REVIEWS

Diagnosis and management of nonvariceal

upper gastrointestinal bleeding
Marc Bardou, Dalila Benhaberou-Brun, Isabelle Le Ray and Alan N. Barkun
Abstract | Nonvariceal upper gastrointestinal bleeding (UGIB) is a major cause of morbidity and mortality
worldwide. Despite the improvements in the management of this condition in western countries, mortality
rates have remained at 510% over the past decade. This article presents the main recommendations for
the management of UGIB. Pre-endoscopic management (including use of scoring scales, nasogastric tube
placement and blood pressure stabilization) is crucial for triage and optimal resuscitation of patients, and
should include a multidisciplinary approach at an early stage. Unless the patient has specific comorbidities,
transfusion should only be considered if their hemoglobin level is 70g/l. Endoscopic therapy, the cornerstone
of therapeutic management of high-risk lesions, should not be delayed for more than 24h following admission.
Several endoscopic techniques, mostly using clips or thermal methods, are available and new approaches are
emerging. When endoscopy fails, surgery or arterial embolization should be considered. Although the efficacy
of prokinetics and high-dose intravenous PPI prior to endoscopy is controversial, the use of an intravenous
PPI following endoscopy is strongly recommended. Antiplatelet therapy should be suspended and resumed in
35days. Finally, all patients should be tested for Helicobacter pylori by serology in the acute setting.
Bardou, M. etal. Nat. Rev. Gastroenterol. Hepatol. 9, 97104 (2012); published online 10 January 2012; doi:10.1038/nrgastro.2011.260

Introduction
The annual incidence of upper gastrointestinal bleeding
(UGIB) is 48160 events per 100,000 adults in the US,
where it is the cause of around 300,000 hospital admissions per year.1,2 In Europe, the annual incidence of
UGIB in the general population ranges from 19.43,4 to
57.03,5 events per 100,000 individuals. Why such wide
ranges exist is not clear, although the European incidences were recorded in countries with different healthcare systems and capacities to record cases, namely the
UK4 and Estonia.5 Additional factors, such as excess of
alcohol intake and Helicobacter pylori prevalence, might
also explain this large variation in prevalence. In both
North America and Europe, around 8090% of acute
UGIB episodes have a nonvariceal etiology; peptic ulcers
and gastroduodenal erosions account for the majority of
such lesions.6,7
UGIB-related mortality rates have decreased slightly
over the past two decades, but are still estimated to be
215%. 8,9 Two studies conducted in the UK showed
that, despite a notable decrease in mortality in patients
with UGIB during 19932007, mortality from peptic
ulcer bleeding is still 1013%.7,9 Consequently, a multi
disciplinary group of 34 experts from 15 countries published international guidelines in 2010 2 (which were
developed from initial guidelines published in 2003)
Competing interests
A.N. Barkun declares associations with the following
companies: AstraZeneca, Takeda Canada. See the article online
for full details of the relationships. The other authors declare no
competing interests.

to help clinicians make informed decisions about the

optimal management of patients with nonvariceal UGIB.
This Review discusses the diagnosis of UGIB and
describes the optimal management of patients with this
condition, in accordance with the current consensus
recommendations and contemporary literature. The
authors examine endoscopy, bleeding management and
pharmacological therapy for patients with UGIB.

Pre-endoscopic management
Resuscitation
Resuscitation should be initiated for patients with
UGIB prior to any other procedure, and should include
stabilizat ion of the blood pressure with continuous
infusion of fluids.10,11 The objectives of this treatment
are reversal of both hypovolemic shock and blood loss
using administration of intravenous fluids and blood
components. No data suggest that any particular type of
colloid solution is safer or more effective than any other
in patients who need fluid replacement.12 Although the
benefit of red blood cell transfusions has been questioned
(studies in a Cochrane review seemed to exclude a large
survival benefit),13 the consensus recommendations indicate that patients with hemoglobin levels 70g/l should
receive blood transfusions to reach a target hemoglobin
level of 7090g/l, provided that the individual has no
coronary artery disease, tissue hypoperfusion or acute
hemorrhage.2 In patients with acute coronary syndrome,
UGIB is associated with a markedly increased mortality,14
and a higher hemoglobin target level, above 10g/l could
be required in patients with cardiorespiratory diseases

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National Institute for

Health and Medical
Research (INSERM),
CICP 803, Department
of Gastroenterology,
Centre Hospitalier
Universitaire de Dijon,
14 rue Gaffarel,
BP77908,
21079Dijon, France
(M.Bardou, I. Le Ray).
5301 McKenna,
Montral, QC H3T 1T9,
Canada
(D.Benhaberou-Brun).
Gastroenterology
Department, McGill
University Health
Centre, Montral
General Hospital site,
Room D16157b,
1650Cedar Avenue,
Montral, QC H3G 1A4,
Canada (A.N.Barkun).
Correspondence to:
M. Bardou
marc.bardou@
u-bourgogne.fr

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REVIEWS
Key points

Table 1 | GlasgowBlatchford score assessment criteria

Resuscitation should be initiated prior to any diagnostic procedure

Gastrointestinal endoscopy allows visualization of the stigmata, accurate
assessment of the level of risk and treatment of the underlying lesion
Combination of endoscopic therapies improves control of the gastrointestinal
hemorrhage
Intravenous PPI therapy after endoscopy is crucial to decrease the risk of
cardiovascular complications and to prevent recurrence of bleeding
Helicobacter pylori testing should be performed in the acute setting

Risk factors at presentation

Threshold

Blood urea nitrogen (mmol/l)

6.57.9
8.09.9
10.024.9
25.0

2
3
4
6

Hemoglobin for men (g/l)

120130
100119
<100

1
3
6

Hemoglobin for women (g/l)

100120
<100

1
6

Systolic blood pressure (mmHg)

100109
9099
<90

1
2
3

Heart rate (bpm)

>100

Melena

Present

Syncope

Present

Hepatic disease

Present

Cardiac failure

Present

to prevent decompensation.2 Nevertheless, avoidance of

unnecessary transfusions is important to reduce the risks
related to administration of blood components, such
as infectious disease or immunological complications,
and to promote adherence to appropriate transfusion
guidelines, as standard practice is not always followed.
For example, the UK audit 7 found that 73% of patients
had a hemoglobin level >80g/l, but 43% of these patients
had received red blood cell transfusions.15 Randomized
trials are needed to determine what the ideal hemoglobin
threshold level is for transfusion according to patient
status, owing to the presence of confounding factors
such as comorbidities or selection bias in the current
cohort studies.
For patients being treated with anticoagulants, such
as warfarin, correction of an increased international
normalized ratio (INR) to 2.5 should be considered.2
An increased INR at initial presentation does not predict
rebleeding in patients with UGIB, which suggests that
endoscopic therapy does not need to be delayed unless
the patients INR (or prothrombin time) is markedly
above the normal range (0.81.2). However, an INR 1.5
has been associated with increased patient mortality,
which probably reflects the presence of cardiovascular
comorbidities;16 indeed, the INR seems to be most useful
as an indicator of comorbidity at the time of initial
assessment in patients with UGIB. The gastrointestinal
tract is the site of hemorrhage in 41% of patients with
a bleeding episode associated with warfarin therapy.17
Such episodes seem to confer considerable morbidity
related to transfusion and hospitalization; approximately
1 in 10 major warfarin-associated bleeds are fatal, and
1 in 12 patients will rebleed after resumption of anti
coagulant treatment, mostly from the original location
of the lesion.17

Risk stratification and initial therapy

As major bleeding episodes can be fatal for high-risk
patients, the initial assessment must be conducted
promptly to predict the need for urgent intervention.
Scoring scales have, therefore, been developed to evaluate
patients upon their arrival at the emergency department.
These scales can be used to identify the need for treatments, such as resuscitation, endoscopic management or
surgery, as well as to estimate the risk of either rebleeding or death.18 The GlasgowBlatchford score (GBS)
considers both clinical features and laboratory data
(Table1).19 Patients with a score of 0 are considered to
be at low risk, and some clinicians recommend that this
subgroup of patients could be managed as outpatients,
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Score

Total score (023). Patients with scores >0 are considered to be at high
risk. Permission obtained from Elsevier Ltd Blatchford, O. et al. Lancet
356, 13181321 (2000).

as they do not require early endoscopy.2022 Nevertheless,

the classification of patients as low risk might not always
be accurate. A retrospective study, in which propensity
scores were used to reassess the need for inpatient or out
patient management, found that outpatients had a higher
mortality rate than inpatients after 30days, suggesting
that initial assessment was not conducted properly.23 The
GBS is used to determine the need for endoscopy, transfusion or surgery and, therefore, enables appropriate
resources to be allocated to critically ill patients.20,24 For
example, the results of one study suggested that patients
with a GBS above the threshold value of 12 are the most
likely to benefit from early endoscopy.25
As the GBS enables the identification of patients who
might need intervention, this score is considered to be
preferable to the pre-endoscopic clinical Rockall score
(not to be confused with the complete Rockall score,26
which includes both clinical and endoscopic variables,
such as diagnosis of the lesion and stigmata of recent
hemorrhage), which can only accurately predict the risk
of mortality and is less accurate than the GBS for predicting rebleeding or the need for surgery (Table2).27 The
risk classification obtained by use of the pre-endoscopic
clinical Rockall score has been refined into three levels:
low (02), intermediate (34) and high (511). 28 The
complete Rockall score, if used at the time of endoscopy,
can identify low-risk patients and facilitate early discharge from hospital.10 Nevertheless, the pre-endoscopic
Rockall score is better than the complete Rockall score
for prediction of rebleeding and mortality in patients
with cirrhosis and variceal bleeding (at least among
patients with UGIB).29
Although the use of such scores is strongly encouraged by professional organizations, such as the British
Society of Gastroenterology, whose guidelines advise
that all patients with suspected UGIB should undergo
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Table 2 | Rockall score assessment criteria
Variables

Table 3 | Progetto Nazional Emorragia Digestiva score

Points

Age (years)

Predictor

Value

Advanced age

80years

Score
2

<60

Time to admission

<8h

6079

Low hemoglobin levels at

presentation

<700g/l

80

Presence of severe comorbidity

Renal failure
Neoplasia
Liver cirrhosis

2
3
3

Recurrent bleeding

Any

Poor health status

ASA class 3
ASA class 4

1
3

Failure of endoscopic therapy

Any

Hemodynamic shock
Heart rate >100bpm

Systolic blood pressure <100mmHg

Coexisting illnesses
Heart failure, ischemic heart disease

Renal failure, hepatic failure, metastatic cancer

Endoscopic signs (diagnostic)

No lesion observed, or MalloryWeiss tear

Peptic ulcer, erosive disease, esophagitis

Cancer of the upper gastrointestinal tract

Endoscopic signs (hemorrhagic)

Clean-base ulcer or flat, pigmented spot

Visible blood, active bleeding, visible vessel,

adherent clot

Scores range from 0 to 11 and are divided into three categories of risk: low
risk 2, moderate risk 35, high risk 6. Permission obtained from BMJ
Publishing Group Ltd Rockall, T.A. et al. Gut 38, 316321 (1996).

risk scoring as part of their initial assessment on presentation,30 the benefit of these scores in daily clinical
practice has been questioned. Insufficient validation
or complexity of use have been cited as problems with
these scoring systems.10,28,31 An independent team of
researchers who conducted validation studies of both
the GBS and Rockall scores (both the pre-endoscopic
and complete scores) did not recommend their use in the
clinical setting.32
Despite the existence of these predictive scores the
clinical endoscopists judgment remains crucial in
assessing the patients actual level of risk, 33 as endoscopic predictors of an increased risk of rebleeding and
mortality include active bleeding, an ulcer size >2cm,
ulcers located on the lesser curve of the stomach or in
the posterior or superior duodenum34 and the presence
of high-risk stigmata, factors that are not all included
in the complete Rockall score. 2 Categories of highrisk lesions include actively spurting (Forrest class Ia),
oozing blood (Forrest class Ib), nonbleeding visible
vessels (Forrest class IIa) and adherent clot (Forrest
class IIb).34 Types of low-risk lesions include flat, pigmented spots (Forrest class IIc) and clean-based ulcers
(Forrest class III).35
The need for accurate risk stratification is widely recognized, but current validated scores are underutilized.
Therefore, attempts have been made to define accurate
scores that are easier to use than the GBS and Rockall
scores. For example, the Progetto Nazional Emorragia
Digestiva (PNED) score has been developed to predict
the risk of mortality and has been suggested, despite
not yet being completely validated, to be superior in

Scores are divided into three categories according to the patients mortality
risk: low 04, medium 58 and high >8 with a maximum score of 24.
Abbreviation: ASA, American Society of Anesthesiology. Permission
obtained from Macmillan Publishers Marmo, R. et al. Am. J.
Gastroenterol. 105, 12841291 (2010).

predictive accuracy to the complete Rockall score

(Table3).36 This superiority was shown by the areas
under the receiver operating characteristic curve (AUC)
of 0.81, 95% CI 0.720.90 for the PNED score versus
0.66, 95% CI 0.600.72 for the Rockall score. However,
the PNED scoring system still needs to be prospectively
validated at the international level. In addition, further
data should be collected to establish whether the PNED
score is any easier to use than the Rockall score in daily
clinical practice.
A retrospective analysis of data on 2,380 patients with
UGIB suggested that artificial neuronal networks, using
17 pre-endoscopic input variables, might be useful in
triage of patients.37 The performance of the neuronalnetwork-based model in the prediction of mortality risk
was significantly superior to that of the complete Rockall
score (AUC 0.95, 95% CI 0.920.98 and 0.67, 95% CI
0.650.69, respectively).37 Again, the validity and applic
ability of this new approach needs to be assessed in a
routine clinical setting.

Use of nasogastric tubes

Placement of a nasogastric tube is not routinely necessary
and opinion is divided on their usefulness.3840 However,
nasogastric tubes might be considered if the presence
of blood in the nasogastric aspirate confirms an upper
gastrointestinal source of bleeding 41 and if any doubt persists as to the origin of the gastrointestinal bleed. Highrisk patients could especially benefit from nasogastric
tube placement, which could facilitate visualizat ion
during the endoscopic procedure;34,42 however, opinions vary as to whether gastric aspiration and lavage are
useful, even in selected, high-risk patients.43,44

Pre-endoscopic pharmacological therapy

Prokinetic agents
The use of prokinetic agents (such as erythromycin)
before gastrointestinal endoscopy shortens the duration
of the procedure,45 and reduces the need for a repeated
examination.4648 Administration of an erythromycin
infusion also improves endoscopic visualization without

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the need for placement of a nasogastric tube or gastric
lavage; however, no incremental benefit is obtained
from combining erythromycin treatment with naso
gastric lavage.40 In a randomized, placebo-controlled
trial that involved patients with bleeding esophageal
varices, use of an erythromycin infusion significantly
increased the proportion of completely empty stomachs
compared with placebo (48.9% with erythromycin versus
23.3% with placebo), reduced the mean endoscopy
duration (19.0min with erythromycin versus 26.0min
with placebo) and shortened the duration of hospital
stay, from 5.1days in the placebo cohort to 3.4days for
patients treated with erythromycin.49 These results are
interesting because the origin of UGIB can only be confidently determined at the time of endoscopy, and because
a recent audit conducted in the UK showed that the frequency of variceal bleeding had more than doubled,
from 4.4% in 1993 to 11% in 2007.7 Consequently, even
in the absence of data indicating that administration of
prokinetic agents can decrease the risk of adverse outcomes (such as mortality and rebleeding) and the need
for surgery,4547,50 we suggest that after ruling out contra
indications to these agents (such as hypokalemia or a
prolonged QT interval) a 250mg erythromycin infusion should be administered over 2030min, followed
by endoscopy approximately 3045min after the end of
the infusion.2,40

PPI treatment prior to endoscopic diagnosis

Despite theoretical pharmacological differences between
different PPIs, no data support the use of a particular
intravenous PPI in preference to another when treating patients with UGIB. In the following paragraphs,
PPI will, therefore, be used as a generic term for all
such agents, including omeprazole, pantoprazole
and esomeprazole.
The clinical efficacy of starting PPI treatment before
endoscopy for UGIB remains a controversial issue. A
large, double-blind, randomized, controlled trial51 and
a meta-analysis that included 2,223 participants from
six other randomized, controlled trials52 both found that
pre-endoscopic PPI treatment could reduce the proportion of patients identified as having high-risk lesions at
early endoscopy and the resultant need for endoscopic
therapy. Despite these advantages, clear evidence that
pre-endoscopic PPI treatment affects mortality, rebleeding or the need for surgery is lacking. Nonetheless,
despite the lack of evidence, this approach is widely
used. 2 No recommendations can be made regarding
the optimal dose of PPIs administered pre-endoscopy
because the dose response has not yet been assessed
in this setting, but a reasonable strategy seems to be to
adopt a high-dose regimen of 80mg PPI (intravenous
bolus) followed by an 8mg/h infusion, as used in two of
the largest published randomized, controlled trials.51,53
This approach could be cost-effective if endoscopy will
be delayed to >16h after admission, or if patients have
a high likelihood of nonvariceal bleedingespecially in
those with high-risk symptoms, such as hematemesis or
blood in the nasogastric aspirate.54,55
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Endoscopic management
Timing and need for early endoscopy
International consensus guidelines recommend that
endoscopy should be performed within 24h of presenta
tion2,54 for all patients who present with acute UGIB,
because early endoscopy is associated with improved
outcomes and a reduced duration of hospitalization
for low-risk patients and high-risk patients. 2 Despite
the strength of this recommendation, highlighted in
the 2003 international consensus conference,41 a 2007
UK audit revealed that only 74% of patients admitted
with acute UGIB underwent endoscopy during their
hospital stay, and only 50% of initial endoscopies took
place within 24h of presentation, even among high-risk
patients who had a pre-endoscopy Rockall score 5.7,56 In
Spain, almost 40% of initial endoscopies were performed
>24h after admission.57 Further support for the need for
24h access to endoscopy came from the UK audit, in
which it was found that mortality was increased, albeit
not significantly, in hospitals that did not have out-ofhours endoscopy facilities (risk-adjusted mortality ratio
1.21, 95% CI 0.961.51).7 Large geographical discrepancies were shown by a retrospective Australian study,
in which only 1.1% of patients admitted for UGIB did
not have an endoscopy performed during their hospital
stay.58 Although very urgent endoscopy (within 612h
of presentation) does not convincingly improve outcomes,59 the results of an observational study suggested
that for a subgroup of very ill patients (GBS 12), the
optimal timing of endoscopy should be within 13h of
presentation.25 In this highly selected population, the
inpatient all-cause mortality rate was 0% when endo
scopy was performed within 13h of presentation, which
increased to 44% when endoscopy was performed >13h
after presentation.25
Patients classified as being at a very low risk of rebleeding could be discharged from hospital immediately after
an early endoscopy (Figure1) if they fulfill specific criteria
(Box1).34 Indeed, randomized, controlled trials of highly
selected patients at very low risk of rebleeding found that
no difference in outcomes resulted from a policy of very
early discharge from the emergency room.2,60
Traditional endoscopic therapy
Several endoscopic techniques are effective for manage
ment of acute hemorrhage. Injection of epinephrine alone improves the clinical outcomes of patients
with a high-risk bleeding lesion, but this treatment
has increased efficacy (and is considered the optimal
approach) when used in combination with another technique, such as clip placement or thermocoagulation,2,11
which are also effective as monotherapies.61,62 Technical
difficulties might reduce the effectiveness of some endoscopic treatments, especially when the bleeding ulcer
is located on the lesser curve of the stomach or on the
duodenal bulb, or when very active bleeding prevents
localization of the lesion.34
A clot in an ulcer bed must be vigorously washed,
through the endoscope, to determine whether it remains
adherent. Optimal treatment of adherent clots remains
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controversial. Endoscopic approaches should be considered, but intensive intravenous PPI therapy alone might
be sufficient.63
Routine second-look endoscopy (that is, after success
ful endoscopic treatment of a bleeding lesion) is not
recommended.2 Two meta-analyses suggested a marginal benefit from this technique in terms of reduced
rebleeding rates;64,65 but in one of these analyses, the
benefit was restricted to patients who received thermo
coagulation as their second treatment.65 However, these
meta-analyses included trials that did not employ todays
standards of care. The current recommendation is that
the need for second-look endoscopy should be considered on a case-by-case basis,2 for example if the effectiveness of endoscopic hemostasis is questionable, or if
the patient is at a particularly high risk of rebleeding.
Second-look endoscopy might also be considered in the
intensive care setting, where assessment of rebleeding
might be difficult because of prolonged transit time or
cardiovascular treatments.

Emerging endoscopic approaches

One emerging modality is a hemostatic powder composed of nanoparticles of inorganic proteins that are
sprayed onto the bleeding lesion.66,67 The powder was
first tested in a porcine model and was then used in 20
patients with active bleeding lesions (Forrest classIa
Ib) in a single-arm pilot study.67 Acute hemostasis was
achieved in all but one patient, who had a pseudo
aneurysm that required arterial embolization. Bleeding
recurred in two patients within 72h of treatment (as indicated by a drop in hemoglobin levels), but neither had
active bleeding at scheduled second-look endoscopy.67
As the powder is applied without direct contact with the
affected gastric or duodenal tissue, the technique is less
demanding than clip placement or thermocoagulation,
requires limited expertise and seems to be effective in
stopping the bleeding. However, this treatment needs to
be tested in patients with acute bleeding.
A method that uses a combination of multiple hemostatic clips and a detachable snare ligation device has
been described, but only in a case report, for treating
bleeding peptic ulcers.68 This technique has subsequently
been used to treat peptic ulcers that were not adequately
controlled.69 Clearly, clinical trials to assess this approach
are needed, but the technique seems to require a high
level of expertise.
Management of continued or recurrent bleeding
If the first attempt at endoscopic hemostasis fails to
control peptic ulcer bleeding, surgery is the option most
likely to achieve hemostasis. However, repeated endoscopic therapy carries a lower risk of complications
than surgery.70 Nonetheless, early surgical intervention
is considered for patients with recurrent massive upper
gastrointestinal hemorrhage (necessitating >19 blood
transfusions) following initial endoscopic treatment.71
However, patients 80years old and those with serious
comorbidities are not suitable candidates for surgery,
and arterial embolization can be considered for these

Assessment and appropriate resuscitation

Risk stratification
Before endoscopy
During early endoscopy

Very low-risk patients

Discharge home

All other patients

Hospitalization

High-risk patients
Endoscopic hemostasis
Initiate high-dose intravenous PPI

Low-risk patients
Initiate oral PPI

Consider secondary prophylaxis

H. pylori testing and treatment
COX2 can be considered as an alternative to NSAIDs
Platelet-inhibiting agents

Figure 1 | Algorithm for optimal management of nonvariceal upper gastrointestinal

bleeding. On presentation with UGIB, appropriate resuscitation should be carried
out. Patients should be assessed and those at very low risk may be discharged. All
other patients should be admitted as inpatients and categorized as low-risk or
high-risk groups to determine treatment options. Oral PPI therapy can be adequate
for low-risk patients but those at high risk should be treated with endoscopy and
intravenous, high-dose PPI. All patients should be considered for secondary
prophylaxis, including Helicobacter pylori testing and treatments, use of COX2
antagonists as an alternative to NSAIDs, and PPI for those taking low-dose aspirin.
Abbreviations: COX2, cyclooxygenase2 (also known as prostaglandin G/H
synthetase 2); UGIB, upper gastrointestinal bleeding.

Box 1 | Low-risk nonvariceal UGIB

The following criteria have been proposed to enable the selection of patients with
low-risk nonvariceal UGIB for an abbreviated hospital stay or outpatient treatment.
Age <60years
Absence of hemodynamic instability* or attainment of hemodynamic stability
within 3h of initial evaluation
Absence of a severe coexisting illness, such as heart failure, chronic
obstructive pulmonary disease, hepatic cirrhosis, hematologic cancer, chronic
renal failure and cerebrovascular accident
Hemoglobin level 80.0100.0g/l after adequate intravascular volume
expansion and no need for blood transfusion
Normal coagulation test results
Onset of bleeding outside the hospital
Presence of a clean-base ulcer or no obvious findings on early endoscopy
(performed within 24h of presentation)
Adequate domestic support and the ability to return promptly to a hospital
*Defined as resting tachycardia (pulse rate 100bpm), hypotension (systolic blood pressure
<100mmHg), or postural changes (increase in pulse of 20bpm or a drop in systolic blood
pressure of 20mmHg [standing]). Abbreviation: UGIB, upper gastrointestinal bleeding.

individuals.72,73 A meta-analysis concluded that successful embolization improves survival, and suggested that
this approach might lead to equivalent rates of mortality and clinical success compared with surgery, despite
the embolization group being older and having a higher
prevalence of comorbidities than the surgical group.74

Pharmacological therapy
PPIs
Opinions differ about the optimal time to begin intra
venous PPI infusion after endoscopic hemostasis.11,51,75
The goal of PPI therapy is to raise the gastric pH suffi
ciently to promote clot stability and to reduce the effect

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of pepsin and gastric acid.76 In a study that aimed to
identify the lowest effective dose of PPI, rather than
using a high (or low) dose, continuous infusion was the
best way to maintain an intragastric pH >6. Two metaanalyses have confirmed that an intravenous PPI bolus
followed by continuous PPI infusion over 72h reduces
the rates of mortality, rebleeding and surgery. Mortality
was particularly reduced in patients who had previously undergone successful endoscopic hemostasis.77,78
A placebo-controlled, randomized trial demonstrated
that in patients with Forrest class IaIIb bleeding lesions,
esomeprazole administered as an 80mg intravenous bolus
over 30min followed by continuous infusion of 8mg/h
for 71.5h, which was started after successful endoscopic
hemostasis and followed by a 40mg esomeprazole
oral regimen for 27days, significantly reduced rates of
rebleeding at 72h (5.9% in the esomeprazole group compared to 10.3% in the placebo cohort). The difference
in rebleeding rates remained significant at 7days and
30days after initial presentation.53 However, in this study,
the 30-day mortality rate was not significantly reduced
by the use of a PPI. As mortality was lower than expected
in the placebo group (2.1%), this finding might reflect
the exclusion of patients with life-threatening systemic
disease (American Society of Anesthesiologists class >3).
High-dose oral PPI treatment after endoscopy was
effective in early trials conducted in India and Iran,79,80
but differences in the physiological and pharmaco
dynamic characteristics of the patients, as well as their
high H.pylori carriage rate and limited comorbidities
make the results of these studies difficult to apply to
other populations. The endoscopic treatment administered was also not the current recommended standard.81
Accordingly, the evidence is currently insufficient to
support the use of either oral PPIs or low-dose intra
venous PPIs. A study published in 2009 assessed gastric
pH in patients receiving a 90mg oral dose of lansoprazole followed by 30mg every 3h (total dose 300mg in
24h), after successful endoscopic treatment for peptic
ulcer bleeding. The primary end point was the proportion of the 24h period that the patients had a gastric
pH >6 (median 55%). However, large differences in this
value were evident between individuals (range 699%).82

Platelet aggregation inhibitors

Antiplatelet therapy should be suspended in patients with
high cardiovascular risk who have an acid-related cause
of bleeding before performing therapeutic endoscopy, but
resumed as soon as the patients risk of cardiovascular
events outweighs their risk of rebleedinggenerally
within 35days.83 Clinicians should be aware of the possibility of an increased risk of cardiovascular events associ
ated with PPI treatment in patients who are also taking
clopidogrel, a prodrug that becomes activated after being
metabolized by the cytochrome P450 2C19 enzymatic
complex that also metabolizes PPIs.84 Nevertheless, the
clinical relevance of this increased risk is controversial85,86
and might not be observed when clopidogrel and lowdose aspirin are used together.87 This possible drug interaction does not apply to the most recently developed
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platelet inhibitors, such as prasugrel or ticagrelor, even

though they are also prodrugs, mostly because they share
the same metabolic pathways.88,89

H.pylori eradication
All patients should be tested for infection with H.pylori,
which is one of the principal causes of bleeding ulcers.
Several testing methods are available.90,91 Urea breath
tests are widely used,92 but serology is preferable in acute
settings as it has the best diagnostic accuracy in this specific condition.93 A second test should be performed if
a negative index result is obtained at the time of acute
upper gastrointestinal bleeding.2 Real-time PCR might
improve H.pylori detection in patients with peptic ulcer
bleeding. Real-time PCR testing for a combination of
H.pylori 16S rRNA and ureaseA had a sensitivity of 64%
and a specificity of 80% in tissue samples that had previously been considered negative by histological testing
alone.94 The low prevalence reported for H.pylori infection in patients with UGIB might be related to the delay
in testing, which is usually not performed until 4weeks
after the bleeding episode.95
Although a full discussion of secondary prophylaxis of
UGIB in patients who bled during antiplatelet treatment
or as a result of H.pylori infection is beyond the scope
of this Review, guidelines on this topic are provided in a
consensus document,2 which urges clinicians to follow a
decision-making algorithm that balances the risks and
benefits associated with the patients medical condition
and the available therapeutic agents.96 After the completion of antibiotic and PPI treatment, a urea breath test
might be the most convenient approach to assess the
effectiveness of H.pylori eradication treatment (unless
repeat endoscopy is indicated, at which point gastric
biopsies can be performed).

Conclusions
The acute management of patients with nonvariceal
UGIB (Figure1) has evolved considerably over the
past 10years. Application of the existing recommenda
tions should lead to improved outcomes. Clinicians are
encouraged to monitor ongoing controversies, such as
the optimal PPI dose following endoscopic therapy,
emerging endoscopic techniques of hemostasis, and the
management of patients with UGIB during treatment
with antiplatelet agents.
Review criteria
We conducted a literature search using the OVID,
MEDLINE, EMBASE, PubMed and ISI Web of Knowledge
4.0 databases to identify articles published in the
English or French languages from January 2008 to
September 2011. A search strategy was used to identify
randomized controlled trials, cohort and casecontrol
studies conducted in adults, using combinations of
search terms, including UGIB, epidemiology, motility
agents, prokinetics, erythromycin, transfusion,
endoscopy and proton pump inhibitors. In addition,
recursive searches and cross-referencing were performed
and manual searches of the reference lists of articles
identified in the initial search were completed.

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Author contributions
All authors contributed substantially to researching
data for the article, discussion of the content, writing
the manuscript and editing the text.

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