Nocturnal gastroesophageal reflux disease: issues, implications, and management strategies

The consequences of nocturnal gastroesophageal reflux disease (GERD) may be greater than daytime GERD in terms of clinical complications such as increased risk of esophageal lesions and respiratory conditions, as well as issues of health-related quality of life, sleep, work productivity, and economics. Proton pump inhibitors (PPIs) are the most effective therapy for patients with GERD; however, treatment success is greater in the improvement of daytime symptoms and acid control. Acid suppression of most PPIs, which are administered once daily before breakfast, wanes during the nighttime hours. Although nighttime heartburn improves with once-daily PPI treatment, PPIs are unable to eliminate nighttime heartburn completely. Increasing the dose of a PPI provides longer acid suppression, but the benefits have not been shown to be consistently greater than standard once-daily dosing. Twice-daily dosing, with a dose given before bedtime, would extend the duration of acid suppression into the nighttime hours; however, nocturnal acid breakthrough remains an issue. As a result, improved PPIs that will more reliably control nighttime symptoms and provide on-demand relief have been developed and studied. These newer PPI formulations offer significant hope for the advancement of treatment opportunities.     

Characteristics of nighttime reflux assessed using multichannel intraluminal impedance pH monitoring and a portable electroencephalograph

Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Although the mechanisms of this association have not been fully elucidated, nighttime reflux plays a central role. However, the detailed characteristics of nighttime reflux occurring during sleep are unknown. The aim of the present study was to examine the characteristics and prevalence of nighttime reflux in the natural sleep environment of GERD patients. Seventeen patients experiencing daily moderate‐to‐severe heartburn and/or regurgitation were studied using multichannel intraluminal impedance pH monitoring and electroencephalography off‐proton pump inhibitor treatment. Nighttime reflux was divided based on reflux type (liquid or gas), acidity (acidic, weakly acidic, or alkaline) and extent (distal only or proximal migration) according to the standard criteria. Nighttime phases were divided as follows: recumbent‐awake before falling asleep, nonrapid eye movement, rapid eye movement, awakening from sleep, and post‐awakening in the morning. Among 184 nighttime refluxes, 43 (23%) occurred during recumbent‐awake before falling asleep, 28 (15%) during nonrapid eye movement, 14 (8%) during rapid eye movement, 86 (46%) during awakening from sleep, and 13 (7%) during post‐awakening in the morning. Liquid reflux was more common in awakening during sleep (92%), nonrapid eye movement (100%), and rapid eye movement (100%) compared with awakening before falling asleep (68%). The prevalence of proximal migration was significantly lower in nonrapid eye movement and rapid eye movement than in the other phases. There were no differences in acidity and bolus clearance time among the phases. Thirteen (65%) of 20 events with GERD symptoms had nighttime reflux, suggesting that only 7.1% (13 of 184) of nighttime refluxes were symptomatic. Nighttime reflux was observed in 48 (11%) of 425 awakening episodes during sleep. Different reflux patterns at each phase during nighttime might explain the pathogenesis of GERD and its related sleep disturbances.     

Therapeutic options in the treatment of nighttime gastroesophageal reflux

Approximately three quarters of individuals who suffer from gastroesophageal reflux disease (GERD) experience its symptoms at night. Nighttime GERD symptoms disturb sleep and diminish quality of life more so than daytime symptoms. Nighttime gastroesophageal reflux is common in individuals with respiratory disorders such as sleep apnea and asthma, and may affect the severity and the frequency of these disorders. The treatments of choice for nighttime GERD symptoms are proton pump inhibitors (PPIs) due to their efficacy in relieving day- and nighttime GERD symptoms and controlling acid secretion. The onset of action, degree of acid suppression, and duration of effect of PPIs have important implications for the use of these therapies in clinical practice. PPIs that exhibit rapid and prolonged control of acid secretion may be particularly useful for treating nighttime GERD symptoms.     

Prevalence of and impact of pantoprazole on nocturnal heartburn and associated sleep complaints in patients with erosive esophagitis

Studies in the United States have revealed that gastroesophageal reflux disease (GERD) patients often suffer from nocturnal symptoms, sleep disturbance, and impaired quality of life. In a large subset of patients, these symptoms persist in spite of acid suppressive therapy. The aim of the present study was to assess the prevalence of heartburn and associated sleep complaints and the response to standard medical therapy with pantoprazole in primary and secondary care esophagitis patients in Belgium. Questionnaires were provided to consecutive patients presenting to primary and secondary care physicians with esophagitis. The questionnaire evaluated the presence of typical reflux symptoms, alarm symptoms, risk factors, and sleep quality impairment as a result of reflux episodes. Results are shown as mean ± standard deviation and compared by Student's t‐test or chi‐square test. A total of 4061 primary and 5261 secondary care patients (50% female, mean age 53 ± 0.2 years, body mass index of 25.7 ± 0.1 kg/m²) were recruited. Eighty‐four percent of patients reported sleep disturbance attributable to nighttime reflux, including typical nighttime supine reflux symptoms (72%), difficulties to fall asleep (39%), waking up during the night (45%), morning fatigue (35%), and reflux symptoms when waking up in the morning (47%). Mild, moderate, or severe nighttime heartburn were reported by, respectively, 30, 35, and 12%, and these numbers were 26, 28, and 6% for nighttime regurgitation. Alcohol (19%), smoking (22%), higher esophagitis grades (grades 2, 3, and 4 in, respectively, 31, 7, and, 7%), alarm symptoms (27%), and more severe heartburn and regurgitation during daytime were all significantly associated with all dimensions of sleep disturbance (P < 0.0001). Obesity was only related to symptoms in supine position and when waking up (P < 0.0001). After 1.4 ± 0.0 months of treatment with pantoprazole, any sleep disturbance had improved in more than 75% of patients, with resolution of nighttime heartburn and regurgitation in, respectively, 75 and 83%. The majority of patients presenting with reflux symptoms and esophagitis in primary or secondary care experience nighttime heartburn and regurgitation, and sleep disturbance by nighttime symptoms is present in 84%. Smoking, alcohol use, higher grades of esophagitis, more severe typical reflux symptoms during daytime, and the presence of alarm symptoms are risk factors for GERD‐related sleep disturbance. On standard therapy with pantoprazole, nighttime symptoms improved in more than 75%. These observations support a direct relationship between GERD and sleep disturbance.     

Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal and intragastric pH in patients with gastroesophageal reflux disease (GERD)

BACKGROUND: Acid plays a significant role in the development of gastroesophageal reflux symptoms, such as heartburn and regurgitation. It is generally assumed that acid suppressive therapy improves or eliminates symptoms by normalizing intraesophageal pH. AIMS: The aim of this article was to assess the efficacy of proton-pump inhibitors (PPIs) in normalizing intraesophageal and intragastric pH in patients with GERD without Barrett's esophagus (BE) rendered symptom free by therapy. METHODS: Patients were evaluated by dual-sensor 24-h pH monitoring while receiving PPI therapy for complete control of GERD symptoms. Analyses of intraesophageal and intragastric pH profiles were then made. RESULTS: Fifty patients, 39 men and 11 women, with GERD, without BE, were studied. All tolerated PPIs well and were asymptomatic at the time of the study. Fifty percent of patients had abnormal intraesophageal pH profiles despite adequate symptom control on PPIs, which was associated with significant breakthrough of intraesophageal acid control in both the upright and supine positions. Low intragastric pH correlated highly with intraesophageal acid reflux only in patients with persistent abnormal esophageal acid exposure (p= 0.001). CONCLUSIONS: Fifty percent of patients with GERD without BE continue to exhibit pathologic GERD and low intragastric pH despite PPI therapy that achieves complete reflux symptom control.     

伴特发性肺纤维化的胃食管反流病患者夜间酸暴露特点

背景:胃食管反流是特发性肺纤维化(IPF)发生的危险因素之一,夜间反流在胃食管反流病(GERD)食管外表现中起重要作用。目的:研究伴IPF的GERD患者夜间食管酸暴露的特点。方法:选取2006年12月～2008年1月北京朝阳医院收治的16例IPF-GERD患者、32例GERD患者和16例健康志愿者(非GERD)。各组患者行24 h食管pH监测,对夜间8 h内(10pm-6am)的酸暴露程度,包括pH4的时间百分比、酸清除时间、反流次数、长反流(5 min)次数、最长反流时间等指标进行分析。结果:14例(87.5%)IPF-GERD患者存在夜间酸暴露,其程度高于非GERD组(P0.05),而与GERD患者无明显差异(P0.05)。IPF-GERD组患者前半夜pH4的时间百分比显著高于后半夜(12.2%±3.9%对1.1%±0.5%,P0.05),GERD组两者无明显差异(10.8%±2.7%对5.1%±1.8%,P0.05)。结论:大部分IPF-GERD患者存在夜间酸暴露,其主要发生于前半夜。     

Associations among gastroesophageal reflux disease,psychological stress,and sleep disturbances in Japanese adults

Background and aim: Gastroesophageal reflux disease (GERD) and psychological stress are associated with sleep disturbances. The aim of the present study was to examine the prevalence of sleep disturbances, anxiety, and depression by GERD subtypes and to identify factors associated with sleep disturbances in general population.

Methods: A total of 2002 Japanese subjects, who underwent annual health checkups, were enrolled and asked to fill out a questionnaire, including the frequency scale for the symptoms of GERD (FSSG), Athens Insomnia Scale (AIS), Rome III questionnaire, and Hospital Anxiety and Depression Scale (HADS). GERD was divided into asymptomatic erosive reflux disease (a-ERD), symptomatic ERD (s-ERD), and non-erosive reflux disease (NERD), according to the presence or absence of esophageal mucosal injury on endoscopy, and the FSSG scores. Sleep disturbances were diagnosed in subjects with AIS score ≥6.

Results: Prevalence of sleep disturbances was significantly higher in GERD subjects than in controls (35.9 and 14.7%, respectively), especially, in the NERD group (45.1%). Sleep duration was significantly shorter in the s-ERD group compared with other groups. Subjects in the NERD and s-ERD groups showed higher HADS scores, resulting in higher incidences of anxiety and depression than those in the control and a-ERD groups. Reflux symptoms, anxiety, depression, and coexisting functional dyspepsia, but not the presence of esophageal mucosal injury, were associated with an increased odds ratio for sleep disturbances.

Conclusion: There were significant positive associations among reflux symptoms, psychological stress, and sleep disturbance in Japanese adults. Further studies investigating the efficacy of therapy are needed.     

Clinical consequences of silent gastroesophageal reflux disease

Silent gastroesophageal reflux disease (GERD) is a very common phenomenon that involves the incidental finding of erosive esophagitis, Barrett’s esophagus, and the evolution of esophageal adenocarcinoma in asymptomatic patients. The reasons for having advanced GERD without clearly identifiable symptoms are poorly understood, primarily due to lack of recognition of this important phenomenon. The clinical implications of silent GERD are vast and should provide the impetus for further research into this group of patients. Recent studies have suggested that sleep disturbances and poor quality of sleep could be the needed clues to identify individuals with silent GERD.     

Unrecognized GERD Symptoms Are Associated with Excessive Daytime Sleepiness in Patients Undergoing Sleep Studies

Sleep disturbances are commonly reported by patients who suffer from gastroesophageal reflux disease (GERD) but it is uncertain if GERD plays a role in patients with sleep disorders of undetermined origin. The prevalence of GERD in patients with sleep disorders of unknown etiology is uncertain; the aim of this study was to determine this prevalence. Three hundred eighty-five consecutive patients reporting to an outpatient clinic for evaluation of sleep disorders were assessed for their sleepiness in relation to reflux symptom intensity. Reflux symptoms that met the survey criteria for a diagnosis of GERD were present in 45 of the 385 subjects (12.8%). These subjects did not have a diagnosis of GERD and were not being treated. Multiple regression analysis showed that excessive sleepiness was associated with intensity of GERD symptoms. Patients with GERD had significantly higher Epworth sleep scores than patients without GERD (12.8 vs. 10.6; p=0.007), indicating more daytime sleepiness. We conclude that unrecognized and untreated GERD are present in many patients presenting with sleep disorders. Patients with GERD had significantly greater sleepiness. Further studies of the impact of GERD treatment in this population are necessary.     

Sleep quality and asthma control and quality of life in non-severe and severe asthma

Purpose

The effect of sleep quality on asthma control independent from common comorbidities like gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) is unknown. This study examined the association between sleep quality and asthma control and quality of life after accounting for OSA and GERD in non-severe (NSA) and severe (SA) asthma.

Methods

Cross-sectional data from 60 normal controls, 143 with NSA, and 79 with SA participating in the Severe Asthma Research Program was examined. Those who reported using positive airway pressure therapy or were at high risk for OSA were excluded.

Results

Both SA and NSA had poorer sleep quality than controls, with SA reporting the worst sleep quality. All asthmatics with GERD and 92% of those without GERD had poor sleep quality (p?=?0.02). The majority (88?C100%) of NSA and SA participants who did not report nighttime asthma disturbances still reported having poor sleep quality. In both NSA and SA, poor sleep quality was associated with worse asthma control and quality of life after controlling for GERD and other covariates.

Conclusions

These results suggest that poor sleep quality is associated with poor asthma control and quality of life among asthmatics and cannot be explained by comorbid GERD and nighttime asthma disturbances.     

Potassium-competitive acid blockers and gastroesophageal reflux disease

Proton pump inhibitors (PPIs), the most commonly used antisecretory medi-cations in the management of reflux illness, virtually eliminate elective surgery for ulcer disease, and relegate anti-reflux surgery to patients with gastroesophageal reflux disease (GERD) who are inadequately managed by medical therapy. However, PPI medications still leave some therapeutic demands of GERD unmet. Furthermore, up to 40%-55% of daily PPI users have chronic symptoms, due to PPI refractoriness. Potassium-competitive acid blockers (P-CABs) transcend many of the problems and limits of PPIs, delivering quick, powerful, and extended acid suppression and allowing for treatment of numerous unmet needs. Recently, it has become clear that compromised mucosal integrity plays a role in the etiology of GERD. As a result, esophageal mucosal protection has emerged as a novel and potential treatment approach. An increasing body of research demonstrates that when P-CABs are used as primary drugs or add-on drugs (to regular treatment), they provide a considerable extra benefit, particularly in alleviating symptoms that do not respond to PPI therapy.     

The proton pump inhibitor test and the diagnosis of gastroesophageal reflux disease

There continues to be significant controversy related to diagnostic testing for gastroesophageal reflux disease (GERD). Symptoms of GERD may be associated with physiologic esophageal acid exposure measured by intraesophageal pH monitoring or pH-impedance monitoring, and a significant percentage of patients with abnormal esophageal acid (or weak acid) exposure have no or minimal clinical symptoms of reflux. On the other hand, endoscopic lesions are only present in a minority of GERD patients. In clinical practice, presumptive diagnosis of GERD is reasonably assumed by the substantial reduction or elimination of suspected reflux symptoms during the therapeutic trial of acid reduction therapy, the so-called proton pump inhibitor (PPI) test. We aimed to assess the optimal cutoff value and duration of this test in GERD patients with and without esophagitis. We conducted a prospective study of 544 patients, endoscopically investigated and treated for 2 weeks with PPIs at double dose, and for an additional 3 months at standard dose. The status of the patient at the end of the study was used as an independent diagnostic standard. We found esophagitis present in 55.8% and absent in 44.2% of patients (corresponding to a diagnosis of nonerosive reflux disease [NERD]). The test was positive in 89.7–97.8% of the patients according to the cutoff or duration of the test used. The sensitivity of the PPI test was excellent, ranging from 95.5 to 98.8%, whereas the specificity was poor, not exceeding 36.3%. Erosive esophagitis patients responded more favorably to the PPI test and subsequent PPI therapy compared with NERD patients. In conclusion, the PPI test is a sensitive but less specific test. Its optimal duration is 1 week, and the optimal cutoff value is a decrease of heartburn score of more than 75%. NERD patients respond less satisfactorily to PPIs, even when functional heartburn patients are excluded and only ‘true’ NERD patients are considered.     

The diagnosis of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is known to cause erosive esophagitis, Barrett esophagus and has been linked to the development of adenocarcinoma of the esophagus. Currently, endoscopy is the main clinical tool for visualizing esophageal lesions, but the majority of GERD patients do not have endoscopic visible lesions and other methods are required. Ambulatory esophageal pH monitoring is the gold standard in diagnosing GERD, since it measures distal esophageal acid exposure and demonstrates the relationship between symptoms and acid reflux. The effectiveness of selective gastric acid suppressive therapy led to the introduction of short trials of proton pump inhibitors (PPIs) to diagnose GERD and they are often used as a first line diagnostic tool in clinical practice and, in particular, in the primary care setting, the current trend being that gastroenterologists are asked to evaluate mainly patients with persistent GERD symptoms while on PPI therapy. In these patients the question is whether the persistent symptoms are or not associated with reflux (acid or nonacid). Recently, either combined multichannel intraluminal impedance and pH monitoring or bilimetry allow to study the mechanisms underlying the persistent symptoms on acid suppressive therapy. Manometry is mandatory prior to any surgical approach and to verify motility disorders that could be associated to GERD.     

Pharmacologic management of gastroesophageal reflux disease

The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short-and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.     

Sleep symptoms and gastroesophageal reflux

BACKGROUND: This study was to determine whether patients with significant nighttime heartburn had more disturbed sleep and more gastroesophageal acid reflux than those without significant nighttime heartburn. METHODS: Thirty-three reflux patients were stratified into 2 groups (nighttime heartburn, without nighttime heartburn). All patients completed questionnaires assessing daytime and nighttime heartburn and subjective sleep by Pittsburgh Sleep Quality Index. All participants underwent 24-hour esophageal pH monitoring and an overnight polysomnographic study. RESULTS: The number of reflux events longer than 5 minutes was significantly greater in patients with nighttime heartburn than in those without nighttime heartburn for the total (P=0.004) and upright (P=0.01) position periods. Acid contact time was significantly greater in patients with nighttime heartburn during the upright (P=0.003) period and during the total (P=0.001) period. Patients with nighttime heartburn reported significantly greater subjective sleep impairment (8.1+/-0.7) than those without nighttime heartburn (6.1+/-0.4; P=0.02), but no difference could be observed in any objective sleep parameter by an overnight polysomnographic study between the groups. CONCLUSIONS: Patients with significant nighttime heartburn seem to have more acid reflux compared with those without nighttime heartburn. Nighttime heartburn together with sleep complaints is associated with excessive gastroesophageal reflux.     

Therapieresistente Refluxkrankheit

Gastro-esophageal reflux disease (GERD) is common. Standard treatment includes lifestyle measures and proton pump inhibitors (PPIs). GERD is considered to be refractory to treatment when a standard dose of PPI fails to sufficiently control symptoms within 8 weeks. Severe reflux esophagitis may require a longer period of treatment. In the event of therapy-resistant GERD, a stratified approach is needed if diagnostic errors and therapeutic confusion are to be avoided. Major stumbling blocks are misdiagnosis, inadequate acid suppression, and a pathophysiological situation in which acid plays only a minor role. When other potential esophageal or extra-esophageal causes have been excluded, the first step is to optimise acid inhibition measures. If problems nevertheless persist, a functional diagnostic workup is indicated, preferably using a combination of pH-metry and impedance monitoring. Depending on the outcome, the therapeutic options that are then most likely to be useful are intensification and optimisation of the antisecretory treatment, measures aimed at relaxing the lower esophageal sphincter, modulation of esophageal sensitivity, and surgical reconstruction of the gastro-esophageal antireflux barrier.     

Extra-Esophageal Manifestations of Gerd: Who Responds to GERD Therapy?

Gastroesophageal reflux disease (GERD) is a common disease that is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms. In addition to the esophageal manifestations of heartburn and regurgitation, the role of GERD in causing extra-esophageal symptoms, such as laryngitis, asthma, cough, chest pain, and dental erosions, is increasingly recognized with renewed interest. Due to the poor sensitivity of endoscopy and pH monitoring, and the poor specificity of laryngoscopy, empiric therapy with proton pump inhibitors (PPI) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. In those who are unresponsive to such therapy, other diagnostic testing such as impedance/pH monitoring may be reasonable in order to exclude continued acid or weakly acid reflux. Recent data suggest that patients with extra-esophageal symptoms who have concomitant typical symptoms, moderate-sized hiatal hernia and moderate reflux on pH testing may respond better to acid suppressive therapy. This group only accounts for 20?30 % of patients commonly referred for suspected GERD. PPI-unresponsive patients usually have causes other than GERD for their extra-esophageal signs and symptoms and continued PPI therapy in this group is not recommended.     

Pharmacologic management of gastroesophageal reflux disease

Opinion statement The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short- and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.