Gastroesophageal reflux

Gastroesophageal Reflux Disease

I. What every physician needs to know.

Gastroesophageal reflux (GER) is a physiologic event associated with the reflux of gastric contents into the esophagus. Nearly everyone has occasional GER-related symptoms.

Gastroesophageal reflux disease (GERD) is a chronic condition when the symptoms of GER become troubling enough for a patient to seek out either prescription and/or over-the-counter (OTC) medication help, or if esophageal or extra-esophageal complications known to be related to GER are noted on any investigation. Symptoms can be typical vs atypical and complications may be esophageal or extra-esophageal. Symptom severity does not correlate to the degree of esophageal injury. Treatment of symptoms improves quality of life while decreasing frequency of complications.

Transient lower esophageal sphincter relaxations (TLSERs) (55%-65%) and swallow induced lower esophageal sphincter (LES) relaxations (10%) account for most reflux episodes in GERD. TLESRs while causing mild to moderate symptoms are less frequently associated with complications. A decreased basal tone of the lower esophageal sphincter is a less common cause and can cause severe reflux especially when intra-abdominal pressure increases or when lying supine.

Certain medications and foods can decrease LES tone. While not all hiatal hernias cause reflux, the associated anatomical displacement of the LES causes impairment of the anti-reflux barrier at the gastroesophageal (GE) junction and larger hiatal hernias contribute to more severe reflux and chronicity of reflux.

Delayed gastric emptying contributes to reflux in only small subpopulations such as in diabetic gastroparesis. Poor esophageal clearance of reflux material because of peristalsis dysfunction can cause severe reflux. Impaired salivary neutralization of refluxed acid in the esophagus and an impaired mucosal barrier are also contributory.

Gastric acid together with gastric pepsin present in refluxate damage the esophagus causing esophagitis. Excessive acid secretion as in the Zollinger-Ellison syndrome is not needed. Pepsin is activated in an acidic medium (pH<4) and causes mucosal injury. Duodenogastroesophageal reflux causes reflux of non-acidic bilious components which adds to the damage.

II. Diagnostic Confirmation: Are you sure your patient has gastroesophageal reflux disease?

The presence of typical symptoms such as heartburn (pyrosis) or acid regurgitation is sufficient to start anti-secretory therapy, preferably proton pump inhibitors (PPIs). Response of symptoms to PPIs confirms the diagnosis. The presence of warning symptoms (dysphagia, odynophagia, gastrointestinal bleeding, anemia, weight loss, and recurrent vomiting), or failure to respond to empiric anti-secretory therapy are other indications for further evaluation including an EGD. In the presence of atypical symptoms (water brash, nausea, vomiting, dysphagia, chest pain, odynophagia) without heartburn or regurgitation, further evaluation needs to be considered.

Complications related to GERD include non-erosive esophagitis, erosive esophagitis, esophageal ulcerations which can occasionally cause bleeding with chronic blood loss anemia, esophageal peptic stricture from chronic esophageal injury, Barrett’s esophagus and adenocarcinoma.

Extra-esophageal complications include cough, laryngitis, asthma and dental erosions while sinusitis, pulmonary fibrosis, pharyngitis and recurrent otitis media are unproven associations.

A. History Part I: Pattern Recognition:

Heartburn and acid regurgitation are the most common symptoms of GERD. They are also the most specific. Waterbrash, nausea, vomiting and hiccups are less common. Dysphagia is an uncommon symptom of GERD and can be the result of many conditions. GERD associated lower esophageal peptic stricture or esophageal ulcerations can cause dysphagia.

Odynophagia is infrequently a result of GERD-typically from infectious esophagitis or pill esophagitis, and occasionally severe ulcerative esophagitis.

Chest pain can be a symptom of GERD especially when associated with esophageal dysmotility and can be seen in functional heartburn as well. Cardiac and other non-cardiac causes of chest pain must be considered and evaluated before considering GER as a cause.

Extra-esophageal symptoms of GERD can include cough, wheezing, hoarseness, bad breath and dental erosions. Rare aspiration events can occur with nocturnal regurgitation.

Non-erosive Reflux Disease (NERD) is the most common presentation of GERD. This is typically seen in the young without a hiatal hernia and typically presents as heartburn.

Reflux symptoms can worsen or develop following a meal or in the recumbent position. They can also be triggered by certain foods (fatty foods, caffeine, chocolate, spicy foods, carbonated beverages, and peppermint). Regurgitation can be associated with bending over, tight fitting clothes and the recumbent position.

Nightime heartburn is frequently associated with erosive esophagitis.

B. History Part 2: Prevalence:

The true prevalence of GERD is difficult to establish as many people with significant symptoms do not seek physician aid. The life-time prevalence of GERD in the US is estimated to be in the range of 25% to 35%. Hispanics appear to have the highest prevalence rate followed by Caucasians and African-Americans, in that order.

Obesity (BMI >30) is associated with a higher prevalence of GERD in both men and women. Smoking and regular alcohol use can contribute to GERD. A family history of GERD increases risk possibly through a genetic link as well as obesity. Pregnancy is the most common ‘risk factor’ for GERD. The high levels of estrogens and progesterone during pregnancy decrease LES tone while the increased abdominal pressure contributes to reflux.

C. History Part 3: Competing diagnoses that can mimic gastroesophageal reflux disease.

Dyspepsia is defined by the Rome III criteria as post-prandial fullness, early satiety or upper epigastric burning or pain. The symptoms are related to the upper gastrointestinal tract and common causes include peptic ulcer disease (PUD) and functional dyspepsia. The criteria exclude predominant reflux symptoms including heartburn which indicate GERD although the two often overlap.

Functional heartburn is the presence of a retrosternal burning sensation or chest pain in the absence of pathologic gastroesophageal reflux. Esophageal hypersensitivity to physiologic reflux, esophageal mechanosensitivity and psychological conditions are contributory.

Pill induced esophagitis can cause odynophagia, chest pain and dysphagia. Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, certain antibiotics including doxycycline and tetracycline, potassium chloride, iron supplements, quinidine preparations and alendronate are commonly implicated. Excessive tobacco use can cause esophagitis.

Infectious esophagitis, mostly Candida esophagitis and less commonly CMV esophagitis and HSV esophagitis, cause odynophagia and occasionally dysphagia. Other infectious agents are very uncommon.

Achalasia typically causes dysphagia to both solids and liquids but also causes heartburn, chest pain and regurgitation less commonly. Esophageal motility disorders including distal esophageal spasm can cause chest pain and dysphagia but are unlikely to cause heartburn. Chest pain is often non-esophageal in origin and other causes including cardiac must be considered first.

Dysphagia can be from many causes including central nervous system conditions (e.g. stroke, Parkinson’s disease), connective tissue disorders (scleroderma), Muscular disorders (muscular dystrophy, Myasthenia Gravis) and external compression (tumors). Esophageal conditions can include achalasia, eosinophilic esophagitis, esophageal stricture (commonly caused by chronic reflux disease but also can result from radiation injury, chemical exposure and chronic pill esophagitis), Schatzki’s ring, esophageal cancer and esophagitis.

D. Physical Examination Findings.

There are no physical findings pertinent to GERD. However, it might be worthwhile looking for any abdominal findings such as an epigastric mass or tenderness, or for lymphadenopathy which might lead to a different diagnosis.

E. What diagnostic tests should be performed?

Diagnostic tests are not necessary in most patients with GERD, especially in the presence of typical heartburn or acid regurgitation that responds to standard anti-secretory therapy. Further testing can be initiated in:

1. Presentation with typical features that do not respond to a trial of standard dose PPIs after at least 2 months of therapy.

2. Atypical symptoms or extra-esophageal symptoms when GERD is suspected.

3. Presence of alarm signs or symptoms.

4. When GERD complications are suspected.

5. Before anti-reflux surgery.

The 24-hour ambulatory pH monitoring is considered the ‘gold standard’ to detect GERD. It can be performed when symptoms do not respond to standard PPI therapy and when an esophagogastroduodenoscopy (EGD) and a manometry fail to detect a significant abnormality.

Transnasal catheter based testing is being replaced by wireless capsule pH testing (which can be performed for longer, up to 48 hours) in many centers. An esophageal manometry study first localizes the LES for probe positioning.

A patient triggered event monitor can link symptoms (as well as mealtimes, position changes and sleep times) with reflux episodes detected as an intraesophageal pH drop below 4. A symptom-reflux association analysis including the symptom index, symptom sensitivity index and symptom association probability can be performed on the results aiding diagnosis.

Combined impedance-pH monitoring can detect reflux episodes that are not acidic that would have been missed by only pH monitoring. This can improve the association between reflux episodes and symptoms.

Esophageal manometry, while having only a small role in GERD, is used to localize the LES prior to pH monitoring studies. It can also detect impaired peristalsis and a poor LES tone which however are uncommon causes of GERD. Esophageal manometry and 24-hour pH monitoring are also performed to document adequate peristalsis and presence of reflux before anti-reflux surgery.

Los Angeles Classification of Esophagitis detected on Endoscopy: An upper endoscopy/EGD is performed when weight loss, dysphagia, odynophagia or chronic blood loss anemia is noted, or if there is sufficient concern for complications of GERD such as esophagitis or Barrett’s esophagus. It can detect visible mucosal injuries from reflux disease with good specificity but with poor sensitivity. It also provides an opportunity to biopsy mucosal abnormalities or therapeutic intervention as in dilatation of esophageal strictures.

Grade A: One or more mucosal breaks smaller than 5mm, none of which extends between the tops of two mucosal folds.

Grade B: One or more mucosal breaks greater than 5mm, none of which extends between the tops of two mucosal folds.

Grade C: One or more mucosal breaks that extend between the tops of two mucosal folds but are not circumferential.

Grade D: Mucosal breaks that are circumferential (>75% of circumference).

There is no utility to performing biopsies of normal appearing mucosa except in dysphagia to rule out eosinophilic esophagitis.

Wireless endoscopic capsule studies perform poorly in detecting GERD complications.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging studies can include a barium esophagogram. A barium esophagogram is more useful in evaluating esophageal anatomy and peristalsis than in detecting reflux. It can be useful during an evaluation of dysphagia – very often the first test performed for dysphagia without other alarming symptoms (presence of alarming symptoms would necessitate an EGD). It can detect esophageal strictures and can pick up subtle strictures missed on an endoscopy, and can also help in assessing hiatal hernias and the length of the esophagus before anti-reflux surgery. It can detect moderate to severe esophagitis with fair sensitivity. However, it is poor at picking up reflux and mild esophagitis and is not used to aid diagnosis of GERD.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

1. A gastrin level is not necessary unless one is suspicious of the Zollinger-Ellison syndrome.

2. Bernstein test/the acid perfusion test. This test is performed to evaluate heartburn symptoms; a Naso-gastric tube is inserted and hydrochloric acid followed by the instillation of sodium chloride solution. Reproduction of symptoms with HCl but not with NaCl solution is suggestive of GERD.

III. Default Management.

Specific evaluation with any test is not necessary in most patients with symptoms typical of GERD. An empirical trial of antisecretory agents (preferably PPIs started as a low dose and once daily regimen) is initiated. Response by resolution of symptoms implies GERD and continuation of treatment is indicated without any tests. Failure to respond is followed by an increase of PPIs to a twice daily or standard regimen. Response to PPIs again indicates GERD.

H₂RAs (Histamine type 2 Receptor Antagonists) are less effective than PPIs for both symptom relief and healing of esophagitis and perform poorly in more severe erosive esophagitis. They can however be tried before proceeding to PPIs. PPIs are taken for at least 2 months before treatment failure is considered. Failure to respond to the higher dose needs to be followed up with adequate testing.

PPIs inhibit the H⁺/K⁺ ATPase proton pump within the parietal cells. They block both meal-related and nocturnal acid secretion to a much greater degree (noncompetitively and irreversibly) and for longer than H₂RAs. They are acid labile pro-drugs and are available as enteric coated delayed release tablets or granules within capsules. They are most effective when taken about half to one hour before breakfast (or dinner), allowing for peak action during post-prandial gastric-acid secretion. They are all equally efficacious except for esomeprazole which appears to have better healing rates with more severe esophagitis. After 5 days dosing, ~66% of steady state acid inhibition is achieved – therefore PPIs should not be used on an “as needed basis.”

Low and standard doses of PPIs are:

• Esomeprazole 20 mg and 40 mg

• Omeprazole 20 mg and 40 mg

• Pantoprazole 20 mg and 40 mg

• Lansoprazole 15 mg and 30 mg

• Rabeprazole 20 mg and 40 mg

H₂RAs block H₂ histamine receptor stimulate gastric acid secretion (competitively and reversibly) at the parietal cell. However, postprandial gastrin or acetylcholine mediated secretion is not inhibited. They are therefore less-effective postprandially and more effective in inhibiting nocturnal acid secretion. Their duration of action is shorter than PPIs and early development of tolerance to their actions is problematic. They are generally less efficacious than PPIs. They can be used on an “as needed basis.”

Standard doses of H₂RAs are:

• Ranitidine 150 mg BID

• Cimetidine 400 mg BID

• Famotidine 20 mg BID

• Nizatidine 150 mg BID

Lifestyle modification is an important component of GERD management and focusses on specific recommendations to certain patients (see long-term management).

If treatment fails, an EGD is the first test ordered. A normal EGD without esophagitis is followed by a 24-hour pH monitoring. However, an esophageal manometry is recommended as a precursor to pH monitoring and can not only detect abnormal peristalsis which can occasionally cause GERD symptoms, but also localizes the LES for pH monitoring. Impedance monitoring is a newer test which is performed with pH monitoring and detects non-acidic reflux episodes.

If all the studies above are normal and reflux symptoms continue, then functional or hypersensitivity syndromes are considered.

Suspected extra-esophageal symptoms or complications such as cough, asthma and laryngitis can be treated with a trial of twice daily PPIs for 2 months if they are accompanied by esophageal symptoms or complications. There is no benefit from PPIs when no accompanying esophageal features are present. There is also no proven benefit from a trial of higher doses of PPIs for longer durations.

For atypical chest pain suspected to be from reflux, an empiric trial of twice daily PPI therapy can be tried for 4 weeks. Cardiac and other non-cardiac causes must be carefully considered and eliminated before treatment with PPIs. Failure to respond to PPIs can be followed up with a manometry study and impedance-pH monitoring.

Prokinetics increase LES tone, increase esophageal peristalsis and gastric clearance. Agents such as Metoclopramide, Bethanechol and Domperidone can cause serious side-effects, have not been proven to be efficacious in GERD treatment and are not approved for this indication.

Cisapride increases acetylcholine in the gastrointestinal myenteric plexus. It performed fairly well (at high doses and frequency) in treatment of GERD with fewer side-effects and efficacy almost equal to H₂RAs. However, it was taken off the US market after causing many fatal arrhythmias. It caused QT interval prolongation, resulting in ventricular arrhythmias and deaths.

A. Immediate management.

Acutely symptomatic reflux can be managed with short-lasting and fast acting antacids. Their actions last for up to half an hour on an empty stomach (due to rapid gastric emptying) or 1-3 hrs postprandially.

Antacids are often used in combination and certain preparations also contain alginates (e.g., sodium alginate in Gaviscon) which provide an additional mechanism of action. Additionally, a local anesthetic can be added to provide additional symptom relief (e.g., ‘GI cocktail’ containing Lidocaine).

Antacids neutralise gastric acid in refluxate, bind and inactivate pepsin, form a mucosal layer and bind bile salts. Sodium alginate floats atop gastric fluid, acting as a mechanical barrier and must be taken about 30 minutes after a meal to ensure gastric flotation. While non-systemic antacids(magnesium and aluminum salts) exert only a local pH neutralising effect, systemic antacids (sodium salts) can cause systemic alkalosis.

Examples include Mylanta (aluminum hydroxide and magnesium hydroxide or calcium carbonate and magnesium hydroxide), Rolaids (calcium carbonate and magnesium hydroxide), Tums (calcium carbonate), Milk of Magnesia or Gaviscon (sodium alginate, aluminum hydroxide and magnesium preparations).

H₂RAs have a faster onset of action than PPIs. However, PPIs are superior to H₂RAs in terms of both symptom relief and healing of esophagitis. PPIs also fare better in maintenance therapy. In uncontrolled GERD despite twice daily PPI usage, can be added at bedtime for additional acid suppression. There have not been any studies supporting this practice in regards to complication reduction, however, observational and clinical data support improvement in symptoms in some patients.

B. Physical Examination Tips to Guide Management.

Features of weight loss, pallor with a positive stool hemoccult can indicate underlying alarming diagnoses and further evaluation with testing needs to be considered.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Symptom response aids in making changes to management as described above. There are no laboratory tests that need to be monitored.

D. Long-term management.

Lifestyle modification is important, but involves specific recommendations applicable to specific patients rather than a broad set of lifestyle modifications to all patients.

Weight loss is recommended for obese patients if it is felt that symptoms initiated or became worse after gaining weight, smoking cessation to smokers, elevation of the head of the bed (by 6 to 8 inches) to individuals with symptoms related to recumbency, or postponing bed-time to 2-3 hours after dinner to those with nocturnal symptoms. Loose clothing can be recommended when tight fitting clothes (e.g. tight belts) appear to trigger regurgitation.

Dietary modifications can include recommendations to decrease meal size and to avoid specific foods that can precipitate reflux or heartburn if history from the patient has determined that any specific foods are causing or worsening symptoms.

Patients with an established esophagitis diagnosis who have completed healing treatment will need indefinite continued daily suppressive or maintenance therapy with a PPI (the dose can be titrated downwards to the least effective dose) to prevent recurrence of symptoms. Most of these patients develop recurrent symptoms or complications in 3 to 6 months off any PPI suppressive therapy or even while on H2RAs.

Patients without esophagitis on evaluation or uninvestigated GERD symptoms can be managed with symptom triggered PPI use. However if frequent relapse is noted, then maintenance therapy with PPIs will have to be initiated.

Patients with extra-esophageal symptoms or complications can remain on maintenance therapy if accompanied by esophageal symptoms/complications. Step down is again attempted to once daily PPI dosing. However, no treatment is recommended in the absence of esophageal symptoms or complications.

Anti-reflux surgery can be recommended in patients who respond well to PPI therapy but are intolerant of their side-effects, and sometimes to patients with persistent severe regurgitation or extra-esophageal complications not responding to PPIs.

The complications and side-effects (see below) of these surgical procedures should be considered before recommending them. The most commonly performed surgeries are the laparoscopically performed Nissen fundoplication and the Toupet partial fundoplication.

E. Common Pitfalls and Side-Effects of Management

PPIs are generally well tolerated. The most commonly associated symptoms are headache, abdominal pain, nausea and diarrhea. This is not a class-effect and patients can be switched to an alternate PPI that they can tolerate.

There is a slightly increased risk of community-acquired pneumonia (CAP), bacterial gastroenteritis and C. Difficile colitis. There is also concern for malabsorption of calcium (and an increased risk for osteoporosis and fractures) and magnesium (potentially requiring magnesium level follow-up in those on long term PPIs) as well as of Vitamin B12 (without any proven deficiency).

It has been reported that PPI use can increase bacterial colonization of the small intestines. There is also concern for atrophic gastritis from long-term use of PPIs. While reactive hypergastrinemia (usually within physiologic ranges) associated with PPI use is reported to cause gastric carcinoids in rats, this has been unproven in humans

PPIs are metabolized by the Cytochrome P450 system (mostly isoenzymes CYP2C19 and CYP3A4) in the liver. However, omeprazole is the only PPI with proven interactions with other medications and slows metabolism of Diazepam, Phenytoin, Warfarin and Disulfiram among other drugs.

While there has been concern for PPIs, specifically Omeprazole, decreasing the efficacy of Clopidogrel in CAD, currently there does not appear to be evidence that there is a clinically significant interaction. However, Clopidogrel labelling warns against its use with potent CYP2C19 inhibitors.

H₂RAs are very well tolerated, side-effects are rare (<4%). The most common side-effects include diarrhea, constipation, nausea and headache and are generally no more frequent than placebo. These drugs increase gastric pH and can decrease absorption of certain drugs which depend on low pH for good absorption. This can potentially cause Vitamin B12 malabsorption and there appears to be a slightly increased risk of pneumonias.

Cimetidine (and Ranitdine to a much lesser extent) causes inhibition of the cytochrome P450 system resulting in drug interactions, increasing or decreasing their levels and actions. Cimetidine can cause gynecomastia and erectile dysfunction in men and galactorrhea in women by inhibiting estrogen metabolism when used for long periods.

Confusion has been seen in elderly hospitalized patients receiving IV H₂RAs. Very occasionally, transaminitis and hematologic cytopenias including thrombocytopenia have been noted. They can very rarely cause hypotension and tachy-brady arrhythmias in seriously ill ICU patients when given as fast IV boluses via their actions on the histaminic receptors in the heart.

Antacids if overused can be associated with side-effects. Magnesium salts can cause diarrhea and accumulate in renal insufficiency causing hypermagnesemia (and are therefore not recommended in later pregnancy); aluminum salts cause constipation, hypophosphatemia and can accumulate in renal insufficiency causing anemia and neuro-toxicity; calcium salts cause constipation and the milk-alkali syndrome. Antacids can also impair absorption of many drugs.

Refer to default management and immediate management above for drugs and dosages.

IV. Management with Co-Morbidities

PPIs and H₂RAs decrease gastric pH and can reduce absorption of certain orally administered drugs.

Severe allergic reactions to penicillins have been noted when concomitantly used with PPIs although they happened in patients with a history of prior allergic reactions to penicillins.

A. Renal Insufficiency.

H₂RA doses need to be reduced by 50% in moderate to severe renal insufficiency. Replacement doses are not required in either hemo or peritoneal dialysis. Cimetidine competes with creatinine for tubular secretion causing a non-significant mild elevation in serum creatinine levels. PPI doses do not have to be changed in renal insufficiency.

B. Liver Insufficiency.

H₂RAs can occasionally cause transaminitis, especially when high doses are given intravenously. However, no dose reduction is necessary in liver insufficiency unless significant renal insufficiency is present concomitantly. PPI use but not H₂RA use has been associated with an increased risk of Spontaneous Bacterial Peritonitis in cirrhotic patients with ascites in some studies.

C. Systolic and Diastolic Heart Failure

H₂RAs can block histaminic receptors in the heart which mediate inotropic and chronotropic effects. High dose, rapid IV administration in seriously ill ICU patients (often with concomitant renal insufficiency) have rarely caused hypotension, tachy-brady arrhythmias, AV nodal blockade and cardiac arrest.

PPIs and H₂RAs can slightly increase the absorption of Digoxin. While the clinical importance of this is unclear, Digoxin levels can occasionally be monitored. More importantly, chronic PPI use (>1 year) can cause hypomagnesemia in spite of Magnesium supplementation resulting in serious side effects including atrial fibrillation, SVT and prolonged QT interval. This is more pronounced in patients on Digoxin and diuretics, therefore requiring Magnesium level monitoring in these individuals.

D. Coronary Artery Disease or Peripheral Vascular Disease

There has been concern for PPIs, specifically omeprazole, decreasing the efficacy of concomitant Clopidogrel when used in CAD. Currently, the latest evidence points to no significant clinical interaction although concerns for an increased risk of recurrent coronary events and ischemic strokes have been expressed.

Clopidogrel labelling warns against its concomitant use with potent CYP2C19 inhibitors such as omeprazole. Similar concerns have been expressed with cimetidine as well. Dose reduction of Cilostazol is recommended when used with omeprazole.

E. Diabetes or other Endocrine issues

Long-term use of PPIs (>5 years and especially >7 years) has been associated with a significantly increased risk of hip, spine and wrist fractures in individuals over 50 years of age possibly related to Ca⁺⁺ malabsorption.

PPIs and H₂RAs can decrease Ketoconazole absorption requiring either their discontinuation or switching to another anti-fungal agent.

F. Malignancy

PPIs and H₂RAs can decrease absorption of Ketoconazole (when used for its anti-androgenic effects) requiring their discontinuation. Absorption of Erlotinib and Gefitinib (EGFR Tyrosine Kinase inhibitors) in non-small cell lung cancer is impaired, requiring their discontinuation.

Concerns expressed for PPI use increasing risks for gastric carcinoids or colorectal cancer in humans have not been validated and have been disproven.

G. Immunosuppression (HIV, chronic steroids, etc).

• HIV/AIDS medications such as Atazanavir (Reyataz), Nelfinavir (Viracept) plasma concentrations are reduced. Saquinavir (Invirase) concentrations can increase.

• Cyclosporine and Tacrolimus levels can increase.

• Prednisone can increase gastric acid secretion sometimes necessitating use of anti-secretory agents.

H. Primary Lung Disease (COPD, Asthma, ILD)

Cimetidine can increase Theophylline levels in COPD. This requires theophylline plasma level monitoring and dose reductions by about 30% to 50%.

I. Gastrointestinal or Nutrition Issues

There is concern for Vitamin B12 deficiency from malabsorption. Studies involving Vitamin B12 levels have been largely unsuccessful in proving this. Also, there is concern for Zinc, Ascorbic acid (Vitamin C) and related Iron malabsorption in chronic PPI use.

Hypomagnesemia is a problem in prolonged PPI use (>3 months). About 75% with hypomagnesemia respond to magnesium supplementation while the remaining poor responders need to have their PPIs discontinued.

Hypocalcemia can result from impaired absorption or hypomagnesemic hypoparathyroidism in chronic PPI use. The resulting hypocalcemia (with normal PTH levels) can occasionally cause tetany, carpo-pedal spasm and seizures. Calcium absorption of Calcium Citrate >Calcium carbonate with increased gastric pH.

J. Hematologic or Coagulation Issues

The presence of anemia with GER symptoms might need to be further evaluated.

H₂RAs are very occasionally associated with decreased cell counts. However, many of these reports involved patients who were on multiple medications. Cimetidine and Omeprazole can decrease warfarin metabolism (moderate level interaction) necessitating closer monitoring of PT/INR levels.

K. Dementia or Psychiatric Illness/Treatment

The very elderly might need to have the doses of H₂RAs decreased by 50%. Intravenous H₂RAs (mostly cimetidine and ranitidine) have very occasionally caused confusion in the hospitalized elderly.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

If the chest pain responded to a ‘GI cocktail’, one can include that in the sign-out process. If the patient has been started on a PPI or H₂RA in the hospital, then mention can be made if this needs to be discontinued on discharge.

Anticipated Length of Stay.

If chest pain necessitated an admission and appears to be atypical or non-typical, then the patient can be potentially discharged home in about 24 hours after serial cardiac enzymes and other diagnostic tests are negative.

C. When is the Patient Ready for Discharge.

If other causes of chest pain including cardiac causes have been considered and ‘ruled out’, if patient is chest pain free and there are no features of an acute GI bleed.

D. Arranging for Clinic Follow-up

Patients can be educated on GI causes of chest pain (when thought to be the culprit) before their discharge and advised to follow-up with their primary physician for further evaluation including referral to a gastroenterologist if necessary.

1. When should clinic follow-up be arranged and with whom.

Primary physician follow-up in 2 weeks; gastroenterologist (if necessary) follow-up in 3-4 weeks.

F. Prognosis and Patient Counseling.

Patients need to be counselled with reference to lifestyle modifications, need for compliance with medications and the timing of PPIs to meals. GERD is a chronic condition and needs to be treated adequately to avoid long term complications

VI. Patient Safety and Quality Measures

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

If there is a high suspicion for GER related chest pain, then the patient can be started on a PPI on discharge. Counselling can also be provided on lifestyle changes that are appropriate.

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