Introduction

Perforated peptic ulcers are a rare but serious complication of peptic ulcer disease, which carries a significant risk of both morbidity and mortality. Perforation occurs in approximately 5% of patients with existing peptic ulcer disease, a condition which affects over 4 million people worldwide each year. Early diagnosis and intervention is crucial to minimise mortality rates, which have been reported to be up to 30%.

Epidemiology

  • Incidence: 7.00 cases per 100,000 person-years
  • Peak incidence: 70+ years
  • Sex ratio: more common in males 1.3:1
Condition Relative
incidence
Acute cholecystitis20.00
Acute pancreatitis5.71
Bleeding peptic ulcer2.14
Mallory-Weiss tear1.14
Perforated peptic ulcer1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

There are a number of risk factors which are strongly related to the development of peptic ulcer disease and therefore perforated peptic ulcers. The prevalence of perforation in those with peptic ulcer disease is approximately 5%. The two most common causes are use of non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H pylori) infection. It is important to note that the majority of peptic ulcer perforations occur in older populations with existing peptic ulcer disease, rather than younger populations.

NSAIDs
  • Chronic NSAID use is associated with peptic ulcer disease
  • In those who use NSAIDs for a long duration, the incidence of developing a peptic ulcer is approximately 25%
  • Furthermore, the incidence of developing a bleeding or perforated peptic ulcer is approximately 2-4%
  • The longer the duration of NSAID use, the higher the risk of developing peptic ulcers

H pylori infection
  • H pylori is a common infection, with an incidence of approximately 50% worldwide, however not all of those infected will develop peptic ulcer disease. Of those infected, an estimated 10% will go on to develop an ulcer in adulthood (extremely rare in childhood).
  • In H pylori infected individuals, the likelihood of developing a peptic ulcer is 6-10 fold higher than non-infected individuals
  • In a patient with both chronic NSAID use and H pylori infection, the risk is even further increased
  • With appropriate treatment and eradication of H pylori infection, the risk of recurrent peptic ulcer disease and perforation is significantly decreased

Smoking
  • The link between smoking and peptic ulcer disease is well established
    • The incidence of ulcers is nearly doubled in current and former smokers (11%) compared to non-smokers (6%)
  • The mechanism is that tobacco is predicted to inhibit bicarbonate secretion from the pancreas, therefore increasing the acidity in the duodenum (therefore linked more to duodenal ulcers than gastric)

Pathophysiology

Peptic ulcer perforation is caused by complete erosion of an existing peptic ulcer through the wall of the viscus (either stomach or duodenum) into the peritoneal cavity. It is well established that a peptic ulcer must first be present for perforation to occur, however the reason as to why some perforate and others do not is still unclear.

Ulcer formation
  • Peptic ulcer formation is linked to a number of risk factors, explained in the section below
  • The primary mechanism leading to ulcer formation is an imbalance between damaging factors to the mucosal lining, and the normal protective defence mechanisms. Therefore, the normal defence mechanisms are overwhelmed
  • Normal defence mechanisms
    • Secretion of mucous which forms a protective coating over the gastric mucosa which is impermeable to acid and pepsin (damaging substances)
    • Secretion of bicarbonate into the mucosal layer which acts as a alkaline buffer to acidic substances which may damage the mucosa
    • Tight junctions between adjacent epithelial cells, preventing entry of harmful substance
    • With any damage to the spaces between these epithelial cells, normally healthy cells will rapidly migrate to the site of injury to heal the defect (the process of restitution)
  • NSAID induced damage
    • Inhibition of cyclooxygenase 1 (COX-1) derived prostaglandins causes reduction in mucous and bicarbonate secretion, rendering the mucosa exposed and more prone to damage
    • Reduction in gastric mucosal blood flow, therefore reducing the ability of epithelial cells to regenerate and heal mucosal injury
  • H pylori induced damage
    • H pylori results in gastric acid hypersecretion
    • The presence of H pylori induces a pro-inflammatory state, as when the H pylori enters the gastric epithelium, it causes release of multiple pro-inflammatory cytokines (e.g. gro-alpha, interleukin-8)
    • Results in ongoing inflammation and subsequent gastritis, which in time can lead to erosions and ulceration

Perforation
  • Without treatment of peptic ulcer disease, the inflammatory and ulcerative process continues
  • As inflammation and acidic damage ensues, the ulcer can continue to deepen and penetrate into deeper layers of the wall
  • If the outermost layer (the serosa) is breached by continued ulceration, this is the point where the perforation occurs, as a full-thickness injury has now occurred to the organ wall
  • The gastric contents are able to exit the stomach or duodenum and enter the peritoneal cavity, resulting in chemical peritonitis and irritation, leading to the clinical features of pain, rigidity, tenderness and distention

Clinical features

The classical triad of features in a perforated peptic ulcer is abdominal pain, tachycardia and abdominal rigidity. In practice, most patients present with symptoms of an acute abdomen.

Symptoms
  • Abdominal pain (98%)
    • Very severe
    • Constant pain
    • Most frequently epigastric in the beginning, but rapidly becomes generalised
  • Abdominal distention (75%)
  • Nausea and vomiting (35%)
  • Dyspepsia (30%)
  • Constipation (30%)
  • Shoulder tip pain (Kehr's sign)
    • Pain may radiate to the tip of the right shoulder, or less commonly both shoulders
    • Due to irritation within the peritoneal cavity from released gastric contents

Signs
  • Abdominal tenderness (90%)
    • Frequently in the epigastric region
  • Peritonitis (70%)
    • Guarding
    • Rigidity
    • Rebound tenderness
  • Fever (20%)
  • Tachycardia
    • Primary - from a systemic inflammatory response
    • Secondary - from reduced fluid intake and increased output from vomiting

It is important to note that there is usually a history of peptic ulcer disease, and therefore it is important to ask whether there is a known diagnosis, or for symptoms/signs of the condition. The clinical features of peptic ulcer disease include:
  • Abdominal pain
    • Typically a chronic and recurrent pain
    • Located in the epigastric region
    • The pain from gastric ulcers tends to worsen with eating, while the pain with duodenal ulcers tends to worsen on an empty stomach
  • Abdominal tenderness
    • Typically in the epigastric region
  • Symptoms of anaemia (fatigue, pallor, shortness of breath)
    • Occurs if the ulcer is bleeding and has caused an iron deficiency anaemia

Investigations

As with most patients who present with an acute abdomen, there are a variety of tests required to promptly identify the cause of the pain. A large number of investigations performed will be to assist in ruling out certain other differential diagnoses.

Blood tests
  • Full blood examination
    • Leukocytosis is likely present, however is also raised in a number of other possible conditions such as cholecystitis, pyelonephritis, pancreatitis and appendicitis
    • Anaemia may be present if significant haemorrhage has occurred
  • Serum urea, electrolytes and creatinine
    • Significant haemorrhage from a bleeding ulcer may result in electrolyte disturbances
    • With significant bleeding, urea may be raised (as digested blood is a source of protein)
    • May help to rule out renal pathology
  • Urine microscopy, culture and sensitivity
    • Will help to rule out urinary pathology such as pyelonephritis and renal stones
    • Usually normal in perforated peptic ulcer disease
  • Liver function tests
    • Will help to rule out biliary pathology such as cholecystitis if elevated liver enzymes
  • Serum amylase and/or lipase
    • To rule out pancreatitis, a similarly presenting condition
    • However, perforated peptic ulcers can also cause a raised amylase

X-ray
  • Although the diagnosis is largely clinical, UptoDate recommend that plain x-rays are the first form of imaging to obtain
  • An upright chest x-ray is usually required when a patient presents with acute upper abdominal pain
  • This is a useful test, as approximately 75% of patients with a perforated peptic ulcer will have free air under the diaphragm
  • If free air is present, BMJ best practice recommend urgent surgical consultation
  • Upright abdominal X-rays will also be useful, as the cause of pneumoperitoneum may be due to another abdominal pathology such as a perforated diverticulum or other perforated viscus

CT scan
  • If there is no evidence of perforation on x-ray, but there is a high clinical suspicion based on the history and examination, UptoDate recommend to perform computer tomography scanning
  • CT scans are recommended as they have a diagnostic accuracy for perforated peptic ulcers of close to 98%, therefore much superior to plain radiography
  • CT scanning will identify free gas within the peritoneal cavity with a higher sensitivity than x-ray
  • Free fluid may also be noted in the peritoneal cavity
  • CT plus contrast
    • In cases where the diagnosis is unclear, UptoDate recommend addition of water soluble oral contrast
    • Leakage of contrast from the stomach or duodenum will indicate peptic ulcer perforation

Differential diagnosis

While there is an extensive list of differential diagnoses for acute abdominal pain, the list can be narrowed down as perforated peptic ulcers tends to present with epigastric pain. The primary differentials in this scenario are pancreatitis, perforated oesophagus, a Mallory-Weiss tear or biliary pathology.

Pancreatitis
  • Similarities
    • Both present with persistent, severe epigastric pain
    • Both have nausea and vomiting
    • Although amylase is a marker used in pancreatitis, amylase can also be raised in a perforated peptic ulcer
  • Differences
    • Pain radiates to the back in 50% of patients
    • Typically a history of gallstones and/or alcohol abuse (the two most common causes of pancreatitis)
    • In patients with severe pancreatitis, other characteristic features may be present such as ecchymosis in the peri-umbilical area (Cullen's sign) or along the flank (Grey Turner sign)
    • On erect chest x-ray, free air will usually only be present in a perforation. This is unlikely to occur in pancreatitis, except in very severe cases where inflammation, ischaemia and necrosis may lead to colonic perforation (most commonly at the splenic flexure)

Bleeding peptic ulcer
  • A peptic ulcer can haemorrhage significantly without perforating the wall
  • Similarities
  • Differences
    • Present with haematemesis, melaena or both
    • With massive haemorrhage, haematochezia may also be present
    • Usually will not have peritonitis as there is no perforation and peritoneal irritation

Perforated oesophagus
  • Similarities
    • Both can present with epigastric pain, constant in nature
    • Both are acute in onset
    • Vomiting present in both
  • Differences
    • Chest pain is the more frequent location of pain, in >70% of patients
    • Frequently have dysphagia as the most common symptom
    • Commonly have odynophagia

Mallory-Weiss tear
  • Similarities
    • Both can present with constant epigastric pain
    • Both are acute in onset
    • Both may present with significant hypotension from severe haemorrhage
  • Differences
    • Typically a recent history of severe and recurrent vomiting
    • Tends to present with haematemesis ('coffee grounds')

Cholecystitis
  • Similarities
    • Both can present with epigastric pain
    • Pain is persistent in cholecystitis, whilst is intermittent with simple biliary colic
    • Both present with nausea and vomiting
  • Differences
    • Can present with right upper quadrant pain
    • Tends to be a gradual increase in pain, rather than a sudden onset
    • Most patient will have experienced episodes similar in the past (>70%)
    • History of biliary colic or gallstones incidentally noted
    • Murphy sign positive

Management

Prompt diagnosis and management is essential for perforated peptic ulcers due to the significant morbidity and mortality if not treated rapidly. The management may either be operative or non-operative.

Initial resuscitation
  • Intravenous fluids
    • IV fluids are necessary for initial resuscitation, as many patients will be fluid deplete due to ulcer bleeding and re-distribution of fluid to the third space
  • Nasogastric tube insertion
    • To reduce amount of gastric fluids in the GIT and therefore reduce the amount to escape into the peritoneum
    • Patients should also be nil by mouth
  • Intravenous proton pump inhibitors
    • UptoDate recommend an initial loading dose and then subsequent maintenance PPI therapy
    • PPI's are thought to enhance fibrin formation and therefore encourage sealing of the perforation
  • Antibiotics
    • Antibiotic therapy is important for perforated peptic ulcers due to the leakage of gastric fluids into the peritoneum
    • Sepsis is a leading cause of death in patients with perforated peptic ulcers and therefore needs to be managed aggressively (accounting for 50% of deaths)
    • The choice of antibiotics varies between hospitals, however it should ensure coverage for enteric gram negative rods, anaerobes and mouth flora, as these are the common bacteria within the gastric tract

Non-operative
  • Non-operative management is considered only if a patient is stable and/or improving after initial resuscitation, as in a portion of patients, spontaneous sealing of the perforation may occur
  • Patients whose perforations seal spontaneously have good outcomes without surgery, as UptoDate explain that <1% of patients with spontaneous sealing will have re-leaking
  • Gastric ulcers are less likely to heal spontaneously than duodenal ulcers

Operative management
  • Operative management is indicated if a patient continues to deteriorate, suggested by either instability of general observations or from ongoing/worsening symptoms
  • Involves closure of the perforation if small (<2cm)
  • If the perforation is large (>2cm), or the tissue is friable, resection of the lesion with subsequent repair may be necessary
  • Alternatively, a piece of omentum may be used to close the perforated area

Post-operative management
  • Upper endoscopy
    • Upper endoscopy should be performed to identify the cause of the perforation (e.g. malignancy, biopsy for H pylori infection)
    • This is also necessary to identify whether the ulcer is healing appropriate after initial management
    • UptoDate recommend waiting at least 2 weeks, ideally up to 8 weeks after perforation, to perform endoscopy as to allow for the original ulcer to heal appropriately
  • H pylori eradication
    • After initial management and stabilisation, if a patient is H pylori positive and this is the likely cause of the ulceration and therefore perforation, eradication is necessary
    • Eradication of H pylori significantly reduces the incidence of ulcer recurrence
    • The current standard for treating H pylori is triple therapy with a proton pump inhibitor and dual antibiotics (clarithromycin and amoxicillin) for 10-14 days

Complications

If perforated peptic ulcers are not treated promptly, there are a number of complications which can lead to high mortality (reported at 10-30%) and morbidity.

Sepsis
  • Sepsis is the leading cause of mortality in patients with perforated peptic ulcers (approximately 50% of deaths)
  • Over 30% of patients with perforation will already have evidence of sepsis on arrival to hospital
  • The septic complications are usually related to three major sources:
    • Intra-abdominal abscess formation
    • Wound infection
    • Generalised bacterial peritonitis
  • Sepsis must therefore be identified and treated rapidly, with fluid resuscitation, multiple blood cultures, empirical antibiotic therapy, and close monitoring

Significant haemorrhage
  • Whilst perforation is not always associated with bleeding, it frequently is
  • Perforations occur secondary to a bleeding ulcer in approximately 1/6 cases
  • If the ulceration and perforation causes erosion into a major blood vessel, it can lead to significant haemorrhage
  • If unable to be managed promptly, this can lead to hypovolaemic shock and subsequent death

Post-operative leakage
  • Leakage is a very uncommon complication of peptic ulcer perforation, however can occur post-operatively
  • Leakages tend to occur if a large perforation is closed via primary suture repair instead of resection and/or omental patching
  • This complication will require ongoing antibiotic therapy as well as a re-do surgery in the operating theatre