Diagnosis and treatment of perforated or bleeding peptic ulcers: 2013 WSES position paper
World Journal of Emergency Surgery
Diagnosis and treatment of perforated or bleeding peptic ulcers: 2013 WSES position paper
Salomone Di Saverio 0 3
Marco Bassi 4
Nazareno Smerieri 0 3 5
Michele Masetti 0 3
Francesco Ferrara 4
Carlo Fabbri 4
Luca Ansaloni 1
Stefania Ghersi 4
Matteo Serenari 0 3
Federico Coccolini 1
Noel Naidoo 7
Massimo Sartelli 6
Gregorio Tugnoli 0 3
Fausto Catena 2
Vincenzo Cennamo 4
Elio Jovine 0 3
0 Emergency and General Surgery Dept, Maggiore Hospital- Bologna Local Health District , Bologna , Italy
1 General and Emergency and Trauma Surgery, I unit, Ospedali Riuniti , Bergamo , Italy
2 Emergency and Trauma Surgery Dept., Maggiore Hospital of Parma , Parma , Italy
3 Emergency and General Surgery Dept, Maggiore Hospital- Bologna Local Health District , Bologna , Italy
4 Department of Gastroenterology and Operative Endoscopy, Maggiore Hospital- Bologna Local Health District , Bologna , Italy
5 Liver and Multivisceral Transplantation Unit, University of Modena&Reggio Emilia - Policlinico Hospital , Modena , Italy
6 Department of Surgery, Hospital of Macerata , Macerata , Italy
7 Port Shepstone Regional Hospital , Port Shepstone , South Africa - Nelson R Mandela School of Medicine, University of KwaZulu-Natal , Durban , South Africa
Diagnosis and treatment of perforated peptic ulcer (Dr. S. Di Saverio MD)
When PPU are diagnosed expeditiously and promptly
treated, outcomes are excellent. Mortality ranges from
6% to 14% in recent studies [22-24]. Poor outcomes have
been associated with increasing age, major medical illness,
peri-operative hypotension , and delay in diagnosis
and management (greater than 24 hours) . With
improvements in resuscitation, hypotension may no longer
be a significant prognostic indicator . Advanced age
(greater than 70 years) is associated with a higher
mortality with rates of approximately 41% [28,29]. Several
scoring systems including the Boey scoring system 
(Table 2) and the Mannheim Peritonitis Index (MPI) 
have been used to stratify the risk of the patients and
predict the outcomes of patients with perforated peptic ulcer.
The Boey score is the most commonly and easily
implemented among these scoring systems, and accurately
predicts perioperative morbidity and mortality.
Moller et al. derived the Peptic Ulcer Perforation score
(PULP score), a clinical prediction rule for 30-day
mortality. The score assesses and compares its prognostic
performance with the American Society of
Anaesthesiologists (ASA) and Boey scores .
Morbidity is common after perforation, with rates
ranging from 17% to 63% [32,33]. Pulmonary and wound
infections are the most common postoperative infections.
Fungal infections after perforation are fairly common
Table 1 Causes of gastro-duodenal perforation
(between 13 and 37%) and when identified are associated
with significant mortality (up to 21.7%) [34,35]. More
recently a study comparing three scoring systems (American
Society of Anesthesiologists (ASA), Boey and peptic ulcer
perforation (PULP)) regarding the ability to predict
mortality in PPU, found that the PULP score had an odds ratio
(OR) of 18.6 and the ASA score had an OR of 11.6, both
with an area under the curve (AUC) of 0.79. The Boey
score had OR of 5.0 and AUC of 0.75. Hypoalbuminaemia
alone (37 g/l) achieved OR of 8.7 and AUC of 0.78 being
the strongest single predictor of mortality . A further
new prognostic score has been proposed for perforated
duodenal ulcers, including as predictors of poor prognosis
factors such as the presence of multiple gut perforations,
the size of largest perforation >0.5 cm, amount of
peritoneal fluid >1000 ml, simple closure, development of
complications, post-operative systemic septicaemia and
winter/autumn season of presentation. The new scoring
system had an overall sensitivity of 85.12% and
specificity of 80.67% .
Prompt diagnosis of gastroduodenal perforation requires
a high index of suspicion based on history and clinical
examination. A history of intermittent abdominal pain or
gastroesophageal reflux is common. Additionally, known
peptic ulcer disease that has been inadequately treated
or with ongoing symptoms and sudden exacerbation of
pain can be suspicious for perforation. A history of recent
trauma or instrumentation followed by abdominal pain
and tenderness should alert the clinician to the potential
for injury. Patients with gastroduodenal perforation
Table 2 Boey score and outcomes
usually present with abdominal pain and peritoneal
irritation from leakage of acidic gastric contents.
However, physical examination findings may be equivocal,
and peritonitis may be minimal or absent, particularly
in patients with contained leaks . Patients in
extremis may also present with altered mental status,
further compromising an accurate and reliable physical
examination. Laboratory studies are not useful in the
acute setting as they tend to be nonspecific, but
leukocytosis, metabolic acidosis, and elevated serum
amylase may be associated with perforation .
Free air under the diaphragm found on an upright
chest X-ray is indicative of hollow organ perforation and
mandates further work-up and/or exploration. In the
setting of an appropriate history and peritonitis on
examination, free air on X-ray is sufficient to justify exploration.
Patients without pneumoperitoneum at admission on
plain chest radiograph, should be evaluated further by
computed tomography (CT) scanning with oral contrast.
The increased use of CT scans has greatly improved our
ability to detect perforation. Suspicious findings on CT
scan include unexplained intraperitoneal fluid,
pneumoperitoneum, bowel wall thickening, mesenteric fat
streaking, mesenteric hematoma and extravasation of contrast.
However, up to 12% of patients with traumatic
perforations may have a normal CT scan. Adding oral contrast
and performing triple contrast CT scan may improve
diagnostic sensitivity and specifity [39,40].
In the setting of trauma, diagnostic peritoneal lavage
(DPL) has essentially been replaced by the focused
assessment by sonography for trauma (FAST), which lacks
specificity for hollow organ perforation [41,42]. Victims
of penetrating trauma with signs of peritonitis require
surgical exploration without further diagnostic workup.
In blunt trauma patients, and in penetrating trauma
patients without peritonitis, in whom the trajectory of the
missile may be unclear, CT scanning of the abdomen
and pelvis with oral and intravenous contrast remains
the diagnostic gold standard.
We suggest Erect CXR as initial routine diagnostic
assessment in case of acute abdomen from suspected
free perforation of PU.
In case of negative AXR and/or erect CXR, we suggest
CT scan as second level diagnostic tool since its higher
sensitivity in detecting intra-abdominal free air.
In case of negative findings of free intra-abdominal
air and persistent suspicion of PPU, we suggest
adding oral water soluble contrast or via NGT.
Non operative management
Crofts TJ et al. in 1989 conducted a prospective randomized
trial comparing the outcome of nonoperative treatment with
that of emergency surgery in patients with a clinical
diagnosis of perforated peptic ulcer. Of the 83 patients
entered in the study over a 13-month period, 40 were
randomly assigned to conservative treatment, which consisted
of resuscitation with intravenous fluids, institution of
nasogastric suction, and intravenous administration of antibiotics
and ranitidine. Eleven of these patients (28 percent) had no
clinical improvement after 12 hours and required an
operation. Two of the 11 had a perforated gastric carcinoma,
and 1 had a perforated sigmoid carcinoma. The other 43
patients were assigned to immediate laparotomy and repair of
the perforation. The overall mortality rates in the two
groups were similar (two deaths in each, 5 percent), and did
not differ significantly in the morbidity rates (40 percent in
the surgical group and 50 percent in the nonsurgical group).
They concluded that in patients with perforated peptic ulcer,
an initial period of nonoperative treatment with careful
observation may be safely allowed except in patients over
70 years old, and that the use of such an observation period
can obviate the need for emergency surgery in more than 70
percent of patients .
Songne B et al. in 2004 conducted a prospective trial of
82 consecutive patients, with diagnosis of perforated
peptic ulcer. They were initially treated with non-operative
procedure (nasogastric suction and intravenous
administration of H2-blockers or proton-pomp inhibitors).
Clinical improvement was obtained with non-operative
treatment in 54% of the patients (44/82). The overall
mortality rate was 1%. In univariate analysis, significant
predictive factors of failure of non-operative treatment were:
size of pneumoperitoneum, heart beat >94 bpm,
abdominal meteorism, pain at digital rectal exam, and age
>59 years. In multivariate analysis, the significant factors
were the size of pneumoperitoneum, heart beat, and
abdominal meteorism. The association of these criteria: size
of pneumoperitoneum > size of the first lumbar vertebra,
heart beat >94 bpm, pain at digital rectal exam and age >
59 years, led to surgical treatment in all cases.
These results suggested that more than 50% of patients
with perforated peptic ulcer respond to conservative
treatment without surgery and that the association of few
criteria (size of pneumoperitoneum, heart beat, pain at digital
rectal exam and age) required emergency surgery .
In conclusion, the most important factor regarding the
likely success or otherwise of non-operative management
of a perforated peptic ulcer is whether the ulcer has sealed.
This can be shown by gastrografin contrast study. In the
authors experience if there is free leak of contrast from the
ulcer, then surgery is needed. If the ulcer has sealed itself
by adherent omentum etc., then non-operative treatment
is indicated provided the patient does not have peritonitis
or severe sepsis. Percutaneous drainage of collections may
be needed later.
There is anecdotal evidence that gastric ulcers are less
likely to seal spontaneously and also can be malignant
therefore non-operative treatment of perforated gastric
ulcers should be approached with caution.
In the last 10 years we have not found in the literature
any study recommending a conservative approach to
Nonetheless we recommend operative treatment of any
PPU with pneumoperitoneum and signs of peritonitis.
We suggest that an initial trial of non-operative
management may be suitable in stable non-peritonitic
and not severely septic patients with PPU in abscence
of significant pneumoperitoneum (i.e. small confined
perforation with limited extraluminal air amount) as
long as an upper GI contrast study has shown that
the ulcer perforation has sealed and there no free
extraluminal leak of contrast.
Open surgery vs laparoscopy
The number of patients who needed surgical
intervention for complications of peptic ulcer, such as
perforation, remained relatively unchanged [45,46].
Limiting surgical delay is of paramount importance in
treating patients with PPU. In fact from the Danish
Clinical Register of Emergency Surgery, a cohort study
including 2668 patients showed that every hour of delay
from admission to surgery was associated with an
adjusted 2 4 per cent decreased probability of survival
compared with the previous hour .
Perforated peptic ulcer disease is a common
abdominal disease and laparoscopic surgery has changed the
way such emergencies are managed. Perforated peptic
ulcer disease is a condition for which the laparoscopic
approach has significant attractions. Laparoscopy allows
the confirmation of the diagnosis and furthermore
allows the identification of the position, site, and size of
the ulcer [27,48,49]. The procedure also allows closure
of the perforation and adequate peritoneal toilette
without the need for a large abdominal incision.
In the rare occurrence of large perforation with a
severe contamination with food debris that can not be
adequately removed laparoscopically, conversion may be
required for complete peritoneal toilette. In such cases
the perforation may be extensive and a resectional
surgery may be needed.
Evidence for laparoscopic repair is equivocal . In
available evidence, the results after laparoscopic repair
are not clinically different from open surgery, and no
difference is found in abdominal septic complications,
pulmonary complications, or abdominal collections .
The first randomized trial comparing laparoscopic and
open repair of perforated peptic ulcer showed that the
total operative time for laparoscopic repair was
significantly increased but did result in a reduced requirement
for postoperative analgesia . However, in the same
study there was no significant difference found in NG
tube drainage, intravenous fluid usage, hospital stay, and
return to normal diet . More recent randomized,
controlled trials have shown that laparoscopic repair is
associated with shorter operative time, decreased
postoperative abdominal drain use, reduced analgesic
requirement, reduced hospital stay, earlier return to normal diet,
and reduced morbidity . Laparoscopic repair allows a
earlier removal of the abdominal drain, NG tube, and an
earlier return to normal diet and mobilization. Even in
recent studies, authors have noted an increased operative
time ; however, a recent study show, with experience,
the time taken for laparoscopic repair can be comparable
to open repair. Previous studies have shown a suture leak
rate of 7% with laparoscopic repair; however, recent study
demonstrate that this can be completely abolished and
can be superior to open surgery, for which a leak rate of
2% has been reported [52,53]. In addition, the decrease in
tissue dissection and the lack of large abdominal incision
reduced the amount of opiate analgesia needed by patients.
Lau et al.  showed similar results in 100 patients, in
whom there was a reduced requirement for opiate
analgesia. In contrast to previous studies, theres a significant
decrease in hospital stay in patient who underwent
laparoscopic surgery  as well as a reduction in overall
morbidity. Many authors have concluded that both open and
laparoscopic repair of peptic ulcer are both effective
Some authors state that laparoscopy is more
dangerous in a situation of prolonged peritonitis . This is
supported by the finding that pneumonia occurred more
often in the laparoscopy group, although the duration of
perforation was similar in both groups .
Experimental animal studies [56,57] have revealed that the increased
intra-abdominal pressure of carbon dioxide
pneumoperitoneum is associated with an increased risk of bacteraemia
and sepsis when the duration of peritonitis exceeds 12 h
27. Pneumonia may also be caused by increased bacterial
translocation from the peritoneal cavity into the
bloodstream, but there is no evidence to support this concept
from clinical studies . There is not yet sufficient
information about the outcome after open and laparoscopic
repair in high-risk patients. Although risk levels (for
example Boey score, Acute Physiology And Chronic
Health Evaluation II) for perforated peptic ulcer affect
the outcome after both open and laparoscopic repair,
any outcome might still be improved by taking (or
avoiding) one or other of the interventions. Some
surgical centres  have suggested choosing the more
familiar open repair for high-risk patients, although
there is no hard evidence that this is necessarily the
better option. Lunevicius et al. suggest that
laparoscopic repair is at least as safe and effective as open
repair in terms of wound infection and mortality rates,
and shorter hospital stays. The minimally invasive method
is associated with a less painful recovery (balanced by a
higher leak rate) and better cosmesis, fewer adhesions and
incisional hernias, and better diagnostic potential. Patients
with no Boey risk factors (prolonged perforation for more
than 24 h, shock on admission and confounding medical
conditions, defined as ASA grade IIIIV) should benefit
from laparoscopic repair .
Sanabria A. et al. in collaboration with the Cochrane
library has made a review in 2010. They showed that there
was a tendency to a decrease in septic intra-abdominal
complications, surgical site infection, postoperative ileus,
pulmonary complications and mortality with laparoscopic
repair compared with open surgery, none of these were
statistically significant. However, there was a tendency to
an increase in the number of intra-abdominal abscesses
and re-operations, but without statistical significance. This
finding could be related to surgeon experience in
laparoscopic surgery. It is not possible to draw any conclusions
about suture dehiscence and incisional hernia with the
two procedures . Recently Guadagni et al. suggests
that laparoscopic repair for PPU is feasible but skill in
laparoscopic abdominal emergencies are required.
Perforations 1.5 cm or larger, posterior duodenal ulcers should be
considered the main risk factors for conversion .
Comparing laparoscopic versus open repair for PPU,
Byrge N et al. has showed that in the laparoscopic group
the rates of wound complications, organ space
infections, prolonged ventilation, postoperative sepsis, return
to the operating room, and mortality tended to be lower
for the LA, although not significantly. Length of hospital
stay was, however, significantly shorter for the
laparoscopic repair. The authors concluded that laparoscopy is
safe in mild to moderately ill patients with perforated
peptic ulcer and may allow a reduced use of hospital
Laparoscopy allows the surgeon to explore and wash
out the entire peritoneal cavity and it is therefore a
powerful diagnostic tool. The benefits of less postoperative
pain, shorter length of hospital stay and earlier return to
work after laparoscopic surgery for perforated peptic
ulcer may offset the costs needed for performing
Laparoscopic repair also offers the advantage of
We recommend laparoscopic approach to
hemodynamically stable patients with free air at
X-ray and/or CT for diagnostic purposes.
We suggest laparoscopic repair of PPU in stable
patients with PPU <5 mm in size and in presence of
appropriate laparoscopic skills.
We recommend laparoscopy for achieving a better
intraperitoneal lavage, even in presence of diffuse
We suggest that laparoscopy may improve patients
outcome with significantly lower morbidity.
We recommend open surgery in presence of septic
shock or in patients with absolute contraindications
We suggest open surgery in presence of perforated
and bleeding peptic ulcers, unless in stable patients
with minor bleeding and in presence of advanced
laparoscpic suturing skills (Additional file 1: Video 1).
We suggest use of intra-operative methylene blue
via NG tube for precise localization of microscopic
perforations (Additional file 2: Video 2).
Primary repair vs sutureless
Laparoscopic sutureless repair was shown to take a
significantly shorter time than laparoscopic suture repair.
Laparoscopic sutureless repair has the advantage over
laparoscopic suture repair because is technically much
less demanding. The technique can be easily performed
by those who have limited experience with laparoscopic
It is arguable if there are standard laparoscopic
procedures to treat PPU. Sutureless repair was once considered
as safe as suture repair  but it carried extra-costs such
as the use of fibrin glue. Although the rationale of this
sutureless technique was to simplify the procedure and
shorten operative time, it did not gain wide acceptance
owing to its high leakage rate as compared to suture repair
(166%) . Siu et al.  proposed a technique of
closing the ulcer with a single stitch plus omental patch for
small perforations (i.e. \10 mm). They obtained
satisfactory results with a conversion rate of only 7.4% [66,27].
Song et al.  further simplified the method by suturing
the perforation without knotting followed by tying the
suture over an omental patch. Although simple and effective
by avoiding applying suture on fragile edge, the draw back
was that no further rescue maneuver could be made if the
single stitch was tied without good security. Ates et al.
 compared the results of laparoscopic simple closure
without omental patch with that of conventional open
repair in patients with small perforated duodenal ulcer and
prove that is was as safe and as effective. On the other
hand, Turner et al.  reported that suture without an
omental patch would result in a significantly higher
mortality rate than with a patch. However, most cases in their
series were perforated gastric ulcers instead of
juxtapyloric perforation. Finally, Lunevicius et al.  reviewed
13 prospective and 12 retrospective studies and concluded
that repair method should best be judged by the properties
of the ulcer edge. In short, although it seems that no single
method is considered being the standard, the literature
showed that there were no differences between these two
most common adopted procedures in terms of
postoperative recovery and incidence of surgical complications. To
summarize, laparoscopic simple closure alone without
adding an omental patch is a safe procedure for
juxtapyloric perforation in low risk patients. In terms of
leakage rate and surgical outcome, the manoeuver to
cover an omental patch on the repaired PPU did not
show any additional advantage .
We suggest that Laparoscopic sutureless repair may
be a viable option in presence of limited laparoscopic
experience, only in presence of small size perforations
(i.e. microscopic or <2 mm perforations) without
significant peritoneal contamination and for low risk
We recommend primary repair in case of perforated
peptic ulcer larger than 5 mm and smaller than 2 cm
(Additional file 3: Video 3).
We suggest routine use omental patch to further
protect the suture line (see Additional file 3: Video 3).
We recommend avoiding use of glue as only method
of closure of PPU.
We suggest use of glue only as an adjunctive measure
to protect suture line or the omental patch.
We suggest avoiding use of glue because of increased
costs and risks of complications if serious doubts exist
on the efficacy of primary closure.
We suggest conversion to open procedure if the primary
repair is deemed to be done not efficaciously.
The resection surgery is a viable option for giant peptic
ulcers, commonly defined as having a diameter greater
than 2 cm. These lesions have a higher risk of
perforation. In gastric lesions, although the risk of malignancy
is less than historically predicted, the incidence is still
around 10% [72,73]. There are no specific surgical
treatment recommendations since the site of perforation and
the secondary effects on the surrounding anatomical
structures must direct the necessary interventions. These
patients are also frequently in septic shock upon
presentation when the amount of peritoneal spillage is large.
This factor alone should significantly influence the choice
of operative intervention. Giant gastric ulcers are most
commonly located on the lesser curvature and will often
require an antrectomy and reconstruction. For perforated
giant duodenal ulcers, the defect is often too large to
perform a primary repair. Leak rates of up to 12% have been
reported from attempted closure with an omental patch
procedure . The proximity of the defect and its
relation to the common bile duct and ampulla of Vater must
also be thoroughly investigated. Intraoperative
cholangiography may even be necessary to verify common bile duct
anatomy. There are several different procedures that have
been described for duodenal defects such as a jejunal
serosal patch, tube duodenostomy, and several variations of
omental plugs antrectomy with diversion is the classic and
most commonly described intervention, if the ampullary
region is not involved. Affected patients are often in
extremis at the time of presentation, and therefore a damage
control procedure will likely be the safest and most
appropriate operation for the patient. An antrectomy, with
resection of the duodenal defect for duodenal ulcers
proximal to the ampulla, will allow a definitive control of the
spillage. Depending upon the location of the duodenal
defect, closure and diversion via antrectomy may be the
safest method for damage control.
The proximal gastric remnant should be decompressed
with a nasogastric tube placed intraoperatively with
verification of its correct position. Anastomoses should be
avoided in presence of hypotension or hemodynamic
instability, especially if the patient requires vasopressors.
After copious abdominal irrigation, a temporary
abdominal closure device can be placed. The patient can then be
resuscitated appropriately in the ICU. The surgeon can
return to the OR for re-exploration, restoration of
continuity, possible vagotomy, and closure of the abdomen once
the patient is hemodynamically stable .
We suggest resectional surgery in case of perforated
peptic ulcer larger than 2 cm (Additional file 4: Video 4)
We suggest resectional surgery in presence of malignant
perforated ulcers or high risk of malignancy (e.g. large
ulcers, endoscopic features of malignancy, presence
of secondary lesions or suspected metastases, etc.)
(Additional file 4: Video 4).
We suggest resectional surgery in presence of
concomitant significant bleeding or stricture.
We suggest use of techniques such as jejunal serosal
patch or Roux en-Y duodenojejunostomy or pyloric
exclusion to protect the duodenal suture line, in case
of large post-bulbar duodenal defects not amenable
to resection (i.e. close to or below the ampulla).
Whenever possible (i.e. stable patient), in case of
repair of large duodenal ulcer, we suggest to perform a
cholecistectomy for external bile drainage (e.g. via
We suggest duodenostomy (e.g. over Petzer tube)
only as an extreme option, in presence of giant
duodenal ulcers with severe tissue inflammation and
when mobilization of the duodenum is not possible
and the patient is in severe septic shock/hemodynamic
Other techniques and future developments
Self-expandable metal stents
Primary stenting and drainage has been shown to be an
effective and safe way to treat esophageal perforations or
anastomotic leaks after gastric bypass surgery.
M. Bergstrom et al. present a case series of eight
patients with perforated duodenal ulcers treated with
covered self-expandable metal stents (SEMS).
Two patients received their stents because of
postoperative leakage after initial traditional surgical closure.
Six patients had SEMS placed as primary treatment due
to co-morbidities or technical surgical difficulties.
Endoscopy and stent treatment in these six patients was
performed at a median of 3 days (range, 07 days) after
initial symptoms. Six patients had percutaneous
abdominal drainage. Early oral intake, 07 days after stent
placement, was possible. All patients except one
recovered without complications and were discharged 936
days after stent placement. This study indicates that in
cases where surgical closure will be difficult, gastroscopy
with stent placement can be performed during the
laparoscopy, followed by laparoscopic drain placement. In
patients with severe co-morbidity or delayed diagnosis,
gastroscopy and stent placement followed by
radiologically guided drain placement can be an alternative to
conservative treatment .
Natural orifice transluminal endoscopic surgery (NOTES)
A NOTES approach may reduce the physiologic impact
of therapeutic intervention after peptic ulcer perforation
and provide a technically less challenging procedure.
Experimental data suggest that the NOTES repair may be
possible with lower intraabdominal pressure .
Preclinical trials of endoscopic omental patch closures for upper
gastrointestinal viscus perforations have been published
. A retrospective review suggested that up to 50% of
patients presenting with perforated ulcer might be
candidates for a NOTES repair .
Bingener et al.  present a pilot clinical study
evaluating the feasibility of endoscopic transluminal
omental patch closure for perforated peptic ulcers,
with the hypothesis that the technique will be
successful at closing ulcer perforations, as evidenced by
intraoperative leak test and post operative water-soluble
After induction of general anesthesia,
pneumoperitoneum (1214 cm H2O) has been established using a
periumbilical trocar in Hasson technique. This served to
confirm the diagnosis of ulcer perforation and for
surveillance of the endoscopic procedure. A standard
diagnostic upper endoscope with CO2 insufflation has been
introduced through the oropharynx into the stomach and
duodenum. The site of perforation was identified and
measured. The endoscope was carefully advanced through the
perforation when possible. Once in the peritoneal cavity,
the endoscopist proceeded with inspection and irrigation.
A viable mobile piece of omentum was identified, and
pulled intraluminally through the site of perforation. The
omentum was then fixed to the mucosa of the luminal wall
with several endoscopic clips. The falciform ligament was
used if a suitable omental patch was not available. If the
NOTES procedure was unsuccessful, either a laparoscopic
or open omental patch repair was considered by the acute
care surgical team .
Initial results from a laparoscopic-assisted NOTES
approach for closure of perforated peptic ulcers appear
promising and enable swift recovery in selected patients.
This is especially important in elderly and/or
immunocompromised patients. Technical details and patient selection
criteria continue to evolve.
We do not recommend NOTES approach for PPU
treatment until further experience and clinical
evidence is gained.
Diagnosis and treatment of bleeding peptic ulcer
(Dr. M. Bassi MD)
Acute upper gastrointestinal bleeding (UGIB) is the most
common gastroenterological emergency and has a
considerable morbidity and mortality. Management strategies
have changed dramatically over recent decades due to the
introduction of acid suppressive therapy, especially proton
pump inhibitors (PPIs), and endoscopic therapy.
The incidence rates of UGIB demonstrate a large
geographic variation ranging from 48 to 160 cases per
100 000 population [81-84].
Possible explanations for the reported geographic
variation in incidence are: differences in definition of UGIB in
various studies, population characteristics, prevalence of
ulcerogenic medication, in particular aspirin and
nonsteroidal anti-inflammatory drugs (NSAIDs), and Helicobacter
pylori (H. pylori) prevalence.
Some but not all time-trend studies have reported a
significant decline in incidence of acute UGIB, especially
peptic ulcer bleeding (PUB), in recent years. This
decline is likely due to a combination of factors,
including decreasing prevalence of gastric colonization with
H. pylori, the use of eradication therapy in patients
with ulcer disease, and the increased use of PPI
therapy, both in general and in patients using aspirin and
NSAIDs in particular [81,85].
At the same time, an increasing proportion of patients
presenting with UGIB are older and a significant
number of patients with UGIB consume NSAIDs and/or
antiplatelet therapy to treat other medical comorbidities.
Given these factors, UGIB continues to have a
considerable impact with respect to patient morbidity and
mortality, as well as health care resource utilization. The
mortality rate of UGIB remains high somewhere
between 7% and 14%. UGIB accounts for > 300 000 annual
hospitalizations in the United States, with an estimated
cost of $ 2.5 billion [86-88].
The majority of deaths do not directly result from
exsanguination, but are related to poorly tolerated blood loss
and resultant shock, aspiration, and therapeutic
procedures. As such, mortality from UGIB is strongly associated
with advanced age and presence of severe comorbidity.
The risk of mortality increases with rebleeding, which is
thus another major outcome parameter.
The incidence of rebleeding in patients with UGIB
shows a wide range from 5% to more than 20%,
depending on the aetiology of the bleeding and the timing of
endoscopic therapy. There is strong evidence that the
risk of rebleeding is highest in the initial period of
admission, and a 24-h time frame for endoscopic therapy
is internationally recommended as the optimal window
of opportunity. Naturally, rebleeding must be prevented
whenever possible [86,89].
PUB is the most common cause of acute UGIB,
accounting for 31%-67% of all cases, followed by erosive
disease, varices, oesophagitis, malignancies and
MalloryWeiss tears (Table 3) [81,83,90].
In the subgroup of patients with PUB, bleeding from
duodenal ulcers is slightly more frequent than from
gastric ulcers .
Emergency surgery for PUB has continued to decrease;
in the UK, the rate of surgery dropped from 8% to 2%
between 1993 and 2006. In the same period in the USA,
admissions to hospital for peptic ulcer bleeding fell by
28,2%, the use of endoscopic treatment increased by
58,9%, and the rate of emergency surgery for PUB
decreased by 21,9% [92-94].
Initial assessment, resuscitation and risk-scores
A primary goal of the initial assessment is to determine
whether the patient requires urgent intervention (e.g.,
endoscopic, surgical, transfusion) or can undergo delayed
endoscopy or even be discharged to outpatient management.
Patients presenting with acute UGIB should be assessed
promptly and resuscitated if needed. Volume should be
replenished initially with crystalloid solutions.
In patients with ongoing blood loss, symptomatic
anaemia, or those at increased risk of impaired tissue
oxygenation (e.g., patients with chronic heart conditions),
blood should be transfused. In haemodynamically stable
patients who are not bleeding actively, the threshold of
transfusion needs to be defined. International guidelines
Table 3 Causes of upper gastrointestinal bleeding
recommend a policy of transfusion to a haemoglobin
concentration of 7 g/dL .
Coagulopathy at presentation is a major adverse
prognostic factor. From the UK National Audit, coagulopathy
defined by an international normalised ratio (INR) above
1,5 was present in 16,4% of patients and was associated
with a 15% mortality rate .
Coagulopathy is also a marker for other comorbidites,
such as chronic liver disease. Bleeding in these patients
is often more severe, and coagulopathy should be
corrected in those with active bleeding. The target INR has
not been defined and is established by the patients
indication for anticoagulation. A study showed that mild to
moderate anticoagulation (INR 1,32,7) at endoscopy
did not increase the risk of recurrent bleeding compared
with an INR of less than 1,3 .
One small cohort study with a historical comparison
showed that aggressive resuscitation including correction
of coagulation (INR <1,8) led to lower mortality rates .
Although numerous factors from the patient history,
physical examination, and initial tests have been
examined for an association with a need for intervention, no
single factor is sufficiently predictive of UGIB severity to
be used for triage .
The most predictive individual factors are a history of
malignancy, presentation with hematemesis, signs of
hypovolemia including hypotension, tachycardia and shock, and
a haemoglobin < 8 g/dL [99,100].
Some factors, such as a history of aspirin or NSAIDs
use, may not be useful for immediate disposition but are
still important to assess for future management (e.g., if
PUB were the aetiology of UGIB, then NSAIDs use
should be discontinued). Patients who have significant
comorbidities may require admission regardless of the
severity of the UGIB [98,101].
Several scoring systems have been created and/or
validated for this purpose, including APACHE II, Forrest
classification, Blatchford score, pre-endoscopic Rockall
score. Some of these may be cumbersome (APACHE II)
or require data not immediately available based on initial
clinical assessment (the Rockall Scoring System, for
instance, requires endoscopic data) and therefore may be
of limited utility in the acute setting [87,102].
The Blatchford score and the pre-endoscopic Rockall
score have been examined in several studies and may
determine the need for urgent endoscopy (Table 4) [103,104].
The Blatchford score uses data on blood urea and
haemoglobin levels, systolic blood pressure, pulse,
presentation with melena, presentation with syncope,
history of hepatic disease, and history of heart failure. A
Blatchford score > 0 was 99% to 100% sensitive for
identifying a severe bleed in 5 studies [103,105].
The specificity of the Blatchford scoring system is low
(4%-44%), but clinically it is more important to be
Blood, adherent clot,
M: Male; F: Female; SBP: Systolic blood pressure; CHF: Congestive heart failure; IHD:
ischemic hearth disease.
comfortable identifying all severe UGIB at the expense
of admitting some patients with minor bleeding
episodes. Patients found to have minor bleeding episodes
typically may be discharged soon after endoscopy. Use
of the Blatchford score may allow early discharge of 16%
to 25% of all patients presenting with UGIB [103,105,106].
The use of a nasogastric tube remains controversial
; in theory, the presence of bright red blood via
nasogastric aspirate suggests active UGIB and should
prompt urgent to esophagogastroduodenoscopy (EGD).
The absence of blood on nasogastric aspirate, however,
does not exclude the presence of a culprit UGIB source .
In a study by Aljebreen et al., 15% of patients with
UGIB and clear or bilious nasogastric aspirate were
ultimately found to have an underlying high risk lesion
during EGD .
Hemoglobin g/dL F: 1011.9
> 100 with SPB 100 1
Pharmacologic therapy prior to endoscopy
Early administration of intravenous PPIs in patients who
present with signs of UGIB is reasonable. A Cochrane
meta-analysis of six randomised controlled trials (n = 2223)
noted a reduction in high-risk stigmata of bleeding (37,2%
vs. 46,5%,) with early use of PPIs and a lower proportion of
patients undergoing endoscopic therapy (8,6% vs. 11,7%).
The reduction in endoscopic treatment leads to early
discharge in some patients with clean-based ulcers and
low-risk stigmata and is cost saving.
However, the use of proton-pump inhibitors should
not replace urgent endoscopy in patients with active
A prokinetic drug given before endoscopy helps to
empty stomach contents and improves viewing at
endoscopy. These drugs are rarely used by endoscopists. Only
five randomised trials and their pooled analysis have
been published: three with the use of erythromycin and
two with metoclopramide.
The use of these drugs reduces the need for a second
endoscopic examination for diagnosis but no significant
difference in other clinical outcomes was recorded [94,108].
At present, insufficient evidence exists to support the
use of tranexamic acid in acute PUB .
Endoscopy in patients with PUB is effective and is
associated with a reduction in blood transfusion
requirements and length of intensive care unit/total hospital
The optimal timing for endoscopy in PUB remains
under debate .
In appropriate settings, endoscopy can be used to assess
the need for inpatient admission.
Several studies have demonstrated that hemodynamically
stable patients who are evaluated for UGIB with upper
endoscopy and subsequently found to have low-risk
stigmata for recurrent bleeding can be safely discharged
and followed as outpatients [110,111].
Patients with unstable haemodynamics and active
haematemesis should be offered urgent endoscopy with a
view to haemostasis. Patients who are stable after initial
resuscitation generally undergo endoscopy the next
morning. Evidence for the use of early endoscopy
(generally defined by endoscopy within 24 h) came from
cohort studies and their meta-analysis and results in
significantly reduction of the hospital stay and
improvement of the outcome [86,94,112].
However, although emergency endoscopy should be
considered in patients with severe bleeding, very early
endoscopy (<12 h) has so far not been shown to provide
additional benefit in terms of reduction of rebleeding,
surgery and mortality, compared with later endoscopy
(within 24 h) [113-115].
The Forrest classification is often used to distinguish
endoscopic appearances of bleeding ulcers (Ia spurting
active bleeding; Ib oozing active bleeding; IIa visible vessel;
IIb adherent clot; IIc flat pigmented spot; III ulcer with a
clean base) .
In PUB, patients with active bleeding ulcers or a
non-bleeding visible vessel in an ulcer bed are at
highest risk of re-bleeding and therefore need prompt
endoscopic hemostatic therapy.
Patients with low-risk stigmata (clean-based ulcer or a
pigmented spot in ulcer bed) do not require endoscopic
Two small randomised trials, and a meta-analysis
suggested that a clot should be removed in search of an artery
and, when it is present, endoscopic treatment should be
given, although the management of peptic ulcers with
overlying adherent clots that are resistant to removal
by irrigation is still controversial [98,117-119].
Endoscopic treatment can be divided into injection
(including epinephrine, sclerosants and even normal saline
solution), thermal (including monopolar or bipolar
cautery and argon plasma coagulation) and mechanical
methods (including hemoclips).
Often, the choice of which endoscopic therapy employ
is based on local preference and expertise.
Injection of diluted epinephrine alone is now judged
to be inadequate .
Cushions of fluid injected into the submucosa
compress the artery to stop or slow down bleeding and allow
a clear view of the artery. A second modality should be
added to induce thrombosis of the artery.
Calvet et al. pooled the results of 16 randomised
controlled trials that compared injection of diluted
adrenaline alone with injection followed by a second modality,
and showed that combination treatment led to
substantial reductions in rate of recurrent bleeding (risk
reduction from 18,4% to 10,6%), surgery (from 11,3% to 7,6%)
and mortality (from 5,1% to 2,6%) .
The investigators also compared studies with or without
second look endoscopies after initial endoscopic
treatment. Rebleeding was higher in the group given
adrenaline injection alone than in the combination treatment
group (15,7% vs. 11,4%).
Two other meta-analyses that summarised studies of
monotherapies versus dual therapies also concluded that
a second modality should be added to injection
The observation suggested that if combination
treatment had been instituted at index endoscopy, a second
look endoscopy would have been unnecessary, so routine
second look endoscopy after initial endoscopic
haemostasis is not recommended .
A new promising endoscopic application is the use of a
chemical compound which, when sprayed as nanopowder
on active bleeding, can lead to immediate hemostasis, with
coverage of the bleeding ulcer with a powder layer. In a
pilot study of 15 patients with active PUB treated with this
nanopowder, immediate hemostasis was achieved in 93%,
and one patient had recurrent bleeding. No adverse events
were reported during the follow-up. Further studies with
this product are ongoing .
Early endoscopy (within 24 h) in PUB results in
significantly reduction of the hospital stay and
improvement of the outcome. Dual endoscopic therapy, rather
than monotherapy, led to substantial reductions in
rate of recurrent bleeding, surgery and mortality .
Pharmacotherapy plays a second major role in the
treatment of PUB. PPIs can be administered orally or
intravenously depending on the rebleeding risk.
In a randomized placebo-controlled trial of 767 PUB
patients treated with endoscopic therapy because of
high-risk stigmata, high-dose intravenous PPIs (80 mg
esomeprazole bolus plus 8 mg/h continuous infusion
for 72 h) significantly reduced rebleeding (5.9% vs.
10.3%, P = 0.03) and the need for endoscopic
Similar results were found by meta-analysis; high-dose
intravenous PPIs after endoscopic therapy significantly
reduced rebleeding, need for surgery and mortality
compared with placebo/no therapy .
PPIs are recommended for 68 weeks following UGIB
and/or endoscopic treatment of PUD to allow mucosal
Once mucosal healing has been achieved, how long it
should last the PPIs use is still controversial.
Studies have shown that in patients who have PUD
complicated by bleeding, there is a 33% risk of rebleeding
in 12 years. Furthermore, there is a 40%-50% rebleeding
risk over the subsequent 10 years following the initial
episode of bleeding .
Randomized prospective trials have demonstrated a
benefit to long-term acid-suppression therapy in two
settings: chronic NSAID users and H. pylori-infected
Testing for H. pylori is recommended in all patients
This should be followed by eradication therapy for
those who are H. pylori-positive, with subsequent
assessment of the effect of this therapy, and renewed
treatment in those in whom eradication fails .
High-dose continuous intravenous PPIs is
recommended in patients with PUB and high-risk stigmata.
Continued and recurrent bleeding
Despite adequate initial endoscopic therapy, recurrent
UGIB can occur in up to 24% of high-risk patients .
Mortality after a surgical salvage in the recent UK
National Audit was 29% .
Large ulcers located in the posterior bulbar duodenum
and lesser curvature of stomach can erode into the
gastroduodenal or the left gastric artery, respectively, which
are predictive of endoscopic treatment failure.
These ulcers often occur in elderly patients who present
with a major bleed in shock and low initial haemoglobin
Patients with massive bleeding who do not respond to
endoscopy are often shifted to surgical treatment.
Angiographic embolization is an alternative when its
expertise is immediately available.
Loffroy et al. summarised outcomes in ten case series
of 75 patients treated with embolization. The rate of
clinical success, rebleeding, and mortality rate was 75%,
25%, and 25%, respectively .
In retrospectives comparisons of angiographic embolization
versus surgery, in patients with PUB who do not respond to
endoscopic haemostatic attempts, angiographic embolization
was associated with reduced treatment-related complications
(2054% vs. 3768%). Mortality after either treatment was
similar (330% vs. 1430%) [131-133].
A randomised controlled trial compared surgery with
further endoscopic treatment for rebleeding. In 75% of
these patients, further endoscopic treatment led to
durable haemostasis. Patients randomly allocated to surgery
had substantially more postoperative complications.
However, a sub-group analysis suggested that ulcers
larger than 2 cm and a major rebleeding with hypotension
were factors that predicted failure in further endoscopic
attempts; thus, in these patients, surgery or angiographic
embolization should be immediately available if repeated
endoscopic treatment fails .
A recent study suggests transcatheter superselective
angioembolization, with reembolization if necessary, is an
effective rescue treatment modality for hemodynamically
unstable patients with active gastrointestinal hemorrhage
and is a reasonable management option. Twenty percent
of patients will fail superselective angioembolization and
require additional intervention. Ischemic complications
are extremely rare .
For patients with intractable ulcer bleeding, Schroeder
et al. from the analysis of large database (ACS-NSQIP)
have found that the surgical procedure of vagotomy/
drainage is associated with significantly lower mortality
than just with simple local ulcer oversew. They futher
suggest that vagotomy/drainage is preferred to local
procedures alone for the surgical management of patients
with bleeding peptic ulcer disease requiring emergency
operation for intractable bleeding ulcers .
Open surgery is recommended when endoscopic
treatments failed and there is evidence of ongoing bleeding +/
hemodynamic instability. The surgeon may not know
preoperatively where the bleeding comes from and
intraoperative endoscopic guidance may be helpful. A retractor
that elevates the sternum might be needed (the so called
Goligher sternal-lifting retractor) and sometimes is
necessary to excise the xiphisterum. Then, after defusing the
spleen, the oesophagus should be taped to enable control
of stomach. In case of bleeding gastric ulcer (GUs), anterior
gastrotomy can be easily performed. In case of bleeding
duodenal ulcer (DUs) it might be needed to perform a
duodenotomy and open across D1 and pylorus, longitudinally.
Bleeding GUs should be resected (even just a local
resection) or at least biopsied for the possibility of
neoplasms. Most of DUs arriving to surgery for persistent
bleeding are usually big and posterior lesions and the
bleeding is often from gastro-duodenal artery. Via
duodenotomy, the bleeding vessel can be seen on the floor of
the ulcer and can be rapidly oversewn; then the
duodenotomy is closed normally with horizontal sutures to avoid
stenosis and without need of routine pyloroplasty.
A Billoth-1 resection with distal gastrectomy might be
needed if D1 is fully shattered by a large duodenal ulcer.
Surgical hemostasis or angiographic embolization
(where readily available) should be performed only
after endoscopic failure.
Open surgery is recommended when endoscopic
treatments failed and there is evidence of ongoing
bleeding +/ hemodynamic instability.
Peptic ulcer bleeding in patients receiving anti-thrombotic
Patients on antiplatelets or anticoagulant therapy with
acute UGIB represent a major challenge and need to be
managed on a individual basis and the best way to treat
patients on antithrombotic drugs with acute UGIB is
These patients are of course at high risk of
thromboembolism because of their underlying cardiovascular illness.
However, discontinuation of anti-thrombotic therapy
may be necessary to control bleeding or prevent rebleeding.
A multidisciplinary and individualized evaluation is
needed to decide either to stop or to resume
antithrombotic, balancing thromboembolic risk against the
risk of bleeding.
In a randomised trial of continuous versus
discontinued aspirin treatment in patients with PUB and high
cardiothrombotic risks, those receiving continuous aspirin
had a twofold increased risk of early recurrent bleeding
(10,3% vs. 5,4% at day 30) but a tenfold reduced risk of
mortality (1,3% vs. 10,3% at 8 weeks) compared with
those remained without aspirin .
In patients at low risk of recurrent bleeding, aspirin
can be resumed the after-bleeding morning.
The antiplatelet effect of aspirin lasts for about 5 days
and the risk of early recurrent bleeding is high in the first
3 days; thus, in high-risk cardiovascular patients, it might
be reasonable to resume aspirin on fourth day after
bleeding to minimise both bleeding and thrombotic risks .
Patients on dual antiplatelet treatment (e.g. aspiring
and clopidogrel), especially after recent placement of
drug-eluting coronary stents, are at high risk of
thrombosis. In patients at low risk of recurrent bleeding, dual
antiplatelet treatment should be continued.
In those at high risk, cessation of both antiplatelet
drugs should be avoided, given the very high risk of stent
In high-risk patients, after endoscopic control of
bleeding, high-dose PPIs infusion and temporarily withholding
of clopidogrel is recommended.
Early resumption of clopidogrel should be
considered in patients who had stent placement within
4 weeks, left main stem disease, and known coronary
artery dissection .
Major gastrointestinal bleeding is often associated with
Rapid correction of the coagulopathy is recommended.
Intravenous vitamin K will reverse the coagulopathy due
to warfarin, but its full effect can take up to 24 hours.
Prothrombin complex concentrates rapidly reverse
coagulopathy, and this treatment is preferred over
fresh frozen plasma, especially in patients with cardiac
and renal failure who poorly tolerate fluid overload .
If anticoagulant therapy has been prescribed there is a
high-probability that this patients are at high risk of
thrombosis; treatment with low-molecular-weight or
unfractionated heparin should be considered in almost
all cases . However the treatment with
unfractionated heparin in the initial stage can be more easily
controlled than low molecolar weight heparin.
Bleeding in patients treated with new oral
anticoagulants (NOACs), which include dabigatran, rivaroxaban,
apixaban, and edoxaban, represents an extreme
challenge. Currently no antidote exists to reverse the effects
of these drugs. Specific antidotes for the reversal of the
anticoagulant effect of these drugs, such as monoclonal
antibodies against the direct thrombin inhibitor
dabigatran or recombinant Xa-analog in the case of factor Xa
inhibitors, are still being investigated in early clinical
trials. In certain situations, as in case of emergency surgery
or life-threatening major bleeding, a rapid reversal
strategy is needed. Several non-specific prohemostatic agents
or coagulation factor concentrates have been suggested
as potential candidates for the reversal of NOACs.
Activated prothrombin complex concentrate seems
promising for the reversal of dabigatran, while non-activated
prothrombin complex concentrates have potential for
the reversal of anti-factor Xa . In such cases a
consultation between critical care speciliast, haematologist
and a nephrologists is recommended.
Additional file 1: Video 1. Laparoscopic suture and repair of perforated
and bleeding ulcer in a patient hemodynamically stable; Operating
Surgeon Dr. Salomone Di Saverio MD.
Additional file 2: Video 2. Difficult localization of a small PPU: use of
Methylene Blue via NGT for localization; Operating Surgeon Dr. Salomone
Di Saverio MD.
Additional file 3: Video 3. Technique of laparoscopic primary suture
and repair of PPU larger than 1 cm; Operating Surgeon Dr. Salomone Di
Additional file 4: Video 4. Laparoscopic finding of a very large
malignant perforated ulcer of the posterior gastric wall: an indication for
conversion and open total gastrectomy; Operating Surgeon Dr. Salomone
Di Saverio MD.
This article contains supplemental online multimedia material.
Study conception and design: SDB, NS, FC, LA, VC, EJ. Acquisition of data: NS,
MB, SDS, VC. Analysis and interpretation of data: MB, SDS, NS, VC. Drafting of
manuscript: NS, MB, SDS. Critical revision: SDS, MB, NS, MM, FF, CF, LA, SG,
MS, FC, NN, MS, GT, FC, VC, EJ. Final approval of the final version. SDS, MB,
NS, MM, FF, CF, LA, SG, MS, FC, NN, MS, GT, FC, VC, EJ. All authors read and
approved the final manuscript.
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