Journal of Clinical Gastroenterology:
Clinical Reviews: Esophageal and Gastric Diseases
Management of Severe Gastroesophageal Reflux Disease
DiPalma, Jack A. M.D.
From the Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A.
Address correspondence and reprint requests to Dr. Jack A. DiPalma, Division of Gastroenterology, University of South Alabama College of Medicine, Knollwood Physicians Group Building, 3301 Knollwood Drive, Mobile, AL 36693, U.S.A. E-mail: firstname.lastname@example.org
Gastroesophageal reflux disease (GERD) affects more than one third of the population. It is generally a chronic condition and has the potential to be serious. Some patients with GERD experience persistent daytime or nighttime heartburn and some sustain severe damage, including ulceration, stricture, and Barrett's esophagus, which can predispose to development of adenocarcinoma. Extraesophageal manifestations of GERD can include otolaryngologic, respiratory, and cardiac problems. Severe GERD responds best to agents that suppress gastric acid secretion. Of these, proton pump inhibitors (PPIs) provide the most effective control of gastric acidity and are, therefore, the medical treatment of choice. In fact, nonresponse to a PPI should raise the suspicion that the diagnosis is not GERD. Proton pump inhibitors are quickly becoming the treatment of choice for GERD, especially for severe or refractory cases. For patients whose GERD is refractory even to PPIs or who are unwilling to face years of PPI therapy, antireflux surgery remains an option.
Gastroesophageal reflux disease (GERD) is a multifaceted condition and is probably the most common disorder of the digestive tract. 1 It is primarily an upper gastrointestinal motility disorder characterized by a prolonged exposure of the esophageal mucosa to refluxed gastric contents. Its presenting symptoms and clinical consequences are manifold but fall into two major groups: those involving effects of reflux of stomach contents into the esophagus and those of a more extensive nature, reflecting reflux effects on neighboring organs in the thoracic region. The severity of esophageal mucosal damage and frequency of symptoms correlate with an increase in the length of time intraesophageal pH is below 4. 2 Although often responsive to short-term treatment, GERD is generally a chronic condition, requiring long-term therapy. 1,3
Aside from having a negative impact on daily life, GERD may lead to serious sequelae. Patients with problematic GERD can present with erosive esophagitis. These patients may have persistent symptoms that can be refractory to therapy, or they may experience rapidly recurring esophagitis when treatment is terminated. Complications such as strictures, ulcers, or Barrett's esophagus may develop, and patients may suffer from acid aspiration effects. 4 Furthermore, patients may experience periods of increased acid production at night that may exacerbate their condition. 5 Persistent heartburn and regurgitation, especially when occurring at night, as well as the presence of Barrett's esophagus, are recognized risk factors for adenocarcinoma development. 6 This review will focus on the management of severe GERD, which, when treated medically, demands aggressive acid suppression, usually through the use of proton pump inhibitors (PPIs), which seem to be the most effective treatment of control and management of acid reflux.
Because GERD is a complex condition that can result in esophageal lesions or more generalized cardiac, respiratory, or otolaryngologic problems, there is no straightforward symptomatic demarcation between mild GERD and its more severe forms. Even in cases in which damage is restricted to the esophagus, the severity of symptoms does not necessarily correlate with the severity of esophageal injury as revealed by endoscopy. Thus, although the majority of patients with severe and/or complicated esophagitis suffer persistent heartburn or dysphagia, 4 symptoms may still be relatively mild in patients with significant injury to the esophageal mucosa and more severe in patients whose mucosa is relatively undamaged. 7 Based upon endoscopic findings alone, more severe GERD would include cases falling under grades 3 and 4 of the Hetzel-Dent scale (Table 1). However, because most patients with heartburn and acid regurgitation will have already tried a variety of simple antacids and other nonprescription remedies, an operational definition of symptomatic severity is a patient's presentation to the clinic in search of relief from the deleterious effects of GERD on daily life. Regardless of either symptomatic or endoscopic severity, GERD presenting with anemia or with alarm symptoms such as dysphagia, odynophagia, bleeding, or weight loss must be accorded immediate attention. 8
The extraesophageal symptoms of GERD are equally complex and even more difficult to relate directly to esophagitis than the esophageal symptoms. As with the esophageal symptoms, the extraesophageal complications are particularly disturbing at night, with similar effects on loss of sleep. 9 Individuals with GERD might suffer from noncardiac chest pain, which may be indistinguishable from angina. 10,11 Pulmonary symptoms may include intrinsic (nonallergenic) asthma, accompanied by nocturnal wheezing and chronic nocturnal cough. 12 Otolaryngologic complications may include hoarseness, reflux-induced laryngitis, apnea, laryngospasm, and chronic sore throat. 9,13 Although these often accompany more typical esophageal symptoms of GERD, extraesophageal problems may be present with none of the usual esophagitis symptoms. It has been reported that approximately 25% to over half of patients exhibit only head and neck symptoms (e.g., excess salivation, hoarseness, sore throat, persistent coughing). 14,15 The diverse variety of nonesophageal symptoms that may accompany GERD requires clinical acumen and specialized testing such as ambulatory 24-hour pH monitoring. 16,17 Several studies have also indicated that more aggressive therapy and longer treatment periods may be required to achieve resolution of most extraesophageal GERD symptoms. 9,18,19 As with esophageal manifestations of GERD, surgery is an option for medically uncontrolled extraesophageal symptoms, in particular for cases of asthma or aspiration secondary to gastroesophageal reflux. 12,20
CONSEQUENCES OF GASTROESOPHAGEAL REFLUX DISEASE
The esophageal consequences of GERD can be severe, the most serious being esophageal adenocarcinoma. A recent study in Sweden found the risk for this cancer to be almost 8 times as high among persons suffering from episodes of heartburn and/or regurgitation at least once a week. For those experiencing symptoms of nighttime reflux, the risk was 11 times greater than for asymptomatic individuals. 6 This is not an isolated finding, as this form of cancer has the most rapidly rising prevalence of any type in the United States. 21 Development of adenocarcinoma has been correlated with the presence of Barrett's esophagus, a condition involving replacement of the normal squamous epithelium of the mucosa by a columnar epithelium resembling the lining of the stomach and intestines. It is usually found in patients with long-standing reflux. 22 The columnar epithelium is more resistant to reflux than the squamous lining it replaces. Consequently, its pathologic spread may even be accompanied by a relief of esophageal symptoms. Some studies suggest that high-dose PPI therapies may facilitate regression of Barrett's metaplasia at least in a subpopulation of patients with Barrett's esophagus. 23,24 However, this monotherapeutic approach remains controversial and appears most appropriate when applied in association with cell ablation. 23,25,26 The association of Barrett's esophagus with cancer makes it a serious consequence of GERD, and a particularly troubling one, because no screening modality has been shown to be useful for the routine detection of the condition.
Other esophageal consequences of severe GERD, although not fatal, are nonetheless serious in their impact on the patient's daily life. As discussed previously, there is no one-to-one correspondence between endoscopic assessment of esophageal damage and severity of GERD symptoms, but the more serious stages of mucosal damage resulting from prolonged exposure to refluxed acid and pepsin 27 do tend to result in persistent heartburn. Table 1 shows the Hetzel-Dent scale for grading esophageal damage and severity of GERD. 28 Up to one half of patients with symptoms of GERD are classified as grade 0 (nonerosive GERD), 29 whereas the remainder have varying degrees of severity of visible reflux esophagitis. It seems that the occurrence of daily or almost-daily symptoms, as opposed to less frequent esophageal symptoms, might predict the endoscopic finding of advanced endoscopic grades. Peptic stricture of the esophagus is found in about 10% of patients with severe reflux esophagitis. Strictures occur in the distal esophagus and typically are a few centimeters in length. They generally result in moderate narrowing, 1.5 to 2.0 cm in diameter, and lead to progressively more serious dysphagia. 30 When the lumen is smaller than 12 mm, the patient may even suffer impaction. 4 Patients who experience nighttime reflux or recumbent reflux for other reasons are more likely to have episodes of longer duration and to develop severe complications such as adenocarcinoma and extraesophageal manifestations. 6,9
The nonesophageal consequences of GERD may include a variety of cardiac, otolaryngologic, and pulmonary problems. In some cases, nighttime reflux and regurgitation have even proved fatal. 1 Patients have experienced nocturnal aspiration and sudden death. Bradycardia has been associated with gastroesophageal reflux in patients with imperfect autonomic control, such as in young children and in those with familial dysautonomia, and may be implicated in sudden infant death syndrome. 10 Aspiration-induced lung injury is of concern for recumbent patients with or without mechanical ventilation 31 and for patients with depressed states of consciousness. 32 Women in labor, especially those undergoing caesarean delivery, are at risk for serious lung injury and even death resulting from acid aspiration. 33,34 These systemic extraesophageal manifestations of GERD are probably not the result of direct acid injury, as the acid is neutralized rapidly. Instead, secondary inflammatory responses involving the recruitment and activation of neutrophils are believed to be responsible for most of the lung damage. 33 Some of these effects may also be potentiated by release of substance P. 35
Otolaryngologic complications of GERD include erythema and edema of the vocal cords and arytenoids, vocal cord nodules, contact granulomas, chronic laryngitis, subglottic stenosis, and possibly carcinoma of the larynx. 9,14,18,36,37 Reported consequences for respiratory function involve pulmonary fibrosis and hypoxia-related seizures, 14 intrinsic asthma, 9 bronchitis, bronchiectasis, and aspiration pneumonia. 14 Pharyngeal acid reflux may contribute to pediatric sinusitis and regurgitated gastric acid may lead to dental erosions. 15
The mechanisms through which acid reflux causes the various systemic manifestations of GERD have yet to be completely defined. 16 Some authors have suggested that esophageal irritation via vagal reflex results in chronic cough or even cardiac arrhythmia. 10 Similarly, it has been proposed that respiratory and otolaryngologic consequences result from reflexes triggered by high esophageal acid concentrations, which lead to release of tachykinins such as substance P from sensory neurons 9,35 or direct irritation caused by spillage of gastric reflux into the bronchial tree. 9 With recumbent patients, both esophageal and systemic effects may reflect the reductions in upper esophageal sphincter pressure and esophageal clearance that accompany sleeping. 38
EPIDEMIOLOGY AND RISK FACTORS
Estimating the incidence of GERD is difficult because of the variability of symptoms and the lack of a precise clinical definition for diagnosis. Recent studies have indicated that the most severe forms of GERD are more common in men than in women and are more common in whites than in blacks. 39 The elderly are more susceptible to pathologic reflux and also suffer more severe esophageal lesions. 40,41 It has been estimated that 7% of the population experience heartburn daily, and 36% experience it at least once per month. Pregnant women were found to be particularly susceptible, with 25% reporting daily heartburn. 42
Erosive esophagitis and extraesophageal complications of GERD are ultimately traceable to excess exposure of the esophageal mucosa to refluxed stomach contents. As such, they reflect the breakdown of one or more of several defense mechanisms, including the muscular barrier at the gastroesophageal junction, clearance of reflux material, and tissue resistance against reflux material. 27 Consequently, any factor contributing to the defeat of these defenses can also exacerbate the severity of GERD.
A number of causes can lead to breakdown of the pressure gradient maintained by the lower esophageal sphincter (LES). These include increases in intra-abdominal pressure caused by obesity, tight belts, or abdominal strain during heavy exertion, gastric distension resulting from large meals, delayed gastric emptying, or increased acid secretion, reduction of sphincter tone by increased levels of estrogen and progesterone during pregnancy, hiatal hernia-induced reduction in the LES surface area that is exposed to intra-abdominal pressure, and reduction of LES pressure or esophageal peristalsis from smoking, from consumption of alcohol, fatty foods or chocolate, or from use of drugs such as calcium channel blockers, nitrates, β-blockers, anticholinergics, and theophylline. 39,43 Drugs that lower LES pressure or affect peristalsis are used for pulmonary and cardiac conditions and may promote acid reflux.
In the upright position, clearance of reflux material is normally facilitated by gravity. Hence, the supine position, whether for routine sleeping or during hospitalization, can increase the frequency and severity of reflux episodes. 39 Analysis of hospitalized patients has revealed that longer bed rest leads to significantly higher incidence of GERD symptoms, 44 and similar observations have been made for patients in surgical intensive care. 45 Clearance may also be impaired in situations of systemic sclerosis or defective salivary secretion 39 or as a result of hiatal hernia. 27
Nonsteroidal antiinflammatory drugs, including aspirin, interfere with mucosal healing and may facilitate the destruction of the esophagus. Long-term use of nonsteroidal antiinflammatory drugs may be involved in the most severe forms of GERD. When an offensive factor is uncovered in esophagitis, it is often nonsteroidal antiinflammatory drugs use, usually aspirin. 46
Pathological gastric acid hypersecretion, characteristic of, may also cause GERD. In this condition, hypergastrinemia caused by a gastrin-secreting tumor results in hypertrophy of the gastric mucosa and more parietal cells. This in turn leads to a dramatic increase in gastric output, up to 10 L/d, as compared with a normal value of 1.5 L. 47 Patients may suffer from diarrhea so severe that it mimics pancreatic cholera. The severe diarrhea may also lead to malabsorption, weight loss, bleeding ulcers, or perforated ulcers. Upon diagnosis, about two thirds of patients with Zollinger-Ellison syndrome suffer from GERD symptoms such as heartburn, and about 10% develop esophageal strictures. 47 In this syndrome, the problem does not reflect any inherent deficiency in the mechanisms that normally protect against reflux but simply results from their being overwhelmed by the extraordinary production of stomach acid.
TREATMENT OF SEVERE GASTROESOPHAGEAL REFLUX DISEASE
Although the great majority of individuals with GERD respond to a variety of acid-neutralizing preparations and mucosal coating agents and never see a physician, those with severe or problematic conditions usually require special attention. Such patients are often refractory to over-the-counter therapeutics and require more powerful pharmacologic intervention or surgery. The prescription drugs used for the treatment of GERD fall into three main groups: PPIs, histamine H2–receptor antagonists (H2RAs), and prokinetic agents. These agents exemplify two major strategies for dealing with excess reflux: PPIs and H2RAs reduce the acidity of gastroesophageal reflux, and prokinetic agents are used to enhance esophageal clearance and the competency of the LES.
Proton Pump Inhibitors
As shown in Table 2, PPIs are clearly superior to H2RAs and prokinetic agents in promoting erosive esophagitis healing. 17,48 The more severe the esophagitis, the stronger the evidence is for instituting a PPI regimen. In fact, lack of symptomatic response to a PPI raises concern that the symptoms are not caused by GERD. 49 In addition to being effective across all grades of esophagitis severity, 23 PPIs are also effective in healing laryngeal complications associated with GERD. 18 Even in cases of peptic stricture, dilatation of the esophagus in combination with maintenance PPI therapy can obviate the need for either repeated dilatations or surgery. 4,50 Proton pump inhibitors may also be effective in the prevention of acid aspiration during emergency surgery, 51 and this use will become more practical with the recent advent of an intravenous (IV) PPI formulation.
The effectiveness of PPIs stems from their mode of action and the direct inhibition of the final step in the acid production process. Proton pump inhibitors are administered as prodrugs. In the canaliculus of the parietal cell, PPIs undergo acid-catalyzed conversion into active derivatives, bind to key cysteine residues on working proton pumps, and inhibit acid production. The proton pump enzyme, a hydrogen-potassium adenosine triphosphatase, transports hydrogen from the cytoplasm into the lumen, exchanging it for potassium and generating HCl (Fig. 1). 52 Owing to the noncompetitive and covalent nature of this inhibition at the end point of acid secretion, PPIs have the potential to provide antisecretory activity for more than 24 hours, even though the PPIs themselves are cleared rapidly from the serum after administration. This acid inhibition is independent of the nature of parietal cell stimulus. Proton pump inhibitors are therefore able to provide much more substantial acid suppression than H2RAs. Moreover, unlike those taking H2RAs, patients requiring long-term administration of PPIs will not develop tolerance to the drug. 2,53
Because recurrence of erosive esophagitis after initial healing is very common, 23 many patients may require long-term PPI therapy. Consequently, safety concerns over the long-term use of PPIs have been expressed. 8,36,54 For example, it is theoretically possible that bacterial overgrowth resulting from diminished bactericidal properties in an acid-suppressed stomach could lead to gastroenteritis, but in fact this has not proved to be a problem in patients receiving long-term PPI therapy. 55 This likely reflects the fact that intragastric pH fluctuates during the day, including periods when suppression is not intense, so that prolonged periods of achlorhydria do not occur. 56 In addition, concerns that long-term suppression of acid therapy might lead to alterations in the gastric mucosa that could lead to gastric carcinoma have proved groundless. 57 To date, there is no definitive evidence of any safety problem despite over a decade of sustained PPI use in the clinic, and both omeprazole and lansoprazole are currently indicated for GERD maintenance therapy. 7,36,54,57
Despite all the clinical successes, standard, once-daily PPI monotherapy is inadequate for some patients with GERD. In fact, recent National Disease and Therapeutic Index data show that physicians are writing more than 20% of omeprazole and lansoprazole prescriptions in combination with other medications, including H2RAs and prokinetic agents, or for twice-daily administration, in an effort to combat difficult cases of acid reflux. 58 However, even multiple drug therapies or higher daily doses cannot guarantee complete pharmacologic or clinical success.
One possible contributing factor may be the significant nighttime acid production or nocturnal acid breakthrough (defined as intragastric pH <4 for more than 1 hour) that appears common in healthy subjects and patients with GERD alike. 59 Recent investigations involving both patients with GERD and healthy subjects show that neither omeprazole nor lansoprazole effectively controlled nighttime and daytime acid production despite being administered twice daily. 5,59 In one study with healthy volunteers, omeprazole proved somewhat more effective than lansoprazole in reducing the time for which gastric pH was below 4.0. 60 Although a third dose of omeprazole at bedtime resulted in only a moderate reduction in nocturnal acid breakthrough, a much more dramatic reduction was obtained by administering bedtime ranitidine. 61 Subsequent work has shown that bedtime ranitidine cannot simply be substituted for the second dose of omeprazole, but rather must be administered in addition to the twice daily dose of the PPI. 62
The full clinical significance of these findings remains to be determined, as the difference in drug treatments may also be affected by the presence of infection with Helicobacter pylori.60,63 Furthermore, it is possible that some acid secretion in the presence of PPIs may be beneficial in many patients, for prevention of achlorhydria (see above). For those patients with GERD who are prone to painful nighttime episodes of reflux, however, nocturnal acid breakthrough is of special concern, and effective control of nighttime acid production remains a desirable goal. The finding that H2RAs may resolve such episodes 61 provides one option for attaining this end.
The four PPIs currently available have been found to be of comparable efficacy in GERD treatment when taken at standard doses (20 mg qd for omeprazole or rabeprazole, 30 mg qd for lansoprazole, and 40 mg qd for pantoprazole) and superior to H2RAs. 54 Likewise, they all have been shown to be superior to H2RAs in the treatment of peptic ulcer disease. Although they all work similarly by inhibiting the parietal cell proton pump, there are distinguishing differences. All four PPIs are structurally similar but not identical (Fig. 2). Consequently, they have somewhat different chemical and pharmacologic properties that may offer specific clinical advantages. 64
Pantoprazole, a newly approved PPI, exhibits several favorable attributes. Among the PPIs marketed in the United States, pantoprazole alone is formulated for both oral and IV administration, making it available for use in patients who cannot take medication via the alimentary canal, as well as for semiconscious or comatose patients with GERD for whom parenteral dosing is the only option. The IV and oral forms are equipotent. 65 Onset of acid suppression occurs 15 to 30minutes after IV administration. 66 Recently, clinical trials have shown IV pantoprazole to be effective in rapidly controlling acid output in patients with Zollinger-Ellison syndrome who are unable to take medications orally 67 and, as part of an IV-to-oral regimen, in achieving esophageal healing in patients with moderate or severe GERD. 68,69
Pantoprazole shows lower affinity than either omeprazole or lansoprazole for the cytochrome P-450 system and, despite being tested in combination with many other agents, has no known clinically significant drug interactions. 53,70,71 In contrast to omeprazole, whose bioavailability is approximately 37% after a single dose and 65% after repeated dosing, pantoprazole shows virtually linear pharmacokinetics after oral and IV administration; its bioavailability is 77% after the first dose and remains constant upon repeated administration. 64
Concomitant intake of food or antacids does not affect pantoprazole absorption, and no dosage adjustments for age or impairment of renal or hepatic function are required. 71 With either oral or IV administration, there appears to be no clinically significant effect on cardiac function or psychomotor or cognitive performance. As with other PPIs, overall adverse effects are few. 71 Standard doses of pantoprazole on a once-a-day regimen provide good elevation of intragastric pH both during the day and at night. 53 These doses are superior to ranitidine (150 mg twice daily) in offering relief of GERD symptoms that are often exacerbated during recumbency. 72 The physiochemical properties of pantoprazole also appear beneficial as they render the drug less likely to accumulate and cause it to activate more slowly in higher pH environments existing outside the parietal cell canaliculi. 73 This property is of potential clinical relevance because many other tissues and organelles outside the stomach express proton pumps, including the distal colon, the kidney, the epithelia of the cornea and the biliary tract, vascular smooth muscle, leukocytes, osteoclasts, heart and liver mitochondria, chromaffin granules, and lysosomes. The greater stability of pantoprazole at higher pH implies a greater specificity for inhibition of the parietal cell as compared with these other sites. 64
Histamine H2-receptor Antagonists
The H2RAs include 4 US licensed products: cimetidine, ranitidine, nizatidine, and famotidine. All are used to decrease intragastric acidity, thereby reducing the toxicity of any reflux. They reduce gastric acid secretion through competitive inhibition of the H2 receptor located on the basolateral membrane of the parietal cell. Although they have proved useful in the management of moderate GERD, several factors limit their effectiveness. Unlike PPIs, which act at the stage of acid secretion, H2RAs inhibit the stimulation of only 1 of the 3 receptor systems on the parietal cell (Fig. 1). Their effectiveness can be counteracted by the stimulation of gastrin and cholinergic receptors of the parietal cell in the postprandial period, when the majority of GERD symptoms arise. Moreover, H2RA therapy can lead to tolerance and the subsequent return of acid production. 2,53 The propensity of H2RAs for interfering with the cytochrome P-450 system is also a concern. 49 Numerous studies have demonstrated that standard doses of H2RAs are less effective than PPIs in healing moderate-to-severe erosive esophagitis and providing symptom relief. 49
As GERD may be exacerbated if a motility disorder is also present, drugs that act to increase visceral muscle contractions and peristalsis would seem to be natural possibilities for therapy. However, the dopamine antagonists metoclopramide and domperidone, which act predominantly on stomach motility and can render symptomatic relief comparable to that of H2RAs, do not provide endoscopic healing. 29 Furthermore, because metoclopramide and domperidone have access to dopamine receptors outside the gastrointestinal tract, their net value in GERD therapy is questionable. 36,74 Cisapride, which acts indirectly to control gut motility through stimulation of acetylcholine release from the mesenteric plexus, 74 has been shown to be a less effective monotherapy than PPIs for erosive esophagitis, especially in cases of severe GERD. However, it can provide both symptom control and healing comparable with those of H2RAs in less severe cases of erosive esophagitis. 17,75
Serious safety issues regarding the use of cisapride have been recently publicized, culminating in an FDA decision to remove it from the American market, as of July 2000. 76 The drug will continue to be made available from its manufacturer (Janssen Pharmaceutica, Inc., Titusville, NJ) to patients meeting specific eligibility criteria for a limited-access protocol. The FDA decision was made in response to at least 341 cases of serious cardiac arrhythmias and QT prolongation and 80 fatalities reported since July 1993. A majority of these cases occurred when cisapride was used in patients taking drugs that either caused QT prolongation, inhibited the cytochrome P450 3A4 enzymes, or depleted serum electrolytes. Cisapride is contraindicated for patients taking macrolide antibiotics, antifungals, protease inhibitors, phenothiazines, Class IA and Class III antiarrhythmics, tricyclic antidepressants, and antipsychotic medications. QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest, and sudden death have, on rare occasions, also been reported in patients taking cisapride without the aforementioned contraindicated medications. Cisapride is contraindicated in patients with a history or family history of prolonged QT intervals; with a personal history of ventricular arrhythmias or ischemic or with valvular heart disease; or other heart defects likely to be associated with arrhythmia. Other arrhythmogenic conditions, such as eating disorders or renal failure, also preclude the use of cisapride. New recommendations, before administering cisapride, include performing a 12-lead ECG, excluding patients in whom the QTc value exceeds 450 milliseconds, and assessing serum electrolytes.
Once considered only when medical therapy failed or when treating special individual cases, antireflux surgery, performed by an experienced surgeon, has become recognized as an acceptable maintenance option for the patient with well-documented GERD. 17 The most common procedure used is the Nissen fundoplication or variants such as the Toupet partial fundoplication. 77 This is often performed using laparoscopic techniques to decrease the duration of postsurgical hospitalization. 78 The basic procedure involves wrapping the upper part of the stomach (fundus) around the lower part of the esophagus, creating a collar in which any excess positive stomach pressure serves to constrict the wrapped esophagus, rather than pushing gastric contents into the esophagus. Where present, hiatal hernias are repaired at the time of surgery.
Results of surgery have generally been good, and overall it has proved more successful than medication in protecting against pulmonary aspiration. Drawbacks include a low but reportable mortality rate (0.3–0.5%) and occasional complications such as splenic trauma, gas bloat syndrome, postoperative plication breakdown, gastric ulceration, and dysphagia. 36,79 In a recent study focusing on long-term (100-month) follow-up of patients with Barrett's esophagus, up to 64% experienced a recurrence of symptoms severe enough to require additional medical therapy. In some cases, patients were also diagnosed with active ulcers, strictures, or erosive esophagitis. In approximately 10% of patients, dysplasia appeared 8 years after surgery. These results were attributed to persistent reflux, reduced from the preoperative figure but not eliminated entirely. 80 Surgery should be avoided in elderly patients with concomitant disease and in patients with impaired peristaltic function who are prone to dysphagia. 36
Severe erosive esophagitis, persistent heartburn or dysphagia, chronic nocturnal heartburn, the presence of esophageal strictures, ulcers or perhaps Barrett's esophagus, or a poor patient response to H2RA treatment indicate severe GERD and the need for profound acid suppression. Proton pump inhibitors are the most effective pharmacologic agents for reducing daytime and nighttime gastric acid production, healing erosive esophagitis, and preventing the recurrence of esophageal strictures after dilatation. Recent introduction of parenteral pantoprazole offers another highly effective option for the hospitalized patient with severe GERD. Once-daily PPI dosing regimens can heal erosive esophagitis and relieve symptoms in patients with moderate-to-severe GERD. A higher daily dose may be required and can be safely administered to patients with problematic GERD or hypersecretory conditions.
1. Krueger KJ, DiPalma JA. Changing clinical perspectives toward gastroesophageal reflux. South Med J 1996; 89:548–50.
2. Howden CW, Freston JW. Setting the `gold standards' in the management of gastroesophageal reflux disease. Gastroenterol Today 1996; 6:32–7.
3. Sontag S, Schnell T, Cheifec G, et al. The benign natural history of GERD: 20 years with rare serious progression [abstract]. American College of Gastroenterology, Annual Meeting, October 18–20.
4. Hirschowitz BI. Management of refractory and complicated reflux esophagitis. Yale J Biol Med 1996; 69:271–81.
5. Peghini PL, Katz PO, Bracy NA, et al. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998; 93:763–7.
6. Lagergren J, Bergström R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340:825–31.
7. Jungnickel PW, Richter JE. Management of heartburn and gastroesophageal reflux disease. Primary Care Special Edition 1998; 2:31–4.
8. Lee JM, O'Morain CA. Trends in the management of gastro-oesophageal reflux disease. Postgrad Med J 1998; 74:145–50.
9. Mujica VR, Rao SSC. Recognizing atypical manifestations of GERD. Asthma, chest pain, and otolaryngologic disorders may be due to reflux. Postgrad Med 1999; 105:53–66.
10. Deschner WK, Benjamin SB. Extraesophageal manifestations of gastroesophageal reflux disease. Am J Gastroenterol 1989; 84:1–5.
11. Richter JE. Chest pain and gastroesophageal reflux disease. J Clin Gastroenterol 2000; 30:S39–41.
12. Sontag SJ. Gastroesophageal reflux disease and asthma. J Clin Gastroenterol 2000; 30:S9–30.
13. Gaynor EB. Laryngeal complications of GERD. J Clin Gastroenterol. 2000; 30:S31–4.
14. Gaynor EB. Otolaryngologic manifestations of gastroesophageal reflux. Am J Gastroenterol 1991; 86:801–8.
15. Jailwala JA, Shaker R. Oral and pharyngeal complications of gastroesophageal reflux disease: globus, dental erosions, and chronic sinusitis. J Clin Gastroenterol 2000; 30:S35–8.
16. Richter JE. Extraesophageal manifestations of gastroesophageal reflux disease. Clinical Perspectives in Gastroenterology, September
17. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 1999; 94:1434–42.
18. Young JL, Shaw GY, Searl JP, et al. Laryngeal manifestations of gastroesophageal reflux disease: endoscopic appearance and management. Gastrointest Endosc 1995; 43:225–230.
19. Katz PO. Medical therapy of extraesophageal gastroesophageal reflux disease. J Clin Gastroenterol 2000; 30(suppl):S42–4.
20. Floch NR. Surgical therapy for atypical symptoms of GERD: patient selection and preoperative evaluation. J Clin Gastroenterol 2000; 30(suppl):S45–7.
21. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991; 265:1287–9.
22. Spechler SJ, Goyal RK. Barrett's esophagus. N Engl J Med 1986; 315:362–71.
23. Hunt RH. Controversial issues in gastroesophageal reflux disease. Can J Gastroenterol 1997; 11(suppl B):87B–90B.
24. Srinivasan R, Ramakrishnan A, Katzka D, et al. Effect of maximal acid reflux control on Barrett's Esophagus (BE) [abstract]. American College of Gastroenterology, Annual Meeting, October 18–20.
25. Fass R, Malagon IB, Hayden CW, et al. High failure rate of acid control in candidates for Barrett's esophagus reversal on very high dose proton pump inhibitor [abstract]. American College of Gastroenterology, Annual Meeting, October 18–20.
26. Van Dam J, Brugge WR. Endoscopy of the upper gastrointestinal tract. N Engl J Med 1999; 341:1738–48.
27. Galmiche JP, Janssens J. The pathophysiology of gastro-oesophageal reflux disease: an overview. J Gastroenterol 1995; 30:7–18.
28. Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988; 95:903–12.
29. Long RG. Reflux esophagitis and its treatment. Br J Clin Pract Symp Suppl 1994; 75:36–40.
30. Hogan WJ, Dodds WJ. Gastroesophageal reflux disease (reflux esophagitis). In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease
, 4th ed. Philadelphia: WB Saunders, 1989:594–619.
31. Torres A, Serra-Batlles J, Ros E, et al. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position. Ann Intern Med 1992; 116:540–3.
32. Huxley EJ, Viroslav J, Gray WR, et al. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978; 64:564–8.
33. Matthay MA, Rosen GD. Acid aspiration induced lung injury: new insights and therapeutic options [editorial]. Am J Respir Crit Care Med 1996; 154:277–8.
34. Stuart JC, Kan AF, Rowbottom SJ, et al. Acid aspiration prophylaxis for emergency Caesarean section. Anesthesia 1996; 51:415–21.
35. Hamamoto J, Kohrogi H, Kawano O, et al. Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways of guinea pigs. J Appl Physiol 1997; 82:738–45.
36. Kahrilas PJ. Gastroesophageal reflux disease. JAMA 1996; 276:983–8.
37. Ormseth E, Wong R. Reflux laryngitis: pathophysiology, diagnosis, and management. Am J Gastroenterol 1999; 94:2812–7.
38. Orr WC, Johnson LF, Robinson MG. Effect of sleep on swallowing, esophageal peristalsis, and acid clearance. Gastroenterology 1984; 86:814–9.
39. Sonnenberg A, El-Serag HB. Epidemiology of gastroesophageal reflux disease. In: Büchler MW, Frei E, Klaiber Ch, et al., eds. Gastroesophageal reflux disease (GERD): back to surgery? Basel, Switzerland: Karger, 1997:20–36.
40. Zhu H, Pace F, Sangaletti O, et al. Features of symptomatic gastroesophageal reflux in elderly patients. Scand J Gastroenterol 1993; 28:235–8.
41. Collen MJ, Abdulian JD, Chen YK. Gastroesophageal reflux disease in the elderly: more severe disease that requires aggressive therapy. Am J Gastroenterol 1995; 90:1053–7.
42. Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Dig Dis 1976; 21:953–6.
43. Petersen H. The clinical significance of hiatus hernia. Scand J Gastroenterol 1995; 30(suppl 211):19–20.
44. Newton M, Kamm MA, Quigley T, et al. Symptomatic gastroesophageal reflux in acutely hospitalized patients. Dig Dis Sci 1999; 44:140–8.
45. Plaisier PW, van Buuren HR, Bruining HA. An analysis of upper GI endoscopy done for patients in surgical intensive care: high incidence of, and morbidity from reflux oesophagitis. Eur J Surg 1997; 163:903–7.
46. Lanas A, Hirschowitz BI. Significant role of aspirin use in patients with esophagitis. J Clin Gastroenterol 1991; 13:622–7.
47. Maton PN. Zollinger-Ellison syndrome: recognition and management of acid hypersecretion. Drugs 1996; 52:33–44.
48. Modlin IM, Borteçen KH, Sandor A, et al.. Solving the GORDian knot. In: Büchler MW, Frei E, Klaiber Ch, et al., eds. Gastroesophageal reflux disease (GERD): back to surgery? Basel, Switzerland: Karger, 1997:60–70.
49. Boyce HW. Therapeutic approaches to healing esophagitis. Am J Gastroenterol 1997; 92:22S–9S.
50. Marks RD, Richter JE, Rizzo J, et al. Omeprazole versus H2
-receptor antagonists in treating patients with peptic stricture and esophagitis. Gastroenterology 1994; 106:907–15.
51. Rocke DA, Rout CC, Gouws E. Intravenous administration of the proton pump inhibitor omeprazole reduces the risk of acid aspiration at emergency cesarean section. Anesth Analg 1994; 78:1093–8.
52. Mears JM, Kaplan B. Proton pump inhibitors: new drugs and indications. Am Fam Physician 1996; 53:285–92.
53. Huber R, Kohl B, Sachs G, et al. Review article: the continuing development of proton pump inhibitors with particular reference to pantoprazole. Aliment Pharmacol Ther 1995; 9:363–78.
54. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors: pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998; 56:307–35.
55. McCloy RF, Arnold R, Bardhan KD, et al. Pathophysiological effects of long-term acid suppression in man. Dig Dis Sci 1995; 40(suppl):96S-120S.
56. Müssig S, Witzel L, Lühmann R, et al. Morning and evening administration of pantoprazole: a study to compare the effect on 24-hour intragastric pH. Eur J Gastroenterol Hepatol 1997; 9:599–602.
57. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2000; 118:661–9.
58. National Disease and Therapeutic Index
. IMS HEALTH, Plymouth Meeting, Pa; 1999.
59. Katz PO, Anderson C, Khoury R, et al. Gastro-esophageal reflux is associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998; 12:1231–4.
60. Katz PO, Hatlebakk JG, Castell DO. Gastric acidity and acid breakthrough with twice-daily omeprazole or lansoprazole. Aliment Pharmacol Ther 2000; 14:709–14.
61. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998; 115:1335–9.
62. Khoury RM, Katz PO, Hammod R, et al. Bedtime ranitidine does not eliminate the need for a second daily dose of omeprazole to suppress nocturnal gastric pH. Aliment Pharmacol Ther 1999; 13:675–8.
63. van Herwaarden MA, Samsom M, van Nispen CHM, et al. The effect of Helicobacter pylori
eradication on intragastric pH during dosing with lansoprazole or ranitidine. Aliment Pharmacol Ther 1999; 13:731–40.
64. Kromer W. Similarities and differences in the properties of substituted benzimidazoles: a comparison between pantoprazole and related compounds. Digestion 1995; 56:443–54.
65. Hartmann M, Ehrlich A, Fuder H, et al. Equipotent inhibition of gastric acid secretion by equal doses of oral or intravenous pantoprazole. Aliment Pharmacol Ther 1998; 12:1027–32.
66. PROTONIX® IV [Manufacturer's Prescribing Information]
. Philadelphia: Wyeth Laboratories, Inc., 1999.
67. Lew EA, Pisegna JR, Starr JA, et al. Intravenous pantoprazole rapidly controls gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Gastroenterology 2000; 118:696–704.
68. Wurzer H, Schütze K, Bethke T, et al. Efficacy and safety of pantoprazole in patients with gastroesophageal reflux disease using an intravenous-oral regimen. Hepatogastroenterology 1999; 46:1809–15.
69. Metz DC, Pratha V, Martin P, et al. Oral and intravenous dosage forms of pantoprazole are equivalent in their ability to suppress gastric acid secretion in patients with gastroesophageal reflux disease. Am J Gastroenterol 2000; 95:626–33.
70. Zech K, Steinijans VW, Huber R, et al. Pharmacokinetics and drug interactions: relevant factors for the choice of a drug. Int J Clin Pharmacol Ther 1996; 34(suppl 1):S3–6.
71. Fitton A, Wiseman L. Pantoprazole: a review of its pharmacological properties and therapeutic use in acid-related disorders. Drugs 1996; 51:460–82.
72. DeVault K, Kovacs TOG, Metz D, et al. Pantoprazole relieves nighttime heartburn more effectively than ranitidine in gastroesophageal reflux disease patients with healed erosive esophagitis [abstract]. American College of Gastroenterology, Annual Meeting, October 18–20.
73. Kromer W, Krüger U, Huber R, et al. Differences in pH-dependent activation rates of substituted benzimidazoles and biologic in vitro correlates. Pharmacology 1998; 56:57–70.
74. Reyntjens A. Rationale for the development of a novel gastrointestinal prokinetic, cisapride. Scand J Gastroenterol 1989; 24:1–6.
75. Achem SR, Robinson M. A prokinetic approach to treatment of gastroesophageal reflux disease. Dig Dis 1998; 16:38–46.
76. Henney JE. Withdrawal of troglitazone and cisapride. JAMA 2000; 283:2228.
77. Cuschieri A. Laparoscopic antireflux surgery:principles governing assessment of patients for endoscopic surgery and options for surgical management. In: Büchler MW, Frei E, Klaiber Ch, et al., eds. Gastroesophageal reflux disease (GERD): back to surgery? Basel: Karger, 1997:146–157.
78. Frantzides CT, Carlson MA. Laparoscopic versus conventional fundoplication. J Laparoendosc Surg 1995; 5:137–43.
79. Koelz HR. Inhibition of acid secretion in gastroesophageal reflux disease. In: Büchler MW, Frei E, Klaiber Ch, et al., eds. Gastroesophageal reflux disease (GERD): back to surgery? Basel: Karger, 1997:71–82.
80. Csendes A, Braghetto I, Burdiles P, et al. Long-term results of classic antireflux surgery in 152 patients with Barrett's esophagus: clinical, radiologic, endoscopic, manometric, and acid reflux test analysis before and late after operation. Surgery 1998; 123:645–57.
81. Modlin IM, Sachs G. Inhibition of the gastric acid pump. In: Modlin IM, Sachs G, eds. Acid related diseases: biology and treatment. Konstanz: Schnetztor-Verlag GmbH Konstanz, 1998:126–45.
This article has been cited 27 time(s).
Journal of Laryngology and Otology
Prevalence of oesophagitis in patients with persistent upper respiratory symptoms
Journal of Laryngology and Otology, 118():
Clinical Drug Investigation
Intravenous esomeprazole 40mg is effective for the control of intragastric acid levels whether given as a 3-minute injection or a 30-minute infusion
Clinical Drug Investigation, 25(8):
Pantoprazole - An update of its pharmacological properties and therapeutic use in the management of acid-related disorders
Current Medical Research and OpinionDoes the treatment of gastroesophageal reflux disease (GERD) meet patients' needs? A survey-based studyCurrent Medical Research and Opinion
Journal of Pharmacology and Experimental TherapeuticsSoraprazan: Setting new standards in inhibition of gastric acid secretionJournal of Pharmacology and Experimental Therapeutics
Digestive and Liver Disease
Analysis of medical compliance in gastro-oesophageal reflux disease patients referred to pre-surgical examination
Digestive and Liver Disease, 34(3):
Esomeprazole - A review of its use in the management of acid-related disorders
American Journal of SurgeryUtilization of laparoscopic antireflux surgery at a single Veterans Affairs facility compared with the Veterans Affairs national trendAmerican Journal of Surgery
Journal of Experimental BiologyMetabolic and blood gas dependence on digestive state in the Savannah monitor lizard Varanus exanthematicus: an assessment of the alkaline tideJournal of Experimental Biology
Esomeprazole versus pantoprazole for healing erosive oesophagitis
Collegium Antropologicum, 30(3):
Intravenous lansoprazole - In erosive oesophagitis
Expert Opinion on Pharmacotherapy
Review of esomeprazole in the treatment of acid disorders
Expert Opinion on Pharmacotherapy, 4(2):
Alimentary Pharmacology & TherapeuticsEsomeprazole 40 mg i.v. provides faster and more effective intragastric acid control than pantoprazole 40 mg i.v.: results of a randomized studyAlimentary Pharmacology & Therapeutics
Lansoprazole An update of its place in the management of acid-related disorders
Journal of Advanced Nursing
Patients' experiences of illness, operation and outcome with reference to gastro-oesophageal reflux disease
Journal of Advanced Nursing, 40(3):
Journal of Surgical ResearchBile acid promotes the proliferation of squamous cell carcinoma of the esophagus, independent of its inducing COX-2 expressionJournal of Surgical Research
Alimentary Pharmacology & TherapeuticsA randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the EXPO studyAlimentary Pharmacology & Therapeutics
Pharmacy World & ScienceTreatment of gastroesophageal reflux diseasePharmacy World & Science
Basic & Clinical Pharmacology & Toxicology
Pharmacokinetics of esomeprazole following varying intravenous administration rates
Basic & Clinical Pharmacology & Toxicology, 97(6):
Cancer EpidemiologyImmunohistochemical analysis of selected molecular markers in esophagus precancerous, adenocarcinoma and squamous cell carcinoma in Iranian subjectsCancer Epidemiology
Current Medical Research and OpinionHow do people with gastro-oesophageal reflux disease perceive their disease? Results of a multinational surveyCurrent Medical Research and Opinion
American Journal of Pharmaceutical Education
Gastroesophageal reflux disease
American Journal of Pharmaceutical Education, 66(2):
The American Journal of Forensic Medicine and PathologyBarrett Esophagus and Unexpected DeathThe American Journal of Forensic Medicine and Pathology
European Journal of Gastroenterology & HepatologyNight-time gastro-oesophageal reflux disease: prevalence, hazards, and managementEuropean Journal of Gastroenterology & Hepatology
Gastroesophageal reflux disease; Proton pump inhibitors; Management
© 2001 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read