BRIEF COMMUNICATIONS Gastroesophageal Reflux Disease n patients who have typical symptoms of gastro- Iesophageal reflux disease, such as heartburn and Presenting with Intractable Nausea acid regurgilation. the diagnosis is usually obvious Ronald J. Brzana. MD, and Kenneth L, Koch. MD (1). A subsel of patients, however, can present with atypical symptoms, including angina-like chest pain, Background: Typical symptoms of gastroesophageal re- cough, wheezing, shortness of breath, and hoarse- flux disease are heartburn and régurgitation. A subset of ness, that hinder immediate diagnosis of gastro- patients present witb atypical symptoms, such as chest esophageal reflux disease. In addition to being a pain, cougb, wheezing, and hoarseness. symptom of gastroesophageal rellux disease, chronic Objective: To review the clinical presentation and treat- nausea ean be a symptom of chronic peptic ulcer ment of patients who presented with nausea as the pri- disease, gastroparesis. occult gastrointestinal cancer, mary symptom of gastroesophageal reflux disease. intestinal pseudo-obstruetion. and increased intra- Design: Case series. craniai pressure secondary to a tumor. Setting: Outpatient department of a university hospital. Patients: 10 outpatients who had chronic, intractable nausea and had not responded to empirical therapies. Measurements: Patients were evaluated by esophago- Methods gastroduodenoscopy, 24-hour esophageal pH studies, gas- tric-emptying tests, electrogastrography, or a Bernstein Patients test. We reviewed the charts of patients who had been Results: Abnormal acid reflux was found to be the cause referred to the gaslroenterology division of the Mii- of intractable nausea in all 10 patients. In 5 of the 10 ton S. Hei'shey Medical Center from September patients, esophagitis was documented by esophagogas- 1991 to August 1995 ior evaluation of ehronie Idio- troduodenoscopy. Six patients had abnormal results on pathie nausea. Three men and seven women (ago the 24-hour esophageal pH study. In these 6 patients, 32 of range. 27 to 67 years) who had received a diagnosis 33 episodes of nausea were accompanied by an episode of of gastroesophageal reflux disease presented with acid reflux. One patient had positive results on the Bern- chronic nausea. The average duration of nausea was stein test. Nausea resolved after treatment with omepra- zole in 7 patients, after treatment with cisapride or raniti- 2.1 years (range, 3 months lo f) years). dine in 2 patients, and after Nissen fundoplication in 1 None of the 10 patients had responded to em- patient. pirical medical therapies for chronic nausea. In Conclusions: Intractable nausea is an atypical symptom some instances, the patients had not responded to that can occur in a subset of patients with gastroesopha- more than one treatment reghnen: Nine did not gea! reflux disease, A 24-hour esophagea! pH study should respond to standard histamine-2 (H.) bloekers (4(10 be considered ¡n patients who have unexplained nausea mg of cimclidine. 150 mg of ranilidine. 20 mg of but normal findings on esophagogastroduodenoscopy, a famotidine. or 150 mg of nizatidhic twice daily); 6 gastric-emptying test, and electrogastrography. Nausea did not respond to inetoclopramide; (^ did not re- related to gastroesophageal reflux disease resolves or is spond to anticmefic agents: 3 did not respond to markedly reduced with proton-pump inhibitors or promo- eisapride; 2 did not respond to omeprazole (20 mg tility drugs. once daily): ! did not respond to high-dose H;, bloekers (300 mg of i'aniiidinc twice dailyj; 1 did not respond fo bethaneclioi: and i did not respond to sucralfate. Six of 10 patients had intermittent vomiting in addition to nausea, ln most patients, the vomiting did noE occur after nicals. Each patient had epi- sodes of nocturnal vomiting. Patients reported two .Inn Intern Med. l'I'H; 120:704-707, to eight episodes of vomiting per week. One patient had insulin-dependent diabetes mellitus, a comorbid hiom Milton S. Herslicy Mediciil Ccnlcr. KcnnsylviiiiiL cuiTfiii auihnr addrcsso, six- end ol (i:xi. condition that can contribute to nausea: however. 704 May 1997 • Annals of Inienial Medicine • Vokime 126 • Number Table 1. Results of Gastrointestinal and Central Nervous System Studies m Patients with Nausea and Gastroesophageal Reflux Disease* Patient Gastric Electrogastrography Abdominal upper Computed Tomography or Emptyingt Ultrasonography Gastrointestinal Series Magnetic Resonance Imaging 1 ND ND ND ND ND J IV Normal (70%) Normal (3 cpm) ND Normal Normal 3 Normal (82%) Normal (3 cpm) Normal Normal Normal 4 Normal (92%) ND Normal ND ND 5 Norma i (76%) Normal (3 cpm) Normal Normal ND 6 ND ND Normal Normal ND 7 Normal (50%) ND Normal ND Normal 8 Normal (77%) Normal (3 cpm) Normal Normal Normal 9 Normal (72%) Normal (3 cpm) Normal Normal Normal 10 Normal (84%) Normal (3 cpm) Normal Normal Normal ' rpm - c/c!ei per minute; ND = no! cipierminpd. t Values yiwn in parentheses are ihe percentages enißtfed at 120 this patient was subsequently found to have normal minute were considered normal (5). Frequencies of gastric emptying. 0 to 2.4 cycles per minute were eonsidered to be After carefully reviewing the medieations of all bradygastrie; frequencies of 3.6 to 9.9 eyeles per patients, we did not believe that any medication was minute were eonsidered to be taehygastrie. causing the nausea. Dietary modifieations had not All patients had normal liver function test re- been prescribed for any patient before our discovery sults; complete blood eell eounts; and levels of amy- of gastroesophageal reflux disease. lase, lipase, electrolytes, blood urea nitrogen, and One patient smoked eigarettes, and three infre- ereatinine. Normal results on other studies are quently drank aleoholic beverages. The referring listed in Table 1. physicians and investigators did not believe that any of the patients had neuropsychiatrie conditions. Results Evaluation All patients had esophageal and gastrie evalua- Either endoseopie studies or 24-hour esophageal tions: Ten had esophagogastroduodenoscopy, 6 had pH studies showed gastroesophageal acid reflux in 24-hour esophageal pH studies, and 1 had a Bern- all 10 patients (Table 2). Esophagitis was doeu- stein test for determination of acid perfusion. An mented in 5 of the 10 patients by esophagogas- ambulatory pH monitoring system (Synecties, Inc. troduodenoscopy and was graded according to a Houston, Texas) with dual monocrystalline anti- published endoseopie grading system (6). Three pa- mony pH catheters was used for the esophageai pH tients had grade 4 esophagitis (ulcération, diffuse studies as deseribed elsewhere (2). erythema, mueosal friability), 1 patient had grade 3 Solid-phase gastric-emptying scans were done in esophagitis (erosions, diffuse erythema, mucosa! fri- eight patients, and electrogastrography was done in ability), and 1 patient had grade I esophagitis (lo- six patients as part of the evaluation. The solid- calized erythema of the gastroesophageal junction). phase gastric-emptying scans were done by the nu- Six patients had 24-hour esophageal pH studies, and clear medicine division as described elsewhere (3). eaeh study showed abnormally increased acid reflux. Eleetrogastrography measures gastric myoelectrieal aetivity. Gastric dysrhythmias that alter upper gas- trointestinal motility may elude diagnosis if tests Table 2. Confirmation of Gastroesophageal Refiux Disease in Patients with Intractable Nausea* other than eleetrogastrography are used. Eleetroga- strography has shown altered gastrie myoeleetrieal Patient Esophogastroduodenoscopy 24-Hour Bernstein activity in patients who have unexplained nausea and Esophagitii pH Studyt Test and vomiting (4). 1 Yes ND ND Eleetrogastrograms were recorded by using four 2 Yes ND ND 3 No Yes (19%) ND standard silver-chloride electrodes positioned on the 4 No Yes (41%) ND epigastrium as described elsewhere (5) The elec- 5 No ND Yes 6 No Yes (9%) ND trodes were eonnected to a rectilinear recorder 7 Yes ND ND through a direct nystagmus coupler (Model 9859, 8 Yes Yes (NA) ND 9 Yes Yes (75%) ND Sensormedies, Inc., Anaheim, California), and a 10 No Yes (20%) ND hard copy of the electrogastrographie signa! was obtained. The signal was also analyzed by computer ' NA --- iioi available; ND = pot de'.ermined. t Values given ii parenthcws ¿ire !ne per(;£?niage5 of tirns^ tna1 esopnageal pH was less (5), and frequencies from 2.4 to 3.6 cycles per !han 4.0. 1 May 1997 • Annals of Internal Medicine • Volume 126 • Number 9 705 During the 24-hour period, the esophageal pH was patients, retrospective analysis, and short-term foi- less than 4.0 between 9% to 759r of the time (av- low-up. However,, gastroesophageal reflux disease erage, 33%). The normal range in our laboratory is should be considered in the differential diagnosis of less than 6%. Diaries of symptoms indicated that 32 chronic nausea, especially in troublesome cases in oí 33 reported episodes of nausea correlated with which gallbladder, pancreatic, neurologic, or peptic episodes of aeid reflux. One patient was believed to ulcer disease has been excluded. have gastroesophageal reflux disease on the basis of Because chronic nausea is not typically attributed positive results on the Bernstein test. to gastroesophageal reflux disease, abnormal acid Gastric emptying and gastric myoelcctrical activ- reflux was not eonsidered in our patients before ity were found to be normal according to a solid- referral. Even when esophagitis was seen on endos- phase gastric-emptying test and eiectrogastrography copy, the association with nausea was not appreci- (Table 1). ated and standard-dose Hj-biocker therapy was fre- After gastroesophageal reflux disease was shown quently unhelpful. Gastroesophagea! reflux disease to cause chronic nausea, treatment was directed cannot be exckided on the basis of normal endo- toward reducing acid reflux. In 7 of the 1Ü patients, scopie findings because endoscopy lacks sufficient nausea was effectively treated with the following sensitivity (11-13). Endoscopie evidence of esoph- dosages of omeprazole: 20 mg twice daily (5 pa- agitis is present in only 50% to 60% of symptomatic tients), 20 mg once daily (1 patient), and 40 mg patients (14, 15).