Abdallah J., George N., Yamasaki T., Ganocy S., Fass R. Most Patients With Gastroesophageal Reflux Disease Who Failed Proton Pump Inhibitor Therapy Also Have Functional Esophageal Disorders // Clinical Gastroenterology and Hepatology 2019;17:1073–1080

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Авторы: Abdallah J. / George N. / Yamasaki T. / Ganocy S. / Fass R.


Most Patients With Gastroesophageal Reflux Disease Who Failed Proton Pump Inhibitor Therapy Also Have Functional Esophageal Disorders

Jason Abdallah1, Nina George1, Takahisa Yamasaki1, Stephen Ganocy2,3 and Ronnie Fass1

1 Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio;
2 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
3 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.


BACKGROUND & AIMS: As many as 45% of patients with gastroesophageal reflux disease (GERD) still have symptoms after receiving once-daily proton pump inhibitor (PPI) therapy. We aimed to compare reflux characteristics and patterns between responders and non-responders to once-daily PPI therapy using combined impedance-pH monitoring.

METHODS: Patients who reported heartburn and/or regurgitation at least twice per week for 3 months while receiving standard-dose PPI therapy were assigned to the PPI failure group (n = 16). Patients who reported a complete resolution of symptoms on once-daily PPIs for at least 4 weeks were assigned to the PPI success group (n = 13). We collected demographic data and subjects completed the short-form 36 and the GERD health-related quality of life questionnaires. Patients then underwent upper endoscopy and combined esophageal impedance-pH monitoring while on PPI therapy.

RESULTS: Four patients in the PPI success group (31%) and 4 patients in the PPI failure group (25%) had abnormal results from the pH test (P = 1.00). Most of the patients in the PPI failure group (75%) were found to have either functional heartburn or reflux hypersensitivity with GERD. Impedance and pH parameters did not differ significantly between the PPI failure and success group.

CONCLUSIONS: We found no difference in reflux characteristics between patients with GERD who had successful vs failed once-daily PPI therapy. Most patients in the PPI failure group (75%) had functional esophageal disorder.

Keywords: Heartburn; Proton Pump Inhibitor; Esophagus; Impedance Test; Regurgitation; Gastroesophageal Reflux.

Abbreviations used in this paper: DGER, duodenogastroesophageal reflux; GERD, gastroesophageal reflux disease; GERD-HQRL, Gastroesophageal Reflux Disease-Health Related Quality of Life; LES, lower esophageal sphincter; MNBI, mean nocturnal baseline impedance; PPI, proton pump inhibitor; SAP, symptom association probability; SF-36, 36-Item Short Form Survey; SI, symptom index.

© 2019 by the AGA Institute 1542-3565/$36.00 ht tps://doi.org/10.1016/j.cgh.2018.06.018



Gastroesophageal reflux disease (GERD) is a condition in which the reflux of stomach content into the esophagus causes troublesome reflux-associated symptoms.1 GERD is a chronic disorder and is highly prevalent, affecting up to 44% of the U.S. adult population at least once a month and 20% once a week.2,3 GERDis the fourth most prevalent gastrointestinal disease in the United States, with an estimated 19 million cases peryear.4 The disease significantly impacts patients’quality of life and incurs the highest cost of the alimentary tractdisorders, posing a large economic burden.5,6


Proton pump inhibitors (PPIs) have revolutionizedthe management of patients with GERD due to their profound and prolonged acid suppression and consequently have become the mainstay of therapy.7 When compared with other acid suppressive medications, PPIs demonstrate superior mucosal healing and symptom control as well as preventing both mucosal and symptom relapse.8,9 In addition, PPIs are generally safe and welltolerated. Despite the success achieved with PPI therapyin the treatment of GERD patients, there remains asubstantial cohort of GERD patients who demonstrate therapeutic failure. It is estimated that between 10% and 45% of patients with GERD remain symptomatic on standard-dose PPI once daily.10 Several mechanism shave been proposed to account for persistent symptoms in GERD patients who failed PPI therapy. These primarily include poor medication compliance and adherence, differences in PPI metabolism, residual reflux (nonacidic, bile, or acidic), concomitant functional bowel disorders, psychological comorbidity, and delayed gastric emptying.11,12

Gasiorowska et al13 showed that the degree of duodenogastroesophageal reflux (DGER) and acid did not differ significantly between responders and nonresponders to once-daily PPI, using combined pH and Bilitec tests. As aresult, the authors suggested that the increase in DGER in patients taking PPI is not unique to those who failed PPI therapy and that esophageal hypersensitivity is likely contributing to symptoms in this population.

None of the studies thus far that physiologically evaluated the underlying mechanisms of refractory heartburn compared impedance-pH test results between patients who failed to respond to PPI once daily with those who were successfully treated with a once-daily PPI. The aim of this study was to compare impedance-pH results in PPI responders versus failure patients to further assess the hypothesis that overlap with functional esophageal disorders and thus esophageal hypersensitivity are the basis for symptom generation in PPI failure patients.
Methods
Patients

We conducted a prospective-based cohort study of 29 adult patients with documented baseline GERD who were on standard-dose PPI (omeprazole 20 mg daily, esomeprazole 40 mg daily, pantoprazole 40 mg daily) for at least 3 months in our Esophageal and Swallowing Center. Patients were enrolled from October 2014 to April 2017.

The PPI success group included patients with a history of heartburn or regurgitation who reported a complete resolution of symptoms on once-daily PPI for at least 4 weeks. Before PPI treatment, the patients reported at least 3 episodes of GERD-related symptoms per week. The PPI failure group included patients who continued to demonstrate GERD-related symptoms on PPI once daily, at least twice per week for the last 3 months. All patients had documented baseline GERD (previous evidence of increased esophageal acid exposure using ambulatory reflux testing or erosive esophagitis, pathology-proven short-segment Barrett’s esophagus, and peptic stricture on endoscopy).

We excluded patients with significant underlying comorbidities (severe heart failure, severe chronic obstructive pulmonary disease, liver cirrhosis, severe kidney failure, active malignancy, neurologic and psychiatric disorders), atypical or extraesophageal manifestations of GERD, diabetes mellitus, scleroderma, gastroparesis, active peptic ulcer disease, or known history of long-segment Barrett’s esophagus (>3 cm) on prior upper endoscopy.

Study Design

This was a prospective study in which patients were enrolled and asked to provide written informed consent. Demographic data such as sex, race, age, alcohol, smoking habits, body mass index, and education level were obtained. Patients filled out the 36-Item Short Form Survey (SF-36) and the GERD-Health Related Quality of Life (GERD-HRQL) symptom severity scale. They then underwent upper endoscopy to assess for esophageal mucosal injury, as well as combined 24-hour esophagea limpedance and pH monitoring while on their current PPI therapy within 2–4 weeks of enrollment.

Upper Endoscopy

Esophagogastroduodenoscopy was performed using an Olympus 190 series upper endoscope (Olympus, Center Valley, PA) on all enrolled subjects after an overnight fast to assess for mucosal abnormalities of theesophagus, stomach, and duodenum. The extent of esophageal mucosal inflammation was determined according to the Los Angeles Classification System.14

Ambulatory 24-Hour Esophageal CombinedImpedance and pH Monitoring

After an overnight fast an esophageal manometry was performed using a solid-state high-resolution catheter toidentify the lower esophageal sphincter (LES). The catheter was inserted via the nostril into the stomach. Thereafter, the proximal margin of the LES was recorded. Subsequently the pH and Impedance catheter (Laborie Medical Technologies, Mississauga, Ontario, Canada) was placed 5 cm above the proximal margin of the LES and connected to a digital portable recorder. Reflux was defined as a pH<4 and reflux time as the interval until pH was >4 again. The test was considered positive whenthe percent total time the pH<4 was>4.2%. Abnormal esophageal acid exposure in the upright and supine positions was defined as a pH<4 for more than 6% and 1% of the time, respectively. In addition to acidic reflux, nonacidic reflux events that included weakly acidic (pH 4–7) and weakly alkaline (pH>7) reflux were recorded and the characteristics of the reflux, liquid, or mixed (liquid and air) were documented.

The mean nocturnal baseline impedance (MNBI) was assessed using the most distal impedance channel andwas then calculated using the mean of three 10-minute nighttime periods (around 1:00 a.m., 2:00 a.m., and 3:00 a.m.) for each patient.

To assess the temporal relationship between reflux and symptoms, the patient’s symptom association probability (SAP) and symptom index (SI) scores were calculated. SAP is calculated using statistical analysis (cross tabulation) of a contingency table consisting of 4 possible combinations of reflux and symptoms and identifies the probability that gastroesophageal reflux episodes and symptoms are associated.15 SI is calculatedas the percentage of heartburn symptoms that occurredwithin 2 minutes of an acid reflux event (pH<4).

Significant symptom-reflux association occurred when the SAP was > 95% or SI was ≥ 50%.15 Analysis of the recorded data was carried out using standard computer software.

Questionnaires

Demographic questionnaire. Demographic data such as sex, race, age, and education level were obtained from all patients. Information about current alcohol and smoking habits was collected as well. Body mass index was calculated using the patient’s weight and height.

36-Item Short Form Survey. The SF-36 is a validated set of generic, coherent, and easily administered quality-of-life measures that has been shown to be useful in evaluating the clinical curative effect of GERD.16,17 This health survey contains 36 items and includes a multi-item scale that assesses 8 health domains: physical functioning, role limitations due to physical and emotional health, bodily pain, general health, vitality, social functioning, and mental health. The SF-36 score srange from 0 to 100, with higher scores indicating better functioning and well-being.

GERD-HRQL Scale. The GERD-HRQL scale is a reliable, valid, responsive, and practical measure of symptom severity in patients with GERD.18 It was developed to survey symptomatic outcomes and therapeutic effects in patients with GERD. The scale has 10 items that focus on heartburn symptoms, dysphagia, bloating, and medication effects on daily life. Each item is scored from 0 (no symptoms) to 5 (worse symptoms).

Statistical Analysis

Categorical data were described with number and percentage, while continuous data were described using mean ±SD and median. A chi-square test was used to compare the proportion between the PPI responsive groups except in instances where small numbers necessitated using the Fisher’s exact test. Where data was normally distributed, groups were compared using Student’s t test. With non-normally distributed data, groups were compared via the nonparametric Kruskal-Wallis test. The P values were adjusted using false discovery rate correction due to multiple comparisons. SAS version 9.4 (SAS Institute, Cary, NC) was used for all statistical data analysis.
Results
Patient Characteristics

There were 29 patients who were enrolled and completed the study. The demographic data are presented in Table 1. Thirteen patients (mean age 54.5 ± 14.5 years; 8 women and 5 men) were asymptomatic on once-daily PPI and were assigned to the PPI success group. Sixteen patients (mean age 46.6 ± 13.1 years; 11 women and 5 men) continued to report heartburn or regurgitation despite once-daily PPI and were assigned to the PPI failure group. The majority of the patients were women (69% failure and 62% success). There were no significant differences in all demographic parameters between the 2 patient groups. There were also no significant differences in PPI dosing or distribution between the 2 patient groups (Table 2).

Questionnaires

The comparison between quality-of-life scores between PPI failure and PPI success groups based on the SF-36 is depicted in Supplementary Table 1. Overall, the PPI success group had higher mean scores in all SF-36 domains. However, the scores did not reach statistical significance. Table 3 compares the GERD symptom characteristics between the PPI failure and success groups based on the GERD-HRQL questionnaire. Heartburn or bloating experienced in the supine position as well as overall degree of heartburn were the most bothersome symptoms for PPI failure patients on a daily basis.


Endoscopy

The majority of patients in both groups had normal endoscopy. In the PPI failure and success groups, 81% (13) and 69% (9), respectively, had a normal upper endoscopy. One (3%) patient, who responded to PPI therapy, had erosive esophagitis (Los Angeles grade A). Short-segment Barrett’s esophagus was seen in 2 patients (7%), both of which were in the PPI success group. Nonobstructive Schatzki rings were noted in 3 (23%) of the PPI success and 2 (13%) of the PPI failure patients. One (6%) PPI failure patient had an esophageal stricture. Hiatal hernia was noted in 5 (38%) of the PPI success and 3 (19%) of the PPI failure patients (P = .41).

Ambulatory 24-Hour Combined Esophageal pH and Impedance Monitoring


Abnormal pH test was present in 4 (31%) patients from the PPI success group and 4 (25%) from the PPI failure group (P = 1.00). Figure 1 depicts the percentages of each type of reflux based on impedance pH testing among the PPI failure and PPI success patients. In the PPI failure group, the total number of reflux events was 1279. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events was 250 (19.6%), 985 (77.0%), and 44 (3.4%), respectively. The number of reflux events per patient was 80. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events per patient was 15.7 (19.6%), 61.6 (77.0%), and 2.72 (3.4%), respectively. In the PPI success group, the total number of reflux events was 1099. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events was 243 (22.1%), 827 (75.3%), and 29 (2.6%), respectively. The number of reflux events per patient was 84.5. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events per patient was 18.7 (22.1%), 63.6 (75.3%), and 2.2 (2.6%), respectively. The comparison among the number of acidic, weakly acidic, and weakly alkaline reflux episodes (total, upright, recumbent) in both groups did not reach statistical significance (P = .1, .6, and .2, respectively).
Table 4 summarizes the comparison of acid reflux parameters between PPI failure and PPI success groups. For PPI failure patients, the mean total time pH <4 was 1.34% (range, 0%–3.6%), the mean number of acidic, weakly acidic, and weakly alkaline reflux events was 15.63, 61.56, and 2.75, respectively. For PPI success patients, the mean total time pH <4 was 4.84% (range, 0%–19.2%), the mean number of acidic, weakly acidic, and weakly alkaline reflux events was 18.69, 63.62, and 2.23, respectively. None of the comparisons reached statistical significance. In addition, the number of acidic, weakly acidic, and weakly alkaline reflux episodes (total, upright, recumbent) in both groups did not reach statistical significance. The mean MNBI was numerically lower in the PPI success group (2710 ± 1614 U) as compared with the PPI failure group (3334 ± 1133 U), but did not reach statistical significance (P =.23).

PPI Failure Groups

Figure 2 shows the different disorders of the PPI failure patients based on Rome IV criteria.19 Ten (62.5%) patients were found to have normal acid exposure and negative symptom reflux association (consistent with functional heartburn with GERD overlap), 2 (12.5%) patients had normal acid exposure and positive symptom reflux association (consistent with reflux hypersensitivity with GERD overlap), and 4 (25%) patients had abnormal esophageal acid exposure despite PPI therapy (consistent with persistent GERD).

Symptom Analysis

Three hundred and fifteen episodes of either heartburn or regurgitation were recorded by the PPI failure group. Four patients had a positive SAP (>95%). Two patients had positive symptom correlation for regurgitation without evidence of acidic or weakly acidic reflux. Two other patients had positive symptom correlation for regurgitation with evidence of acidic and weakly acidic reflux. The mean SI and SAP for GERD-related symptoms were 4.4% and 21.2%, respectively.
Discussion
Our study demonstrated that there is no statistically significant difference in the number of reflux events, acid exposure, or nonacidic reflux parameters between GERD patients who failed versus those who were successfully treated with once-daily PPI. In addition, most GERD patients who failed PPI once daily appear to have an overlap with a functional esophageal disorder (either reflux hypersensitivity or functional heartburn). Thus, our results support the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity.

To our knowledge, this is the first study to compare impedance parameters combined with pH analysis between PPI success versus PPI failure patients. All impedance parameters, including weakly acidic and alkaline reflux, did not differ significantly between the 2 groups. This implies that the shift to nonacidic reflux is a general PPI phenomenon, as opposed to being unique to PPI failure patients. In a similar study, Gasiorowska et al13 used combined ambulatory 24-hour esophageal pH and Bilitec monitoring to demonstrate that the degree of DGER and acid exposure were not significantly different between PPI once daily responders and nonresponders. The authors also proposed based on the results of the study that the degree of DGER seen in PPI failure patients was a general PPI phenomenon and not unique to PPI failure. Furthermore, in patients who failed to respond to PPI once daily, persistent acidic reflux played an important role in symptom generation and most of the GERD-related symptoms were associated with acid reflux events, as compared with DGER. Similarly, our study showed that 25% of patients who failed PPI therapy had persistent abnormal esophageal acid exposure. These findings further support the current practice of optimizing acid suppression throughout the day by doubling or splitting the PPI dose (a.m. and p.m.) in GERD patients who failed to respond to once-daily PPI.7,12,20

It is important to note that while all of the study patients had documented GERD at baseline, the majority (62.5%) of the PPI failure patients were found to have an overlap with functional heartburn. Two patients demonstrated an overlap with reflux hypersensitivity while on PPI therapy. Because there was also no difference in impedance-pH parameters between patients who failed as compared with those who responded to PPI treatment, this further lends evidence that functional esophageal disorders and thus esophageal hypersensitivity drive most of the symptoms reported by GERD patients who failed PPI once daily.

In our study, we evaluated patients with GERD symptoms who either responded or failed PPI once daily. To our knowledge, all of the studies that assessed the underlying mechanisms of refractory GERD using esophageal impedance pH included only patients who were taking PPI twice daily.21–23 As the majority of patients who report GERD-related symptoms respond to standard dose PPI once daily,10 the purpose of the study was to compare impedance-pH parameters between patients who failed versus those who responded to PPI once daily. In addition, although it is common practice to double the dose in those GERD patients who do not respond to PPI once daily, this is not an approved indication by the Food and Drug Administration.

MNBI is a novel parameter used to calculate baseline impedance not affected by swallows and gastroesophageal reflux.24 Recently, it has been demonstrated that MNBI increases the diagnostic yield of impedance pH monitoring. In addition, nocturnal baseline impedance level has been found to be useful in distinguishing between nonerosive reflux disease patients versus those with functional heartburn.24 MNBI is significantly lower in patients with erosive reflux disease or nonerosive reflux disease than in those with functional heartburn. Our results demonstrated that even baseline impedance, as measured by MNBI, were similar between the 2 patient groups, which further supports the underlying role of esophageal hypersensitivity in patients who failed PPI therapy.

There were no differences in quality-of-life symptoms between the PPI success and failure groups as measured by the SF-36 (Supplementary Table 1). We found that many patients with GERD symptoms, regardless of response to PPI, have underlying impairments of physical functioning, role limitations, and mental and general health, which are likely caused by underlying psychosocial comorbidity. In addition, the SF-36 is a general HRQL tool and not specific for GERD-related symptoms.

Our study is limited by a small cohort size of 29 patients, which may have affected the results of the study. Recruitment into the study was hampered by the invasive nature of some of the procedures. In addition, it is our experience that many patients who have responded to PPI are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but, at the same time, provide essential insight into the understanding of refractory GERD. Although our cohort size was small, our results are supported by another study13 demonstrating no difference in the degree of esophageal reflux exposure between patients who failed to respond and those who achieved symptom resolution while taking once-daily PPI. Furthermore, a study conducted by Rohof et al25 showed that partial responders to PPI are most likely explained by increased proximal reflux in a hypersensitive esophagus, as opposed to number of reflux events, increased mucosal permeability, or the position of the acid pocket.

In summary, our study is the first to demonstrate that reflux characteristics, using impedance pH, were not significantly different between patients who responded to those who failed PPI once daily. The high degree of weakly acidic reflux observed in patients who do not respond to PPI treatment appears to be a general PPI phenomenon and it is not unique to PPI failure patients. In the PPI failure group, most of the patients had normal esophageal acid exposure. The vast majority of GERD patients who failed PPI once a day demonstrated an overlap with functional heartburn or reflux hypersensitivity, supporting the important role of esophageal hypersensitivity in this patient population. Thus, patients who do not respond to PPI once daily may benefit from adding a neuromodulator and possibly psychological intervention such as cognitive behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.26–28
Supplementary Material
Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at ww w.cghjournal.org, and at ht tps://doi.org/10.1016/j.cgh.2018.06.018.
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