Anda di halaman 1dari 27

Overview of the complications of peptic ulcer disease

Authors
Andrew H Soll, MD
Nimish B Vakil, MD, AGAF, FACP, FACG, FASGE
Section Editors
Mark Feldman, MD, MACP, AGAF, FACG
David I Soybel, MD
Deputy Editor
Shilpa Grover, MD, MPH
Disclosures: Andrew H Soll, MD Nothing to disclose. Nimish B Vakil, MD, AGAF, FACP, FACG,
FASGE Consultant/Advisory Boards: AstraZeneca [GERD (Esomeprazole)]; Baxter [Probiotics]. Other Financial
Interest: Salix [GERD (web-based review article)]. Mark Feldman, MD, MACP, AGAF, FACG Nothing to disclose. David
I Soybel, MD Nothing to disclose. Shilpa Grover, MD, MPHEmployee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2015. | This topic last updated: Dec 02, 2013.
INTRODUCTION Complications of peptic ulcer disease (PUD) include bleeding, perforation,
penetration, and gastric outlet obstruction. With time, there have been major shifts in the etiologies of
complicated peptic ulcers and in the affected patient populations. In addition, management has
undergone dramatic changes. Management now includes the early use of high-dose intravenous
proton pump inhibitors (PPIs), treatment to eradicate Helicobacter pylori (H. pylori), improved
endoscopic methods for control of hemorrhage, and changes in surgical indications and procedures.
(See "Treatment regimens for Helicobacter pylori" and "Overview and comparison of the proton pump
inhibitors for the treatment of acid-related disorders" and "Overview of the treatment of bleeding peptic
ulcers".)
This topic will provide an overview of the major complications of PUD. The approach to patients with
complicated PUD, the endoscopic management of peptic ulcer bleeding, and the surgical approaches
to complications of PUD are discussed separately. (See "Diagnosis of peptic ulcer
disease" and "Overview of the natural history and treatment of peptic ulcer disease" and "Overview of
the treatment of bleeding peptic ulcers" and "Surgical management of peptic ulcer disease".)
INCIDENCE With time, there has been a dramatic fall in the prevalence of peptic ulcer disease
(PUD) in developed countries. While older studies suggested that hospitalizations for potentially lifethreatening ulcer complications were stable or even increasing [1-7], several more recent studies
indicate a consistent decrease in hospitalization rates and in the incidence of bleeding and perforation
[8]. For example, using analysis of a large database from the United States found an approximate 30
to 40 percent fall in hospitalizations for PUD complications between 1993 and 2006 [9]. Another study
from the United States evaluated the National Inpatient Database and found that the rate of
perforation and bleeding has been decreasing in the United States, presumably reflecting the fall in H.
pylori prevalence [10]. A large systematic review estimated that the annual incidence of peptic ulcer
hemorrhage is on the order of 19 to 57 cases per 100,000 individuals, and that the annual incidence
of ulcer perforation is on the order of 4 to 14 cases per 100,000 individuals [11]. (See "Epidemiology
and etiology of peptic ulcer disease", section on 'Epidemiology'.)
Peptic ulcer bleeding is seen most commonly in older patients [1,2,5-8]. Sixty percent of patients are
above the age of 60 years and 20 percent are over the age of 80 years [12]. This age distribution

likely reflects increasing nonsteroidal anti-inflammatory drug (NSAID) use among older adults,
combined with decreasing prevalence of H. pylori infection among younger patients.
Complications of PUD vary in frequency geographically. In the United States, hemorrhage is the most
common complication of PUD (73 percent), followed by perforation (9 percent), and obstruction (3
percent) [9]. The mortality rate from complications of PUD is more than 10 times that of acute
appendicitis or acute cholecystitis. Perforation has the highest mortality rate, followed by obstruction
and hemorrhage. By contrast, a 13-year review of all surgical procedures for peptic ulcer
complications at a Nigerian hospital found that obstruction was the most common complication (56
percent), followed by perforation (30 percent), and bleeding (10 percent) [13]. Some regional factors
that may account for these differences include the rates of NSAID use, the prevalence of H. pylori
infection, and the distribution and extent of gastritis. (See "Epidemiology and etiology of peptic ulcer
disease", section on 'Regional and other demographic variation'.)
ETIOLOGY AND RISK FACTORS FOR COMPLICATED PUD Complications can occur in patients
with peptic ulcer disease (PUD) due to any etiology. (See"Epidemiology and etiology of peptic ulcer
disease".) Although controversial in early studies because of difficulty detecting H. pylori in the setting
of acute bleeding, evidence now clearly implicates both H. pylori and nonsteroidal anti-inflammatory
drugs (NSAIDs), including low-dose aspirin, as the primary causes of ulcer bleeding and perforation
[14-17]. (See "Indications and diagnostic tests for Helicobacter pylori infection", section on 'Recently
bleeding gastric or duodenal ulcers'.)
NSAIDs The use of NSAIDs is the most commonly identified risk factor for peptic ulcer bleeding,
especially in the elderly. Studies have found relative risks for bleeding ranging from 2.7 to 33.9 [11].
Studies have also shown that the risk is drug-specific and dose-dependent. As an example, in a study
of 2777 patients, the overall relative risk (RR) of bleeding associated with NSAID use was 5.3 (95% CI
4.5-6.2). However, the risk varied by drug and was lowest for aceclofenac (RR 3.1, 95% CI 2.3-4.2)
and was highest for ketorolac (RR 14.4, 95% CI 5.2-39.9) [18]. The risk was higher in patients taking
high-dose NSAIDs compared with those taking medium- or low-dose NSAIDs (RR 6.8, 95% CI 5.3-8.8
versus 4.0, 95% CI 3.2-5.0). There was also an increased risk of bleeding with aspirin use (RR 5.3)
that again was dose-dependent (RR 7.5 with 500 mg per day versus 2.7 with 100 mg per day). The
concurrent use of aspirin and NSAIDs conferred an even greater risk of bleeding than was seen with
either agent alone (RR 12.7). Finally, the risk was highest in the first 30 days of NSAID use, with a RR
of 7.6 (95% CI 6.0-9.5). The risk remained high between days 31 and 90 days (RR 7.3, 95% CI 4.013.2), but dropped after 91 days (RR 2.6, 95% CI 1.6-4.1).
NSAID use has also been identified as a risk factor for ulcer perforation [16,19]. In a study of 176
patients from Spain, NSAID use was the only risk factor that was significantly associated with
perforation (odds ratio [OR] 3.6) [16].
H. pylori infection Multiple studies have identified H. pylori infection as a risk factor for
complicated PUD [20-22]. In one study with 370 patients with peptic ulcers, patients with H. pylori
were at significantly increased risk for bleeding from duodenal (RR 6.0, 95% CI 2.9-12.3) but not
gastric ulcers (RR 1.7, 95% CI 0.7-4.1) [21]. However, identifying H. pylori can be difficult in the
setting of acute bleeding or in patients receiving PPIs. (See "Indications and diagnostic tests for
Helicobacter pylori infection", section on 'Recently bleeding gastric or duodenal ulcers'.)
With regard to testing for H. pylori, it should be kept in mind that:
Biopsy-based tests for H. pylori, such as the rapid urease test, are less sensitive in a patient
with recent bleeding [14]. However, specificity remains high.

A stool H. pylori antigen test provides a useful adjunct to diagnosis; however, the sensitivity and
specificity of this test may be compromised by the presence of blood [23,24].
A urea breath test for H. pylori performed as soon as the patient has resumed oral feedings is a
reasonably sensitive predictor of H. pylori infection, even following initiation of PPIs. In one
study, 113 of 131 patients (86 percent) had positive urea breath tests performed the day after
resuming oral feeding [25]. The sensitivity was better early in the hospitalization. Of the 18
patients who were initially negative, 15 had positive urea breath tests two weeks after stopping
the PPI.
Any H. pylori test dependent upon the number of organisms present may be falsely negative
with recent use of PPIs, antibiotics, or bismuth. Two weeks off of these agents provides
adequate time for recovery of test sensitivity.
Serology is a useful test for complicated ulcers [26], especially when there is concern about
false-negative results on other tests due to the presence of blood or medication use. Although a
positive serology when other H. pylori tests are negative may be a false-positive, it may be a
true-positive if there has been suppression of organism number or if there is isolated duodenal
H. pylori colonization [27], an important cause of apparent H. pylori-negative, NSAID-negative
ulcer. (See"Unusual causes of peptic ulcer disease".)
In the face of a demonstrated peptic ulcer the pretest probability of H. pylori is high, so any positive
test has high predictive value for H. pylori infection. However, a single negative test has low predictive
value, so two tests must be performed under appropriate conditions to confirm that H. pylori is absent.
For tests dependent upon the number of organisms (eg, biopsy urease test, urea breath test, stool
antigen test, or histology), the patient must have been off of PPIs, antibiotics, or bismuth for at least
two weeks before negative results can be interpreted as reflecting a true absence of organisms. Some
patients are very reluctant to stop PPIs, in particular, so it is important to confirm that the drugs have
been stopped. (See "Indications and diagnostic tests for Helicobacter pylori infection".)
NSAID use in patients with H. pylori Studies looking at the relationship between H. pylori and
NSAID use in patients with peptic ulcer complications have had variable results [21,28,29]. A metaanalysis that identified nine case-control studies that assessed the prevalence of H. pylori infection
and NSAID use in patients with peptic ulcer bleeding suggested that the H. pylori infection combined
with NSAID use increases the risk of bleeding above that seen with either risk factor alone [30]. The
analysis found that individually, the odds ratios for bleeding peptic ulcers associated with H. pylori and
NSAIDs use were 1.8 (95% CI 0.97-3.3) and 4.9 (95% CI 3.8-6.2), respectively, whereas the odds
ratio increased to 6.1 when both H. pylori and NSAID were present (95% CI 3.9-9.6).
Non-H. pylori, non-NSAID ulcers The development of complications in patients with non-H.
pylori, non-NSAID ulcers is an increasing problem, with a high incidence of recurrent ulcer bleeding.
Many H. pylori negative, non-NSAID ulcers are associated with medical comorbidity. (See "Unusual
causes of peptic ulcer disease", section on 'Comorbid peptic ulcers'.)
Once H. pylori and NSAIDs have been confidently excluded, acid hypersecretion should be
considered in patients with complicated ulcers. While acid hypersecretion leading to complicated PUD
may be due to gastrinoma, idiopathic acid hypersecretion should also be considered [31,32].
(See "Clinical manifestations and diagnosis of Zollinger-Ellison syndrome (gastrinoma)".)
Ulcer characteristics Certain ulcer characteristics are associated with an increased risk of
complications. Refractory, giant (>2 cm), and pyloric channel ulcers are associated with higher
complications rates. In addition, most complicated ulcers are chronic and fibrosed. Chronic ulcers may
penetrate deeply into the wall to form a dense fibrotic scar that is slow to heal, erodes blood vessels,
or reaches the serosa. However, some complicated ulcers, especially in new NSAID users or in

hospitalized patients (stress ulcers), are acute and occur without dense fibrosis or a prolonged ulcer
history. (See "Clinical manifestations of peptic ulcer disease".)
Pregnancy Complicated peptic ulcers are very uncommon during pregnancy, with fewer than 100
cases reported in the literature [33]. However, peptic ulcers are in the differential diagnosis for the
very common dyspeptic symptoms of pregnancy and for the very uncommon events of upper
gastrointestinal bleeding or gastrointestinal perforation [33].
PREDICTORS OF POOR OUTCOMES Risk factors associated with poor outcomes in patients
with complicated peptic ulcer disease (PUD) include comorbid disease, older age, and the patient's
physiological status at the time of presentation.
Comorbid disease Comorbid disease is a consistent risk factor for poor outcomes [9,34-45]. For
example:
In a study of 96 patients with perforated peptic ulcers, there was a ninefold increase in
postoperative complications in patients with concomitant medical illness [36].
In a study of 9375 patients with peptic ulcer bleeding, overall mortality was 6.2 percent; 80
percent of the deaths were associated with comorbid disease, primarily multiorgan failure,
pulmonary conditions, and advanced malignancy [41].
In a large population study, diabetic patients had significantly increased 30-day mortality from
ulcer bleeding (RR 1.40, 95% CI 1.15-1.70) and perforation (RR 1.51, 95% CI 1.15-1.98) [35].
Advanced age Age is clearly linked to comorbid disease. However, a population-based study of
7232 patients hospitalized for bleeding ulcers indicated that age was also an independent risk factor
for poor outcomes [46], as have other studies [39,45]. Increased age has also been shown to be
associated with increased mortality after ulcer perforation [11].
The magnitude of the physiological insult Hypotension upon admission [39,40,47,48], metabolic
acidosis, acute renal failure, or hypoalbuminemia [39,48] predicts poor outcomes. In a study of 101
patients who underwent surgery for gastric ulcer bleeding after failing endoscopic treatment, mortality
was 5 percent with Apache II scores (calculator 1) less than 15 and 58 percent with scores of 15 or
greater [49].
Complication-specific risk factors Factors that delay ulcer healing, large ulcer size, and dense
fibrosis are also risk factors for poor outcomes. (See "Peptic ulcer disease: Genetic, environmental,
and psychological risk factors and pathogenesis".)
Bleeding Active bleeding at presentation, hematemesis, rebleeding, and the need for surgery
all predict increased overall risk [38]. Certain factors predict failure of endoscopic therapy, such
as hypotension and ulcers larger than 2 cm.
Perforation Persisting or advancing signs of peritonitis and a preoperative delay of greater
than 12 hours increase risk [39,40,48,50,51]. Perforated gastric ulcers appear to have a poorer
prognosis than duodenal ulcers [51].
Obstruction Poor nutritional status predicts poor outcomes. Preoperative gastric atony
predicts postoperative emptying problems.
PRECEDING SYMPTOMS Although a careful history will reveal typical ulcer symptoms in many
patients with complications [52], there is an important subset of patients with silent ulcers in whom
complications develop with no or insufficient heralding dyspeptic symptoms to bring them to timely
medical attention [53-56]. One study using gastric distension with a nutrient meal suggested that
patients with bleeding ulcers have lower visceral sensitivity compared with patients with

uncomplicated ulcers [57], providing a possible mechanism for the absence of symptoms.
(See "Clinical manifestations of peptic ulcer disease".)
In particular, older patients with complicated ulcers related to nonsteroidal anti-inflammatory drugs
(NSAIDs) or medical comorbidity tend to not report antecedent dyspeptic symptoms. This point was
underlined in an autopsy study of 2121 individuals over age 70 years who died suddenly; acute
abdominal causes were found in 111 cases and peptic ulcer perforation and hemorrhage accounted
for one-fourth of these 111 deaths [58].
GENERAL APPROACH TO PATIENTS WITH COMPLICATED ULCERS All patients with
complicated peptic ulcer disease (PUD) require appropriate supportive care, such as taking in nothing
by mouth and fluid resuscitation. (See "Approach to acute upper gastrointestinal bleeding in adults",
section on 'General management'.)
In addition, certain management principles apply to all patients with complicated ulcers, regardless of
the type of complication (bleeding, perforation, penetration, or gastric outlet obstruction). These
principles include coordination of care among the medical, surgical, and radiologic teams,
administration of acid suppressive therapy, treatment of H. pylori if present, and discontinuation of
NSAIDs if possible (table 1).
Coordination of care The importance of early collaboration among the medical, surgical, and
radiologic teams for patients with ulcer complications cannot be overemphasized. In addition to aiding
in resuscitation of an unstable patient, collaboration between the gastroenterologist/endoscopist, the
intensive care unit team, the surgical team, and the radiologist permits the establishment of goals and
limits for initial nonoperative therapy. Early surgical consultation also allows more time for
preoperative preparation and evaluation and for education of patients and families, should urgent
surgical intervention become necessary.
If surgery is indicated, it should be done as soon as the indication is clear and the patient is
appropriately resuscitated. Excellent results are possible with well coordinated, skilled, timely
decision-making and implementation. For example, with skilled, timely care, in one study all 66 highrisk patients with ulcer bleeding (shock on admission, age older than 65 years, an ulcer size greater
than 2 cm, stigmata of recent bleeding, or a history of prior gastric surgery) survived five years [59].
Acid suppressive therapy All patients with complicated peptic ulcers should receive acid
suppressive therapy with an intravenous proton pump inhibitor (PPI). Although omeprazole has been
the most extensively studied intravenous PPI, other intravenous formulations given in doses that are
known to inhibit gastric acid secretion are probably acceptable
alternatives. Pantoprazole and esomeprazole are the only intravenous formulations available in the
United States, and lansoprazole, which was previously available, has been removed from the world
market. For patients with bleeding ulcers, the suggested doses of intravenous pantoprazole,
omeprazole, and esomeprazole are all 80 mg bolus followed by 8 mg/hr infusion. However,
considerable evidence is accumulating that lower-dose continuous infusions and bolus intravenous
dosing may produce comparable results [60-63]. Frequent, high-dose oral PPI use may also be
comparable in effectiveness [64]. In light of the currently available evidence (and the inability to
identify rapid metabolizers who are likely to benefit from higher dosing), use of either continuous
infusions or intravenous bolus dosing appears reasonable. (See "Approach to acute upper
gastrointestinal bleeding in adults", section on 'Acid suppression'.)
Intravenous PPIs have a dramatic impact on ulcer bleeding, which starts to take effect within hours
[65]. Starting intravenous PPI therapy before endoscopy decreased the rate of active bleeding, the

need for endoscopic treatment, and the number of patients with clean based ulcers [66]. These
findings suggest a very rapid effect of profound acid inhibition on fibrin formation and ulcer healing.
Once patients are tolerating oral medications, they should be switched to an oral PPI. Initially, highdose twice daily treatment is reasonable to enhance healing (eg,omeprazole 40 mg twice daily), but
dosing should generally be reduced to once daily after four weeks. However, for patients with giant
ulcers, it is reasonable to continue twice daily dosing until a repeat endoscopy has been performed
and confirmed ulcer healing (see 'Follow-up' below).
Treatment of H. pylori Early diagnosis of H. pylori is important to guide management. Since curing
H. pylori dramatically reduces recurrent ulcers and complications, management must include careful
investigation for H. pylori infection, appropriate antibiotic treatment, and a confirmation of cure after
antibiotic treatment. As noted above, H. pylori testing in the setting of bleeding or PPI use may result
in false-negative results, so repeat testing is required for patients whose initial tests are negative [14].
(See "Indications and diagnostic tests for Helicobacter pylori infection" and "Treatment regimens for
Helicobacter pylori" and 'H. pylori infection' above.)
The efficacy of intravenous antibiotics for the treatment of H. pylori has not been established.
Therefore, it is necessary to wait until patients are tolerating oral feedings to start oral antibiotics.
Interrupted treatment may encourage resistance and should be avoided.
We emphasize that because curing H. pylori reduces the recurrence of complications, following
treatment for H. pylori it is critical to confirm successful eradication of the organism. (See "Treatment
regimens for Helicobacter pylori", section on 'Eradication confirmation'.)
Discontinue NSAIDs If aspirin or non-aspirin NSAIDs can be discontinued, even complicated
ulcers readily heal and uncommonly recur. If non-aspirin NSAIDs must be continued, the incidence of
recurrent PUD can be decreased by switching to a COX-2 inhibitor with concomitant therapy with a
PPI or misoprostol (for patients who are unable to take PPIs or have contraindications to PPI use).
Likewise, when continued low-dose aspirin is justified, concomitant co-therapy with a PPI is indicated.
(See"NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity".)
Urgent or emergent surgery Urgent or emergent surgery is necessary in patients with
uncontrolled hemorrhage or with a perforated ulcer with continued leakage [67]. The specifics of the
surgery depend on the complication, ulcer location and characteristics, and the patient's overall
status. (See 'Bleeding' below and 'Operative versus nonoperative management' below and "Surgical
management of peptic ulcer disease", section on 'Management of peptic ulcer disease
complications'.)
BLEEDING Upper gastrointestinal bleeding secondary to peptic ulcer disease (PUD) is a common
medical condition that results in high morbidity and medical care costs. Patients often present with
hematemesis, melena, or both. However, in the setting of massive bleeding, hematochezia may be
seen. The diagnosis of a bleeding ulcer is typically made with upper endoscopy. (See "Approach to
acute upper gastrointestinal bleeding in adults".)
Most patients with bleeding ulcers can be managed acutely with fluid resuscitation, blood
transfusions, proton pump inhibitor (PPI) therapy, and endoscopic intervention, as appropriate. As
noted above, early intravenous PPI treatment promotes rapid ulcer healing and reduces rebleeding
rates. (See "Overview of the treatment of bleeding peptic ulcers".)
However, in a minority of patients with bleeding ulcers, surgery will be required. Surgery for peptic
ulcer hemorrhage is indicated in the following circumstances:
Failed endoscopic therapy.

Hemodynamic instability despite vigorous volume resuscitation (>3 unit transfusion during
initial resuscitation).
Recurrent hemorrhage following initial hemostasis, especially with hypotension, after a second
attempt at endoscopic treatment. Repeat endoscopic treatment is suggested in most cases of
recurrent hemorrhage because a second attempt has a reasonable chance of success and
lower risk than surgery [68]. However, if two attempts have failed to achieve permanent
hemostasis, additional attempts at endoscopy are unlikely to be successful.
Continued slow bleeding with a transfusion requirement exceeding three units per day.
Secondary or relative indications for surgery include rare blood type or difficult crossmatch, or refusal
of transfusion.
An alternative to surgery for some patients is angiography (see "Angiographic control of nonvariceal
gastrointestinal bleeding in adults"). Indications for angiography for acute nonvariceal upper
gastrointestinal bleeding have been suggested in a consensus statement from the American College
of Radiology [69]:
Endoscopy is the best initial diagnostic and therapeutic procedure.
Surgery and transcatheter arteriography/intervention (TAI) are equally effective following failed
therapeutic endoscopy and the choice of procedure should be based upon local experience and
expertise. However, TAI should be considered in patients at high risk for surgery.
TAI is less likely to be successful in patients with impaired coagulation.
TAI is the best technique for treatment of bleeding into the biliary tree or pancreatic duct.
Delaying surgery for high-risk patients compromises outcomes. Prolonged resuscitation, large volume
transfusion, and periods of hypotension are poorly tolerated in high-risk patients. Therefore, risks such
as giant ulcers, very rapid bleeding rates, shock on presentation, advanced age, severe comorbid
disease, acute coronary syndromes, and transient ischemic attacks are relative indications for early
surgery. As noted above, urgent surgery may be appropriate when hemodynamic instability persists
after 3 units of rapid resuscitation. However, continued management with transfusion and pressors
may be necessary while comorbidities are being evaluated or consent obtained, and in patients who
refuse surgery.
The specifics of the surgery depend upon the ulcer location, ulcer characteristics, and the patient's
overall status. (See "Surgical management of peptic ulcer disease", section on 'Bleeding peptic
ulcer'.)
PERFORATION Ulcer perforation should be suspected in patients who suddenly develop severe,
diffuse abdominal pain. Perforations complicate 2 to 10 percent of peptic ulcers [70]. Duodenal, antral,
and gastric body ulcers account for 60, 20, and 20 percent of perforations due to peptic ulcer disease
(PUD), respectively [71,72].
Clinical manifestations The following three phases have been described when there is free
perforation [73]:
In the initial phase (within two hours of onset), abdominal pain is usually sudden, sometimes
producing collapse or syncope. Localization is usually epigastric, but it quickly becomes
generalized. This catastrophic onset reflects bathing of the peritoneal cavity with acidic fluid,
which likely results in the release of the vasoactive mediators that underlie the physiologic
response. Tachycardia, a weak pulse, cool extremities, and a low temperature are characteristic
features. The stage may last only a few minutes or up to two hours. The severity of the onset

depends upon how much fluid is released. Pain may radiate to the top of the right shoulder or to
both shoulders. As this phase progresses, abdominal rigidity begins to develop.
In the second phase (usually 2 to 12 hours after onset), abdominal pain may lessen and an
inexperienced observer may be led to believe that the patient is getting better. Pain is usually
generalized, often markedly worse upon movement, and the abdomen consistently displays
marked board-like rigidity. There may be obliteration of liver dullness to percussion due to
peritoneal air. The pelvic peritoneum, palpated at rectal examination, is often tender due to
irritation from collected inflammatory fluid. Right lower quadrant tenderness may develop from
fluid moving down the pericolic gutter.
In the third phase (usually >12 hours after onset), increasing abdominal distention is noted, but
abdominal pain, tenderness, and rigidity may be less evident. Temperature elevation and
hypovolemia due to "third-spacing" into the peritoneal cavity develop and acute cardiovascular
collapse may occur as peritonitis advances. Persisting or advancing signs of peritonitis and a
preoperative delay greater than 12 hours increase the risk of a poor outcome
[39,40,48,50,51,74]. In addition, perforated gastric ulcers appear to have a poorer prognosis
than duodenal ulcers [51].
If the perforation is walled off or if the gastric fluid is confined by fibrosis, symptoms may be much less
severe and these phases may not be apparent. Posterior (retroperitoneal) perforation is another
situation where symptoms are less dramatic. Compared to free intraperitoneal perforations, the upper
abdominal pain is more insidious, the presentation often delayed, and the abdominal examination is
frequently equivocal [75].
Diagnosis Rapid diagnosis is essential, since the prognosis is excellent within the first six hours,
but deteriorates with more than a 12-hour delay [50,73]. Perforation is largely a clinical diagnosis with
the history and physical examination providing essential clues (see 'Clinical manifestations' above).
If imaging is required, plain x-rays are typically obtained first. Careful interpretation of upright chest
and abdominal films can detect diagnostic free air in many cases of perforated gastric and duodenal
ulcers [76]. The presence of free air on abdominal imaging is highly indicative of a perforated viscus
(image 1 and image 2 and image 3), although about 10 to 20 percent of patients with a perforated
duodenal ulcer will not have free air [76]. If free air is found, no other diagnostic studies are
necessary. Leakage of water soluble oral contrast may be useful in selected cases. Once the oral
contrast is given, the patient should be rotated 360 degrees and placed on the right side to fill the
antrum and duodenum with contrast. However, many perforations have already sealed spontaneously
by the time of presentation [77], so the absence of a leak does not exclude the diagnosis of a
perforated ulcer.
If there is no free air on the plain film, computed tomography (CT) or ultrasound can be useful to
detect small amounts of free air or fluid. In a small proportion of cases, free fluid will be the only clue
indicating perforation on imaging studies and a few percent of cases will have neither free air nor fluid
[76]. Spiral and multidetector-row CTs, especially 64 slice scanners, allow the entire abdomen to be
examined on a single breath-hold and improve detection of small amounts of air and indirect findings
(eg, fluid, phlegmon, abscess, wall pathology and adjacent inflammation) and can provide very useful
indirect clues to pathology (image 3) [78,79]. Spiral CTs are undoubtedly much more sensitive than
ultrasound for detecting fluid, air, or other clues to perforation. Spiral CT with oral contrast sensitively
detects persisting leaks across perforated ulcers.
Management Once the diagnosis of an ulcer perforation has been made, initial management
includes insertion of a nasogastric tube, intravenous volume replacement, treatment with an

intravenous proton pump inhibitor (PPI), and broad spectrum antibiotics. A decision is then made
about whether the patient requires surgery. (See'Operative versus nonoperative management' below.)
Intravenous PPI Although high-dose intravenous PPIs given at presentation promote the
cessation of bleeding and healing of ulcers, the impact of such early treatment on perforated ulcers
has not yet been reported. Based on the experience with bleeding, it is reasonable to anticipate that
intravenous PPIs will enhance fibrin formation and promote rapid sealing of perforations. Therefore,
we recommend starting an intravenous PPI as early as possible, with an 80 mg loading dose and 8
mg per hour of the PPI; however, lower doses and twice daily bolus dosing may be equally effective,
as noted above. (See 'Acid suppressive therapy' above.)
Antibiotics The antibiotic regimen for a patient with a perforated ulcer should cover enteric gram
negative rods, anaerobes, and mouth flora. The antimicrobial susceptibility patterns for gram negative
rods such as Escherichia coli have changed, with increasing resistance to antibiotics. Thus,
knowledge of local and regional susceptibility patterns for Enterobacteriaceae is essential in selecting
empiric therapy [80-82].
Reasonable choices for initial empiric antibiotic therapy in the setting of perforated ulcer include a
combination beta lactam/beta lactamase inhibitor (such as ampicillin-sulbactam, ticarcillin-clavulanic
acid, or piperacillin-tazobactam), or a combination of a third-generation cephalosporin
and metronidazole. In areas where the local prevalence of extended spectrum beta-lactamase (ESBL)
producing organisms and pathogenic E. coli is common, empiric monotherapy with a carbapenem
such asertapenem, imipenem, or meropenem is appropriate. (See "Pathogenic Escherichia
coli" and "Extended-spectrum beta-lactamases".)
The importance of administering an appropriate initial empiric antibiotic regimen was illustrated in a
review of 425 patients who required surgery for community-acquired secondary peritonitis, including
patients with perforated peptic ulcers [83]. In 13 percent of patients, the initial antibiotic regimen was
inappropriate, defined as not covering all bacteria subsequently isolated or not covering both aerobic
and anaerobic organisms in the absence of culture results. Resolution of the infection after primary
surgery was significantly less likely with an inappropriate regimen (53 versus 79 percent) and failure
to achieve clinical success was associated with a six-day prolongation in hospitalization (20 versus 14
days).
Operative versus nonoperative management A major decision when treating patients with ulcer
perforation is whether and when to operate. After resuscitation, emergent operation and closure with a
piece of omentum is the standard of care for patients with an acute perforation and a rigid abdomen
with free intraperitoneal air. If the patient is stable or improving, especially if spontaneous sealing of
the perforation has been demonstrated, nonoperative management with close monitoring is a
reasonable option. With any free perforation, regardless of the presence or size of the leak, if the
patients status is deteriorating, urgent surgery is indicated. Prolonged efforts to establish a diagnosis
or pursue nonoperative care despite worsening status can be counterproductive, since a needed
operation will be delayed. In addition, surgery is indicated in circumstances where the cause of an
acute abdomen has not been established or the patients status cannot be closely monitored.
(See "Surgical management of peptic ulcer disease", section on 'Management of peptic ulcer disease
complications'.)
The management of patients with small to moderate leaks who are clinically stable is less clear.
Currently, the standard of care for such patients is surgery, but some studies suggest that these
patients can be managed nonoperatively:

The efficacy of initial conservative therapy with a nasogastric tube, antibiotics, and H2 blockers
was compared with immediate laparoscopic surgical repair in a randomized trial of 83 patients
with a perforated peptic ulcer [84]. Surgery was required in 11 of 40 patients (28 percent) in the
conservative therapy group because of failure to improve clinically after 12 hours. The other 29
patients in the conservative therapy arm were successfully managed without surgery. The two
groups did not differ significantly in terms of morbidity or mortality. However, the hospital stay
was 35 percent longer in the group treated conservatively. Also, patients over 70 years old were
less likely to respond to conservative treatment. The authors concluded that an initial period of
nonoperative treatment with careful observation was safe in patients under age 70 years.
A prospective study of 82 patients with perforated peptic ulcers treated patients with
nasogastric suction and intravenous H2 receptor antagonists [85]. If patients did not show
clinical improvement after 24 hours, surgery was performed. With this approach, surgery was
avoided in 44 patients (54 percent). Factors associated with surgery included the size of the
pneumoperitoneum, abdominal distension, heart rate >94 beats per minute, pain on digital rectal
examination, and age >59 years. Overall mortality in the study was 1 percent.
Data also suggest that if spontaneous sealing occurs, patients do well without surgery. A study of 152
patients whose perforations sealed spontaneously found re-leakage in only two patients, comparing
favorably with postoperative re-leak rates [77]. The probability of sealing with nonoperative care and
intravenous PPIs or H2 receptor antagonists has not been studied; however, over 50 percent of
patients with perforated duodenal ulcers have sealed spontaneously when first examined.
Some patients require nonoperative management because severe comorbid illnesses preclude
surgery [86,87]. In a retrospective series of 30 high-risk patients treated nonoperatively, 11 patients
were treated with H2 receptor antagonists (prior to 1996) and 19 were treated with omeprazole 40 mg
daily (1996 and later) [86]. Mortality was 64 percent in the early period and 11 percent in the later
period. Hypotension upon presentation was a major risk factor for a poor outcome. These data raise
the hypothesis that PPI treatment promotes sealing of perforations. However, a low mortality rate (3.5
percent) was also seen in a series of 84 high-risk patients treated with percutaneous drainage and H2
receptor antagonists [87].
Nonoperative management may also be considered for patients with delayed presentations. If the
patient has a persistent leak across the perforation, surgery may be indicated, but can be complicated
by peritoneal contamination. Other options in this setting include nonoperative care with percutaneous
peritoneal drainage, especially for patients who are not good surgical candidates [87].
Patients with perforated ulcers should have an upper endoscopy to look for evidence of malignancy,
to biopsy for H. pylori, and to assess for ulcer healing. To allow the perforation to heal, we suggest
waiting at least two weeks prior to performing an upper endoscopy. If the procedure does not need to
be done urgently, we prefer to wait six to eight weeks to allow for ulcer healing. At that time, biopsies
can be obtained to look for infection with H. pylori and to rule out malignancy (particularly in the case
of a nonhealing gastric ulcer). (See "Overview of the natural history and treatment of peptic ulcer
disease", section on 'Follow-up after initial therapy for peptic ulcer'.)
Surgical approach For patients who require surgery for a perforated ulcer, the surgical approach
depends upon the location of the ulcer. This topic is discussed in detail elsewhere. (See "Surgical
management of peptic ulcer disease", section on 'General principles of ulcer surgery'.)
PENETRATION Ulcer penetration refers to penetration of the ulcer through the bowel wall without
free perforation or leakage of luminal contents into the peritoneal cavity. A longstanding ulcer history is
common, but not invariable, in patients who develop penetration. Penetration often comes to attention
because of a change in symptoms or involvement of adjacent structures. The change in symptom

pattern may be gradual or sudden; it usually involves a loss of cyclicity of the pain with meals, and
loss of food and antacid relief. The pain typically becomes more intense, of longer duration, and is
frequently referred to the lower thoracic or upper lumbar region.
Surgical series suggest that penetration occurs in 20 percent of ulcers, but only a small proportion of
penetrating ulcers become clinically evident [88]. Penetration occurs in descending order of frequency
into the pancreas, lesser omentum, biliary tract, liver, greater omentum, mesocolon, colon, and
vascular structures. Antral and duodenal ulcers can penetrate into the pancreas. Pyloric or prepyloric
ulcers can penetrate the duodenum, eventually leading to a gastroduodenal fistula evident as a
"double" pylorus.
Penetration can be associated with a wide array of uncommon complications including perivisceral
abscess (evident on computed tomography or ultrasonography) [89], erosion into vascular structures
leading to exsanguinating hemorrhage (aortoenteric fistula) [90], or erosion into the cystic artery [91].
Rare biliary tract complications include erosion into the biliary tree with choledochoduodenal fistula,
extrahepatic obstruction, or hemobilia [92]. Fistulization into the pancreatic duct has also been
reported with penetrating duodenal ulcers [93].
Gastrocolic fistulae are seen with greater curvature gastric ulcers, particularly marginal ulcers [72,94].
Typical features of this complication include pain, weight loss, and diarrhea; feculent vomiting is an
uncommon, but diagnostic, symptom. A duodenocolic fistula can also occur.
A penetrating ulcer is suspected clinically when an ulcer in the proper region is found (image 4) [68].
Mild hyperamylasemia can develop with posterior penetration of either a gastric or duodenal ulcer, but
clinical pancreatitis is uncommon.
No rigorous studies are available to guide the management of penetrating ulcers. Management should
follow the intensive measures outlined for refractory ulcers. (See"Refractory or recurrent peptic ulcer
disease".)
GASTRIC OUTLET OBSTRUCTION Gastric outlet obstruction is the least frequent complication of
peptic ulcer disease (PUD) in developed countries. Most cases are associated with duodenal or
pyloric channel ulceration. As peptic ulcers have become less frequent, malignancy has emerged as a
predominant cause of gastric outlet obstruction despite the lower overall rates of gastric cancer.
Peptic ulcer disease accounts for only about 5 percent of gastric outlet obstructions [72,95,96].
(See "Gastric outlet obstruction in adults", section on 'Etiology'.)
Epidemiology and pathogenesis Obstruction accounted for 10 to 30 percent of patients
undergoing ulcer surgery in past series, but this proportion appears to be dropping relative to bleeding
and perforation. Some of this decrease may be due to more effective endoscopic and medical
management, including the ability to identify and reverse underlying causes [72,97].
No distinct pathophysiologic factors have been identified that promote obstruction, though several
elements can contribute to the development of gastric outlet obstruction:
Rapidly reversible elements include spasm, edema, inflammation, and pyloric dysmotility
related to the ulcer or inflammatory changes
Fibrosis, scarring, and deformity underlie slowly reversible or irreversible obstruction
Gastric atony, which develops after prolonged obstruction, contributes to gastric retention
Clinical manifestations Symptoms of gastric retention include early satiety, bloating, indigestion,
anorexia, nausea, vomiting, epigastric pain, and weight loss [72,98]. In a surgical series, vomiting was
the presenting symptom in 80 percent of cases; it occurred more frequently than once daily in 41

percent of patients, once daily in 34 percent, and less often in 25 percent [99]. The presence of
recognizable food more than 8 to 12 hours after eating was uncommon, but highly suggestive of
gastric retention. The presence of a succussion splash on abdominal examination several hours after
eating or drinking is a useful clue if present. The average duration of symptoms was one month,
although one-third had symptoms for longer than three months.
Patterns drawn from surgical series are useful, but the presentation in a general medical setting may
be different. Important variables include the patient's response to these symptoms, age, comorbid
conditions, and general health status. Some patients with chronic organic disease (peptic ulcers in
particular) have visceral hyposensitization (see 'Preceding symptoms' above). In such patients, highgrade outlet obstruction may be present without perceived gastric distress. Appetite and food intake
may be preserved in association with delayed, large volume vomiting of undigested food. Conversely,
some patients may have minimal or intermittent obstruction, but complain of considerable nausea,
pain, and indigestion.
Diagnosis and differential diagnosis The first step is to determine whether the symptoms are
due to gastric retention and, if so, whether outlet obstruction is the underlying cause. Measuring
gastric residual volumes and performing a saline load test (table 2) can establish the diagnosis of
mechanical outlet obstruction.
Definitive diagnosis of gastric pathology must await gastric cleansing, decompression, and correction
of fluid and electrolyte abnormalities. Endoscopic inspection and biopsy are indicated in suspected
cases of gastric outlet obstruction and usually provide a definitive diagnosis of the underlying
pathology, especially for excluding malignancy. Conventional upper gastrointestinal radiography can
provide useful information, but is often not definitive [100]. A computed tomographic
scan and/or surgery may be required if there is a heightened suspicion for malignancy and biopsies
are unrevealing.
A number of entities must be excluded in the differential diagnosis of gastric outlet obstruction, which
is described separately. (See "Gastric outlet obstruction in adults", section on 'Etiology'.)
Management After correction of fluid and electrolyte abnormalities, the initial step in the
management of presumed gastric outlet obstruction is to confirm the diagnosis of gastric retention. If
gastric retention is confirmed, the nasogastric tube should be replaced by a large bore Ewald tube
and the stomach lavaged to remove debris. The nasogastric tube should then be reinserted, good
function confirmed, and intermittent suction continued for three to five days to decompress the
stomach while intravenous fluid and electrolytes are administered.
Prolonged vomiting and poor fluid intake may lead to prerenal azotemia, hyponatremia, and a
hypokalemic, hypochloremic metabolic alkalosis. Intravenous saline will restore the volume status and
urine output; potassium chloride should also be administered as indicated. Intravenous proton pump
inhibitors (PPIs) are used, as considered below. Careful assessment of nutritional status is required
and intravenous hyperalimentation should be considered in malnourished patients. (See "Nutrition
support in critically ill patients: An overview".)
In the past, patients with gastric outlet obstruction due to PUD traditionally were sent to surgery if they
failed to respond to three days of nasogastric suction. However, in cases where the cause can be
reversed (eg, H. pylori or NSAIDs), a more conservative approach deserves consideration.
Approximately one-half of cases of gastric outlet obstruction due to peptic ulcer and associated
spasm, edema, inflammation, or pyloric dysmotility respond initially to medical treatment, although
some initial responders may eventually require surgery [101] or endoscopic dilatation.

Gastric outlet obstruction is not an emergency; in patients who fail to respond to medical therapy, both
endoscopic and surgical intervention should be delayed until the patient has been stabilized and fluid
and electrolyte balance restored. Delays are also appropriate if the patient's nutritional status is
compromised (a serum albumin levelless than 2.8 g/dL is a strong predictor of a poor surgical
outcome) or if the stomach is markedly dilated (postoperative gastric atony is more likely and may be
prevented by preoperative decompression).
Identifying and treating underlying causes Once the patient has been stabilized and gastric
outlet obstruction has been confirmed, the next steps are to identify and treat the underlying cause of
the obstruction. Even cases with a good clinical response require endoscopy and biopsy to exclude
malignancy, diagnose ulcer disease, and determine if H. pylori is present. (See "Gastric outlet
obstruction in adults", section on 'Diagnosis'.)
There is evidence for [102-104] and against [105] an association between H. pylori and obstruction,
probably due to the low frequency of the complication, the small size of the studies, and patient
selection. There are case reports and small series which indicate that cure of H. pylori infection heals
the ulcers, resolves the outlet obstruction, and prevents recurrence of obstruction in most, but not all,
cases [102,106-108].
Although data are limited, there is sufficient evidence to indicate that nonsteroidal anti-inflammatory
drugs (NSAIDs) are an important cause of obstruction. Furthermore, a substantial proportion of
patients with outlet obstruction due to NSAID-induced PUD respond to medical therapy as long as
NSAID use is discontinued [109]. In a study of 119 elderly patients undergoing endoscopy for PUD, 12
cases with obstruction were found, 11 of whom were consuming NSAIDs [110]. All cases responded
to medical management alone. If NSAID use is continued, there is a risk of recurrent obstruction
[109]. In particular, great caution should be exercised in using surgical intervention in patients who are
likely to continue NSAID use, since continued use predicts postoperative ulcer recurrence [111].
(See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)
Antisecretory agents Even though the benefit of antisecretory therapy has not been formally
established for the acute or long-term management of ulcer obstruction, these agents are the
mainstay of initial treatment. Intravenous PPI therapy is warranted during the initial gastric
decompression phase to reduce intravenous fluid requirements, control gastric pH, and facilitate ulcer
healing. Based on the precedent for the acute management of bleeding peptic ulcers, a high-dose PPI
regimen using an 80 mg loading dose, followed by 8 mg per hour of omeprazole or equivalent PPI,
seems appropriate until the obstruction has resolved; however, lower doses and twice daily bolus
dosing may be equally effective, as noted above (see 'Acid suppressive therapy' above).
After the patient resumes oral intake and is emptying liquids, a liquid antisecretory preparation is
needed, such as omeprazole and sodium bicarbonate powder. Since standard preparations of the five
proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole)
use enteric-coated formulations, good emptying of solids is required for effective drug delivery; their
oral use is therefore limited until the obstruction has resolved and motility has recovered.
(See"Pharmacology of antiulcer medications".)
Oral antisecretory therapy with PPIs or H2 receptor antagonists is appropriate for long-term
management of patients who have had a gastric outlet obstruction due to PUD. After H. pylori
infection is treated (if present), full dose oral antisecretory medication should probably be continued
until successful cure of the infection has been confirmed and antral-duodenal deformities have
resolved. Although only documented anecdotally, the combination of curing H. pylori infection,
continued antisecretory therapy, and time will eventually reverse antral-duodenal deformity and
tendency for recurrent obstruction.

Endoscopic balloon dilation Patients who fail to respond to medical therapy may require
endoscopic dilation or surgery. Before surgery is contemplated, endoscopy with biopsy is required to
identify the cause of the obstruction and to rule out malignancy, which has been reported in as many
as 66 percent of patients in this setting [95,112].
If the pyloric channel can be identified and a balloon passed, dilation is an appropriate option in
experienced hands. A Gastrografin study may be helpful to define the anatomy of the pylorus before
dilation. If the pylorus can be opened sufficiently to allow the patient to tolerate a liquid diet, especially
when an underlying cause can be reversed, then continuing medical treatment is a reasonable option
as long as the patient is carefully monitored to ensure that retention does not recur. Monitoring
symptoms is important, but it is advisable to also check a gastric residual, especially in patients who
were previously asymptomatic despite large gastric residuals. Cases that clearly warrant surgery are
ones where the pylorus is obstructed and cannot be safely dilated, or where the obstruction persists
or recurs during medical and endoscopic management.
Dilation can be accomplished by using endoscopy and a through-the-scope (TTS) balloon dilator, or
by using a balloon placed over a guidewire positioned under fluoroscopic guidance. While fluoroscopy
may not be required for dilation using a TTS balloon in the case of mild strictures (eg, strictures that
allow passage of an endoscope), most other stricture dilations are carried out using fluoroscopic
guidance. The amount of dilation in a single session is determined by the initial diameter of the
stricture. Narrow strictures may require stepwise dilation performed over multiple sessions, as is done
with esophageal strictures. (See "Management of benign esophageal strictures", section on
'Technique'.)
Balloon dilation should be monitored by a pressure gauge. The balloon is inflated to the chosen
diameter and inflation is sustained for thirty to sixty seconds. The dilation may then be repeated at the
same diameter, though it is not certain that repeated dilations to the same diameter yield better
results. Using dilute contrast medium to fill the balloon allows progress to be followed fluoroscopically;
a waist forms initially during dilation, but is effaced during balloon distention. Successful dilation is
usually confirmed by pulling the balloon through the strictured segment, although failure to accomplish
this does not preclude a successful procedure. Symptoms are usually considerably improved with
successful dilation to 12 mm. There may be an advantage to postponing dilation beyond 15 mm until
after a period of medical management [72].
Long duodenal strictures are the most difficult to dilate. Multiple sessions using stepwise dilation for
tight obstructions will likely lower the risk of perforation. Nevertheless, because of the risk of
perforation, patients should be appropriately prepared for surgery before duodenal dilation and
monitored closely after dilation before resuming oral intake. If there is concern about a possible
perforation or if the dilation is unusually difficult to perform, an immediate postprocedure Gastrografin
study should be obtained.
Multiple sessions of endoscopic balloon dilation are necessary in some cases [98,109,113,114]. In
one study, for example, 24 of 30 patients (80 percent) achieved sustained symptom relief; 17 had a
single procedure, while seven required multiple sessions [98]. Dilation failed in four patients with long
duodenal strictures, while two dilated to 18 mm suffered perforation; both recovered uneventfully after
surgery. A good long-term response following dilation is achieved when H. pylori can be cured or
NSAID use discontinued [109].
Surgery For patients who require surgery, the choice of procedure is usually made during the
operation. (See "Surgical management of peptic ulcer disease".)

FOLLOW-UP Upper endoscopy is indicated for most patients after four to six weeks to exclude
neoplasia and other diagnoses and to establish healing. In addition, biopsies should be obtained to
look for H. pylori or to confirm H. pylori eradication in those who have been treated. To increase the
yield for diagnosing H. pylori, patients should be switched to H2 receptor antagonists for the two
weeks prior to the endoscopy. In addition, they should be off of antibiotics and bismuth for two weeks.
(See"Overview of the natural history and treatment of peptic ulcer disease", section on 'Follow-up
after initial therapy for peptic ulcer' and "Treatment regimens for Helicobacter pylori", section on
'Eradication confirmation'.)
PREVENTION OF RECURRENCE The natural history of complicated peptic ulcer disease (PUD)
is for the recurrence of complications unless the underlying cause can be treated.
Stop NSAIDs The recurrence of ulcer complications with continuing nonsteroidal anti-inflammatory
drug (NSAID) use is well established [115,116] and is an indication for co-therapy with antisecretory
agents, which reduces recurrences. (See "NSAIDs (including aspirin): Secondary prevention of
gastroduodenal toxicity".) The decision to discontinue aspirin should be based on a careful appraisal
of the patient's cardiovascular risk.
Although we are unaware of rigorous studies, when NSAIDs are the cause of ulceration and are
stopped, complicated and refractory ulcers tend to heal rapidly and do not recur [117]. Important
exceptions are giant or densely fibrosed ulcers for which healing may be delayed.
It is important to recall that a subset of patients who consume NSAIDs fail to disclose their use even
when directly asked [118]. Such patients are also likely to continue NSAID use even in the face of
ulcer complications, clear instructions to stop the medication, and even failed ulcer surgery
[100,119,120]. Therefore, particularly with complicated ulcers, a diligent search for NSAID use is
critical. In addition, some patients with a history of complicated ulcers are prescribed NSAIDs. In a
study of 26,618 NSAID prescriptions, 2244 patients reported a prior peptic ulcer and 489 reported
upper gastrointestinal tract bleeding. However, among patients with a history of bleeding, physicians
recorded the history of prior bleeding in only 8 percent of cases [121], suggesting that NSAIDs are
frequently prescribed when they are contraindicated in the absence of proton pump inhibitor (PPI)
cotherapy or careful monitoring.
Ulcers can recur despite definitive ulcer surgery (eg, vagotomy) in the setting of continued NSAID
use. Uncontrolled series and case reports highlight problematic recurrences following definitive ulcer
surgery when NSAIDs, and aspirin in particular, are continued [111,119,120,122]. Therefore, every
effort should be made to discover NSAID use in patients with complicated ulcers, especially before
surgery; a careful history from the patient and family and, in selected cases, measuring salicylate
levels and platelet function may be justified [111]. Any role of definitive ulcer surgery in patients with
continued NSAID use remains to be elucidated.
Treat H. pylori A confident diagnosis of H. pylori is essential because treatment can prevent lifethreatening recurrences. However, as noted above, making a diagnosis of H. pylori in the setting of
acute bleeding may be difficult. (See 'H. pylori infection' above and "Indications and diagnostic tests
for Helicobacter pylori infection".)
With H. pylori-associated ulcer bleeding, successful cure of the infection dramatically reduces
recurrent ulceration and recurrent complications [123,124]. Although much less extensively studied, in
two randomized trials with a total of 173 patients with perforated ulcers, H. pylori antibiotic treatment
reduced the recurrence rate of duodenal, prepyloric, and pyloric ulcers after simple surgical closure of
the perforation from 30 to 6.1 percent in the first study and from 38 percent to 4.8 percent in the

second [15,125]. Three other case series support similar conclusions [53,126,127]. Following
treatment for H. pylori, patients should be tested to confirm successful eradication of the organism.
(See "Treatment regimens for Helicobacter pylori", section on 'Eradication confirmation'.)
The role of H. pylori in ulcer recurrences following acid reducing surgery remains controversial [122].
Postoperative ulcer recurrences can clearly result from incomplete vagotomy and continued NSAID
use. No studies resolve the question of whether curing H. pylori reduces recurrences following
definitive ulcer surgery in the subset of patients with H. pylori. However, two reports indicated that
persistent postoperative H. pylori infection is associated with advancing atrophic gastritis or precursor
lesions that may underlie the increased rate of gastric cancer observed after definitive peptic ulcer
surgery [128,129]. Considering these factors and the weight of evidence implicating H. pylori in ulcer
recurrence, we suggest that the organism be eradicated (if present) even in patients who have
undergone definitive ulcer surgery [122].
Non-H. pylori, non-NSAID ulcers While less common, ulcers not due to H. pylori infection or
NSAIDs are prone to frequent recurrences that often require continued maintenance medical therapy
or surgery. This point was illustrated in a prospective study that compared 120 patients with a history
of H. pylori-negative, NSAID-negative bleeding ulcers to 213 patients with a history of H. pylori
positive bleeding ulcers who were treated successfully with eradication therapy [130]. At follow-up of
up to seven years, the H. pylori negative patients had a significantly higher rate of recurrent bleeding
(42 versus 11 percent). (See "Epidemiology and etiology of peptic ulcer disease", section on 'H.
pylori'.)
In patients with presumed non-H. pylori, non-NSAID ulcers, every effort must be made to exclude H.
pylori infection and NSAID use and to determine the cause of the ulcer. A cause for most non-H.
pylori, non-NSAID ulcers can be established (table 3). For example, crack cocaine use can cause
perforated ulcers. The ulcers should be diligently treated and reversible factors contributing to ulcer
development should be addressed to decrease the risk of recurrent complications. (See "Unusual
causes of peptic ulcer disease".)
Maintenance acid suppressive therapy Patients with complicated PUD due to an identifiable
cause that can be addressed (eg, treatment for H. pylori or discontinuation of NSAIDs) generally do
not require maintenance acid suppressive therapy. Such patients are typically treated with a PPI for at
least four to six weeks. The duration of therapy depends upon the etiology and characteristics of the
ulcer (particularly size and presence of dense scarring):
In patients with H. pylori infection, eradication should be confirmed prior to stopping
antisecretory treatment (see "Treatment regimens for Helicobacter pylori", section on
'Eradication confirmation')
In patients requiring endoscopic confirmation of ulcer healing (eg, gastric ulcers at high-risk of
malignancy, giant duodenal ulcers, or deformed ulcers with dense scarring), the PPI should be
continued until healing has been demonstrated (see "Overview of the natural history and
treatment of peptic ulcer disease", section on 'Follow-up after initial therapy for peptic ulcer')
For patients with NSAID-associated ulcer complications where NSAIDs have been stopped
(and H. pylori excluded or eradicated), it is reasonable to stop maintenance therapy after healing
has been confirmed
Although the natural history of complicated non-NSAID, non-H. pylori ulcers has received only
limited study, recurrence rates are likely to be high and sustained maintenance therapy is
probably indicated

Any patient who has had a prior ulcer complication should be carefully educated about the
ways recurrent complications can present and about the critical importance of immediately
seeking emergent medical attention for any suspicion of recurrent complications
In patients requiring maintenance therapy, once the ulcer has healed, the PPI can be tapered by
cutting the dose by 50 percent every week until the patient is on a low dose of the medication
(eg, omeprazole 20 mg daily). (See "Overview of the natural history and treatment of peptic ulcer
disease", section on 'Maintenance therapy' and"Overview of the natural history and treatment of
peptic ulcer disease", section on 'Antisecretory therapy after H. pylori eradication' and "Overview of
the natural history and treatment of peptic ulcer disease", section on 'Antisecretory therapy'.)
Acid-reducing surgical procedures Although definitive acid-reducing surgical procedures
(parietal cell vagotomy or vagotomy with drainage or partial gastrectomy) have the potential of
decreasing recurrent complications, their performance (especially during emergency ulcer surgery)
adds operative time, perioperative risk, and long-term adverse side effects, such as dumping
syndrome. Most large studies of definitive ulcer surgery were performed prior to the recognition of H.
pylori, the role of NSAIDs, and potent antisecretory agents [131-134]. Over the past two decades,
gastric resections and definitive acid-reducing procedures have continued to decline with no changes
in outcomes [135].
An illustrative report included 159 patients who were followed more than 10 years after vagotomy and
pyloroplasty for perforated duodenal ulcer [133]. The perioperative mortality was 5.5 percent, ulcers
recurred in 8.8 percent, and postoperative digestive sequelae, notably diarrhea and dumping,
developed in 16 percent. Similar recurrence rates (but with less morbidity) have been described in
patients who underwent parietal cell vagotomy [134].
Even though no data are available to compare the risks of definitive ulcer surgery to current medical
treatment, a few points are relevant:
In light of the demonstrated benefits of medical treatment (curing H. pylori, eliminating NSAIDs,
and using potent antisecretory agents) for decreasing complicated ulcer recurrence, the rates of
performing definitive ulcer procedures during emergency surgery have fallen dramatically,
without any obvious deleterious impact on outcomes [38,56,135,136]. As a result, there is a
decline in surgical expertise for performing these definitive procedures, especially in the
community, which inevitably further compromises the outcomes of surgery.
If patients who require emergency surgery for ulcer complications have failed all forms of
medical management, definitive surgery deserves consideration.
By contrast, definitive surgery is generally not appropriate if medical management has not been
tried. Although the cause of the ulcer disease may not be known at the time of surgery, all forms
respond quite well to medical management. However, the proportion of patients who will not
tolerate, be adherent with, or respond to medical treatment is likely to be very small and elective
definitive ulcer surgery can be reserved for this subset [137].
In patients with acid hypersecretion, definitive ulcer surgery (eg, vagotomy) should be avoided
because there is a high risk of postoperative ulcer recurrence. This approach is well established
for patients with gastrinomas, but also appears to pertain to patients with nongastrinoma acid
hypersecretion [138]. (See "Management and prognosis of the Zollinger-Ellison syndrome
(gastrinoma)".)
SUMMARY AND RECOMMENDATIONS

The major complications of peptic ulcer disease (PUD) include perforation, gastric outlet
obstruction, penetration, and bleeding. For reasons that have not been defined, the relative
prominence of these complications varies in different regions. (See 'Introduction' above.)
Although a history of preceding ulcer symptoms is common, many patients have no preceding
typical peptic ulcer symptoms or known disease. (See 'Preceding symptoms' above.)
Certain management principles apply to all patients with complicated ulcers, regardless of type
(table 1). These principles include coordination of care among the surgical and medical teams,
early administration of intravenous proton pump inhibitors (PPIs) for acid suppression, treatment
of H. pylori if present (after the patient resumes oral feedings), and discontinuation of
nonsteroidal anti-inflammatory drugs (NSAIDs), at least until healing has been established.
(See 'General approach to patients with complicated ulcers' above.)
Appropriate treatment for patients with bleeding ulcers generally includes fluid resuscitation to
correct hypovolemia; blood transfusions as necessary; early, high-dose intravenous PPI (80 mg
loading and 8 mg per hour of omeprazole or equivalent is usually recommended, though lower
doses administered by intravenous bolus appear equally effective); and endoscopic intervention
for ulcers with stigmata of active bleeding. Surgery or angiography is required when two
endoscopic treatment sessions have failed or bleeding recurs after these interventions,
especially in hemodynamically unstable patients. (See 'Bleeding' above and 'Acid suppressive
therapy' above.)
Ulcer perforation should be suspected in patients with or without a history of peptic ulcer
symptoms or disease who develop the sudden onset of severe epigastric or diffuse abdominal
pain or, especially in elderly patients, sudden decompensation. Once the diagnosis of an ulcer
perforation has been made, initial management includes insertion of a nasogastric tube,
intravenous volume replacement, treatment with an intravenous PPI, and appropriate antibiotics.
A decision then is made about whether the patient requires surgery. (See 'Perforation' above.)
For patients with an acute perforation and a rigid abdomen with free intraperitoneal air,
emergent operation and closure with a piece of omentum is the standard of care. Furthermore,
with an established ulcer perforation, regardless of the presence or size of the leak, if the
patients status is deteriorating, urgent surgery is indicated. Lastly, surgery is indicated in
circumstances where the cause of an acute abdomen has not been established or the patients
status cannot be carefully monitored. (See 'Management' above.)
Despite this standard of care, there are several situations where continuing nonoperative care
appears justifiable, especially because there are no rigorous data available to guide treatment
decisions. If the patient is stable or improving, especially if imaging studies show spontaneous
sealing of the perforation, then continued nonoperative management with close monitoring is a
reasonable option. Furthermore, for patients with small to moderate leaks who are clinically
stable, some studies suggest that nonoperative management with close monitoring is
reasonable. Lastly, patients who are at very high risk for surgery because of comorbidity can
have surprisingly low mortality with rigorous, nonoperative management. There are two critical
unknowns: the ability of intravenous PPIs to accelerate sealing of the perforation and the role for
percutaneous drainage. The latter appears to be very useful for patients with persisting leaks
across perforated ulcers who are adequately stable to tolerate nonoperative care.
(See 'Operative versus nonoperative management' above.)
Ulcer penetration refers to penetration of the ulcer through the bowel wall without free
perforation and leakage of luminal contents into the peritoneal cavity. Penetration often comes to
attention because of a change in symptoms or involvement of adjacent structures. Patients are
typically managed in a manner similar to patients with refractory peptic ulcers.

(See 'Penetration' above and "Refractory or recurrent peptic ulcer disease", section on
'Treatment'.)
Gastric outlet obstruction is the least common ulcer complication. Most cases are associated
with duodenal or pyloric channel ulceration. Symptoms of gastric outlet obstruction include early
satiety, bloating, indigestion, anorexia, nausea, vomiting, epigastric pain, and weight loss.
Malignancy is a more common cause of gastric outlet obstruction and must be excluded. Some
patients can be managed medically, whereas others require endoscopic balloon dilation or
surgery. (See 'Gastric outlet obstruction' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1.

Ohmann C, Imhof M, Ruppert C, et al. Time-trends in the epidemiology of peptic ulcer


bleeding. Scand J Gastroenterol 2005; 40:914.

2.

Kang JY, Elders A, Majeed A, et al. Recent trends in hospital admissions and mortality rates
for peptic ulcer in Scotland 1982-2002. Aliment Pharmacol Ther 2006; 24:65.

3.

Post PN, Kuipers EJ, Meijer GA. Declining incidence of peptic ulcer but not of its
complications: a nation-wide study in The Netherlands. Aliment Pharmacol Ther 2006; 23:1587.

4.

Lassen A, Hallas J, Schaffalitzky de Muckadell OB. Complicated and uncomplicated peptic


ulcers in a Danish county 1993-2002: a population-based cohort study. Am J Gastroenterol 2006;
101:945.

5.

Bardhan KD, Royston C. Time, change and peptic ulcer disease in Rotherham, UK. Dig Liver
Dis 2008; 40:540.

6.

Thomopoulos KC, Vagenas KA, Vagianos CE, et al. Changes in aetiology and clinical
outcome of acute upper gastrointestinal bleeding during the last 15 years. Eur J Gastroenterol
Hepatol 2004; 16:177.

7.

Sonnenberg A. Time trends of ulcer mortality in Europe. Gastroenterology 2007; 132:2320.

8.

Sadic J, Borgstrm A, Manjer J, et al. Bleeding peptic ulcer - time trends in incidence,
treatment and mortality in Sweden. Aliment Pharmacol Ther 2009; 30:392.

9.

Wang YR, Richter JE, Dempsey DT. Trends and outcomes of hospitalizations for peptic ulcer
disease in the United States, 1993 to 2006. Ann Surg 2010; 251:51.

10.

Bashinskaya B, Nahed BV, Redjal N, et al. Trends in Peptic Ulcer Disease and the
Identification of Helicobacter Pylori as a Causative Organism: Population-based Estimates from the
US Nationwide Inpatient Sample. J Glob Infect Dis 2011; 3:366.

11.

Lau JY, Sung J, Hill C, et al. Systematic review of the epidemiology of complicated peptic
ulcer disease: incidence, recurrence, risk factors and mortality. Digestion 2011; 84:102.

12.

Sung JJ, Tsoi KK, Ma TK, et al. Causes of mortality in patients with peptic ulcer bleeding: a
prospective cohort study of 10,428 cases. Am J Gastroenterol 2010; 105:84.

13.
14.

Irabor DO. An audit of peptic ulcer surgery in Ibadan, Nigeria. West Afr J Med 2005; 24:242.
Snchez-Delgado J, Gen E, Surez D, et al. Has H. pylori prevalence in bleeding peptic
ulcer been underestimated? A meta-regression. Am J Gastroenterol 2011; 106:398.

15.

Ng EK, Lam YH, Sung JJ, et al. Eradication of Helicobacter pylori prevents recurrence of
ulcer after simple closure of duodenal ulcer perforation: randomized controlled trial. Ann Surg 2000;
231:153.

16.

Gisbert JP, Legido J, Garca-Sanz I, Pajares JM. Helicobacter pylori and perforated peptic
ulcer prevalence of the infection and role of non-steroidal anti-inflammatory drugs. Dig Liver Dis 2004;
36:116.

17.

Kumar S, Mittal GS, Gupta S, et al. Prevalence of Helicobactor pylori in patients with
perforated duodenal ulcer. Trop Gastroenterol 2004; 25:121.

18.

Lanas A, Garca-Rodrguez LA, Arroyo MT, et al. Risk of upper gastrointestinal ulcer bleeding
associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal antiinflammatory drugs, aspirin and combinations. Gut 2006; 55:1731.

19.

Collier DS, Pain JA. Non-steroidal anti-inflammatory drugs and peptic ulcer perforation. Gut
1985; 26:359.

20.

Kuyvenhoven JP, Veenendaal RA, Vandenbroucke JP. Peptic ulcer bleeding: interaction
between non-steroidal anti-inflammatory drugs, Helicobacter pylori infection, and the ABO blood group
system. Scand J Gastroenterol 1999; 34:1082.

21.

Santolaria S, Lanas A, Benito R, et al. Helicobacter pylori infection is a protective factor for
bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users. Aliment Pharmacol Ther
1999; 13:1511.

22.

Labenz J, Peitz U, Khl H, et al. Helicobacter pylori increases the risk of peptic ulcer bleeding:
a case-control study. Ital J Gastroenterol Hepatol 1999; 31:110.

23.

Demiray E, Yilmaz O, Sarkis C, et al. Comparison of invasive methods and two different stool
antigen tests for diagnosis of H pylori infection in patients with gastric bleeding. World J Gastroenterol
2006; 12:4206.

24.

van Leerdam ME, van der Ende A, ten Kate FJ, et al. Lack of accuracy of the noninvasive
Helicobacter pylori stool antigen test in patients with gastroduodenal ulcer bleeding. Am J
Gastroenterol 2003; 98:798.

25.

Gisbert JP, Esteban C, Jimenez I, Moreno-Otero R. 13C-urea breath test during


hospitalization for the diagnosis of Helicobacter pylori infection in peptic ulcer bleeding. Helicobacter
2007; 12:231.

26.

Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of


Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007; 56:772.

27.

Pietroiusti A, Forlini A, Magrini A, et al. Isolated H. pylori duodenal colonization and idiopathic
duodenal ulcers. Am J Gastroenterol 2008; 103:55.

28.

Okan A, Tankurt E, Aslan BU, et al. Relationship between non-steroidal anti-inflammatory


drug use and Helicobacter pylori infection in bleeding or uncomplicated peptic ulcers: A case-control
study. J Gastroenterol Hepatol 2003; 18:18.

29.

Lanas A, Fuentes J, Benito R, et al. Helicobacter pylori increases the risk of upper
gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther 2002; 16:779.

30.

Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal antiinflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002; 359:14.

31.

Hirschowitz BI, Simmons J, Mohnen J. Clinical outcome using lansoprazole in acid


hypersecretors with and without Zollinger-Ellison syndrome: a 13-year prospective study. Clin
Gastroenterol Hepatol 2005; 3:39.

32.

Wilcox CM, Seay T, Arcury J, Hirschowitz BI. Presentation, response to lansoprazole therapy,
and outcome of Zollinger-Ellison syndrome-like gastric acid hypersecretors. Scand J Gastroenterol
2011; 46:277.

33.

Cappell MS. Gastric and duodenal ulcers during pregnancy. Gastroenterol Clin North Am
2003; 32:263.

34.

Taha AS, Angerson WJ, Prasad R, et al. Clinical trial: the incidence and early mortality after
peptic ulcer perforation, and the use of low-dose aspirin and nonsteroidal anti-inflammatory drugs.
Aliment Pharmacol Ther 2008; 28:878.

35.

Thomsen RW, Riis A, Christensen S, et al. Diabetes and 30-day mortality from peptic ulcer
bleeding and perforation: a Danish population-based cohort study. Diabetes Care 2006; 29:805.

36.

Sharma SS, Mamtani MR, Sharma MS, Kulkarni H. A prospective cohort study of
postoperative complications in the management of perforated peptic ulcer. BMC Surg 2006; 6:8.

37.

Ahsberg K, Hglund P, Kim WH, von Holstein CS. Impact of aspirin, NSAIDs, warfarin,
corticosteroids and SSRIs on the site and outcome of non-variceal upper and lower gastrointestinal
bleeding. Scand J Gastroenterol 2010; 45:1404.

38.

Chiu PW, Ng EK, Wong SK, et al. Surgical salvage of bleeding peptic ulcers after failed
therapeutic endoscopy. Dig Surg 2009; 26:243.

39.

Mller MH, Adamsen S, Thomsen RW, Mller AM. Preoperative prognostic factors for
mortality in peptic ulcer perforation: a systematic review. Scand J Gastroenterol 2010; 45:785.

40.

Noguiera C, Silva AS, Santos JN, et al. Perforated peptic ulcer: main factors of morbidity and
mortality. World J Surg 2003; 27:782.

41.

Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer
bleeding: a randomized trial. Ann Intern Med 2010; 152:1.

42.

Klebl FH, Bregenzer N, Schfer L, et al. Comparison of inpatient and outpatient upper
gastrointestinal haemorrhage. Int J Colorectal Dis 2005; 20:368.

43.

Mller T, Barkun AN, Martel M. Non-variceal upper GI bleeding in patients already


hospitalized for another condition. Am J Gastroenterol 2009; 104:330.

44.

Schemmer P, Decker F, Dei-Anane G, et al. The vital threat of an upper gastrointestinal


bleeding: Risk factor analysis of 121 consecutive patients. World J Gastroenterol 2006; 12:3597.

45.

Schimke K, Chubb SA, Davis WA, et al. Antiplatelet therapy, Helicobacter pylori infection and
complicated peptic ulcer disease in diabetes: the Fremantle Diabetes Study. Diabet Med 2009; 26:70.

46.

Christensen S, Riis A, Nrgaard M, et al. Short-term mortality after perforated or bleeding


peptic ulcer among elderly patients: a population-based cohort study. BMC Geriatr 2007; 7:8.

47.

Chiu PW, Ng EK, Cheung FK, et al. Predicting mortality in patients with bleeding peptic ulcers
after therapeutic endoscopy. Clin Gastroenterol Hepatol 2009; 7:311.

48.

Kocer B, Surmeli S, Solak C, et al. Factors affecting mortality and morbidity in patients with
peptic ulcer perforation. J Gastroenterol Hepatol 2007; 22:565.

49.

Wang BW, Mok KT, Chang HT, et al. APACHE II score: a useful tool for risk assessment and
an aid to decision-making in emergency operation for bleeding gastric ulcer. J Am Coll Surg 1998;
187:287.

50.

Svanes C, Lie RT, Svanes K, et al. Adverse effects of delayed treatment for perforated peptic
ulcer. Ann Surg 1994; 220:168.

51.

Hermansson M, Stal von Holstein C, Zilling T. Surgical approach and prognostic factors after
peptic ulcer perforation. Eur J Surg 1999; 165:566.

52.

Jordan PH Jr, Thornby J. Twenty years after parietal cell vagotomy or selective vagotomy
antrectomy for treatment of duodenal ulcer. Final report. Ann Surg 1994; 220:283.

53.

Rodrguez-Sanjun JC, Fernndez-Santiago R, Garca RA, et al. Perforated peptic ulcer


treated by simple closure and Helicobacter pylori eradication. World J Surg 2005; 29:849.

54.

Pounder R. Silent peptic ulceration: deadly silence or golden silence? Gastroenterology 1989;
96:626.

55.

Wilcox CM, Clark WS. Features associated with painless peptic ulcer bleeding. Am J
Gastroenterol 1997; 92:1289.

56.

Sarosi GA Jr, Jaiswal KR, Nwariaku FE, et al. Surgical therapy of peptic ulcers in the 21st
century: more common than you think. Am J Surg 2005; 190:775.

57.

Gururatsakul M, Holloway RH, Talley NJ, Holtmann GJ. Association between clinical
manifestations of complicated and uncomplicated peptic ulcer and visceral sensory dysfunction. J
Gastroenterol Hepatol 2010; 25:1162.

58.

Ng CY, Squires TJ, Busuttil A. Acute abdomen as a cause of death in sudden, unexpected
deaths in the elderly. Scott Med J 2007; 52:20.

59.

Bender JS, Bouwman DL, Weaver DW. Bleeding gastroduodenal ulcers: improved outcome
from a unified surgical approach. Am Surg 1994; 60:313.

60.

Songr Y, Balkarli A, Acartrk G, Senol A. Comparison of infusion or low-dose proton pump


inhibitor treatments in upper gastrointestinal system bleeding. Eur J Intern Med 2011; 22:200.

61.

Javid G, Zargar SA, U-Saif R, et al. Comparison of p.o. or i.v. proton pump inhibitors on 72-h
intragastric pH in bleeding peptic ulcer. J Gastroenterol Hepatol 2009; 24:1236.

62.

Andriulli A, Loperfido S, Focareta R, et al. High- versus low-dose proton pump inhibitors after
endoscopic hemostasis in patients with peptic ulcer bleeding: a multicentre, randomized study. Am J
Gastroenterol 2008; 103:3011.

63.

Wang CH, Ma MH, Chou HC, et al. High-dose vs non-high-dose proton pump inhibitors after
endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of
randomized controlled trials. Arch Intern Med 2010; 170:751.

64.

Laine L, Shah A, Bemanian S. Intragastric pH with oral vs intravenous bolus plus infusion
proton-pump inhibitor therapy in patients with bleeding ulcers. Gastroenterology 2008; 134:1836.

65.

Leontiadis GI, Sreedharan A, Dorward S, et al. Systematic reviews of the clinical


effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal
bleeding. Health Technol Assess 2007; 11:iii.

66.

Lau JY, Leung WK, Wu JC, et al. Omeprazole before endoscopy in patients with
gastrointestinal bleeding. N Engl J Med 2007; 356:1631.

67.

Smith BR, Stabile BE. Emerging trends in peptic ulcer disease and damage control surgery in
the H. pylori era. Am Surg 2005; 71:797.

68.

Lau JY, Sung JJ, Lam YH, et al. Endoscopic retreatment compared with surgery in patients
with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999;
340:751.

69.

Millward SF. ACR Appropriateness Criteria on treatment of acute nonvariceal gastrointestinal


tract bleeding. J Am Coll Radiol 2008; 5:550.

70.

Behrman SW. Management of complicated peptic ulcer disease. Arch Surg 2005; 140:201.

71.

Gunshefski L, Flancbaum L, Brolin RE, Frankel A. Changing patterns in perforated peptic


ulcer disease. Am Surg 1990; 56:270.

72.

Graham DY. Ulcer complications and their nonoperative treatment. In: Gastrointestinal
Disease, 5th ed, Sleisenger M, Fordtran J (Eds), WB Saunders, Philadelphia 1993. p.698.

73.

Silen W. Cope's Early Diagnosis of the Acute Abdomen, Oxford University Press, New York
1996.

74.

75.

Su YH, Yeh CC, Lee CY, et al. Acute surgical treatment of perforated peptic ulcer in the
elderly patients. Hepatogastroenterology 2010; 57:1608.
Wong CH, Chow PK. Posterior perforation of gastric ulcer. Dig Dis Sci 2004; 49:1882.

76.

Grassi R, Romano S, Pinto A, Romano L. Gastro-duodenal perforations: conventional plain


film, US and CT findings in 166 consecutive patients. Eur J Radiol 2004; 50:30.

77.

Donovan AJ, Berne TV, Donovan JA. Perforated duodenal ulcer: an alternative therapeutic
plan. Arch Surg 1998; 133:1166.

78.

Furukawa A, Sakoda M, Yamasaki M, et al. Gastrointestinal tract perforation: CT diagnosis of


presence, site, and cause. Abdom Imaging 2005; 30:524.

79.

Yeung KW, Chang MS, Hsiao CP, Huang JF. CT evaluation of gastrointestinal tract
perforation. Clin Imaging 2004; 28:329.

80.

Dumont R, Cinotti R, Lejus C, et al. The Microbiology of Community-acquired Peritonitis in


Children. Pediatr Infect Dis J 2011; 30:131.

81.

Johnson JR, Johnston B, Clabots C, et al. Escherichia coli sequence type ST131 as the major
cause of serious multidrug-resistant E. coli infections in the United States. Clin Infect Dis 2010;
51:286.

82.

Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli O25b-ST131: a pandemic,
multiresistant, community-associated strain. J Antimicrob Chemother 2011; 66:1.

83.

Krobot K, Yin D, Zhang Q, et al. Effect of inappropriate initial empiric antibiotic therapy on
outcome of patients with community-acquired intra-abdominal infections requiring surgery. Eur J Clin
Microbiol Infect Dis 2004; 23:682.

84.

Crofts TJ, Park KG, Steele RJ, et al. A randomized trial of nonoperative treatment for
perforated peptic ulcer. N Engl J Med 1989; 320:970.

85.

Songne B, Jean F, Foulatier O, et al. [Non operative treatment for perforated peptic ulcer:
results of a prospective study]. Ann Chir 2004; 129:578.

86.

Bucher P, Oulhaci W, Morel P, et al. Results of conservative treatment for perforated


gastroduodenal ulcers in patients not eligible for surgical repair. Swiss Med Wkly 2007; 137:337.

87.

Rahman MM, Islam MS, Flora S, et al. Mortality in perforated peptic ulcer patients after
selective management of stratified poor risk cases. World J Surg 2007; 31:2341.

88.

NORRIS JR, HAUBRICH WS. The incidence and clinical features of pentration in peptic
ulceration. JAMA 1961; 178:386.

89.

Ranschaert E, Rigauts H. Confined gastric perforation: ultrasound and computed tomographic


diagnosis. Abdom Imaging 1993; 18:318.

90.

Odze RD, Bgin LR. Peptic-ulcer-induced aortoenteric fistula. Report of a case and review of
the literature. J Clin Gastroenterol 1991; 13:682.

91.

Ford GA, Simpson AH, Gear MW, Wilkinson SP. Duodenal ulceration into the cystic artery.
Postgrad Med J 1990; 66:144.

92.

Van Steenbergen W, Ponette E, Marchal G, et al. Distal common bile duct stenosis secondary
to benign duodenal ulceration: report of a case. Gastrointest Radiol 1990; 15:215.

93.

Merrill JR. Fistulation to the pancreatic duct complicating duodenal peptic ulcer.
Gastroenterology 1984; 87:957.

94.

Soybel DI, Kestenberg A, Brunt EM, Becker JM. Gastrocolic fistula as a complication of
benign gastric ulcer: report of four cases and update of the literature. Br J Surg 1989; 76:1298.

95.

Shone DN, Nikoomanesh P, Smith-Meek MM, Bender JS. Malignancy is the most common
cause of gastric outlet obstruction in the era of H2 blockers. Am J Gastroenterol 1995; 90:1769.

96.

Johnson CD, Ellis H. Gastric outlet obstruction now predicts malignancy. Br J Surg 1990;
77:1023.

97.

Greiser WB, Bruner BW, Shamoun JM, et al. Factors affecting mortality in patients operated
upon for complications of peptic ulcer disease. Am Surg 1989; 55:7.

98.

DiSario JA, Fennerty MB, Tietze CC, et al. Endoscopic balloon dilation for ulcer-induced
gastric outlet obstruction. Am J Gastroenterol 1994; 89:868.

99.

KOZOLL DD, MEYER KA. OBSTRUCTING GASTRODUODENAL ULCERS. GENERAL


FACTORS INFLUENCING INCIDENCE AND MORTALITY. Arch Surg 1964; 88:793.

100.
Shaffer HA Jr. Perforation and obstruction of the gastrointestinal tract. Assessment by
conventional radiology. Radiol Clin North Am 1992; 30:405.

101.
Weiland D, Dunn DH, Humphrey EW, Schwartz ML. Gastric outlet obstruction in peptic ulcer
disease: an indication for surgery. Am J Surg 1982; 143:90.
102.
Taskin V, Gurer I, Ozyilkan E, et al. Effect of Helicobacter pylori eradication on peptic ulcer
disease complicated with outlet obstruction. Helicobacter 2000; 5:38.
103.
Kate V, Ananthakrishnan N, Badrinath S, et al. Helicobacter pylori infection in duodenal ulcer
with gastric outlet obstruction. Trop Gastroenterol 1998; 19:75.
104.
Misra SP, Misra V, Dwivedi M, Singh PA. Helicobacter pylori-induced lymphonodular
hyperplasia: a new cause of gastric outlet obstruction. J Gastroenterol Hepatol 1998; 13:1191.
105.
Gibson JB, Behrman SW, Fabian TC, Britt LG. Gastric outlet obstruction resulting from peptic
ulcer disease requiring surgical intervention is infrequently associated with Helicobacter pylori
infection. J Am Coll Surg 2000; 191:32.
106.
Annibale B, Marignani M, Luzzi I, Delle Fave GF. Peptic ulcer and duodenal stenosis: role of
Helicobacter pylori infection. Ital J Gastroenterol 1995; 27:26.
107.
de Boer WA, Driessen WM. Resolution of gastric outlet obstruction after eradication of
Helicobacter pylori. J Clin Gastroenterol 1995; 21:329.
108.
Gisbert JP, Pajares JM. Review article: Helicobacter pylori infection and gastric outlet
obstruction - prevalence of the infection and role of antimicrobial treatment. Aliment Pharmacol Ther
2002; 16:1203.
109.
Boylan JJ, Gradzka MI. Long-term results of endoscopic balloon dilatation for gastric outlet
obstruction. Dig Dis Sci 1999; 44:1883.
110.
Geraghty RJ, Black D, Bruce SA. The successful medical management of gastric outflow
obstruction associated with the use of non-steroidal anti-inflammatory drugs in the elderly. Postgrad
Med J 1991; 67:1004.
111.

Hirschowitz BI, Lanas A. Intractable upper gastrointestinal ulceration due to aspirin in patients
who have undergone surgery for peptic ulcer. Gastroenterology 1998; 114:883.

112.
Benjamin SB, Cattau EL, Glass RL. Balloon dilation of the pylorus: therapy for gastric outlet
obstruction. Gastrointest Endosc 1982; 28:253.
113.
Solt J, Bajor J, Szab M, Horvth OP. Long-term results of balloon catheter dilation for benign
gastric outlet stenosis. Endoscopy 2003; 35:490.
114.
Cherian PT, Cherian S, Singh P. Long-term follow-up of patients with gastric outlet obstruction
related to peptic ulcer disease treated with endoscopic balloon dilatation and drug therapy.
Gastrointest Endosc 2007; 66:491.
115.
Cebollero-Santamaria F, Smith J, Gioe S, et al. Selective outpatient management of upper
gastrointestinal bleeding in the elderly. Am J Gastroenterol 1999; 94:1242.
116.
Godil A, DeGuzman L, Schilling RC 3rd, et al. Recent nonsteroidal anti-inflammatory drug use
increases the risk of early recurrence of bleeding in patients presenting with bleeding ulcer.
Gastrointest Endosc 2000; 51:146.
117.
Lanas A, Remacha B, Sinz R, Hirschowitz BI. Study of outcome after targeted intervention
for peptic ulcer resistant to acid suppression therapy. Am J Gastroenterol 2000; 95:513.

118.
Hirschowitz BI, Lanas A. Atypical and aggressive upper gastrointestinal ulceration associated
with aspirin abuse. J Clin Gastroenterol 2002; 34:523.
119.
Hlscher AH, Klingele C, Bollschweiler E, et al. [Postoperative recurrent ulcer after gastric
resection--results of surgical treatment]. Chirurg 1996; 67:814.
120.
Perrault J, Fleming CR, Dozois RR. Surreptitious use of salicylates: a cause of chronic
recurrent gastroduodenal ulcers. Mayo Clin Proc 1988; 63:337.
121.
Fourrier-Rglat A, Lacoin L, Pariente A, et al. When patients report diseases that prescribers
seem unaware of: discordance between patient and physician reporting of risk-related previous
history in NSAID users from the CADEUS study. Clin Pharmacol Ther 2010; 88:668.
122.
Turnage RH, Sarosi G, Cryer B, et al. Evaluation and management of patients with recurrent
peptic ulcer disease after acid-reducing operations: a systematic review. J Gastrointest Surg 2003;
7:606.
123.
Gisbert JP, Khorrami S, Carballo F, et al. Meta-analysis: Helicobacter pylori eradication
therapy vs. antisecretory non-eradication therapy for the prevention of recurrent bleeding from peptic
ulcer. Aliment Pharmacol Ther 2004; 19:617.
124.
Gisbert JP, Calvet X, Feu F, et al. Eradication of Helicobacter pylori for the prevention of
peptic ulcer rebleeding. Helicobacter 2007; 12:279.
125.
El-Nakeeb A, Fikry A, Abd El-Hamed TM, et al. Effect of Helicobacter pylori eradication on
ulcer recurrence after simple closure of perforated duodenal ulcer. Int J Surg 2009; 7:126.
126.
Bose AC, Kate V, Ananthakrishnan N, Parija SC. Helicobacter pylori eradication prevents
recurrence after simple closure of perforated duodenal ulcer. J Gastroenterol Hepatol 2007; 22:345.
127.
Yetkin G, Uluda M, Akgn I, et al. Late results of a simple closure technique and
Helicobacter pylori eradication in duodenal ulcer perforation. Acta Chir Belg 2010; 110:537.
128.
Giuliani A, Galati G, Demoro M, et al. Screening of Helicobacter pylori infection after
gastrectomy for cancer or peptic ulcer: results of a cohort study. Arch Surg 2010; 145:962.
129.
Lindsetmo RO, Eide TJ, Johnsen R, Revhaug A. Helicobacter pylori-induced damage to the
gastric mucosa is not modulated by previous vagotomy or medical treatment of peptic ulcer disease: a
comparative study of vagotomized patients, medically treated peptic ulcer patients and community
control subjects. World J Surg 2008; 32:2267.
130.
Wong GL, Wong VW, Chan Y, et al. High incidence of mortality and recurrent bleeding in
patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Gastroenterology 2009; 137:525.
131.
Tanphiphat C, Tanprayoon T, Na Thalang A. Surgical treatment of perforated duodenal ulcer:
a prospective trial between simple closure and definitive surgery. Br J Surg 1985; 72:370.
132.
Wara P, Kristensen ES, Srensen FH, et al. The value of parietal cell vagotomy compared to
simple closure in a selective approach to perforated duodenal ulcer. Operative morbidity and
recurrence rate. Acta Chir Scand 1983; 149:585.
133.
Robles R, Parrilla P, Lujan JA, et al. Long-term follow-up of bilateral truncal vagotomy and
pyloroplasty for perforated duodenal ulcer. Br J Surg 1995; 82:665.
134.
Jordan PH Jr, Thornby J. Perforated pyloroduodenal ulcers. Long-term results with omental
patch closure and parietal cell vagotomy. Ann Surg 1995; 221:479.

135.
Smith BR, Wilson SE. Impact of nonresective operations for complicated peptic ulcer disease
in a high-risk population. Am Surg 2010; 76:1143.
136.
Abe N, Takeuchi H, Yanagida O, et al. Surgical indications and procedures for bleeding peptic
ulcer. Dig Endosc 2010; 22 Suppl 1:S35.
137.
Stabile BE. Redefining the role of surgery for perforated duodenal ulcer in the Helicobacter
pylori era. Ann Surg 2000; 231:159.
138.
Hirschowitz BI, Fineberg N, Wilcox CM, et al. Costs and risks in the management of patients
with gastric acid hypersecretion. J Clin Gastroenterol 2010; 44:28.