activebleeding.14 The effectiveness of second-look endoscopy afterhemostasis of peptic ulcer bleeding has previously beenshown,55,56 although the effectiveness of second-look endos-copy after gastric cancer ESD based on a retrospective analy-sis is still controversial and a future prospective study isneeded.21

Acid-suppressing drugsIn general, acid-suppressing drugs are used after gastric ESD.Kakushima et al. reported that healing occurred within8 weeks with proton pump inhibitor (PPI) administration for8 weeks irrespective of ulcer size or location.57 It has alsobeen reported that administration of PPI for 2 weeks forartificial ulcers after ESD may be sufficient in helping them toheal.58 Uedo et al. reported that PPI therapy was more effec-tive in preventing delayed bleeding in ulcers created by ESDthan H2-receptor antagonist treatment.59 In contrast,Yamagu-chi et al. reported that there were no differences in the inci-dence of delayed bleeding or ulcer size 30 days and 60 daysafter gastric EMR between PPI and H2-receptor antagonisttreatment.60 As for the type and duration of acid-suppressingdrugs given after gastric ESD, there is still room for furtherresearch.

Stenosis

Endoscopic balloon dilatationBleeding and perforations usually occur during ESD orwithin 24 h of the procedure. In contrast, stenosis can mani-fest a few weeks after endoscopic resection during the ESDulcer healing process. When a patient with considerablestenosis complains of dysphagia, endoscopic dilatation iscarried out until dysphagia is resolved with a 15–18-mmballoon dilator (CRE™ Wireguided Balloon Dilators;Boston Scientific Japan Corp.). In our published series, dys-phagia and significant stenosis were fully resolved in allpatients in response to repeated balloon dilatation withoutcomplications.18 Perforations related to endoscopic balloondilation have been reported, however, so early intervention isrecommended for patients with high-risk factors to avoid aperforation during balloon dilation.13,26 Enhanced effortsshould also be made to preclude the actual development ofpost-ESD stenosis. In this regard, a biodegradable esoph-ageal stent reportedly used in patients with benign esoph-ageal stenosis may be effective in preventing post-ESDstenosis from developing in patients with cardiac or pyloricresections.61,62

CONCLUSION

GASTRIC ESD FACILITATES en-bloc resection evenin patients with large or ulcerative lesions, but it is

associated with various complications, most importantly,bleeding and perforation. Endoscopists must be aware of notonly the risk factors for, and incidence of, complications, butalso how to effectively treat such complications.

CONFLICT OF INTERESTS

AUTHORS DECLARE NO conflict of interests for thisarticle.

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Complications of Gastric Endoscopic Submucosal Dissection