Peptic ulcer disease

1. Description of the problem

What every clinician needs to know

While the incidence of peptic ulcer disease (PUD) has dropped significantly, it still is a common problem. Over the past 25 years, with the advent of H2-blocking agents and proton-pump inhibitors and the diagnosis and treatment of H. pylori infections, PUD has been changed from a surgical disease to one predominantly treated medically. However, in severe cases, such as the ones that would require critical care management, joint management between internists, surgeons, gastroenterologists and interventional radiologists is essential.

While the discussion of PUD can take many, many forms, for the purposes of this chapter it will focus on aspects of PUD that affect a patient in a critical care setting. Those aspects are:

Bleeding
Perforation
Obstruction

Clinical features

The clinical findings in the patient with uncomplicated PUD are minimal. Therefore, the onset of severe symptoms that might prompt a requirement for ICU care may be very sudden. The symptoms that should alarm any caretaker of a severe presentation of PUD would be:

Signs of upper GI bleeding – including hematemesis, melena, bright red blood per rectum, unexplained anemia and hypotension without the above signs
Sudden onset of severe, sharp abdominal pain, sometimes preceded by a gnawing or burning sensation that occurs after meals for the immediate few weeks preceding the presentation. Pain radiating through to the back should raise suspicion of a perforated peptic ulcer involving the pancreas.
Recent sustained weight loss, progressive dysphagia or odynophagia, recurrent vomiting – with or without pain – should raise the suspicion of an outlet obstruction from a duodenal ulcer. Patients will usually report complaints of bloating and fullness with nausea and vomiting occurring several hours after eating, not immediately after a meal as might be assumed.

Key management points

The management depends on the manifestation.

UGI bleed

Treatment of hemorrhage
Rapid diagnosis of bleeding location (upper GI vs. lower GI) in unclear cases by nasogastric tube (NGT) lavage
Upper GI endoscopy in severe bleeding cases to visualize bleeding site and perform sclerosing therapy if warranted
Prompt initiation of parenteral anti-acid therapy
Embolization via interventional radiological approach if needed
Surgical intervention

Perforation

Abdominal CT scanning
Surgical repair and washout
Antibiotics

Obstruction

Proper evaluation – including upper endoscopy and CT scanning if needed
Stabilization of patient from metabolic and hemodynamic derangements
Surgical repair with provision for ability to start early enteral feeding

2. Emergency Management

Emergency management steps are essentially the same as above. The common practice of early nasogastric lavage has not been supported in the literature as effective, yet remains commonly performed. Upper GI endoscopy must be performed as soon as possible for patients without a known source of GI bleeding in order to quickly locate the source of bleeding, perform endoscopic therapeutics to stop the bleeding, and target the therapy.

3. Diagnosis

Establishing the diagnosis

Definitive diagnosis is made by upper GI endoscopy (Figure 1). Testing for H. pylori should be done at that time, because 95% of duodenal and 70% of gastric ulcers are associated with H. pylori. Eradication of H. pylori reduces the relapse rate of ulcers, and a 1- to 2-week course of H. pylori eradication therapy is an effective treatment for H. pylori-positive peptic ulcer disease.

Diagnosis can also be made occasionally radiographically by either upper GI series or abdominal CT scanning, but these have historically had high error rates. New CT scanning technology may be changing that.

Differential diagnosis

On the basis of symptoms, the differential diagnosis includes a list of other processes since the symptoms of the PUD itself can be rather vague and nonspecific – gastritis, gastroesophageal reflux disease (GERD), cholecystitis and biliary colic all can cause pain in the same general area, differing mostly in character, timing with regards to meals, severity and frequency.

Pain can also be referred from the chest, in the form of referred pain from pleurisy or even inferior wall myocardial infarction.

Some more serious abdominal conditions, such as a carcinoma of the stomach, pancreatitis, hepatic diseases, superior mesenteric artery syndrome, and intestinal ischemia, all can cause pain in the same area.

Once the upper endoscopy is performed, depending on the location, it may be necessary to wait for biopsy results before ruling out carcinoma in the differential, especially for gastric ulcers. Patients with refractory PUD or recurrent PUD need to be evaluated for gastrinoma and Zollinger-Ellison syndrome.

H. Pylori evaluation

In the critical care setting, most patients will have their H. pylori (HP) evaluation done during endoscopy. Diagnostic endoscopy, the “gold standard” for diagnosing active HP infection, is more costly and invasive than the non-invasive tests. Non-invasive HP testing is currently recommended for uncomplicated dyspepsia patients and individuals with a history of PUD.

Two general categories of noninvasive HP tests are now available:

tests that identify active infection.
tests that detect antibodies (exposure)

This distinction is important because antibodies (i.e. positive immune response) only indicate the presence of HP at some time. Antibody tests do not differentiate between previously eradicated HP and currently active HP. Therefore, testing for active HP infection is more appropriate in areas with a low prevalence of active HP infection. In these areas, serologic tests are more likely to be positive due to previously eradicated infections, resulting in unnecessary treatment of individuals who are not actively infected.

Compared to tests for active infection, tests for antibodies are simpler to administer, provide a faster result, and are less expensive. However, the probability that a positive antibody test reflects active infection will decrease as the proportion of patients with previously eradicated HP increases.

Testing for active infection may be more cost-effective in populations likely to have had past HP exposure, but not ongoing infection.

Successfully treated patients include:

patients given antibiotics specifically for HP
patients with undiagnosed HP who were given antibiotics for another infection and the antibiotics also eradicated the HP
spontaneous eradication of HP infection

In the absence of rates for population infection and eradication, the selection of the type of non-invasive HP test to use for an individual patient is a clinical judgment based on factors such as:

probability of a previously eradicated infection
probability of a current active infection
need to document active infection
need for rapid result
patient preferences
cost (both of test and possible unnecessary treatment)

Tests for active HP include fecal HP antigen testing and urea breath testing.

The stool antigen test has been reported to have a sensitivity and specificity of more than 90% in untreated patients with suspected HP infection. The test requires collection of a stool sample the size of an acorn by either the clinician or the patient. This test must be performed in a laboratory by trained personnel. (An office-based stool test may be available in the near future.)

For the urea breath test, the patient drinks an oral preparation containing 13C or 14C-labeled urea. This test has a sensitivity and specificity of more than 90% for active infection. However, this test requires more patient preparation and is more expensive. A number of drugs can adversely affect the accuracy of urea breath tests. Prior to urea breath testing, antibiotics and bismuth should be withheld for at least 4 weeks, proton pump inhibitors should be withheld for at least 7 days, and patients should fast for at least 6 hours.

Antibody testing

Serologic testing for HP is an alternative cost-effective method for diagnosis of HP infection in untreated patients. HP serologic tests detect antibodies to HP with a sensitivity and specificity of approximately 90%. In populations with a low disease prevalence, the positive predictive value of the test falls dramatically, leading to unnecessary treatment. Since the incidence of PUD does not increase with age, a positive serology in older persons is less likely to predict the presence of active PUD. If a symptomatic patient has negative serology in the absence of NSAIDs use, the diagnosis of PUD is very unlikely.

Office-based serologic tests are less accurate than laboratory-based ELISA tests. Office-based serologic tests have the advantage of providing a result within a half-hour.

Serology tests should be used only for initial diagnosis of HP since antibody levels often remain elevated after HP is eliminated. Serology tests should not be used after a patient has been treated for HP to confirm cure.

4. Specific Treatment

First-line and other therapies

Therapy for the ulcer specifically is two-fold. Once the status of the HP is known, the patient should be started on anti-HP therapy. Because of growing antibiotic resistance and the fact that the therapy takes a while to work and does NOT influence the acute ulcer, only the relapse rate, it is preferable to wait until the infection is confirmed prior to starting treatment. Treatment should be guided, when possible, by specific sensitivity data, and, in the absence of such data, local resistance patterns.

Current therapy for HP infections takes on a multimodal approach – a gastric acid inhibitor, bismuth, and two or more antibiotics, which is considered a “quadruple” regimen in the literature. Antibiotics that are commonly used include amoxicillin, metronidazole, clarithromycin, tetracycline, levofloxacin, and tinidazole. This is an advance from the classical “triple” therapy of clarithromycin, amoxicillin and a proton-pump inhibitor (PPI).

Using omeprazole as the gastric acid inhibitor seems to increase treatment efficacy. Metronidazole resistance is the largest factor in decreasing treatment efficacy, and therapy for 10-14 days is needed to reach highest eradication rates. When omeprazole is used in the quadruple regimen and it is continued for 10-14 days, eradication rates are greater than 85% in areas of high metronidazole resistance and 90-100% in areas of clarithromycin resistance.

Alternatively, this compares to eradication rates of 25-61% for triple therapy. However, a more recent meta-analysis shows similar eradication rates between triple and quadruple therapy regimens, maybe owing to increasing resistance.

Therapy for the ulcer when acute bleeding is encountered is multifactorial. The first thing that is usually done is to start the patient on intravenous PPI or H2 blocker therapy. PPI treatment initiated before endoscopy for upper GI bleeding might reduce the proportion of participants with stigmata of recent hemorrhage (SRH; active bleeding, nonbleeding visible vessel or adherent clot) at index endoscopy and significantly reduces the requirement for endoscopic therapy during index endoscopy. However, there is no evidence that PPI treatment affects clinically important outcomes, namely mortality, rebleeding or need for surgery.

One recent meta-analysis found that low-dose intravenous PPI can achieve the same efficacy as high-dose PPI following endoscopic hemostasis, but what is “high dose” and what is “low dose” may not be entirely standard. Based on one analysis, PPIs have been shown to lower mortality compared to H2 blockers and placebo for acute UGI bleed, and this may be due to slightly superior achievement of a pH greater than 6.0 and a tolerance effect of H2 antagonists. Because of this, consensus guidelines such as those listed below call for the use of PPI over H2 antagonists in the acute UGI bleed setting.

The next step in therapy for upper GI bleeding due to PUD is endoscopic management. Identification of the bleeding site, with injection of epinephrine plus some method of cautery, either electrical or thermal, or use of clips on vessels, is optimal. Injection of epinephrine alone without cauterization or clipping is not as successful. Clipping may be the most effective single therapy if it can be done.

Treatment of perforations is predominantly surgical repair. Many times the repair can be done with an omental (Graham) patch. Much less commonly, if the perforation has eroded into another organ, that can become complicated because of the high likelihood of scar tissue making surgical exploration very difficult.

Treatment of the least common complication of refractory PUD in the ICU, obstruction, can be difficult, since it is usually a longstanding problem, associated erosion into underlying organs and structures can make surgical dissection difficult, and patients are usually relatively malnourished and not optimally able to handle an intensive surgical procedure.

In either case, it is essential to make provision at the initial operation for some sort of enteral feeding. This can be in the form of a naso-jejunal tube placed in the OR, or a jejunostomy tube placed and coming out the abdominal wall. Planning for enteral feeding will allow it to start faster and allow reaching the target amount of calories faster and more consistently than if feeding orally or through a nasogastric tube.

Drugs and dosages

Drug Therapy of HP

Gastric Acid Inhibition
Proton Pump Inhibitors

Omeprazole 20 mg bid

Lansoprazole 15 mg or 30 mg bid

H2 Blockers

Cimetidine 400 mg bid

Famotidine 20 mg bid

Nizatidine 150 mg bid

Ranitidine 150 mg bid
Bismuth
Pepto-Bismol – 2 tablets daily
Antibiotics
Amoxicillin 1 gm bid

Clarithromycin 500 mg bid

Metronidazole 500 mg bid

Tetracycline 500 mg daily

International consensus recommendations for management of patients with nonvariceal upper gastrointestinal bleeding

Resuscitation, risk assessment, and pre-endoscopy management
Immediately evaluate and initiate appropriate resuscitation.

Prognostic scales are recommended for early stratification of patients into low- and high-risk categories for rebleeding and mortality.

Consider placement of a nasogastric tube in selected patients because the findings may have prognostic value.

Blood transfusions should be administered to a patient with a hemoglobin level <70 g/L.

In patients receiving anticoagulants, correction of coagulopathy is recommended but should not delay endoscopy.

Pro-motility agents should not be used routinely before endoscopy to increase the diagnostic yield.

Selected patients with acute ulcer bleeding who are at low risk for rebleeding on the basis of clinical and endoscopic criteria may be discharged promptly after endoscopy.

Pre-endoscopic PPI therapy may be considered to downstage the endoscopic lesion and decrease the need for endoscopic intervention but should not delay endoscopy.
Endoscopic management
Develop institution-specific protocols for multidisciplinary management. Include access to an endoscopist trained in endoscopic hemostasis.

Have available on an urgent basis support staff trained to assist in endoscopy.

Early endoscopy( within 24 hours of presentation) is recommended for most patients with acute upper gastrointestinal bleeding.

Endoscopic hemostatic therapy is not indicated for patients with low-risk stigmata (a clean-based ulcer or a nonprotuberant pigmented dot in an ulcer bed).

A finding of a clot in an ulcer bed warrants targeted irrigation in an attempt at dislodgement, with appropriate treatment of the underlying lesion.

The role of endoscopic therapy for ulcers with adherent clots is controversial. Endoscopic therapy may be considered, although intensive PPI therapy alone may be sufficient.

Endoscopic hemostatic therapy is indicated for patients with high-risk stigmata (active bleeding or a visible vessel in an ulcer bed).

Epinephrine injection alone provides suboptimal efficacy and should be used in combination with another method.

No single method of endoscopic thermal coaptive therapy is superior to another.

Clips, thermocoagulation, or sclerosant injection should be used in patients with high-risk lesions, alone or in combination with epinephrine injection.

Routine second-look endoscopy is not recommended.

A second attempt at endoscopic therapy is generally recommended in cases of rebleeding.
Pharmacologic management
Histamine-2 receptor antagonists are not recommended for patients with acute ulcer bleeding.

Somatostatin and octreotide are not routinely recommended for patients with acute ulcer bleeding.

An intravenous bolus followed by continuous-infusion PPI therapy should be used to decrease rebleeding and mortality in patients with high-risk stigmata who have undergone successful endoscopic therapy.

Patients should be discharged with a prescription for a single daily-dose oral PPI for a duration as dictated by the underlying etiology.
Nonendoscopic and nonpharmacologic in-hospital management
Patients at low risk after endoscopy can be fed within 24 hours.

Most patients who have undergone endoscopic hemostasis for high-risk stigmata should be hospitalized for at least 72 hours thereafter.

Seek surgical consultation for patients for whom endoscopic therapy has failed.

Where available, percutaneous embolization can be considered as an alternative to surgery for patients for whom endoscopic therapy has failed.

Patients with bleeding peptic ulcers should be tested for
H. pylori and receive eradication therapy if it is present, with confirmation of eradication.

Negative H. pylori diagnostic tests obtained in the acute setting should be repeated.
Postdischarge, ASA, and NSAIDs
In patients with previous ulcer bleeding who require an NSAID, it should be recognized that treatment with a traditional NSAID plus PPI or a COX-2 inhibitor alone is still associated with a clinically important risk for recurrent ulcer bleeding.

In patients with previous ulcer bleeding who require an NSAID, the combination of a PPI and a COX-2 inhibitor is recommended to reduce the risk for recurrent bleeding from that of COX-2 inhibitors alone.

In patients who receive low-dose ASA and develop acute ulcer bleeding, ASA therapy should be restarted as soon as the risk for cardiovascular complication is thought to outweigh the risk for bleeding.

In patients with previous ulcer bleeding who require cardiovascular prophylaxis, it should be recognized that clopidogrel alone has a higher risk for rebleeding than ASA combined with a PPI.

Refractory cases

Management of cases refractory to the above measures will usually require additional interventions. Early surgical consultation is essential so that if a surgical repair is needed it can occur without delay. Such surgical interventions for bleeding may include oversewing of an ulcer, an emergency Billroth II gastrectomy, or some other such procedure.

Some patients, especially those who may present an excessive surgical risk, can be managed with percutaneous arterial catheter embolization. While once reserved for patients deemed too high a risk for surgery, evidence is now mounting that it may become equal to or even first-line therapy for bleeding that fails endoscopic management.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

The mortality from acute upper GI bleeding from a duodenal ulcer used to be quoted at about 10% despite the best therapy. But over the past 15-20 years both the incidence of hospitalization for complications of bleeding and the mortality rate have fallen dramatically. This is felt to be due to the paradigm shift in the management of PUD, which included early endoscopic treatment, the use of intravenous PPIs before and after endoscopic treatment, and endoscopic retreatment for recurrent bleeding instead of surgery.

Between 1993 and 2006, there was a significant reduction in hospital admissions for acute UGI bleeding from 222,601 to 156,108 annually, and the inpatient mortality of PUD also dropped from 3.8% to 2.7%.

The start of the decrease in the incidence of bleeding peptic ulcer also coincided with the introduction of PPIs. In another study, comparing cohorts from 1983-85 to 2002-4, there was a 35.5% decrease in the incidence of UGI bleeds between the two periods. In contrast to this reduction, there was a significant increase in the mean age, comorbidities, use of NSAIDs and in-hospital UGI bleeds. There was a significant reduction of rebleeding, from 32.5% to 7.4%. The need for surgery also dropped, from 10.2% to 2.0%, with significant reduction in the overall mortality. The authors postulated that a further reduction in the incidence of UGI bleeding would necessitate preventive strategies towards development of ulcer in elderly and hospitalized patients.

These trends mean that while we see fewer patients with upper GI bleeds from PUD, they also are sicker and older and more likely to require a critical care setting.

Incorrect diagnosis?

The diagnosis is usually clear. The problem is not a wrong diagnosis but delayed diagnosis and delayed and inadequate resuscitation.

Follow-up

Re-endoscopy to verify cessation of bleeding is not recommended. Patients should get 2 weeks of H. pylori and PPI therapy. If symptoms do not resolve, they will need evaluation for hypersecretory syndromes and referral for possible surgical correction.

Pathophysiology

Historically, the pathophysiology of PUD centered on abnormalities of amounts of gastric acid and pepsin. Treatment, then, centered on neutralization of that acid as the primary strategy.

Today, gastric hypersecretion of all types is thought of still needing consideration and understanding, but it is rare. Newer understanding of the role of stress, smoking, and alcohol and of medications such as NSAIDs and immunosuppressive steroids have added new contributing factors to the development of PUD that need to be modified.

It has been the relatively recent discovery of the role and widespread extent of H. pylori infection that has radically changed PUD from one of primarily abnormal physiology to one of an infectious etiology. It has led to better understanding of role of inflammation and cytokines in the secretion of gastric acid.

It also has led to a deeper understanding of the difference in the mechanisms of injury duodenal and gastric ulcers.

This, in turn, has led to a better understanding of the exact mechanism of NSAID-induced GI tract injury from a rather primitive “erosive” etiology to one that includes local hypersecretion, prostaglandins, and cyclo-oxygenase.

The isolation of H. pylori and its identification as the most important cause of PUD led to exploration of the role of inflammation and its associated cytokine cascade in gastric acid secretion.

H. pylori evades attack by the host immune system and causes chronic, indolent inflammation by several mechanisms.

H. pylori can damage the mucosal defense system by reducing the thickness of the mucous gel layer, diminishing mucosal blood flow, and interacting with the gastric epithelium throughout all stages of the infection.

H. pylori infection can also increase gastric acid secretion by producing various antigens, virulence factors, and soluble mediators, H. pylori induces inflammation, which increases parietal-cell mass and, therefore, the capacity to secrete acid. The H. pylori cytotoxin associated gene CagA also has an important role: it interferes with gastric epithelial cell-signaling pathways, thereby regulating cellular responses and possibly contributing to apical junction barrier disruption, interleukin-8 secretion and phenotypic changes to gastric epithelial cells.

Duodenal ulcer is essentially an H. pylori-related disease and is caused mainly by an increase in acid and pepsin load, and gastric metaplasia in the duodenal cap.

Gastric ulcer, at least in Western countries, is most commonly associated with NSAID ingestion, although H. pylori infection might also be present. Chronic, superficial and atrophic types of gastritis predominate in patients with gastric ulcers, when even normal acid levels can be associated with mucosal ulceration.

In both conditions, ulcer is associated with an imbalance between protective and aggressive factors, with inflammation being a leading cause of this imbalance.

Eradication of H. pylori infection is now the mainstay of treatment for PUD, and has resulted in very high ulcer healing rates and recurrence rates that have dropped dramatically, especially for individuals with a duodenal ulcer.

The greater recognition of the role of NSAIDs and aspirin in gastrointestinal tract injury has led to the development of therapeutic and preventive strategies that rely on the use of antisecretory drugs, the prostaglandin analog misoprostol, or selective cyclo-oxygenase (COX)-2 inhibitors (coxibs).

Epidemiology

Roughly 10% of the population will develop PUD during their lifetime.

HP infection rates go up with and the rates of infection roughly match age, so that 30% of the population will have it by age 30 and 80% of the population will have it by age 80. A distinctly small minority of these patients will ever develop PUD. A far larger proportion will develop nonspecific gastric complaints.

Both the incidence of PUD and the morbidity and mortality from it dropped precipitously after the development of effective anti-acid therapies, endoscopic therapies and, now, H. pylori management.

Hospitalizations for PUD in the US decreased from 220K in 1993 to 156K in 2006. Duodenal ulcers decreased more (95K to 60K) than gastric ulcers (107K to 86K). The mortality rate from PUD decreased from 3.8% to 2.7%.

Hemorrhage was the most common complication (72% in 1993, 73% in 2006) but perforation had the higher mortality (15% in 1993, 11% in 2006).

Patients in 2006 had a higher chance of having endoscopy (22% vs 13%). Among operations, the use of oversewing of ulcer was similar (7.6% vs 7.4%) but the percentage of gastrectomies decreased (4.4% vs 2.1%) with less use of vagotomy as well (5.7% vs 1.7%).

The determinants of mortality were the same during both time periods.

Prognosis

Special considerations for nursing and allied health professionals.

What’s the evidence?

Napolitano, L. “Refractory Peptic Ulcer Disease”. Gastroenterol Clin N Am. vol. 38. 2008. pp. 267-288. Excellent review of peptic ulcer disease with a strong bent towards the management in an acute hospital or ICU setting.

Sreedharan, A, Martin, J, Leontiadis, GI. “Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding”. Cochrane Database Syst Rev. vol. 7. 2010. pp. CD005415Meta-analysis of uses of PPI before endoscopy to improve management.

Ford, AC, Delaney, B, Forman, D. “Eradication therapy for peptic ulcer disease in Heliocobacter pylori positive patients (Review)”. Cochrane Database Syst Rev. vol. 19. 2006. pp. CD003840Review of eradication therapy for H. pylori.

Endo, M, Higuchi, M, Chiba, T. “Present state of endoscopic hemostasis for non-variceal upper gastrointestinal bleeding”. Dig Endosc. vol. 22. 2010. pp. S31-4. Review of therapeutic endoscopy in upper GI bleed.

Loffroy, R, Rao, P, Ota, S, De Lin, M. “Embolization of acute nonvariceal upper gastrointestinal hemorrhage resistant to endoscopic treatment: results and predictors of recurrent bleeding”. Cardiovasc Intervent Radiol. vol. 33. 2010. pp. 1088-100. Latest review of embolization procedures in UGI bleed.

Greenspoon, J, Barkun, A, Bardou, M. “Management of patients with non-variceal upper gastrointestinal bleeding”. Clin Gastroenterol Hepatol. 2011 Aug 3. Summary document from same authors who wrote the latest international consensus guidelines for the management of UGI bleed – updated.

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Critical Care Medicine