Fujishiro Et Al-2016-Digestive Endos

Digestive Endoscopy 2016; 28: 363378
doi: 10.1111/den.12639
Guideline
Guidelines for endoscopic management of non-variceal upper

gastrointestinal bleeding
Mitsuhiro Fujishiro, Mikitaka Iguchi, Naomi Kakushima, Motohiko Kato, Yasuhisa Sakata,
Shu Hoteya, Mikinori Kataoka, Shunji Shimaoka, Naohisa Yahagi and Kazuma Fujimoto
Japan Gastroenterological Endoscopy Society, Tokyo, Japan
Japan Gastroenterological Endoscopy Society (JGES) has compiled
a set of guidelines for endoscopic management of non-variceal upper gastrointestinal bleeding using evidence-based methods. The
major cause of non-variceal upper gastrointestinal bleeding is peptic gastroduodenal ulcer bleeding. As a result, these guidelines
mainly focus on peptic gastroduodenal ulcer bleeding, although
bleeding from other causes is also overviewed. From the epidemiological aspect, in recent years in Japan, bleeding from
drug-related ulcers has become predominant in comparison with
bleeding from Helicobacter pylori (HP)-related ulcers, owing to an
increase in the aging population and coverage of HP eradication
therapy by national health insurance. As for treatment, endoscopic
hemostasis, in which there are a variety of methods, is considered
to be the first-line treatment for bleeding from almost all causes. It
is very important to precisely evaluate the severity of the patients
EPIDEMIOLOGY AND CAUSES OF

NON-VARICEAL UPPER GASTROINTESTINAL
BLEEDING
MONG PATIENTS WITH non-variceal upper gastrointestinal (GI) bleeding, the major cause is peptic gastroduodenal ulcer. Mallory-Weiss syndrome, vascular abnormalities,
iatrogenic causes after endoscopic procedures and surgical
operation with anastomosis, and so on, are known as other
causes of bleeding, although there have been little
epidemiological data to date.
The prevalence of peptic ulcer is decreasing in both Eastern
and Western countries;15 however, according to a population
survey report in Japan, death as a result of these diseases has
remained at over 3000 per year after 2000 despite their continuous decrease until the 1990s.6 Helicobacter pylori (HP) and
low-dose aspirin are important risk factors for these ulcers.7,8
According to a recent meta-analysis, the relative risks of HP
Corresponding: Mitsuhiro Fujishiro, Japan Gastroenterological
Endoscopy Society, 3-2-1 Kandasurugadai, Chiyoda-ku, Tokyo 1010062, Japan. Email: digestive_endoscopy@jges.or.jp
Received 1 December 2015; accepted 17 February 2016.
bs_bs_banner
2016 Japan Gastroenterological Endoscopy Society
condition and stabilize the patients vital signs with intensive care
for successful endoscopic hemostasis. Additionally, use of
antisecretory agents is recommended to prevent rebleeding after
endoscopic hemostasis, especially for gastroduodenal ulcer bleeding. Eighteen statements with evidence and recommendation
levels have been made by the JGES committee of these guidelines
according to evidence obtained from clinical research studies.
However, some of the statements that are supported by a low
level of evidence must be confirmed by further clinical research.
Key words: bleeding peptic ulcer, endoscopic hemostasis,

endoscopic examination, gastroduodenal ulcer bleeding, upper
gastrointestinal bleeding
infection, use of non-steroidal inflammatory agents

(NSAIDs), and both for peptic-ulcer disease were 18.1, 19.4,
and 61.1, respectively. Moreover, the relative risks of HP
infection, NSAIDs use, and both for hemorrhagic peptic ulcer
were 1.79, 4.85, and 6.13, respectively.9 HP-related ulcers are
divided into gastric ulcers and duodenal ulcers. The former is
characterized by hypoacidity as a result of pangastritis and the
latter is characterized by hyperchlorhydria as a result of antral
predominant gastritis.10 It is reported that the former is
commonly found in developing countries, and the latter is
found in developed countries.11 There have only been a few
large-scale studies in Japan evaluating the association between
peptic gastroduodenal ulcers and NSAIDs. In an epidemiological study of 1008 rheumatoid arthritis patients conducted by
Shiokawa et al. in 1991, gastric ulcer was found in 15.6%
and duodenal ulcer was found in 1.9% of the patients, and
these were higher than the prevalences obtained in a survey
conducted by the Japanese Society of Gastrointestinal Cancer
Screening in the same year.12
As for hemorrhagic peptic gastroduodenal ulcer, many
studies reported that the total number of cases had not changed
or had slightly decreased.5,1315 This is because the incidence
of hemorrhagic peptic gastroduodenal ulcer is decreasing in
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M. Fujishiro et al.
the young population, whereas it is increasing in the elderly

population.1316 According to a study by Asagi,16 the proportion of hemorrhagic ulcers among older individuals with
peptic ulcers increased from 9.2% in 19671972 to 27.8% in
19851990. One of the reasons is speculated to be an increase
in the prescription of low-dose aspirin. Therefore, it is
expected that the number of cases of hemorrhagic peptic
gastroduodenal ulcer will increase with population aging.
FORMATION OF STATEMENTS ON ENDOSCOPIC MANAGEMENT OF NON-VARICEAL

UPPER GASTROINTESTINAL BLEEDING
TATEMENTS IN THIS set of guidelines have been

produced by referring to the 2007 version of the Medical
Information Network Distribution Service (MINDS).17 In
brief, literature searches were conducted in PubMed and Japan
Centra Revuo Medicina (the Japan Medical Abstracts Society)
databases over the period of 2000 to 2013, by using related
key words such as upper gastrointestinal bleeding and
endoscopy. In order to select important research papers
published before 2000, reference lists of review articles
published after 2000 were checked and the relevant papers
were added to create statements. The Working Committee
created 18 statements with various evidence levels (Table 1)
and recommendation levels (Table 2), the Evaluation Committee then evaluated them, and final agreement on all statements
was obtained by both the Working and the Evaluation
committees.
INITIAL MANAGEMENT OF NON-VARICEAL UPPER GASTROINTESTINAL BLEEDING

E SEARCHED FOR articles using the key words nonvariceal, upper gastrointestinal, and bleeding. The
reference lists of 494 original studies and review articles that
appeared in the search results were screened to ensure all
potentially relevant studies were included. A total of 85
Table 1 Classification of evidence levels

I Systematic review/meta-analysis of randomized controlled trial
II At least one randomized controlled trial
III Non-randomized controlled trial
IVa Analytical epidemiological study (cohort study)
IVb Analytical epidemiological study (casecontrol study, crosssectional study)
V Case series, case report
VI Not based on patient data, or based on opinions from a
specialist committee or individual specialists
Table 2 MINDS grades of recommendation

A Strong scientific evidence exists, strongly recommended to do
B Scientific evidence exists, recommended to do
C1 No scientific evidence, but recommended to do
C2 No scientific evidence, recommended not to do
D Scientific evidence that it is ineffective or harmful, recommended
not to do
relevant papers were referred to in order to create the following

statements.
Hematemesis, melena, and hematochezia are symptoms that
reflect gastrointestinal bleeding.1821 Generally, hematemesis
or melena reflects bleeding from the upper gastrointestinal
tract and hematochezia reflects bleeding from the lower
gastrointestinal tract. However, even upper gastrointestinal
bleeding could cause hematochezia in cases in which there
is a large amount of bleeding. In a prospective observational
study by Wilcox et al.,22 hematochezia was seen in 104
(14%) out of 727 patients with upper gastrointestinal bleeding. A meta-analysis by Srygley et al.23 revealed that melena,
bloody nasogastric tube aspiration, and blood urea nitrogen
(BUN)/creatinine ratio >30 are risk factors for upper gastrointestinal bleeding. Therefore, physicians should confirm the
presence or the absence of hematemesis, melena or bloody
nasogastric tube aspiration, or whether the BUN/creatinine
ratio is elevated, in order to distinguish between upper and
lower gastrointestinal bleeding (evidence level I, recommendation level A).
It is important to predict the cause of bleeding prior to
endoscopy, as the procedure of endoscopic hemostasis or the
prognosis varies depending on whether the cause of bleeding
is variceal or non-variceal. According to studies concerning
the prediction of the cause of bleeding, past history of liver
cirrhosis or variceal bleeding, heavy drinking, presence of
ascites, thrombocytopenia, hyperbilirubinemia, or elevation
of prothrombin timeinternational normalized ratio (PT-INR)
is associated with variceal bleeding, whereas dosage of antiplatelet or anticoagulant drug is associated with non-variceal
bleeding such as hemorrhagic gastroduodenal ulcer.2426
Moreover, among patients with chronic liver disease or cirrhosis, patients with higher spleen diameter (platelet/spleen
diameter ratio) and worse ChildPugh score were reported to
have a higher risk of variceal bleeding.2733 Therefore, it is
important to discriminate variceal bleeding from non-variceal
bleeding by reviewing the patients past history, physical
findings, and laboratory findings (evidence level IVb, recommendation level C1).
The Glasgow-Blatchford score (GBS)21 and the Rockall
score (RS)34 are scoring systems for risk stratification of upper
gastrointestinal bleeding. The former consists of vital signs
and laboratory findings, and the latter consists of these as well
Guidelines for upper GI bleeding
Table 3 Glasgow-Blatchford score21

Admission risk marker
Score component value
Blood urea (mmol/L)

6.5 <8.0
8.0 <10.0
10.0 <25.0
25
2
3
4
6
Hemoglobin (g/dL) in men

120 <130
100 <120
<100
1
3
6
Hemoglobin (g/dL) in women

100 <120
<100
1
6
Systolic blood pressure (mmHg)

100109
9099
<90
1
2
3
Other markers
Pulse rate 100 (per min)
Presentation with melena
Presentation with syncope
Hepatic disease
Cardiac failure
1
1
2
2
2
365
as endoscopic findings. Moreover, the clinical RS, which

consists of clinical data only, is also used (Tables 3, 4). The
GBS and RS should be used to determine the necessity for
intervention, the degree of risk of rebleeding, and the risk of
mortality (evidence level III, recommendation level B).
Moreover, recently, a simple risk factor named AIMS 65,
which consists of plasma albumin level, PT-INR, mental status
(based on Glasgow coma scale), systolic blood pressure and
age >65 years, has been suggested. It was reported to have a
high predictive value for in-hospital mortality, length of
hospitalization and cost by a multicenter retrospective study
of approximately 30 000 non-variceal upper gastrointestinal
bleeding patients.35
Concerning mortality, area under the receiver operating
characteristic curve (AUROC) of GBS and RS is reported to
range from 0.65 to 0.90 and from 0.64 to 0.85,
respectively.19,21,3644 Concerning the necessity for transfusion, the AUROC of GBS and RS ranged from 0.81 to 0.94
and from 0.70 to 0.79, respectively.40,42,45,46 Concerning the
necessity for endoscopic hemostasis, the AUROC of GBS
and RS ranged from 0.604 to 0.960 and from 0.653 to
0.822, respectively.19,21,36,37,39,40,42,43,4550 Both GBS and
RS are useful to identify low-risk cases. They could predict
the necessity for endoscopic hemostasis or transfusion with a
sensitivity of >95% and without any deaths when GBS <2
or RS <2 was selected as a cut-off value; therefore, these cases
could be managed on an outpatient basis.38,43,48,5057
Concerning the primary treatment, a prospective study
assessed the outcomes of patients with hemodynamic instability as a result of upper gastrointestinal bleeding, and compared
Table 4 Rockall score34

Variable
Age
Shock
Comorbidity
Diagnosis
Major SRH
Score
0
<60 years
No shock
Systolic BP >100 b.p.m.
Pulse <100 b.p.m.
No major comorbidity
6079 years
Tachycardia
Systolic BP >100 b.p.m.
Pulse >100 b.p.m.
Mallory-Weiss tear,
No lesion identified
No SRH
None or dark spot only
All other diagnoses
>80 years
Hypotension
Systolic BP <100 b.p.m.
Cardiac failure
Ischemic heart disease
Any major comorbidity
Malignancy of upper GI tract
Renal failure
Liver failure
Disseminated malignancy
Blood in upper GI tract

Adherent clot
Visible or spurting vessel
Clinical Rockall score (RS) consists of age, shock, and comorbidity.
b.p.m., beats per minute; GI, gastrointestinal; SRH, stigmata of recent hemorrhage.
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M. Fujishiro et al.
them with historical controls. The study revealed that patients

who underwent intensive resuscitation had significantly
decreased mortality and decreased interval from admission
to stabilization of hemodynamics.58
According to the guidelines for management of upper gastrointestinal bleeding by the American Society of Gastrointestinal
Endoscopy59 and the American College of Gastroenterology,
60
it is recommended that the patients hemodynamic state be
stabilized by infusion of crystalloid fluids as an initial treatment based on expert opinion. Moreover, according to the
guidelines for endoscopic hemostasis (third edition) by
JGES, endoscopic hemostasis with both a sufficient amount
of crystalloid infusion and precise monitoring of vital signs is
recommended in case the hemodynamic instability cannot be
controlled by endoscopic hemostasis such as in patients with
spurting bleeding.61
Therefore, in patients with hemodynamic instability,
crystalloid infusion should be prioritized over endoscopic
intervention (evidence level IVa, recommendation level C1).
There has been controversy about the target value of hemoglobin level for red blood cell transfusion. In a randomized
controlled trial conducted in Spain, patients who underwent
transfusion when the hemoglobin fell <7 g/dL had a significantly higher 6-week survival rate (95% vs 91%, hazard ratio
0.55 with 95% confidence interval [CI] 0.330.92) and lower
rebleeding rate (10% vs 16%, hazard ratio 0.66 with 95% CI
0.470.98) than patients who underwent transfusion when
the hemoglobin fell <9 g/dL.62 This subject was discussed
in some meta-analyses; however, the target value of hemoglobin level for transfusion has been controversial because of the
small number of reports included.63,64 Currently, a multicenter
randomized controlled trial that compares the outcomes of
upper gastrointestinal bleeding between a target hemoglobin
level of 8 g/dL or 10 g/dL is being conducted in the UK
through cluster randomization in which six hospitals were
randomly allocated and the transfusion strategy was chosen
according to the institution.65 Excessive red blood cell transfusions should be avoided because it might increase the risk of
rebleeding or mortality (evidence level II, recommendation
level B).
Regarding the coagulation system, a systematic review
published in 2011 revealed that a PT-INR >1.5 was an independent risk factor for mortality (hazard ratio 1.96, 95% CI
1.133.41).66 A multicenter prospective observational study
of 4500 non-variceal upper gastrointestinal bleeding cases in
the UK also revealed that the PT-INR was an independent risk
factor for in-hospital mortality (hazard ratio 5.63, 95% CI
3.0910.27).67
Regarding the threshold for platelet transfusion, a systematic review was reported in 2012. However, meta-analysis
could not be carried out as a result of heterogeneity of the
patients backgrounds and, based on the guidelines of the British Committee for Standards in Hematology (2006),68 a platelet count of 50 000/L was recommended as the threshold.69
As mentioned earlier, upper gastrointestinal bleeding should
be managed so that patients maintain a PT-INR <1.5 and
platelet count >50 000/L (evidence level IVa, recommendation level C1).
Regarding the timing of endoscopy, urgent endoscopy
within 24 h is reported to reduce the risk of mortality and
surgical intervention in high-risk cases of upper gastrointestinal bleeding,7072 and it is recommended that endoscopy be
carried out within 24 h in various guidelines.73 In contrast,
many studies have concluded that there is no difference in
outcomes between patients who underwent endoscopy within
24 h and those who underwent endoscopy within
12 h.72,7476 Therefore, urgent endoscopy within 24 h is
recommended for patients who are suspected of having
upper gastrointestinal bleeding (evidence level III, recommendation level B).
ENDOSCOPIC HEMOSTASIS
Injection therapy
Injection of absolute ethanol
HIS METHOD DEVELOPED by Asaki77,78 is based on
the principle of tissue dehydration and fixation with absolute ethanol. In this procedure, the bleeding vessels are
dehydrated and fixed with consequent vasoconstriction and
necrosis of the vascular wall, including its endothelial lining,
thereby facilitating thrombogenesis and hemostasis. Aliquots
of 0.10.2 mL absolute ethanol are injected locally at several
sites 12 mm from the bleeding vessel. A change in the color
of the mucosa around the bleeding vessels to whitish or dark
brown indicates appropriate hemostasis. A total volume of
23 mL per session should not be exceeded in order to avoid
perforation.
Injection of hypertonic saline epinephrine

solution
Injection of hypertonic saline epinephrine solution (HSE) for
hemostasis was developed by Hirao et al.7981 The hemostatic
effect of HSE is based on the principle of vasoconstrictive
action and vascular tamponade by epinephrine, and the principle of tissue swelling, fibrinoid degeneration of the arterial
wall and thrombus formation by hypertonic saline solution.
Hirao et al.7981 selected two saline concentrations according
to the visibility of bleeding vessels. Worldwide, epinephrine
injection is most commonly carried out using 1:10 000
epinephrine solution diluted in normal saline.
367
Mechanical therapy
Direct spraying of drug
Endoscopic clip placement
Thrombin or sodium alginate is sprayed on the bleeding area

directly through the scope. This method is usually carried
out in combination with other hemostatic methods.
The endoscopic clipping technique was devised by Hayashi

et al.,82 and improved by Hachisu et al.83,84 This method of
hemostasis is achieved by mechanical compression of the
bleeding vessels. Tight and accurate placement of the clip is
important to avoid rebleeding. It is difficult to carry out sufficient compression in conditions such as chronic fibrous ulcer
base or tangential approach. It is necessary to pay attention to
possible perforation as a result of tear of the muscular layer
and to obstacles in the visual field as a result of improper
clipping.
Endoscopic band ligation

Commonly, endoscopic band ligation (EBL) has been carried
out for the treatment of esophageal varices. Recently, its use
has been expanded to various causes of non-variceal gastrointestinal hemorrhage such as Dieulafoys lesion, Mallory-Weiss
syndrome, gastric antral vascular ectasia (GAVE), diffuse
antral vascular ectasia (DAVE), and colonic diverticular
hemorrhage.85
Thermal therapy
Hemostatic forceps
Hemostatic forceps is a contact electrocoagulation device.
There are two types of electrical circuit: multipolar/bipolar
and monopolar. The operator can grasp a bleeding vessel using
hemostatic forceps in the same way as using a biopsy forceps.
It is very important to detect the bleeding vessel to avoid
excessive electrocautery which results in delayed perforation.
Argon plasma coagulation

Argon plasma coagulation (APC) is a non-contact
electrocoagulation device in which current is applied to target
tissues through ionized argon gas.86 APC is suitable for the
hemostasis of superficial, diffuse hemorrhage rather than for
spurting hemorrhage. The operator is required to have accurate control of the endoscope in order to maintain an appropriate distance between the tip of the applicator and the target
tissue.
Heater probe thermocoagulation

A heater probe is a contact thermocoagulation device.87
Contact thermal probes are based on the principle of coaptive
coagulation. The vessel is sealed by a combination of mechanical pressure and heat, which causes coagulation and
thrombosis.
MANAGEMENT OF PATIENTS WITH ACUTE

PEPTIC GASTRODUODENAL ULCER BLEEDING
E SEARCHED FOR articles using the keywords

peptic ulcer bleeding, endoscopic hemostasis,
proton pump inhibitor, rebleeding, and arterial embolization. The reference lists of 354 original studies and review
articles that appeared in the search results were screened to
make sure all potentially relevant studies were included. A
total of 51 relevant papers were referred to in order to create
the following statements.
Choice of endoscopic hemostatic method

If peptic gastroduodenal ulcer bleeding is detected by endoscopy, endoscopic hemostasis should be carried out (evidence
level Ia, recommendation A). Several methods such as
absolute ethanol injection, epinephrine injection, hemoclip,
hemostatic forceps and heater probe are available for endoscopic hemostasis. The efficacy of these methods has been
shown in randomized trials.8890,92,100 In the randomized
trials, the initial hemostasis rates were approximately 90%
regardless of the hemostatic method, and rebleeding rates were
210% except with epinephrine injection. There was no
significant difference in the rate of achieving initial hemostasis
among the monotherapies. Endoscopic hemostasis for bleeding peptic ulcer is more effective than no endoscopic therapy
in reducing further bleeding and the need for surgery.
Although epinephrine injection is effective in achieving initial
hemostasis in patients with active ulcer bleeding, the
rebleeding rate is reported to be 1230%.9195 Epinephrine
plus a second hemostatic method can be expected to reduce
the rate of rebleeding compared to epinephrine alone.9698
Furthermore, epinephrine injection can diminish or stop
bleeding, improving endoscopic visualization for a second
hemostatic method, and pre-injection of epinephrine can
reduce the rate of severe bleeding induced by removal of
adherent clots. Epinephrine injection should be combined with
a second hemostatic method because of its high rate of
rebleeding (evidence level IVa, recommendation B).
Absolute ethanol injection is easy to carry out and inexpensive, but the volume of ethanol should be limited to avoid
tissue damage with ethanol.99,100 If a second hemostatic
method is added to ethanol injection, thermal coagulation after
ethanol injection may incur an increased risk of gastrointestinal perforation.101 Although one clinical trial indicated that
368
M. Fujishiro et al.
hemoclips were less effective in achieving initial hemostasis

than thermal coagulation, the difference in hemostatic effect
between hemoclips and other methods has not been fully
elucidated.92,102104 Heterogeneity in the results of these studies can be caused by variation among different endoscopists
and different types of clip. Hemoclips have the theoretical
advantage of less tissue injury compared with thermal coagulation or ethanol injection; therefore, hemoclips may be useful
to achieve hemostasis in patients on antithrombotic therapy.
There are some important points to keep in mind when using
hemoclips. Endoscopists should note that deployment of
hemoclips on a fibrotic ulcer base or tangential lesions can
be difficult. In addition, thermal coagulation combined with
hemoclips is occasionally insufficient for hemostasis, because
the electrical current passing through the hemoclip results in
less thermal conductivity. Recently, soft coagulation using
hemostatic forceps has become widely used for the treatment
of gastrointestinal bleeding. Several studies suggest that
hemostatic forceps with soft coagulation is superior to
hemoclips in reducing the rate of rebleeding, the need for a
second modality, and the time required to achieve
hemostasis.105107
Management after successful endoscopic

hemostasis
Proton pump inhibitors (PPI) or H2 receptor antagonists
(H2RA) should be given to patients to prevent rebleeding after
successful endoscopic hemostasis (evidence level IVa,
recommendation B). High-dose i.v. PPI therapy (80 mg bolus
followed by 8 mg/h continuous infusion for 72 h) after
endoscopic hemostasis has been adopted in Western countries
and was demonstrated to be superior to placebo/no treatment
in reducing the rates of rebleeding, surgery, and mortality.108111
Meta-analysis of studies of oral or i.v. regular-dose PPI
versus placebo after endoscopic therapy revealed a significant reduction in rebleeding, but no significant differences
in surgery and mortality.112 Studies comparing high-dose
PPI versus regular-dose PPI indicate that rates of rebleeding
are low even in patients with regular-dose PPI; therefore,
regular-dose PPI is recommended in patients with low-risk
stigmata.113115 Randomized trials of i.v. PPI (pantoprazole,
omeprazole) versus i.v. H2RA (ranitidine, famotidine) after
endoscopic therapy showed no significant differences in the
rate of rebleeding.116119 However, other studies have shown
that PPI is superior to H2RA in reducing the rebleeding rate,
the need for blood transfusion, and duration of
hospitalization.120,121 Different hemostatic methods or different dose of PPI may have affected the different outcomes.
Second-look endoscopy is defined as routine repeat endoscopy within 24 h after initial hemostatic therapy. It has been
reported that second-look endoscopy slightly but significantly

reduced the rate of rebleeding, but did not reduce the need for
surgery and mortality.122124 However, these studies were
carried out without high-dose i.v. PPI therapy after endoscopic
hemostasis. A randomized trial of high-dose i.v. PPI therapy
versus second-look endoscopy without PPI after endoscopic
therapy revealed no significant difference in reducing
rebleeding between the two groups.125 Therefore, second-look
endoscopy should be considered in patients with risk factors
for early rebleeding after initial hemostasis. Risk factors for
early rebleeding include unstable hemodynamic status, severe
anemia (Hb <8 g/dL), active bleeding (Forrest Ia/Ib), largesized ulcer >2 cm, hematemesis, and exposed blood vessels
>2 mm in diameter. Patients with a white, protruded and
peripheral non-bleeding visible vessel (Forrest IIA) also have
a high risk of rebleeding.126132 From the above, second-look
endoscopy should be carried out in patients with a high risk of
rebleeding when PPI therapy is given after initial hemostasis
(evidence level IVb, recommendation C1).
A few reports have addressed the time to start oral feeding
after initial hemostasis. A randomized trial of fasting versus
oral feeding started at 24 h after endoscopic therapy among
patients with bleeding gastroduodenal ulcers (Forrest Ib/IIa)
revealed no significant difference in rebleeding rate.133 Moreover, a randomized trial comparing patients who received oral
diet from day 1 and patients who had nothing by mouth for
3 days after endoscopic hemostasis showed no significant
difference in rebleeding rate and early feeding could effectively shorten the hospital stay.134 Endoscopic hemostasis
followed by medical therapy allows early oral feeding.
However some reports recommended that clear liquid diet
should be provided for 3 days after initial hemostasis, because
recurrent bleeding mainly occurred within 3 days. Thus, oral
feeding could be started after 24 h for patients who had
successful endoscopic hemostasis (evidence level IVb, recommendation C1).
Interventional radiology (IVR) or surgery should be carried
out in patients with peptic gastroduodenal ulcer bleeding in
whom endoscopic hemostasis fails (evidence level IVb, recommendation C1). Large ulcer size and the presence of hypovolemic shock are factors related to failure to achieve
hemostasis in patients with recurrent bleeding after initial
treatment.126132 IVR for peptic gastroduodenal ulcer bleeding
can be done with a high technical success rate (90100%), but
the clinical success rate varies from 50% to 83%.135 It should
be kept in mind that IVR does not always achieve permanent
hemostasis. Predictors of rebleeding after IVR treatment are
the presence of coagulopathy, large-volume red blood cell
transfusion, and a long procedure time, and the effectiveness
of the IVR procedure can be limited as a result of vessel tortuosity, arterial dissection, vasospasm and multiple bleeding

points.136 Studies comparing IVR with surgery revealed no
significant differences in rebleeding rate, mortality, volume
of blood transfusion, and duration of hospital stay, whereas
longer hospital stay and higher mortality rate in patients
receiving surgery were reported in other studies.137,138 Although the IVR technique cannot be used in all facilities,
IVR should be considered a first-line treatment option after
failure of endoscopic hemostasis in terms of a minimally invasive procedure.
MANAGEMENT OF PATIENTS WITH

NON-VARICEAL UPPER GASTROINTESTINAL
BLEEDING FROM CAUSES OTHER THAN PEPTIC
GASTRODUODENAL ULCER
E SEARCHED FOR articles using the key words

artificial ulcer, non-ulcer non-variceal gastrointestinal bleeding, endoscopic mucosal resection, stomach,
endoscopic resection, endoscopic submucosal dissection,
bleeding, hemorrhage, Mallory-Weiss, gastroduodenostomy,
gastrectomy, anastomosis, telangiectasia, angiodysplasia,
vascular malformation, and endoscopic hemostasis. The reference lists of original studies and review articles were screened to
make sure all potentially relevant studies were included. A total of
315 articles were identified and 88 articles were included after
full-text assessment.
In patients with non-variceal upper gastrointestinal bleeding
from causes other than peptic gastroduodenal ulcer, the most
common cause is Mallory-Weiss syndrome. Other causes
include bleeding after endoscopic procedures, postoperative
anastomotic bleeding and vascular abnormalities.
Mallory-Weiss syndrome
Mallory-Weiss syndrome refers to a laceration in the mucosa,
most commonly at the gastroesophageal junction. The incidence of bleeding as a result of Mallory-Weiss syndrome is
reported as 311% among cases of upper GI bleeding.139,140.
In many cases, procedures for hemostasis are not required as
the bleeding is usually self-limited.141 If an active bleeding
point is detected by endoscopy, hemostasis using endoclips
is effective.142 The merit of using endoclips is that it is possible
to achieve precise hemostasis as well as closing of the mucosal
tear.140143 Other endoscopic hemostatic procedures include
EBL,144,145 HSE injection, and endoscopic coagulation.
Endoclip hemostasis and EBL are mechanical hemostatic procedures with similar efficacy;146 rebleeding after mechanical
hemostatic procedures is reported to be less than rebleeding
after HSE injection,142 whereas others have reported that the
rates of rebleeding, hemostatic effect and safety were similar
to those after HSE injection.147,148 However, HSE injection
369
may cause adverse events to the cardiovascular system among

patients with cardiac disease.146 Hemostasis with bipolar
coagulation may induce thermal damage to deeper layers and
has a risk of perforation when applied to the thin wall of the
esophagus, especially in cases with mucosal tears.149 Therefore, hemostasis with endoclips is effective for continuous
bleeding as a result of Mallory-Weiss syndrome (evidence
level II, recommendation B). Almost all cases of MalloryWeiss syndrome may be effectively treated by endoscopic
hemostasis; however, lethal outcomes may occur among
elderly patients and those who present with shock on arrival
to the hospital.150 If endoscopic hemostasis is impossible
because of impaired visualization, IVR or emergency surgery
should be considered. After endoscopic hemostasis, to prevent
rebleeding and to promote mucosal healing, treatment according to that of peptic gastroduodenal ulcer bleeding is carried
out. Bed rest, fasting, hemostatic drugs, antacids and mucosal
protectives may be considered. Eating may be resumed if there
is no underlying disease and follow-up endoscopy shows no
sign of rebleeding. One of the differential diagnoses is idiopathic esophageal perforation (Boerhaaves syndrome), which
is rather easy to diagnose in typical cases; however, chest
X-ray or computed tomography (CT) should be considered
for cases with deep laceration that carries a possibility of
esophageal perforation.
Post-procedural bleeding
Post-biopsy bleeding
The risk of bleeding after endoscopic biopsy is reported to be
0.480.58%.151,152 The risk of bleeding did not increase even
under continuation of antithrombotic agents, although the
number of hemostatic procedures immediately after biopsy
increased.151 However, emergency endoscopy as a result of
bleeding from the biopsy site is sometimes required. If the
bleeding point is identified, hemostasis can be achieved by
hemostatic forceps or by endoclips. Other hemostatic procedures such as HSE or ethanol injection, SB tube placement,
use of a topical hemostatic spray as well as treatment by
fasting, PPI, and transfusion have also been reported.153,154
Bleeding during and after endoscopic mucosal

resection/endoscopic submucosal dissection
Further details of bleeding during and after endoscopic
endoscopic mucosal resection (EMR)/endoscopic submucosal
dissection (ESD) are reported in the Guidelines for
endoscopic submucosal dissection and endoscopic mucosal
resection for early gastric cancer.155
Bleeding during EMR/ESD is inevitable, and it is recommended that hemostasis be done by using hemostatic forceps
in order not to hinder the subsequent resection procedure
370
M. Fujishiro et al.
(evidence level VI, recommendation C1).106,156158 However,

endoclips or injection therapies may be options under certain
circumstances.159
The incidence of delayed bleeding after EMR/ESD is
reported as 015.6%.155 Delayed bleeding mostly occurs
within 24 h, and may occur up to 2 weeks later.160 The risk
of delayed bleeding can be reduced by prophylactic coagulation of visible vessels using hemostatic forceps or endoclips
immediately after the resection.161,162 Appropriate preventive
measures should be carried out on visible vessels of ulcers
after EMR/ESD (evidence level V, recommendation C1).
However, excessive coagulation should be avoided to prevent
the risk of delayed perforation. Hemostatic procedures using
hemostatic forceps or endoclips are effective for delayed
bleeding after EMR/ESD.156158 In rare cases, IVR may be
selected for those who are unable to achieve hemostasis by
endoscopic procedures.162
After EMR/ESD, giving a PPI or H2RA is recommended
(evidence level V, recommendation B).163174 The treatment
duration of PPI is reported as 18 weeks after
EMR/ESD.163166 For ulcer healing and for reducing the incidence of delayed bleeding, some papers reported that PPI was
more efficient than H2RA,167171 whereas others reported that
there was no significant difference.172174 Especially for ulcers
after ESD, a meta-analysis showed that PPI was superior to
H2RA in reducing the risk of delayed bleeding.171Higher
quality of ulcer healing could be achieved by concomitant
use of mucosal protectives.175178 There is a risk of benign
ulcer recurrence at the EMR/ESD ulcer scar among patients
with a past history of peptic gastroduodenal ulcer or those with
HP infection, with an incidence of 2%.179
Reported risk factors for bleeding during or after EMR/ESD
are location, size of resection, lesions with ulcerative findings,
low platelet count/coagulation abnormalities, use of
antithrombotics, older age, hypertension, high body mass index
(BMI), and patients receiving maintenance hemodialysis.180188
In patients taking oral antithrombotics, some papers reported
that periprocedural cessation did not reduce the incidence of
intraprocedural or delayed bleeding,181,183,189,190 whereas
others reported that both intraprocedural and delayed
bleeding increased.182,191,192 Some studies reported that
second-look endoscopy has little effect on reducing the
incidence of delayed bleeding.193196 The impact of giving
PPI before EMR/ESD to decrease the risk of delayed
bleeding is still being debated.197,198
Anastomotic bleeding after surgery

The incidence of anastomotic bleeding after surgery is reported
as 0.32%,199203 and it mostly occurs within 1224 h after the
surgery.203 Diagnosis can be made by detecting blood from a
nasogastric tube. Although anastomotic bleeding may spontaneously stop, endoscopic hemostasis (endoclip,203,204 heater
probe,205 or HSE injection) is required in cases with continuous
bleeding or in those manifesting hypotension or tachycardia.
Blood transfusion201,203,204 or re-surgery202204 may be required
if endoscopic hemostasis is unsuccessful or if the bleeding
site cannot be reached by endoscopy. After endoscopic
hemostasis, attention should be paid to any sign of perforation
or intraperitoneal abscess.203,206
Bleeding from vascular abnormalities, GAVE,

DAVE, angiodysplasia, arteriovenous malformation, and hereditary hemorrhagic
telangiectasia
Bleeding from vascular abnormalities may cause chronic anemia. The incidence of bleeding as a result of GAVE is reported
as 4% among cases with upper GI bleeding other than variceal
bleeding.207 The etiology of GAVE is unknown; however, it is
occasionally observed among patients with cirrhosis, scleroderma, diabetes mellitus, hypothyroidism, and chronic renal
failure.208 GI bleeding was observed in 33% of patients with
hereditary hemorrhagic telangiectasia (HHT),209 with multiple
telangiectasia or arteriovenous malformation (AVM) mainly in
the stomach and duodenum, but also in the ileum, colon and
esophagus.210 Endoscopic hemostasis is usually carried out
by coagulation using APC or laser. Blood transfusion may
be required for patients with multiple lesions and patients with
bleeding that cannot be controlled by endoscopic hemostasis.
Hemostasis using APC is effective for bleeding from vascular abnormalities (evidence level V, recommendation C1).
APC is often used for lesions spreading in broad areas or multiple lesions as its coagulation depth is uniform and the risk of
perforation is less than that of laser.211219 Multiple treatment
sessions are required to eliminate the lesion and to confirm
that there is no further progress of anemia, although high remission (8890%) is reported.212,216 However, the recurrence
rate is reported to be 750% within 1 year215,217 and 5965%
within 3 years.215,219 For patients with a few lesions or localized lesions, hemostasis using hemostatic forceps has also
been reported.220 EBL has been reported to be a useful method
of hemostasis with less recurrence than that of APC, and to be
efficient even for recurrent lesions after APC.221223 Hormone
therapy has been considered to be useful to decrease the
number of blood transfusions for HHT in patients with
multiple telangiectasias;210 however, long-term efficacy was
not demonstrated in a randomized controlled study.224
Recently, the efficacy of oral thalidomide or octreotide has
been reported for HHT patients; however, both agents are
not currently approved in Japan.225,226
ACKNOWLEDGMENT
LL EXPENSES ASSOCIATED with formulation of

these guidelines were borne by Japan Gastroenterological Endoscopy Society (JGES).
CONFLICTS OF INTEREST
HE MEMBERS OF the Guidelines Committee were

asked to declare any possible conflicts of interest as
follows.
8
1. Any companies or organizations (in alphabetical order)

from which the committee member, or any dependents
living with them, received any form of payment in connection with these Guidelines.
The disclosure criteria were as follows: directorship or

consultancy (1 M), shares (1 M), patent royalties
(1 M), speaking fees (1 M), manuscript fees
(1 M), research expenses (2 M in an individuals
name), or other payments (1 M).
Eisai Co., Ltd, AstraZeneca Plc, Daiichi Sankyo Co.
10
11
12
2. Any companies or organizations engaged in physician

industry cooperation with a committee members affiliated department (excluding clinical trials), in connection
with these Guidelines.
The disclosure criteria were as follows: financial endowment (2 M), collaborative research or trust fund
(2 M), transfer of license agreement or rights
(2 M), or scholarship endowment (2 M).
Eisai Co., Ltd, Astellas Pharma Inc., AstraZeneca Plc,
Daiichi Sankyo Co., Ltd, Takeda Pharmaceutical, Co.
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Digestive Endoscopy 2016; 28: 363378

Guidelines for endoscopic management of non-variceal upper

EPIDEMIOLOGY AND CAUSES OF

2016 Japan Gastroenterological Endoscopy Society

Key words: bleeding peptic ulcer, endoscopic hemostasis,

infection, use of non-steroidal inflammatory agents

the young population, whereas it is increasing in the elderly

FORMATION OF STATEMENTS ON ENDOSCOPIC MANAGEMENT OF NON-VARICEAL

TATEMENTS IN THIS set of guidelines have been

INITIAL MANAGEMENT OF NON-VARICEAL UPPER GASTROINTESTINAL BLEEDING

Table 1 Classification of evidence levels

2016 Japan Gastroenterological Endoscopy Society

Digestive Endoscopy 2016; 28: 363378

Table 2 MINDS grades of recommendation

relevant papers were referred to in order to create the following

Digestive Endoscopy 2016; 28: 363378

Guidelines for upper GI bleeding

Table 3 Glasgow-Blatchford score21

Score component value

Blood urea (mmol/L)

Hemoglobin (g/dL) in men

Hemoglobin (g/dL) in women

Systolic blood pressure (mmHg)

as endoscopic findings. Moreover, the clinical RS, which

Table 4 Rockall score34

All other diagnoses

Blood in upper GI tract

Clinical Rockall score (RS) consists of age, shock, and comorbidity.

2016 Japan Gastroenterological Endoscopy Society

them with historical controls. The study revealed that patients

2016 Japan Gastroenterological Endoscopy Society

Digestive Endoscopy 2016; 28: 363378

Injection of hypertonic saline epinephrine

Digestive Endoscopy 2016; 28: 363378

Guidelines for upper GI bleeding

Direct spraying of drug

Endoscopic clip placement

Thrombin or sodium alginate is sprayed on the bleeding area

The endoscopic clipping technique was devised by Hayashi

Endoscopic band ligation

Argon plasma coagulation

Heater probe thermocoagulation

MANAGEMENT OF PATIENTS WITH ACUTE

E SEARCHED FOR articles using the keywords

Choice of endoscopic hemostatic method

2016 Japan Gastroenterological Endoscopy Society

hemoclips were less effective in achieving initial hemostasis

Management after successful endoscopic

2016 Japan Gastroenterological Endoscopy Society

Digestive Endoscopy 2016; 28: 363378

reported that second-look endoscopy slightly but significantly

Digestive Endoscopy 2016; 28: 363378

MANAGEMENT OF PATIENTS WITH

E SEARCHED FOR articles using the key words

Guidelines for upper GI bleeding

may cause adverse events to the cardiovascular system among

Bleeding during and after endoscopic mucosal

2016 Japan Gastroenterological Endoscopy Society

(evidence level VI, recommendation C1).106,156158 However,

Anastomotic bleeding after surgery

2016 Japan Gastroenterological Endoscopy Society

Digestive Endoscopy 2016; 28: 363378

Bleeding from vascular abnormalities, GAVE,