Joel E. Richter

Asthma and gastroesophageal reflux : Acid suppressive therapy improves asthma outcome

PURPOSE To determine (1) the appropriate omeprazole (Prilosec) dose required for adequate acid suppression in asthmatics with gastroesophageal reflux, (2) whether aggressive acid suppressive therapy of gastroesophageal reflux improves asthma outcome in asthmatics with gastroesophageal reflux, (3) the time course of asthma improvement, and (4) demographic, esophageal, or pulmonary predictors of a positive asthma response to antireflux therapy. PATIENTS AND METHODS Thirty nonsmoking adult asthmatics with gastroesophageal reflux (asthma defined by American Thoracic Society criteria and reflux defined by symptoms and abnormal 24-hour esophageal pH testing) were recruited from the outpatient clinics of a 900-bed university hospital. Patients underwent baseline studies including a demographic questionnaire, esophageal manometry, dual-probe 24-hour esophageal pH test, barium esophogram, and pulmonary spirometry. During the 4-week pretherapy phase, patients recorded reflux and asthma symptom scores and peak expiratory flow rates (PEFs) upon awakening, 1 hour after dinner, and at bedtime. Patients began 20 mg/d omeprazole, and the dose was titrated until acid suppression was documented by 24-hour pH test. Patients remained on this acid suppressive dose for 3 months. Responders were identified by a priori definitions: asthma symptom reduction by >20% and/or PEF increase by >20%. Asthma symptom scores, PEFs baseline and posttherapy pulmonary spirometry were analyzed. RESULTS Twenty-two (73%) patients were asthma symptom and /or PEF responders: 20 (67%) were asthma symptom responders, and 6 (20%) were PEF responders. Responders reduced their asthma symptoms by 57% (P<0.001), improved their morning and night PEFs by 8% and 9% (both P <0.005), and had improvement in forced expiratory volume at 1 second (P <0.02), mean forced expiratory flow during the middle half (25% to 75%) of the forced vital capacity (P <0.04), and peak expiratory flow (P <0.01) with acid suppressive therapy. Mean acid suppressive dose of omeprazole was 27 mg/d (+/-2.2) with 27% (8) patients requiring more than 20 mg/d. The presence of regurgitation or excessive proximal esophageal reflux predicted asthma response with 100% sensitivity, 100% negative predictive value, specificity of 44% and a positive predictive value of 79%. CONCLUSIONS Acid suppressive therapy with omeprazole improves asthma symptoms and/or PEFs by >20% and improves pulmonary function in 73% of asthmatics with gastroesophageal reflux after 3 months of acid suppressive therapy. Many asthmatics (27%) required >20 mg/d of omeprazole to suppress acid. The presence of regurgitation and/or excessive proximal esophageal reflux predicts a positive asthma outcome.

Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age, and gender.

Although the most sensitive and specific test for diagnosing gastroesophageal reflux disease, normal standards for prolonged esophageal pH monitoring are based on small sample sizes with questions raised about the effects of pH electrode, older age, gender, and methods of data analysis on pH variables. Recently three groups have established normal data bases using similar methodology. Multiple regression and nonparametric analyses showed that the values for the six traditional pH parameters were comparable across study centers. Therefore, the groups were combined for a total study population of 110 healthy subjects (47 men, 63 women, mean age 38 years with a range of 20–84 years). Further nonparametric analyses revealed the following: (1) type of pH electrode (antimony vs glass) is not significantly related to parameters of physiologic acid reflux; (2) age is not independently related to pH parameters; (3) men tend to have more physiologic reflux than women; and (4) older men tend to experience longer episodes of reflux than younger men and women. There was a significant effect of gender and a significant interaction between age and gender on the number of episodes >5 min (P=0.008). Nearly significant differences were found for percentage of total acid exposure time (P=0.03), total reflux episodes (P=0.02), and the longest reflux episode (P=0.02). We believe these normal esophageal pH values can be used confidently as standards in any laboratory, and consideration should be given to developing separate standards for men and women.

Altered pain perception and psychosocial features among women with gastrointestinal disorders and history of abuse: A preliminary model

OBJECTIVES To evaluate the relationships between sexual/physical abuse, pain perception, environmental events, coping strategies, and psychiatric morbidity in a sample of female patients with painful gastrointestinal disorders. PATIENTS Fifty paid volunteers from a tertiary care center including 13 patients with gastroesophageal reflux disease (GERD), 26 with noncardiac chest pain (NCCP), and 11 with irritable bowel syndrome (IBS). MEASUREMENTS (1) Sexual and physical abuse interview questions; (2) Structured psychiatric interview; (3) Self-report questionnaires: demographics, clinical pain measurement, Millon Behavioral Health Inventory, Hassles and Uplifts Scales, Sickness Impact Profile, Life Experiences Survey, Pain Beliefs and Perceptions Inventory, and Coping Strategies Questionnaire; (4) Pain Perception and Sensory Decision Theory tasks. RESULTS Fifty-six percent of the sample reported a history of sexual/physical abuse. Abuse was significantly more prevalent among patients with GERD (92%) and IBS (82%) compared with those with NCCP (27%). Abused patients, relative to nonabused patients, had significantly lower pain threshold levels in response to finger pressure stimuli and significantly lower cognitive standards for judging stimuli as noxious. Abused patients reported significantly higher levels of functional disability and a significantly greater number of psychiatric disorders, minor daily hassles, and pain syndromes unrelated to gastrointestinal disorders. In addition, abused patients more frequently blamed themselves for their pain and reported significantly greater use of maladaptive pain coping strategies than nonabused patients. CONCLUSION These data suggest that the relationships between abuse, disability, multiple pain syndromes, and health care seeking behavior are mediated by abnormal pain perception, psychiatric disorders, disruption of physical function, and environmental stressors.

Synergism of acid and duodenogastroesophageal reflux in complicated Barrett's esophagus

BACKGROUND The role of acid and duodenogastroesophageal reflux (DGER) in the development of complications in Barretts esophagus is controversial. We characterized the esophageal reflux constituents in patients with and without complications of Barretts esophagus. METHODS Using a new fiber-optic system we studied 12 normal subjects (six male; mean age, 46 years) and 20 patients with Barretts esophagus (17 male; mean age, 58 years), nine with uncomplicated (seven male; mean age, 55 years) and 11 with complicated Barretts esophagus (seven with stricture, two with ulcer, and two with dysplasia; 10 male; mean age, 61 years). Fasting gastric bile acid concentrations were measured. Twenty-four-hour ambulatory acid and bilirubin measurements were obtained with the fiber-optic system by using a glass electrode and fiber-optic sensor. The data were then analyzed for percent total time pH < 4 and > 7 and bilirubin absorbance > 0.14%. RESULTS Percent times pH < 4, bilirubin absorbance > 0.14%, and fasting gastric bile acid concentrations were significantly greater in patients with complicated Barretts esophagus compared with patients with uncomplicated Barretts esophagus with both being higher than the controls. Acid reflux paralleled bile reflux in the two Barretts esophagus groups (r = 0.44, p < 0.05), but percent time pH > 7 did not differentiate between the two groups. CONCLUSIONS (1) Patients with complicated Barretts esophagus reflux significantly greater amounts of both acid and duodenal contents than patients with uncomplicated Barretts esophagus. (2) Complications in Barretts esophagus may be due to synergism between acid and bile rather than either constituent alone.

Gastrointestinal Motility Disorders during Pregnancy

In 1991, an estimated 4.1 million babies were delivered in the United States [1]. If one includes the estimated number of abortions (1.5 million), the number of pregnancies approaches 5.5 million for 1991. Disorders of the gastrointestinal tract are common problems in normal, uncomplicated pregnancies. Most, if not all, of these patients will be managed by their obstetricians; however, internists and gastroenterologists sometimes are consulted. Because of the concern about the use of systemic medications during pregnancy, it is important for all physicians to understand the pathogenesis and natural history of and diagnostic and therapeutic options available for treating pregnant patients who have gastrointestinal disorders. Pregnancy has little effect, if any, on gastrointestinal secretion or absorption, but it has a major effect on motility throughout the gastrointestinal tract. Recent studies suggest that motility changes are related to increased levels of circulating female sex hormones rather than, as once believed, to the enlarging uterus. Given the number of pregnancies per year, the costs in managing these problems can be substantial. Thus, our purpose was to review the effects of pregnancy on gastrointestinal motility to expand the knowledge of internists, gastroenterologists, and obstetricians about these common problems. Methods To compile a thorough review of pregnancy-related gastrointestinal motility disorders, their pathophysiology, associated clinical manifestations, and treatment, we used a variety of sources. We first did computerized literature searches of Index Medicus and MEDLINE using pregnancy and gastrointestinal system as the key words. Further references (including abstracts) were obtained by hand searches. References were selected for analysis if the article focused on alteration of motility during pregnancy, particularly if they emphasized hormonal effects. Animal studies, both in vivo and in vitro, that tried to illustrate hormonal effects on the gastrointestinal tract were also included. The latest editions of standard drug textbooks (PDR, American Hospital Formulary Service) and references pertaining to drug therapy during pregnancy were used to provide most of the information on the appropriate pharmacologic management of these disorders during pregnancy. Specific pharmaceutical corporations were contacted to obtain information about drug safety during pregnancy. We did not receive financial support from these companies. Esophagus Gastroesophageal Reflux Disease Heartburn is estimated to occur in 30% to 50% of all pregnancies, with the incidence approaching 80% in some patient groups [2]. Although some authors [3] find that most women experience reflux symptoms after 5 months of gestation, Castro [4] suggests that these symptoms are reported only when they become most troublesome and that they begin much earlier in pregnancy. After detailed interviews of 60 patients, he noted that 52% first experienced heartburn during the first trimester of pregnancy; 24%, in the second trimester; and 8.8%, in the last trimester. Although heartburn tends to recur in subsequent pregnancies, no significant differences were noted in the incidence of heartburn among multiparous and primiparous women [5]. Pathophysiology The pathogenesis of gastroesophageal reflux during pregnancy involves both mechanical and intrinsic factors that adversely affect lower esophageal sphincter tone. Early in pregnancy, lower esophageal sphincter pressure falls, returning to normal in the postpartum period. Van Thiel and colleagues [6] studied four previously asymptomatic pregnant patients sequentially at 12, 24, and 36 weeks of gestation and 1 to 4 weeks postpartum. Figure 1 shows that during all stages of pregnancy, resting lower esophageal sphincter pressures were less than the lower limits of normal for their motility laboratory, reaching a nadir at 36 weeks and returning to normal in the postpartum period. All four patients complained of frequent heartburn by 36 weeks. Fisher and colleagues [7] studied eight women during early pregnancy (mean gestation, 16 weeks) and 6 weeks after elective abortion. A mean lower esophageal sphincter pressure of 22.1 2.4 mm Hg ( SE) was found before abortion, which was unchanged from the postabortion mean sphincter pressure of 22.6 2.3 mm Hg. Although these patients had normal resting lower esophageal sphincter pressures, their sphincter pressures did not increase appropriately when challenged with injections of pentagastrin, edrophonium chloride, metacholine, and a protein meal. During each of these maneuvers, lower esophageal sphincter pressure was significantly lower during early pregnancy than after abortion. Thus, during pregnancy, not only is lower esophageal sphincter pressure decreased but adaptive responses of the sphincter may be reversibly inhibited. Figure 1. Lower esophageal sphincter pressures. Animal and human experiments have helped elucidate the important effects of female hormones on the lower esophageal sphincter. Fisher and colleagues [8] used in vitro studies to examine strips of circular smooth muscle from the lower esophageal sphincter of opossums. Dose-response curves were constructed for gastrin and acetylcholine alone and with 17--estradiol, progesterone, or the combination of sex hormones added to the system. The lower esophageal sphincter dose-response curve to acetylcholine and gastrin was blunted by estradiol as well as progesterone; progesterone was more effective in inhibiting the maximum response. The combination of progesterone and estradiol, however, was more potent than either hormone alone. In vivo models using the opossum show a substantial reduction of lower esophageal sphincter pressure with the administration of both estradiol and progesterone [9]. Whether the decrease in lower esophageal sphincter function is due to estrogen, progesterone, or both is unclear. Filipone and colleagues [10] attempted to address this issue by studying five transsexual patients during a control period without hormonal stimulation, followed by periods of administration of estrogen, progesterone, or both. Resting lower esophageal sphincter pressure was significantly decreased during combination hormonal therapy (5.0 0.1 mm Hg, mean SE) when compared with the control period (11.2 2.1 mm Hg). No decrease in sphincter pressure was observed during either estrogen or progesterone administration alone. In addition, the adaptive lower esophageal sphincter pressure response to a protein meal was diminished by progesterone and by combination hormone therapy but not by estrogen alone. Similar observations were made by Van Thiel and colleagues [11] after examining normal menstruating women taking sequential oral contraceptives. The womens baseline mean lower esophageal sphincter pressure was 20.8 1.7 mm Hg (mean SE) and did not change significantly during estrogen administration. Sphincter pressure, however, decreased to 9.4 1.2 mm Hg during the administration of estrogen and progesterone. These studies suggest that progesterone is the mediator of lower esophageal sphincter smooth muscle relaxation; however, estrogen may be needed as a primer for this action to occur. It was assumed for many years that the gravid uterus was responsible for an increase in abdominal pressure that overcame lower esophageal sphincter pressure and produced gastroesophageal reflux. However, Van Thiel and Wald [12] presented evidence that refuted this theory in a novel study using adult men with tense ascites as a model of pseudopregnancy. Before diuresis, the mean lower esophageal sphincter pressure was 30.9 1.7 mm Hg (mean SE), which decreased significantly to 24.0 1.6 mm Hg after loss of ascites. Thus, a compensatory increase in lower esophageal sphincter pressure usually parallels any increase in intra-abdominal pressure. This protective mechanism should prevent the enlarging uterus from promoting acid reflux. Presentation and Diagnosis The clinical features of gastroesophageal reflux in pregnancy do not differ from those found in the general population. Heartburn and regurgitation are the predominant symptoms, worsening as pregnancy advances. Not unexpectedly, Castro [4] found that most patients reported the adverse effects of food ingestion, causing some to restrict their meals to once a day because of intense postprandial heartburn. Likewise, the recumbent position aggravated heartburn in 82% of the patients, requiring some to sleep upright in a chair. The diagnostic evaluation of pregnant patients with gastroesophageal reflux disease generally requires only a complete history. Barium studies should be avoided because of the radiation risk to the fetus. Endoscopy, although not commonly needed, is safe especially with current monitoring equipment [4]. Prolonged esophageal pH monitoring may be useful in atypical presentations. Fortunately, complications of reflux disease during pregnancy, such as esophagitis, are quite uncommon [4], and reflux symptoms are usually limited to pregnancy with no prolonged adverse effects on the mother or fetus. Treatment Because of potential teratogenicity of systemic drugs taken during gestation, lifestyle modifications are particularly important in treating pregnant patients with troubling heartburn. Patients are instructed to elevate the head of the bed and to avoid stooping, bending, or assuming other positions that tend to worsen reflux symptoms. Eating small frequent meals and refraining from ingesting foods or liquids other than water within 3 hours of bedtime are advised. Nonsystemic drug therapy with antacids is the first step in treating the pregnant patient who does not respond to lifestyle modifications. Animal studies show no teratogenic effects from constant ingestion of antacids during pregnancy [13]. Adverse effects of antacids include interference with iron absorption and, specifically, metabolic alkalosis and fluid overload in both the fetus an

The symptom index. Differential usefulness in suspected acid-related complaints of heartburn and chest pain.

The symptom index is a quantitative measure developed for assessing the relationship between gastroesophageal reflux and symptoms. Controversy exists, however, over its accuracy and the appropriate threshold for defining acid-related symptoms of heartburn and chest pain. Therefore, a retrospective review was done of 153 consecutive patients referred to our esophageal laboratory. Three groups were identified: patients with normal 24-hr pH tests and no esophagitis, patients with abnormal 24-hr pH tests and no esophagitis, and patients with abnormal 24 hr pH values and endoscopic esophagitis. If symptoms occurred during the pH study, a symptom index (number of acid related symptoms/total number of symptoms x 100%) was calculated separately for heartburn and chest pain. Heartburn and chest pain episodes were similar among the three groups. However, the mean symptom index for heartburn was significantly (P<0.001) higher in the patient groups with abnormal pH values [abnormal pH/no esophagitis: 70±7.1% (±se); abnormal pH/esophagitis: 85±4.6%] as compared to those with normal studies, ie, functional heartburn (26±10.7%). The mean symptom index for chest pain was similar for all three groups. Using receiver operating characteristic curves, a heartburn symptom index≥50% had excellent sensitivity (93%) and good specificity (71%) for acid reflux disease, especially if patients complain of multiple episoldes of heartburn. In contrast, an optimal symptom index threshold for defining acid-related chest pain episodes could not be defined.

Relaxation training reduces symptom reports and acid exposure in patients with gastroesophageal reflux disease

BACKGROUND/AIMS Previous studies have shown that psychological factors play a role in symptom perception among patients with gastroesophageal reflux disease. This report describes the first controlled study showing the effects of relaxation training on symptom reports and esophageal acid exposure in patients with reflux disease. METHODS Twenty subjects with documented reflux disease were studied during psychologically neutral and stressful tasks, followed immediately by either a relaxation or attention-placebo control intervention. RESULTS Stressful tasks, relative to neutral tasks, produced significant increases in blood pressure, subjective ratings of anxiety, and reports of reflux symptoms. Despite increased symptom reports, stressful tasks did not significantly increase objective measures of esophageal acid exposure. Subjects who received a relaxation intervention after the stressful task had significantly lower heart rate values and subjective ratings of anxiety compared with subjects who received the attention-placebo control intervention. Subjects who received relaxation training also had significantly lower reflux symptom ratings and total esophageal acid exposure than subjects who received the attention-placebo control intervention. CONCLUSIONS Relaxation may be a useful adjunct to traditional antireflux therapy in patients who experience increased symptoms during stress.

Acid perfusion test and 24-hour esophageal pH monitoring with symptom index. Comparison of tests for esophageal acid sensitivity.

The acid perfusion (Bernstein) test and esophageal pH monitoring are the two most popular tests for identifying esophageal acid sensitivity in difficult cases of reflux disease. Therefore, we prospectively compared these test results in 75 consecutive noncardiac chest pain patients who had both an acid perfusion test and chest pain during 24-hr pH testing. A positive acid perfusion test was defined by the replication of the patients typical chest pain twice by the acid infusion. Esophageal pH testing identified abnormal amounts of acid reflux and correlated symptoms with acid reflux-the “symptom index.” Fifteen patients (20%) had a positive acid perfusion test while 45 patients (59%) had a positive symptom index (range 6–100%). Only 9/34 (26%) patients with abnormal reflux had a positive acid perfusion test. Although it had excellent specificity (83–94%), the acid perfusion test had poor sensitivity (32–46%) when compared to the symptom index regardless of the percent positive cutoff level. The best positive predictive value for the acid perfusion test was 87%, but this occurred when the test sensitivity was 32%. Modifying the end point of a positive acid perfusion test to include heartburn improves the sensitivity (52–67%) while markedly compromising specificity and positive predictive value. Thus, esophageal pH monitoring correlating symptoms with acid reflux is superior to the acid perfusion test for identifying an acid sensitive esophagus in patients with noncardiac chest pain.

Psychosocial and psychophysical assessments of patients with unexplained chest pain

It is imperative to assess the psychosocial factors that may influence the subjective experiences and pain behavior of persons with chronic unexplained chest pain. Both psychologists and physicians tend to rely on self-report measures of psychological distress, which provide little unique information about patients with chronic chest pain to differentiate them from patients with other painful disorders such as irritable bowel syndrome, gastroesophageal reflux disease, or coronary artery disease. However, assessment of pain-coping strategies, spouse responses to the patients pain behaviors, and pain thresholds for esophageal balloon distention do differentiate patients with chronic chest pain from healthy controls and patients with various other chronic pain disorders. Specifically, chronic chest pain patients tend to use relatively passive pain-coping strategies such as praying and hoping, and to report relatively high levels of spouse reinforcement of pain behaviors. Finally, in response to esophageal balloon distention, chronic chest pain patients display low pain thresholds that do not generalize to stimulation by mechanical finger pressure. Preliminary evidence suggests these low thresholds are due primarily to a tendency to set low standards for making pain judgments regarding esophageal stimuli of moderate-to-high intensity levels.

Effects of oral erythromycin on esophageal pH and pressure profiles in patients with gastroesophageal reflux disease

Erythromycin, a possible motilin agonist, is a potent gastrokinetic agent that may increase the lower esophageal sphincter pressure. Therefore, we assessed the effects of erythromycin in two dosages (250 and 500 mgper os four times a day) on esophageal pH and pressure profiles in reflux patients using prolonged ambulatory monitoring systems. Studies were blinded, placebo-controlled with randomized crossover design. Patients took each drug for three days prior to studies, with erythromycin serum levels obtained the day of esophageal studies. Erythromycin 250 mg four times a day had no effect on esophageal contraction pressures or peristalsis during the day or meal periods. In the supine position, however, erythromycin significantly (P=0.012) decreased esophageal contraction velocity and showed a strong trend (P=0.059) towards increasing the percentage of peristaltic waves. Despite these potentially beneficial effects on esophageal clearance, no significant difference in acid exposure times during 24-hr pH studies were observed between placebo and low-dose erythromycin. High-dose erythromycin (500 mg four times a day) was associated with drug levels in the typical antibiotic efficacy range (normal 1–3 µg/ml; patients 1.7–7.0 µg/ml), but, here again, there was no significant difference in all acid reflux parameters between placebo and erythromycin phases. Therefore, “standard” doses of erythromycin have no important clinical effects on esophageal pressures or acid reflux parameters.