CHAPTER 45 Esophageal Disorders Caused by Medications, Trauma, and Infection
MEDICATION-INDUCED ESOPHAGEAL INJURY
Medication-induced esophageal injury may occur at any age and with a variety of commonly used medications. Nevertheless, medication-induced esophageal injury is most likely underdiagnosed in clinical practice for several reasons. First, initial consideration of common and more serious problems such as an acute coronary syndrome or pulmonary embolism may occur due to the severe chest pain, often pleuritic in nature, that may be associated with pill-induced esophagitis. Second, patients may be assumed to be having a severe episode of acid reflux, a far more common condition than a medication-induced esophageal ulceration. Third, several of the medications that may cause medication-induced esophagitis are over-the-counter medications (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]) or may have been taken safely for years (e.g., tetracycline) without injury and therefore not considered by patients to be a possible contributor to their symptoms. Fourth, because it is not routinely reported or recognized, medication-induced esophageal injury is often considered an uncommon entity.1,2 As a result, medication-induced esophageal injury often may not be considered. This can be problematic because recognition of this entity might result in failure to discontinue the offending agent or to give the patient proper instruction in avoiding future injury. It may also lead to extensive and erroneous evaluation and treatment of other conditions. This chapter provides a detailed overview of medication-induced esophageal injury, with particular attention to suspecting this entity both by its symptoms and by the medications that are potentially culpable.
MECHANISMS
Medications may cause esophageal injury through several mechanisms. These can initially be divided into those that cause direct injury to esophageal mucosa because of their caustic nature or by facilitation of injury through another mechanism such as induction of acid reflux (e.g., calcium channel antagonists). When medications directly damage the esophageal mucosa, it may be through one of four known mechanisms: (1) production of a caustic acidic solution (e.g., ascorbic acid and ferrous sulfate); (2) production of a caustic alkaline solution (e.g., alendronate); (3) creation of a hyperosmolar solution in contact with esophageal mucosa (e.g., potassium chloride); and (4) direct drug toxicity to the esophageal mucosa (e.g., tetracycline). For many medications, the mechanism of esophageal injury does not fall into any of these known categories. Other factors may influence the toxicity of the pill, particularly contact time, pills coated with gelatinous material,3 sustained release formulations, and a wax matrix form of the drug.4 Cellulose fiber and guar gum pills may swell and lodge in the esophagus, causing complete obstruction because of their water-absorbing capacity.
It is commonly assumed in medication-induced esophagitis that injury is predisposed by an anatomic or motility disorder of the esophagus or that the medication was taken incorrectly, in either case allowing for prolonged exposure of the medication to esophageal mucosa. For example, studies have shown that patients with left atrial enlargement,5 esophageal strictures,6 esophageal dysmotility,7 and esophageal diverticula8 (either Zenker’s or epiphrenic diverticula) have greater risk of pill injury. Similarly, in the patient with normal esophageal function, the site of drug-induced injury most commonly occurs where there are areas of normal hypomotility or extrinsic compression such as in the trough zone of the esophagus (where the smooth and skeletal muscle overlap) or at the level of the aortic or left bronchial impression on the esophagus.9,10 These locations of relative stasis allow for a pill, when taken incorrectly, to cause injury. However, any part of the esophagus may be involved. Methods of taking a medication incorrectly that predispose to injury include ingesting a pill without enough water or assuming a recumbent position or sleeping immediately after pill ingestion, or both. The latter two factors are particularly problematic, by eliminating the help of gravity in esophageal transit and by reducing saliva production and frequent swallowing, which occur normally while awake. Importantly, however, many, if not most, patients who suffer pill-induced esophageal injury presumably have normal esophageal function and do not necessarily ingest their medication in a faulty manner. That pill-induced esophageal injury can occur under “normal” conditions is supported by data demonstrating prolonged radiographic retention of capsules in the esophagus by normal subjects even when taken with water in the upright position.3,11
CLINICAL FEATURES AND DIAGNOSIS
Patients typically note an acute onset of chest pain, which may radiate over the central chest and to the back. The pain is commonly accentuated with inspiration and may be accompanied by severe odynophagia, even to small sips of liquids. Some patients may complain of a severe acute onset or heartburn-type symptoms. This set of symptoms associated with a potentially injurious medication taken incorrectly (particularly just before bedtime without enough water) strongly suggests the diagnosis. If objective confirmation of the diagnosis is necessary, endoscopy or radiography can be used. Endoscopy is felt to be more sensitive, although trials comparing the two have not been performed. Findings range from discrete ulcers to diffuse severe esophagitis with pseudomembranes, as may be seen with bisphosphonates12 or with sodium polystyrene sulfonate suspension (Kayexalate), in which the appearance may mimic candidal esophagitis.13 Occasionally, severe inflammatory reactions causing stenoses and tumor-like appearances may occur.14,15 Similar findings may be seen radiographically, particularly when double-contrast radiography is used.16,17 The range of findings described on esophagography may also include solitary or multiple ulcers; small or large ulcerations; ulcers with punctate, ovoid, linear, serpiginous, or stellate collections of barium; confluent ulcers; or areas of normal-appearing mucosa separating ulcers (Fig. 45-1).9 The occurrence of multiple esophageal septa has also been described.18 Rarely, severe complications of medication-induced injury may occur. These may include esophagorespiratory fistula, esophageal perforation, hemorrhage secondary to ulceration, and chronic stricture formation.
PREVENTION, TREATMENT, AND CLINICAL COURSE
No specific treatments have been shown to be beneficial in altering the course of medication-induced injury. Treatment is aimed at symptom control, prevention of superimposed injury from acid reflux, maintenance of adequate hydration, and removal of the offending medication. Symptom control may be achieved topically by local anesthetics such as viscous lidocaine solution. Occasionally, narcotics are necessary. Prevention of superimposed reflux is best achieved with a twice-daily proton pump inhibitor, although no data clearly suggest that prevention of acid reflux hastens symptomatic or pathologic improvement of pill-induced injury. For patients who have severe odynophagia prohibiting adequate oral intake, intravenous hydration may be necessary for a few days. Removal of the cause of injury is self-evident, although this is not always easily achieved. This is particularly true in clinical situations in which there may not be an adequate substitute such as in aspirin prophylaxis for cardiovascular disease, bisphosphonates for severe osteoporosis, or high-dose NSAIDs for pain from chronic inflammatory arthritides. No data address the question of whether rechallenge with a pill that induced prior esophagitis poses higher risk of recurrent injury if the pill is taken with better caution, with the possible exception of bisphosphonates. It is also unclear if patients with a theoretical underlying risk (e.g., esophageal dysmotility) have even greater risk of esophagitis with rechallenge. In the absence of stricture formation or catastrophic presentation, most patients have clinical resolution of symptoms within two to three weeks, and radiographic resolution has been described in 7 to 10 days.16
Because no treatment has been proven effective, it is hoped that proper administration of potentially injurious medications will help avoid occurrence of esophageal injury. On the basis of the sometimes normally slow transit of medications through the esophagus, particularly for gelatin capsules and larger tablets,3 the following recommendations are made: (1) medications should be swallowed with at least 8 ounces of a clear liquid; (2) patients should remain upright for at least 30 minutes following ingestion of the medication; (3) in patients with potential underlying increased risk for pill-induced injury (e.g., inability to follow the previous instructions, poor esophageal motility, anatomic compromise of the esophageal lumen), one should search for alternative safer medications or carefully weigh the risks and benefits of this medication against the disease for which this medication is necessary.
SPECIFIC MEDICATIONS
Antibiotics (Table 45-1)
Tetracycline, doxycycline, and their derivatives are by far the most common causes of pill-induced esophagitis, with almost as many cases reported as all other cases combined.10 Its commonality of injury may be more a reflection of how frequently the drug is used than a strong propensity of tetracycline to produce such injury. This relatively low incidence of esophageal ulceration from tetracycline for all users is suggested by a lack of any cases of esophageal injury seen in a recent survey of 491 Gulf War veterans treated with doxycycline.2 The mechanism of injury is felt to be corrosive damage because tetracycline dissolved in water produces a solution with a very low pH.11 Symptoms typically last several days to several weeks. Ulcerations may vary in appearance but are typically small and superficial, located in the mid-esophagus just above the aortic arch or left mainstem bronchus9 with a burn-like appearance (see Fig. 45-1). Stricture formation is uncommon.
Table 45-1 Medications Commonly Associated with Esophagitis or Esophageal Injury
Injury from other antibiotics is uncommon and mostly documented in case reports. These include clindamycin,19,20 rifampin,21 and penicillin,22 but the incidence is still exceedingly low given their common use. If a history is compatible with pill-induced esophageal injury, any antibiotic currently being used should be considered a possible culprit, although rare.
Antiviral agents, particularly those used for treatment of human immunodeficiency virus, also have been reported to cause medication-induced esophageal injury. These include zalcitabine,23 zidovudine,24 and nelfinavir.25
Bisphosphonates
To date, injury has been reported mostly with alendronate12,26–32 but also with etidronate33 and pamidronate.34 Although the overall incidence of injury is probably small (fewer than 100 cases reported)10 when considering the millions of patients using the medication, injury can be serious and even fatal. Unfortunately reflux-type symptoms are common and can be difficult to distinguish from medication-induced mucosal injury. Risedronate has low potential for causing esophageal injury, if at all.35 Part of this might be explained by the rapid esophageal transit and subsequently minimal contact time of the drug with esophageal mucosa.36 In one study prospectively following 255 patients treated with risedronate and undergoing endoscopy 8 and 15 days later, no patients developed esophageal ulceration. This study also underscored the overall safety of bisphosphonates in general in that only 3 of 260 patients receiving alendronate developed esophageal ulceration.37
Diagnosis is best made endoscopically, with marked exudates and inflammation seen. Biopsies show an intense inflammatory exudate and granulation tissue that may contain polarizable crystals and multinucleated giant cells.38 Stricture formation occurs in up to one third of patients,10 and life-threatening hemorrhage30 and esophageal perforation28 have been reported. Patients who sustain injury are described commonly to take the bisphosphonate not in accordance with directions (i.e., in the upright position with at least 8 ounces of beverage, remaining upright for at least 30 minutes). Still, as with other pill-induced esophagitides, patients taking the medication correctly may sustain esophageal injury. One question frequently answered anecdotally, but not clearly addressed scientifically, is whether patients with a history of gastroesophageal reflux disease (GERD) should avoid bisphosphonates. Furthermore, if GERD is a risk factor, it is unclear what degree of reflux constitutes risk. The decision should weigh the severity of osteoporosis and risk of fracture against the risk of esophagitis. Patients with GERD that predisposes to stasis such as those with stricture or severe ineffective esophageal motility should be particularly cautious.
Nonsteroidal Anti-inflammatory Drugs
NSAIDs are another common cause of pill-induced esophageal injury. Similar to the other common causes or medication-induced esophageal injury, they occur in a small fraction of all NSAID users. Aspirin, naproxen, indomethacin, and ibuprofen account for the majority of cases,10 but most other NSAIDs have been reported to cause esophageal injury in case reports. Not surprisingly, hemorrhage, which may be severe,39 is a common complication of these esophageal ulcers, especially when compared with other medication causes of esophagitis. Bronchoesophageal fistula has also been reported.40 Notably, it is over-the-counter use of NSAIDs that is most commonly associated with injury,41 in keeping with their more commonly used venue.
In a study of 1122 patients hospitalized for gastrointestinal bleeding, any dose of aspirin including a low dose was associated with increased risk of developing esophagitis.42 Other studies have also identified NSAIDs in general as a risk factor for erosive esophagitis.43 Whether the esophagitis in these studies is all directly due to these medications or whether they act synergistically with reflux-induced injury is unclear, although one study has suggested that aspirin makes the esophageal mucosa more sensitive to acid and pepsin.44
Other Medications Commonly Associated with Pill-Induced Injury
Potassium chloride (KCl) pills have been associated with esophageal injury. Injury can be severe, as documented by reports of esophageal stricture formation45,46 or of perforation into the left atrium,47 bronchial artery,48 or mediastinum.49 Patients who sustain esophageal injury from KCl commonly report associated conditions such as cardiac, including left atrial, enlargement, or prior cardiac surgery.50–52 Whether these processes truly predispose to pill stasis and injury because of extrinsic esophageal compression by the heart is unclear, because patients using KCl have a high prevalence of cardiac disease.
Quinidine is another cardiac medication with the potential for severe esophagitis.15 Endoscopically, quinidine may be associated with anything from mild ulceration to a marked inflammatory response with edema suggesting carcinoma.14,15 Ferrous sulfate,53 theophylline,54,55 oral contraceptives,56 ascorbic acid,22 and multivitamins57 have caused esophageal ulceration. Numerous other medications have been reported to cause esophageal ulceration in single case reports. Examples include sildenafil,58 phenytoin,11 warfarin,59 glyburide,60 lansoprazole,61 valproic acid,62 chlorazepate,63 captopril,64 foscarnet,65 and throat lozenges.66,67
Chemotherapy-Induced Esophagitis
Dactinomycin, bleomycin, cytarabine, daunorubicin, 5-fluorouracil, methotrexate, vincristine, and chemotherapy regimens used in hematopoietic stem cell transplantation may cause severe odynophagia as a result of oropharyngeal mucositis, a process that can also involve the esophageal mucosa.68 Esophageal damage is unusual in the absence of oral changes. Although mucositis is self-limited in most cases, some patients have oral and esophageal damage that persists for weeks to months. Chemotherapy that is given months after thoracic irradiation to the esophagus, particularly doxorubicin, may cause a “recall” esophagitis. Vinca alkaloid drugs are neurotoxic, and dysphagia may complicate vincristine therapy.69
Esophageal Injury from Variceal Sclerotherapy
Complications from variceal sclerotherapy can be divided into two main categories: gross structural injury and esophageal motility change. There is a wide range of gross injury from variceal injection. Injection of sclerosant into and around varices causes necrosis of esophageal tissues and mucosal ulceration; the risk is related to the number of injections and the amount of sclerosant. Small ulcers appear within the first few days after sclerotherapy in virtually all patients; larger ulcers develop in roughly one half of patients. Other complications include intramural esophageal hematoma,70 strictures,71 and perforation.72 Strictures occur in approximately 15% of patients undergoing sclerotherapy71,73,74 and are usually amenable to Savary or balloon dilation. Unusual manifestations of sclerotherapy with deep needle penetration include pericarditis, esophageal-pleural fistula, and tracheal obstruction due to compression by an intramural hematoma.75,76 One case of squamous cell carcinoma of the esophagus was attributed to a course of variceal sclerotherapy five years earlier.77
Several studies have demonstrated abnormal esophageal motility after completed courses of sclerotherapy. These abnormalities may be related to wall injury or vagal dysfunction.78 Specific motility abnormalities include delay in esophageal transit and decreased amplitude and coordination of esophageal contractions.74,79 There is debate over whether these changes are reversible, with different studies demonstrating worsening74 or resolution80 of motility abnormalities over four weeks’ time. Whether these studies reflect the effects of irreversible fibrosis or reversible inflammatory neuropathy, respectively, is unclear. One potential consequence of motility dysfunction is the occurrence of pathologic gastroesophageal reflux, as documented by abnormal esophageal pH monitoring81 and by abnormal scintigraphy and barium studies after sclerotherapy.74 Other studies have also shown abnormal reflux following sclerotherapy that correlated with esophageal dysmotility, and this did not occur in patients undergoing band ligation.79 Furthermore, the amount of sclerosant injected paravariceally appears to correlate with increased acid reflux.81
The only agent that has been shown effective in preventing postsclerotherapy strictures and in healing ulcers is sucralfate, either alone or in combination with antacids and cimetidine.82,83 Acid suppressive therapy alone, with either H2 receptor antagonists or proton pump inhibitors, has not been shown to be effective in preventing or healing postsclerotherapy ulcers or strictures.84,85
ESOPHAGEAL INJURY FROM NASOGASTRIC AND OTHER NONENDOSCOPIC TUBES
Nasogastric tubes have long been recognized as a potential source of esophageal injury and stricture formation (Fig. 45-2). The putative mechanism is gastroesophageal reflux. In patients undergoing elective laparotomy, recent data have demonstrated an esophageal pH of less than 4 for nearly 9 of the first 24 hours compared with less than one half hour in a control group without tube placement.86 One study demonstrated an increase in acid exposure even in normal volunteers undergoing nasogastric tube placement.87 When strictures occur, they are characteristically long, narrow, and difficult to manage endoscopically. Whether general use of potent acid-suppressing therapies has decreased the incidence of these strictures is unknown.
Respiratory luminal devices have also been reported as potential sources of esophageal trauma. Esophageal laceration with use of a Combitube,88 tracheoesophageal fistula with a cuffed tracheal tube,89 and esophageal perforation from a thoracostomy tube90 or transesophageal echocardiography probes91 have been reported.
More recently, several authors have reported the occurrence of an atrial-esophageal fistula complicating cardiac radiofrequency ablation procedures.92–96 This serious and often fatal complication has been described to occur anywhere from 10 days to five weeks after ablation. The initial presentation includes fever and neurologic abnormalities, the latter as a result of air emboli to the brain from the esophagus through the fistula into the left heart. Laboratory studies may reveal leukocytosis and positive blood cultures. Imaging studies may reveal gas bubbles in the left atrium. Although generally fatal due to sepsis and upper gastrointestinal (GI) hemorrhage, a recent report describes one patient who survived with surgical repair of the fistula,95 suggesting that prompt recognition may reduce mortality.
ESOPHAGEAL INJURY FROM PENETRATING OR BLUNT TRAUMA
Noniatrogenic traumatic injury to the esophagus may occur through either penetrating or, less commonly, blunt injuries. Blunt trauma resulting in esophageal perforation is exceedingly rare; most cases have occurred in the cervical esophagus after motor vehicle accidents from the steering wheel97 or seat belt.98 Penetrating injuries to the esophagus are usually caused by gunshot or knife wounds, although cervical esophageal perforation secondary to cervical spine surgery has been well recognized.99 In general, injuries from penetrating wounds are divided into those of the cervical and lower esophagus. Perforation of the cervical esophagus may be diagnosed initially by the finding of extramural air on radiographic studies such as lateral views of the neck or computed tomography. Gastrografin contrast studies confirm the diagnosis, although this test is not always possible in patients with severe traumatic injuries. Although routine endoscopy is relatively contraindicated in these patients, intraoperative endoscopy may be a valuable diagnostic tool for the diagnosis of perforation.100
Cervical esophageal penetrating injuries are usually associated with concurrent tracheal, carotid, or spinal injury. One area of debate in management of these injuries is whether surgical exploration is necessary in all patients. The concern in waiting is the development of sepsis, airway compromise, or tracheoesophageal fistulae,101 estimated to occur in approximately 4% of penetrating esophageal wounds102
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