Chapter 20 Acid-Related Diseases of the Upper Gastrointestinal Tract (2024)

Helicobacter pylori-Related Ulcers

H. pylori is a spiral-shaped, gram-negative bacterium that, when acquired, resides in the lining of the stomach or the duodenum. It attaches to the gastroduodenal lining and secretes toxic substances that cause chronic gastritis and peptic ulcers. Although 30% to 40% of the U.S. population is infected with the organism, only 20% of infected individuals develop ulcer symptoms.20 A small number (1%) of individuals with long-standing H. pylori-related gastritis will develop gastric cancer.20 The prevalence of H. pylori varies worldwide, but it is linked to poor socioeconomic conditions. Most individuals acquire H. pylori during childhood and likely co-infect other individuals living in the same household.

Nonsteroidal Anti-inflammatory Drug-Induced Ulcers

NSAIDs, including aspirin (acetylsalicylic acid; ASA), are available by prescription and OTC and rank among the most widely used class of medications in the United States, especially in individuals older than 65 years.19 There is overwhelming evidence linking NSAIDs with stomach erosions, stomach ulcers, and ulcer-related complications, as hospitalizations and mortality are increased in chronic NSAID users.19 NSAIDs act directly on the stomach lining to cause erosions, but ulcers (which are deeper than erosions) are related to the ability of the NSAID to systemically inhibit naturally occurring protective prostaglandins in the stomach lining (see the section on Anatomy and Physiology).

Prostaglandins in the body are produced by two pathways: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 pathway promotes gastroduodenal protection while the COX-2 pathway mediates inflammation and pain. Thus, depletion of COX-1 by NSAIDs and ASA promotes the formation of ulcers and bleeding. Currently available NSAIDs inhibit both COX-1 and COX-2 to varying degrees and have both a beneficial anti-inflammatory action and a potentially toxic effect on the stomach lining. Rofecoxib (Vioxx) and valdecoxib (Bextra), previously available selective COX-2 inhibitors, were withdrawn from the U.S. market because of risk for cardiovascular events (eg, myocardial infarction and thrombotic stroke). Celecoxib (Celebrex) remains available but has a similar risk profile to nonselective COX inhibitors.

The risk of developing an NSAID-induced ulcer increases in individuals with a previous ulcer or ulcer complication, those older than 60 years of age, taking multiple or high dosages of NSAIDs, taking an NSAID plus ASA (even low cardioprotective ASA dosages such as 81 mg/day), and those taking concomitant corticosteroids, anticoagulants, or antiplatelet drugs.19

Helicobacter pylori-Related Ulcers

Successful eradication of H. pylori and ulcer healing require combining an antisecretory drug (eg, PPI) with multiple antibiotics with or without a bismuth salt. The effectiveness of clarithromycin triple therapy is limited in areas where H. pylori resistance exceeds 15%.2 Typically, three- and four-drug regimens are recommended, but only those regimens that have been adequately studied should be used for eradication and ulcer healing.20

The recommended treatment for H. pylori infection (Table 20-2) in the United States consists of either bismuth quadruple therapy or concomitant (non-bismuth quadruple) therapy. It is recommended not to substitute for the primary antibiotics with either of these regimens. Bismuth-containing quadruple therapy (10 or 14 days) is a first-choice treatment as it results in satisfactory eradication rates, but nonadherence to the complicated drug regimen can make this challenging for patients if not previously used. This regimen consists of metronidazole, tetracycline, a PPI or H₂RA, and bismuth subsalicylate. All medications except the PPI should be taken four times a day with meals and at bedtime.

The concomitant (non-bismuth quadruple) therapy (10 or 14 days) is another first-line treatment with good efficacy. This regimen consists of clarithromycin, amoxicillin, metronidazole, and a PPI. All medications should be taken twice daily. The PPI should be taken 30–60 minutes before a meal along with the three antibiotics, but it should not be continued beyond 2 weeks after stopping the antibiotics unless it is used to treat another disease (eg, GERD). A single daily PPI dose may be less effective than twice daily when used as part of a four-drug H. pylori treatment regimen.

A three-drug regimen containing a PPI, clarithromycin, and either amoxicillin or metronidazole for 7, 10, or 14 days has a higher incidence of resistance in the United Sates. This combination should only be used in areas where clarithromycin resistance is < 15%. Sequential treatment consisting of 5 days of a PPI plus amoxicillin, followed by 5 additional days of a PPI plus clarithromycin plus metronidazole has been shown to be more effective than the combination of a PPI plus both amoxicillin and clarithromycin for 7 days.20

Third-choice treatment options are used when other regimens are unsuccessful and typically include antibiotics from other classes, such as a fluoroquinolone (eg, levofloxacin), LOAD (levofloxacin, omeprazole or other PPI, nitazoxanide, [brand name Alinia^®], and doxycycline) therapy, or hybrid therapy (Table 20-2).

The antibiotics that have been most studied as part of an initial H. pylori regimen are clarithromycin, amoxicillin, metronidazole, tinidazole, nitazoxanide, rifabutin, doxycycline, and tetracycline.2^,20 Substitution of clarithromycin for tetracycline is acceptable, but adverse effects are increased. Other antibiotic substitutions may be less effective. Specifically, ampicillin should not be substituted for amoxicillin, doxycycline should not be substituted for tetracycline, and azithromycin or erythromycin should not be substituted for clarithromycin.

Adverse effects vary with different drug regimens. Metronidazole increases the frequency of adverse effects when the dose is greater than 1 g/day. Taste disturbances (metallic taste) may occur with metronidazole and clarithromycin. Antibiotic-associated diarrhea may also occur.

Nonsteroidal Anti-inflammatory Drug-Induced Ulcers

Drugs used to treat acid-related diseases are also used to heal an active ulcer caused by NSAIDs and to reduce the risk of (prevent) an NSAID-induced ulcer and ulcer-related UGI complications (eg, bleeding). When the patient has an active ulcer, the NSAID should be discontinued. Consider switching to acetaminophen, tramadol, or a short-acting narcotic. Most ulcers heal with a standard dosage regimen of an H₂RA, PPI, or sucralfate (Medication Table 20-1) if the NSAID is stopped. Treatment with a PPI is preferred because it provides a more rapid rate of symptom relief and ulcer healing (4 weeks) than an H₂RA or sucralfate (6–8 weeks).1^,2 The PPIs are interchangeable for this indication as long as they are used in their recommended oral dosages (Medication Table 20-1).

If NSAID therapy must be continued despite ulceration, consideration should be given to using a potentially less ulcerogenic NSAID or reducing the NSAID daily dose. Ulcer healing can occur if the NSAID is continued, but it will take longer (12 weeks) and requires the use of a potent acid suppressant.1^,2 Thus, the PPIs are also the drugs of choice when the NSAID cannot be discontinued.1^,19 If H. pylori is present, the patient should be treated with an eradication regimen that contains a PPI.1^,2

Various management strategies have been used to reduce the risk of NSAID-induced ulcers and UGI bleeding in high-risk patients. The use of enteric-coated preparations such as aspirin reduces the irritating effects on the stomach but does not stop ulcers from forming. Taking an NSAID with food or milk may reduce NSAID-related dyspepsia but does not prevent ulcers. Antacids and sucralfate should not be used for preventive purposes, as there is insufficient evidence to support their use for this indication. Taking an H₂RA along with the NSAID (cotherapy) works to reduce NSAID dyspepsia, but it is not effective in reducing the risk of stomach ulcers when given in standard prescription dosages (eg, famotidine 40 mg/day).2 It is possible that higher H₂RA dosages (eg, famotidine 40 mg twice daily) may reduce the risk of NSAID-induced stomach ulcers, but it most likely does not reduce the risk of UGI bleeding. Misoprostol (Medication Table 20-1) cotherapy reduces the risk of NSAID-induced stomach ulcers and ulcer-related complications such as UGI bleeding. However, multiple daily dosing, abdominal cramping, dose-related diarrhea, and abortive effects limit adherence as well as its effectiveness.

The PPIs are as effective as misoprostol for reducing the risk of NSAID ulcers and have the added advantage of fewer troublesome adverse effects. The PPIs are superior to the H₂RAs when used for this indication. All PPIs, when used in recommended oral dosages, reduce the risk of NSAID-induced stomach ulcers and ulcer-related UGI complications. All the PPIs have a similar efficacy and safety profile and are interchangeable.

Selective COX-2 inhibitors such as rofecoxib and valdecoxib are associated with a lower risk of GI toxicity, but they are no longer available in the United States because of their association with serious cardiovascular thrombotic effects. Celecoxib is a currently available COX-2 inhibitor; however, it bears the same FDA labeling in regard to GI and cardiovascular risks as all other available NSAIDs. Data shows that celecoxib has a lower relative risk of GI and cardiovascular events compared to nonselective NSAIDS and therefore may be used more in practice. Gastroprotective benefits are reduced in patients using aspirin with celecoxib. Thus, it is recommended to use PPI cotherapy with celecoxib if low-dose aspirin is being used. Finally, increased cardiovascular risk and the acute side effects possible with NSAIDs (eg, fluid retention, hypertension, renal toxicity) require that the lowest effective dose of celecoxib be used as it is at least as beneficial as a nonselective NSAID plus a PPI.

CASE?

What are the most serious consequences that could result from Mrs. Dryden’s GERD?

PRACTICE POINT

Patients should keep a diary to record their GERD symptoms and attempt to relate them to lifestyle or diet. This diary should be brought to their healthcare provider for discussion and review to determine the best course of action in eliminating the patient’s symptoms.

CASE?

Why do you think Mrs. Dryden’s doctor changed her medication for GERD from famotidine to omeprazole?

Mild Disease

Most patients with mild or infrequent heartburn can be managed with OTC medications, sometimes with advice from a pharmacist. Patients must first be evaluated to determine if they are a candidate for self-treatment. Exclusions for self-treatment include evidence of alarm symptoms, and nonesophageal or severe symptoms as described in the Clinical Presentation, Complications, and Diagnosis section under the Gastroesophageal Reflux Disease heading.3 Those who present with these symptoms should be referred to their physician for further evaluation. Antacids and H₂RAs remain the OTC drugs of choice for managing mild and infrequent symptoms. Antacids (Medication Table 20-1) provide the fastest relief of symptoms and can be dosed every 1–2 hours as long as the maximum dosage is not exceeded and adverse effects are not problematic. For patients who do not respond adequately to antacids or who require substantial doses to control symptoms, an OTC H₂RA or PPI may be considered.

The OTC H₂RAs are indicated for patients with infrequent mild to moderate heartburn. They have a longer duration of action than antacids but can take up to an hour for the onset of symptom relief. They can be taken before meals or at bedtime before most heartburn occurs. The OTC H₂RAs may be taken at either one half or full prescription dose (Medication Table 20-1). They are all similar in potency when used in recommended dosages. Patients should not use more than two doses a day or continue treatment for more than 2 weeks at a time.

Another option is the OTC PPIs omeprazole and lansoprazole, but they should be reserved for patients with frequent heartburn (2 or more days per week). Although the onset of symptom relief (2–3 hours) is slower than with the H₂RAs, they provide superior relief of symptoms throughout the day and night when compared to the H₂RAs. Patients should be instructed to take OTC PPIs 30 minutes prior to breakfast on an empty stomach to maximize its acid-inhibiting action.

Moderate to Severe Disease

Patients with moderate to severe GERD symptoms will most likely require a PPI, and 75%–85% of patients will obtain acceptable relief with this option.1 Studies have also suggested that patients may not gain any greater heartburn relief by increasing to maximum doses. Healing of esophageal erosions is possible after 8–12 weeks of continuous H₂RA therapy, but it requires the highest doses and only approximately 50% of patients will achieve complete healing.1 One of the factors that may be responsible for these findings is that tolerance (the body becomes less responsive to the drug’s effects) develops with continued therapy.

The PPIs are the drugs of choice for most patients because of their ability to reduce stomach acid for a prolonged period. Numerous studies have demonstrated that the PPIs are superior to the H₂RAs in relief of symptoms and healing of erosive esophagitis.22 The majority of patients will have an acceptable response to once daily dosing; however, those with severe or nocturnal symptoms and those presenting with severe esophagitis may require twice daily dosing. There is little data to suggest that one PPI is better than another when used in equivalent doses, but newer options may be more beneficial in healing patients with very severe disease when dosed once a day.1

Some patients may have nocturnal (nighttime) symptoms despite once or twice daily PPI therapy and may require the addition of an H₂RA at bedtime. There is no conclusive evidence for this practice as tolerance to the H₂RA may develop with continued use.4^,23 One way to avoid potential tolerance is for the patient to take the H₂RA only at bedtime if nighttime symptoms are anticipated (eg, after eating foods known to cause late-night symptoms or eating within 3 hours of bedtime).

Clinical Presentation, Complications, and Clinical Course

Patients with bleeding peptic ulcers usually present with coffee ground emesis (coagulated blood in vomit), hematochezia (red or maroon blood in stools—typically from a massive GI bleed), or melena (dark tarry stools). 21^` Patients with these signs or symptoms represent a medical emergency that must be dealt with immediately as these patients can quickly go into hypovolemic shock (cardiovascular instability caused by a substantial loss in blood volume). The patient needs to be rapidly stabilized with volume resuscitation by giving large amounts of intravenous (IV) fluids (e.g. normal saline) and may potentially require blood products. 24

The patient will usually have a nasogastric tube inserted and be placed on suction to determine if the GI tract is the source of the bleed, to remove gastric contents (lavage), and to determine if the patient is continuing to bleed. Most patients will have an endoscopy performed within 24 hours of admission to the hospital to determine the site and significance of the bleeding.24 This will allow the physician to test for H. pylori infection and perform interventions to attempt to stop the bleeding. Most identified peptic ulcers have a low risk of rebleeding with appropriate therapy. However, some ulcers are so deep that a blood vessel is visible, or the ulcer continues to bleed. These ulcers are associated with a high risk of rebleeding and mortality. Patients with UGI bleeding require close monitoring and medications aimed at reducing stomach acid to allow for more rapid ulcer healing.

Pharmacotherapy

Drug therapy directed toward reducing stomach acid is the preferred way to improve hemostasis and prevent rebleeding in patients with peptic ulcer bleeding. Although once a mainstay in managing patients with UGI bleeding, the H₂RAs have fallen out of favor because of their inability to maintain a stomach pH of > 6 (near neutral) over a 24-hour period and because tolerance to their effects may develop. The PPIs are the drugs of choice for prevention of PUD rebleeding after successful endoscopy as they reduce rates of rebleeding, the need for surgery, and additional endoscopic procedures.

The most appropriate PPI dose and method of administration remains uncertain. Patients at low risk of bleeding are usually managed with an oral PPI and discharged from the hospital after endoscopic intervention. Patients at high risk of rebleeding are usually started on IV PPI therapy consisting of a rapid IV loading dose (80 mg of pantoprazole or esomeprazole) and a continuous IV infusion (8 mg/hr of esomeprazole or pantoprazole). The IV infusion should be continued for up to 72 hours (as the patient is at highest risk of rebleeding during this time), after which the patient should be converted to oral PPI therapy, which is continued for at least 8–12 weeks.21

Clinical Presentation, Complications, and Clinical Course

Patients with SRMB may present with small amounts of blood in the stomach contents when a nasogastric tube is being used for feedings or medication administration, or small amounts of blood may be identified in stool samples that are tested for its presence. Others may present with large amounts of blood or coffee ground–like material in the patient’s vomit, in nasogastric aspirates, or with bloody diarrhea.1 This type of bleeding, along with a drop in blood pressure, increase in heart rate, or drop in laboratory blood volume measurements, is considered life-threatening bleeding and must be evaluated immediately.

The stomach ulcerations associated with SRMD differ from chronic peptic ulcers in that they are numerous, do not extend as deeply into the stomach lining, develop very early in the critically ill hospitalized patient, and progress to a very serious condition, which can lead to increased hospital lengths of stay or even death. One major drawback in managing SRMB is that, due to their extensive distribution throughout the stomach, they usually cannot be managed with endoscopic therapy and must be treated with medications.1 Thus, the most important consideration in SRMB is prevention of the bleeding.

Goals of Therapy

The primary goal of therapy associated with SRMD is prevention of bleeding. Patients must be assessed for risk and started on optimal prophylactic therapy when warranted. Patients with one of the three primary indications (intubation, blood clotting disruption, or sepsis) or who have two or more of the other risk factors discussed should have SRMB prophylaxis started immediately, unless contraindicated.

Pharmacotherapy

Numerous options exist for the prevention of SRMB, with the majority directed at reducing stomach acid. The use of liquid antacids is superior to placebo, but their administration is cumbersome because of the need for frequent administration (eg, every 1–2 hours) and the need to provide continuous stomach acid pH monitoring. Liquid antacids are also associated with a number of adverse events (eg, electrolyte abnormalities, constipation, and diarrhea).2

Sucralfate is another option with proven benefit, but up to four doses per day are needed, and the fact that it does not increase stomach pH may limit its usefulness. Sucralfate only acts as a barrier between the acidic environment and the stomach lining. It also inhibits the absorption of other medications, may clog nasogastric tubes, cause constipation, and may cause aluminum toxicity in renal failure.2

The H₂RAs have been widely used for SRMB prophylaxis. Benefits include the fact they can be given IV as a continuous or intermittent infusion and have demonstrated superiority in reducing SRMB when compared to antacids and placebo. All the H₂RAs require a dosage reduction in renal dysfunction (a common finding in critically ill patients).1 The H₂RAs also have the potential to cause pneumonia in hospitalized patients since acid is protective against microbes within the stomach. When stomach pH is increased, these pathogens might survive, and if stomach contents are aspirated into the lungs this could lead to the development of pneumonia.1 The PPIs are the preferred option for prevention of SRMB because of their profound effect on stomach acid. Although there is very little evidence to indicate that PPIs are superior to H₂RAs, more potent acid suppression appears to provide improved efficacy, but the potential for pneumonia remains.1

As noted earlier, there are a number of PPI administration options available (Table 20-1), which allow for use in different circ*mstances encountered in the critical care setting (eg, patients who cannot take anything by mouth, have nasogastric tubes, or have difficulty swallowing). Adverse events associated with PPI prophylaxis are rare, but there may be an increased risk of hospital-acquired pneumonia and increased GI infections due to bacterial overgrowth.1^,2

Regardless of which SRMB prophylaxis regimen is selected, the patient must be continually monitored for signs and symptoms of bleeding (presence of blood in nasogastric aspirate, vomit, or stool). Finally, it is important to ensure that medications used to prevent SRMB are discontinued when the patient is no longer at risk or has been transferred from the critical care setting, as many are continued and eventually the patient is discharged on these medications without an appropriate indication.