Journal of Pediatric Gastroenterology & Nutrition:
Clinical Practice Guideline
Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)
Co-Chairs:; Vandenplas, Yvan*; Rudolph, Colin D†; Committee Members:; Di Lorenzo, Carlo‡; Hassall, Eric§; Liptak, Gregory||; Mazur, Lynnette¶; Sondheimer, Judith#; Staiano, Annamaria**; Thomson, Michael††; Veereman-Wauters, Gigi‡‡; Wenzl, Tobias G§§
*UZ Brussel Kinderen, Brussels, Belgium
†Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
‡Division of Pediatric Gastroenterology, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
§Division of Gastroenterology, Department of Pediatrics, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada
||Department of Pediatrics, Upstate Medical University, Syracuse, NY, USA
¶Department of Pediatrics, University of Texas Health Sciences Center Houston and Shriners Hospital for Children, Houston, TX, USA
#Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA
**Department of Pediatrics, University of Naples “Federico II,” Naples, Italy
††Centre for Paediatric Gastroenterology, Sheffield Children's Hospital, Western Bank, Sheffield, UK
‡‡Pediatric Gastroenterology & Nutrition, Queen Paola Children's Hospital-ZNA, Antwerp, Belgium
§§Klinik für Kinder- und Jugendmedizin, Universitätsklinikum der RWTH Aachen, Aachen, Germany
Received 27 May, 2009
Accepted 31 May, 2009
Address correspondence and reprint requests to Colin D. Rudolph, MD, PhD, Professor of Pediatrics & Vice Chair for Clinical Affairs, Chief, Pediatric Gastroenterology, Hepatology, and Nutrition, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Wisconsin, Medical College of Wisconsin, 9000 W Wisconsin Ave, Milwaukee, WI 53226 (e-mail: email@example.com).
Carlo Di Lorenzo, Eric Hassall, Gregory Liptak, Lynnette Mazur, Judith Sondheimer, Annamaria Staiano, Michael Thomson, Gigi Veereman-Wauters, and Tobias G. Wenzl contributed equally to the development of these guidelines. Abstract adapted by Gregory Liptak.
Authors' disclosures are listed in Appendix D.
Objective: To develop a North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) international consensus on the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population.
Methods: An international panel of 9 pediatric gastroenterologists and 2 epidemiologists were selected by both societies, which developed these guidelines based on the Delphi principle. Statements were based on systematic literature searches using the best-available evidence from PubMed, Cumulative Index to Nursing and Allied Health Literature, and bibliographies. The committee convened in face-to-face meetings 3 times. Consensus was achieved for all recommendations through nominal group technique, a structured, quantitative method. Articles were evaluated using the Oxford Centre for Evidence-based Medicine Levels of Evidence. Using the Oxford Grades of Recommendation, the quality of evidence of each of the recommendations made by the committee was determined and is summarized in appendices.
Results: More than 600 articles were reviewed for this work. The document provides evidence-based guidelines for the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population.
Conclusions: This document is intended to be used in daily practice for the development of future clinical practice guidelines and as a basis for clinical trials.
This synopsis contains some essentials of the guidelines, but does not convey the details, nuances, and complexity of the issues addressed in the complete guidelines, and therefore can be interpreted only with reference to the full article.
1. RATIONALE The purpose of these guidelines is to provide pediatricians and pediatric subspecialists with a common resource for the evaluation and management of patients with gastroesophageal reflux (GER) and gastroesophageal reflux disease (GERD). These guidelines are not intended as a substitute for clinical judgment or as a protocol for the management of all pediatric patients with GER and GERD.
2. METHODS “Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)” is a document developed by a committee of 9 pediatric gastroenterologists from NASPGHAN and ESPGHAN and 2 pediatric epidemiologists from the United States. Using the best-available evidence from the literature, the committee critically evaluated current diagnostic tests and therapeutic modalities for GER and GERD.
3. DEFINITIONS AND MECHANISMS GER is the passage of gastric contents into the esophagus with or without regurgitation and vomiting. GER is a normal physiologic process occurring several times per day in healthy infants, children, and adults. Most episodes of GER in healthy individuals last <3 minutes, occur in the postprandial period, and cause few or no symptoms. In contrast, GERD is present when the reflux of gastric contents causes troublesome symptoms and/or complications. Every effort was made to use these 2 terms strictly as defined.
4.1. History and Physical Examination In infants and toddlers, there is no symptom or symptom complex that is diagnostic of GERD or predicts response to therapy. In older children and adolescents, as in adult patients, history and physical examination may be sufficient to diagnose GERD if the symptoms are typical.
4.2. Esophageal pH Monitoring This test is a valid quantitative measure of esophageal acid exposure, with established normal ranges. However, the severity of pathologic acid reflux does not correlate consistently with symptom severity or demonstrable complications. In children with documented esophagitis, normal esophageal pH monitoring suggests a diagnosis other than GERD. Esophageal pH monitoring is useful for evaluating the efficacy of antisecretory therapy. It may be useful to correlate symptoms (eg, cough, chest pain) with acid reflux episodes and to select those infants and children with wheezing or respiratory symptoms in whom GER is an aggravating factor. The sensitivity, specificity, and clinical utility of pH monitoring for diagnosis and management of possible extraesophageal complications of GER are not well established.
4.3. Combined Multiple Intraluminal Impedance (MII) and pH Monitoring This test detects acid, weakly acid, and nonacid reflux episodes. It is superior to pH monitoring alone for evaluation of the temporal relation between symptoms and GER. Whether combined esophageal pH and impedance monitoring will provide useful measurements that vary directly with disease severity, prognosis, and response to therapy in pediatric patients has yet to be determined.
4.4. Motility Studies Esophageal manometry may be abnormal in patients with GERD but the findings are not sufficiently sensitive or specific to confirm a diagnosis of GERD, nor to predict response to medical or surgical therapy. It may be useful to diagnose a motility disorder in patients who have failed acid suppression and who have a normal endoscopy, or to determine the position of the lower esophageal sphincter to place a pH probe. Manometric studies are useful to confirm a diagnosis of achalasia or other motor disorders of the esophagus that may mimic GERD.
4.5. Endoscopy and Biopsy Endoscopically visible breaks in the distal esophageal mucosa are the most reliable evidence of reflux esophagitis. Mucosal erythema, pallor, and increased or decreased vascular pattern are highly subjective and nonspecific findings that are variations of normal. Histologic findings of eosinophilia, elongated rete pegs, basilar hyperplasia, and dilated intercellular spaces, alone or in combination, are insufficiently sensitive or specific to diagnose reflux esophagitis. Conversely, absence of these histologic changes does not rule out GERD. Endoscopic biopsy is important to identify or rule out other causes of esophagitis, and to diagnose and monitor Barrett esophagus (BE) and its complications.
4.6. Barium Contrast Radiography This test is not useful for the diagnosis of GERD but is useful to confirm or rule out anatomic abnormalities of the upper gastrointestinal (GI) tract that may cause symptoms similar to those of GERD.
4.7. Nuclear Scintigraphy The standards for interpretation of this test are poorly established. According to limited published literature, scintigraphy may have a role in the diagnosis of pulmonary aspiration in patients with chronic and refractory respiratory symptoms. A negative test does not rule out possible pulmonary aspiration of refluxed material. Gastric emptying studies by themselves do not confirm the diagnosis of GERD and are recommended only in individuals with symptoms of gastric retention. Nuclear scintigraphy is not recommended for the routine evaluation of pediatric patients with suspected GERD.
4.8. Esophageal and Gastric Ultrasonography These tests are not recommended for the routine evaluation of GERD in children.
4.9. Tests on Ear, Lung, and Esophageal Fluids Evaluation of middle ear or pulmonary aspirates for lactose, pepsin, or lipid-laden macrophages have been proposed as the tests for GERD. No controlled studies have proven that reflux is the only reason these compounds appear in ear or lung fluids, and no controlled studies have shown that the presence of these substances confirms GER as the cause of ear, sinus, or pulmonary disease. Diagnosis of duodeno-gastroesophageal reflux by detection of bilirubin in the esophagus is not recommended for the routine evaluation for possible GERD in children. The role of bile reflux in causing GERD that is resistant to proton pump inhibitors (PPIs) therapy has not been established.
4.10. Empiric Trial of Acid Suppression as a Diagnostic Test Expert opinion suggests that in an older child or adolescent with typical symptoms suggesting GERD, an empiric trial of PPIs is justified for up to 4 weeks. However, improvement of heartburn, following treatment, does not confirm a diagnosis of GERD because symptoms may improve spontaneously or respond by a placebo effect. There is no evidence to support an empiric trial of acid suppression as a diagnostic test in infants and young children where symptoms suggestive of GERD are less specific.
5.1. Lifestyle Changes
5.1.1. & 5.1.2. Lifestyle Changes in the Infant Parental education, guidance, and support are always required and usually sufficient to manage healthy, thriving infants with symptoms likely because of physiologic GER. Milk protein sensitivity is sometimes a cause of unexplained crying and vomiting in infants. Therefore, formula-fed infants with recurrent vomiting may benefit from a 2- to 4-week trial of an extensively hydrolyzed protein formula that has been evaluated in controlled trials. Use of a thickened formula (or commercial antiregurgitation formulae, if available) may decrease visible regurgitation but does not result in a measurable decrease in the frequency of esophageal reflux episodes. Prone positioning decreases the amount of acid esophageal exposure measured by pH probe compared with that measured in the supine position. However, prone and lateral positions are associated with an increased incidence of sudden infant death syndrome (SIDS). The risk of SIDS outweighs the benefit of prone or lateral sleep position on GER; therefore, in most infants from birth to 12 months of age, supine positioning during sleep is recommended.
5.1.3. Lifestyle Changes in Children and Adolescents In older children, there is no evidence to support the routine elimination of any specific food for management of GERD. In adults, obesity, large meal volume, and late night eating are associated with symptoms of GERD. Prone or left-side sleeping position and/or elevation of the head of the bed may decrease GER, as shown in adult studies.
5.2. Pharmacologic Therapies The major pharmacologic agents currently used for treating GERD in children are gastric acid–buffering agents, mucosal surface barriers, and gastric antisecretory agents. Acid-suppressant agents are the mainstay of treatment for all but the patient with occasional symptoms. The potential adverse effects of acid suppression, including increased risk of community-acquired pneumonias and GI infections, need to be balanced against the benefits of therapy.
5.2.1. Histamine-2 Receptor Antagonists (H2RAs) H2RAs exhibit tachyphylaxis or tolerance but PPIs do not. Tachyphylaxis is a drawback to chronic use. H2RAs have a rapid onset of action and, like buffering agents, are useful for on-demand treatment.
5.2.2. Proton Pump Inhibitors For healing of erosive esophagitis and relief of GERD symptoms, PPIs are superior to H2RAs. Both medications are superior to placebo. Administration of long-term acid suppression without a diagnosis is inadvisable. When acid suppression is required, the smallest effective dose should be used. Most patients require only once-daily PPI; routine use of twice-daily doses is not indicated. No PPI has been approved for use in infants younger than 1 year of age, and there are special concerns pertaining to prescription of PPIs in infants, as described in the Guideline.
5.2.3. Prokinetic Therapy Potential adverse effects of currently available prokinetic agents outweigh the potential benefits of these medications for treatment of GERD. There is insufficient evidence of clinical efficacy to justify the routine use of metoclopramide, erythromycin, bethanechol, cisapride, or domperidone for GERD. Baclofen reduces the frequency of transient relaxations of the lower esophageal sphincter (TLESR), but it has not been evaluated in controlled trials for treatment of GERD in children.
5.2.4. Other Agents Buffering agents, alginate, and sucralfate are useful on demand for occasional heartburn. Chronic use of buffering agents or sodium alginate is not recommended for GERD because some have absorbable components that may have adverse effects with long-term use. Special caution is required in infants. If long-term use is required, more effective therapy is available.
5.3. Surgical Therapy Antireflux surgery may be of benefit in selected children with chronic-relapsing GERD. Indications include failure of optimized medical therapy, dependence on long-term medical therapy, significant nonadherence to medical therapy, or pulmonary aspiration of refluxate. Children with respiratory complications, including asthma or recurrent aspiration related to GERD, are generally considered most likely to benefit from antireflux surgery when medical therapy fails but additional study is required to confirm this assumption. Children with underlying disorders predisposing to the most severe GERD are at the highest risk for operative morbidity and postoperative failure. Before surgery it is essential to rule out non-GERD causes of symptoms and ensure that the diagnosis of chronic-relapsing GERD is firmly established. It is important to provide families with appropriate education and a realistic understanding of the potential complications of surgery, including symptom recurrence.
6. EVALUATION AND MANAGEMENT OF PEDIATRIC PATIENTS WITH SUSPECTED GERD The following sections describe the relation between reflux and several common signs, symptoms, or symptom complexes of infants and children.
6.1. Recurrent Regurgitation and Vomiting The practitioner's challenge is to distinguish regurgitation and vomiting caused by GER from vomiting caused by numerous other disorders.
6.1.1. Infants With Uncomplicated Recurrent Regurgitation A history of disease and physical examination, with attention to warning signs, are generally sufficient to allow the clinician to establish the diagnosis of uncomplicated GER. Parental education, reassurance, and anticipatory guidance are recommended. In formula-fed infants, thickened formula (or antiregurgitation formula if available) reduces the frequency of overt regurgitation and vomiting.
6.1.2. Infants With Recurrent Vomiting and Poor Weight Gain A diagnosis of physiologic GER should not be made in an infant with vomiting and poor weight gain. Expert opinion suggests that initial evaluation in an infant with normal physical examination but poor weight gain should include diet history, urinalysis, complete blood count, serum electrolytes, blood urea nitrogen, and serum creatinine. Additional testing should be based on suggestive historical details or results of screening tests. Management may include a 2-week trial of extensively hydrolyzed formula or amino acid–based formula to exclude cow's milk allergy, increased caloric density of formula and/or thickened formula, and education as to appropriate daily formula volume required for normal growth. Careful follow-up of interval weight change and caloric intake is essential. If management fails to improve symptoms and weight gain, referral to a pediatric gastroenterologist is recommended.
6.1.3. Infants With Unexplained Crying and/or Distressed Behavior Reflux is not a common cause of unexplained crying, irritability, or distressed behavior in otherwise healthy infants. Other causes include cow's milk protein allergy, neurologic disorders, constipation, and infection (especially of the urinary tract). Following exclusion of other causes, an empiric trial of extensively hydrolyzed protein formula or amino acid–based formula is reasonable in selected cases, although evidence from the literature in support of such a trial is limited. There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants. If irritability persists with no explanation other than suspected GERD, expert opinion suggests the following options: the practitioner may continue anticipatory guidance and training of parents in the management of such infants with the anticipation of improvement with time; additional investigations to ascertain the relation between reflux episodes and symptoms or to diagnose esophagitis may be indicated (pH monitoring ± impedance monitoring, endoscopy); a time-limited (2-week) trial of antisecretory therapy may be considered, but there is a potential risk of adverse effects. Clinical improvement following empiric therapy may be due to spontaneous symptom resolution or a placebo response. The risk/benefit ratio of these approaches is not clear.
6.1.4. The Child Older Than 18 Months of Age With Chronic Regurgitation or Vomiting Physiologic regurgitation, episodic vomiting, or regurgitation followed by swallowing of refluxate in the mouth are frequent in infants. Whether of new onset or persisting from infancy, these symptoms are less common in children older than 18 months of age. Although these symptoms are not unique to GERD, evaluation to diagnose possible GERD and to rule out alternative diagnoses is recommended based on expert opinion. Testing may include upper GI endoscopy and/or esophageal pH/MII, and/or barium upper GI series.
6.2. Heartburn Extrapolation from adult data suggests that in older children and adolescents, on-demand therapy with buffering agents, sodium alginate, or H2RA may be used for occasional symptoms. Adolescents with typical symptoms of chronic heartburn should be treated with lifestyle changes if applicable (diet changes, weight loss, smoking avoidance, sleeping position, no late night eating) and a 2- to 4-week trial of PPI. If symptoms resolve, PPIs may be continued for up to 3 months. Heartburn that persists on PPI therapy or recurs after this therapy is stopped should be investigated further by a pediatric gastroenterologist.
6.3. Reflux Esophagitis In pediatric patients with endoscopically diagnosed reflux esophagitis or established nonerosive reflux disease, PPIs for 3 months constitute initial therapy. Not all reflux esophagitis are chronic or relapsing, and therefore trials of tapering the dose and then withdrawal of PPI therapy should be performed at intervals. Most but not all of the children with chronic-relapsing reflux disease have one of the GERD-predisposing disorders described below. In most cases of chronic-relapsing esophagitis, symptom relief can be used as a measure of efficacy of therapy, but in some circumstances repeat endoscopy or diagnostic studies may be indicated. Recurrence of symptoms and/or esophagitis after repeated trials of PPI withdrawal usually indicate that chronic-relapsing GERD is present, if other causes of esophagitis have been ruled out. At that point, therapeutic options include long-term PPI therapy or antireflux surgery.
6.4. Barrett Esophagus BE occurs in children with less frequency than it does in adults. Multiple biopsies documented in relation to endoscopically identified esophagogastric landmarks are advised to confirm or rule out the diagnosis of BE and dysplasia. In BE, aggressive acid suppression is advised by most experts. Symptoms are a poor guide to the severity of acid reflux and esophagitis in BE, and pH studies are often indicated to guide treatment. BE per se is not an indication for surgery. Dysplasia is managed according to adult guidelines.
6.5. Dysphagia, Odynophagia, and Food Refusal Dysphagia, or difficulty in swallowing, occurs in association with oral and esophageal anatomic abnormalities, neurologic and motor disorders, oral and esophageal inflammatory diseases, and psychological stressors or disorders. Of the mucosal disorders, eosinophilic esophagitis is increasingly recognized to be a more common cause of dysphagia or odynophagia than GERD, although this finding is not consistently reported in all geographic regions. Odynophagia, or pain caused by swallowing, must be distinguished from heartburn (substernal pain caused by esophageal acid exposure) and dysphagia. Although odynophagia may be a symptom of peptic esophagitis, it is more often associated with other conditions such as oropharyngeal inflammation, esophageal ulcer, eosinophilic esophagitis, infectious esophagitis, and esophageal motor disorders. Although GERD is not a prevalent cause of difficulty in swallowing or pain with swallowing, an evaluation including barium upper GI series and possibly upper endoscopy should be considered if physical examination and history of disease do not reveal a cause. Therapy with acid suppression without earlier evaluation is not recommended. In the infant with feeding refusal, acid suppression without earlier diagnostic evaluation is not recommended.
6.6. Infants With Apnea or Apparent Life-threatening Event In the majority of infants with apnea or apparent life-threatening events (ALTEs), GER is not the cause. In the uncommon circumstance in which a relation between symptoms and GER is suspected or in those with recurrent symptoms, MII/pH esophageal monitoring in combination with polysomnographic recording and precise, synchronous symptom recording may aid in establishing cause and effect.
6.7. Reactive Airways Disease In patients with asthma who also have heartburn, reflux may be a contributing factor to the asthma. Despite a high frequency of abnormal reflux studies in patients with asthma who do not have heartburn, there is no strong evidence to support empiric PPI therapy in unselected pediatric patients with wheezing or asthma. Only 3 groups—those with heartburn, those with nocturnal asthma symptoms, and those with steroid-dependent difficult-to-control asthma—may derive some benefit from long-term medical or surgical antireflux therapy. Finding abnormal esophageal pH exposure by esophageal pH monitoring, with or without impedance, before considering a trial of long-term PPI therapy or surgery may be useful, although the predictive value of these studies for this purpose has not been established. The relative efficacy of medical versus surgical therapy for GERD in children with asthma is unknown.
6.8. Recurrent Pneumonia Recurrent pneumonia and interstitial lung disease may be the complications of GER due to aspiration of gastric contents. No test can determine whether GER is causing recurrent pneumonia. An abnormal esophageal pH test may increase the probability that GER is a cause of recurrent pneumonia but is not proof thereof. Nuclear scintigraphy can detect aspirated gastric contents when images are obtained for 24 hours after enteral administration of a labeled meal. Aspiration during swallowing is more common than aspiration of refluxed material. A trial of nasogastric feeding may be used to exclude aspiration during swallowing as a potential cause of recurrent disease. A trial of nasojejunal therapy may help in determining whether surgical antireflux therapy is likely to be beneficial. In patients with severely impaired lung function, antireflux surgery may be necessary to prevent further pulmonary damage, despite lack of definitive proof that GER is causative.
6.9. Upper Airway Symptoms The data linking reflux to chronic hoarseness, chronic cough, sinusitis, chronic otitis media, erythema, and cobblestone appearance of the larynx come mainly from case reports and case series. The association of reflux with these conditions and response to antisecretory therapy have not been proven by controlled studies. Patients with these symptoms or signs should not be assumed to have GERD without consideration of other potential etiologies.
6.10. Dental Erosions An association between GERD and dental erosions has been established. The severity of dental erosions seems to be correlated with the presence of GERD symptoms and, in adults, with the severity of proximal esophageal or oral exposure to an acidic pH. Young children and children with neurologic impairment appear to be at the greatest risk. Factors other than reflux that cause similar dental erosions include juice drinking, bulimia, and racial and genetic factors affecting the characteristics of enamel and saliva.
6.11. Dystonic Head Posturing (Sandifer Syndrome) Sandifer syndrome (spasmodic torsional dystonia with arching of the back and opisthotonic posturing, mainly involving the neck and back) is an uncommon but specific manifestation of GERD. It resolves with antireflux treatment.
7. GROUPS AT HIGH RISK FOR GERD Certain conditions are predisposed to severe, chronic GERD. These include neurologic impairment, obesity, repaired esophageal atresia or other congenital esophageal disease, cystic fibrosis, hiatal hernia, repaired achalasia, lung transplantation, and a family history of GERD, BE, or esophageal adenocarcinoma. Although many premature infants are diagnosed with GERD because of nonspecific symptoms of feeding intolerance, apnea spells, feeding refusal, and pain behavior, there are no controlled data that confirm reflux as a cause. Although reflux may be more common in infants with bronchopulmonary dysplasia, there is no evidence that antireflux therapy affects the clinical course or outcome of this condition.
PEDIATRIC GER GUIDELINE
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) published the first clinical practice guidelines on pediatric gastroesophageal reflux (GER) and gastroesophageal reflux disease (GERD) in 2001 (1). Consensus-based guidelines on several aspects of GER and GERD were developed in Europe at about the same time but were not officially endorsed by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) (2,3). In 2007, the Councils of ESPGHAN and NASPGHAN established a joint committee to review, update, and unify these guidelines as a means of improving uniformity of practice and quality of patient care (4,5).
The committee used the 2001 NASPGHAN guidelines as an outline, adding new sections on certain pediatric populations at high risk for GERD. In all deliberations, the committee attempted to distinguish physiologic GER events from GERD. Furthermore, in response to evidence that the diagnosis of GERD is applied excessively to healthy infants with bothersome but harmless symptoms of physiologic GER (6–9), the committee reevaluated the 2001 diagnostic and therapeutic algorithms to clarify the distinction between physiologic GER and GERD. In its recommendations for testing, the committee confronted the ongoing problem that current reflux tests may identify variations from normal but cannot predict symptom severity, natural history, or response to therapy.
These guidelines are designed to assist pediatric health care providers in the diagnosis and management of GER and GERD. They are intended to serve as general guidelines and not as a substitute for clinical judgment, or as a protocol applicable to all patients.
Selection of Committee Members
The NASPGHAN–ESPGHAN Joint Guideline Committee included 5 European and 4 North American pediatric gastroenterologists with extensive experience in GER and GERD, selected by their respective societies, and 2 North American primary care pediatricians experienced in clinical epidemiology. Both pediatric epidemiologists, members of the American Academy of Pediatrics Section on Epidemiology, were selected because of their contribution to the previous NASPGHAN GERD guidelines.
Guideline Preparation Process
The previous guidelines developed by NASPGHAN (1) and ESPGHAN (2,3) were used as the foundation for the current guidelines. Articles written in English and published between March 1999 (the date of the previous review) and October 2008 were identified using PubMed and Cumulative Index to Nursing and Allied Health Literature. Letters, editorials, case reports, and reviews were eliminated from the initial evaluation. Additional articles were identified by members of the committee from bibliographies found in other articles and study results in the public domain on the US National Institutes of Health Web site. These included review articles as well as articles that involved the care of adults. A total of 377 articles related to therapy and 195 articles related to etiology, diagnosis, and prognosis were reviewed for this guideline.
Using the best-available evidence from the literature, the committee evaluated current diagnostic tests and therapeutic modalities for GER and GERD. Evidence of a causal relation between GER/GERD and several common symptoms or symptom complexes were evaluated. Diagnostic tests were evaluated by the following criteria: ability to confirm a diagnosis of GERD; ability to exclude other diagnoses with similar presentation; ability to detect complications of GERD; and ability to predict disease severity, natural history of disease, and response to treatment. Therapy was evaluated considering efficacy, appropriate clinical indications, and potential risks and complications.
The committee convened face to face 3 times and had several conference calls. It based its recommendations on its study of the literature review combined with expert opinion and the evidence available in the adult literature when pediatric evidence was insufficient. Consensus was achieved for all of the recommendations through nominal group technique, a structured quantitative method (10). Articles were evaluated using the Oxford Centre for Evidence-based Medicine Levels of Evidence (11). Using the Oxford Grades of Recommendation (11), the quality of evidence of each of the recommendations made by the committee was determined and is summarized in Appendices A to C. Sections of the document were written by individual committee members, then reviewed and edited by a separate committee member; in most instances both a NASPGHAN and an ESPGHAN member participated in preparing the initial draft of each section. These sections and other evidence available in previously prepared tables that listed references and graded the quality of each reference were distributed, then reviewed and discussed to achieve consensus agreement in conference sessions. The document was then distributed to the entire NASPGHAN membership for comment. Further revisions were made based on their suggestions following telephone conference and e-mail communications among committee members. Complete voting anonymity could not be maintained through the revision process because voting was done by e-mail, but only 1 of the co-chairs (C.D.R.) was aware of e-mail votes. Following final committee approval, the document was endorsed by the Executive Councils of NASPGHAN and ESPGHAN.
Management of Potential Conflict of Interest
Disclosures of potential conflicts of interest of committee members or immediate family were documented and shared with committee members before the first meeting of the committee and updated before the review of the final document. Disclosures included paid or donated services of any kind, research support, stock ownership or options, and intellectual property rights. During the process of preparing the guidelines, the scientific data were reviewed by all of the members of the committee, and recommendations were voted on by all of the members. No section of the document was written solely by any 1 member. Chairs or committee members did not require that any individual be removed from discussions or voting based on potential conflicts of interest. Potential conflicts of interest are listed in Appendix D. No industry support was used for the production of these guidelines.
DEFINITIONS AND MECHANISMS
GER is the passage of gastric contents into the esophagus with or without regurgitation and vomiting. GER is a normal physiologic process occurring several times per day in healthy infants, children, and adults. Most episodes of GER in healthy individuals last <3 minutes, occur in the postprandial period, and cause few or no symptoms (12). In contrast, GERD is present when the reflux of gastric contents causes troublesome symptoms and/or complications (13). Every effort was made to use these 2 terms strictly as defined.
Regurgitation in pediatrics is defined as the passage of refluxed gastric contents into the pharynx or mouth and sometimes expelled out of the mouth. Regurgitation is generally assigned as effortless and nonprojectile, although it may sometimes be forceful in infants (13). Other terms such as “spitting-up,” “posseting,” and “spilling,” are considered equivalent to regurgitation. Spitting up, which occurs daily in about 50% of the infants younger than 3 months of age, is the most visible symptom of regurgitation. Regurgitation resolves spontaneously in most healthy infants by 12 to 14 months of age (14–18).
Reflux episodes sometimes trigger vomiting, a coordinated autonomic and voluntary motor response, causing forceful expulsion of gastric contents through the mouth. Vomiting associated with reflux is probably a result of the stimulation of pharyngeal sensory afferents by refluxed gastric contents. Rumination refers to the effortless regurgitation of recently ingested food into the mouth with subsequent mastication and reswallowing. Rumination syndrome is a distinct clinical entity with regurgitation of ingested food within minutes following meals because of the voluntary contraction of the abdominal muscles (19,20).
Reflux episodes occur most often during transient relaxations of the lower esophageal sphincter (LES) unaccompanied by swallowing, which permit gastric contents to flow into the esophagus (21–23). A minor proportion of reflux episodes occur when the LES pressure fails to increase during a sudden increase in intra-abdominal pressure or when LES resting pressure is chronically reduced. Alterations in several protective mechanisms allow physiologic reflux to become GERD: insufficient clearance and buffering of refluxate, delayed gastric emptying, abnormalities in epithelial restitution and repair, and decreased neural protective reflexes of the aerodigestive tract. In hiatal hernia (HH), all of the antireflux barriers at the LES (including the crural support, intraabdominal segment, and angle of His) are compromised (24–27) and transient LES relaxations (TLESR) also occur with greater frequency (25). Erosive esophagitis by itself may promote esophageal shortening and consequent hiatal herniation (25). HH is prevalent in adults and children with severe reflux complications (28–31), and hernia size is a major determinant of GERD severity (30,32).
Significant clusterings of reflux symptoms, HH, erosive esophagitis, Barrett esophagus (BE), and esophageal adenocarcinoma occur in families, suggesting some heritability of GERD and its complications (33–37). A large Swedish Twin Registry study found an increased concordance for reflux in monozygotic compared with dizygotic twins (33). Several other pediatric patient populations appear to be at higher risk for GERD than healthy infants, children, or adolescents. These include individuals with neurologic impairment (NI), obesity, certain genetic syndromes, esophageal atresia (EA), chronic lung diseases, and those with a history of premature birth. These are discussed in Section 7.
The diagnosis of GERD is often made clinically based on the bothersome symptoms or signs that may be associated with GER (Table 1). However, subjective symptom descriptions are unreliable in infants and children younger than 8 to 12 years of age, and many of the purported symptoms of GERD in infants and children are nonspecific. The diagnosis of GERD is inferred when tests show excessive frequency or duration of reflux events, esophagitis, or a clear association of symptoms and signs with reflux events in the absence of alternative diagnoses.
Although many tests have been used to diagnose GERD, few studies compare their utility. Importantly, it is not known whether tests can predict an individual patient's response to therapy. Tests are useful to document the presence of pathologic reflux or its complications to establish a causal relation between reflux and symptoms, to evaluate therapy, and to exclude other conditions. Because no test can address all of these questions, tests must be carefully selected according to the information sought, and the limitations of each test must be recognized.
History and Physical Examination
The major role of the history of disease and physical examination in the evaluation of GERD is to exclude other more worrisome disorders that present with vomiting and to identify complications of GERD (Table 2). Typical presenting symptoms of reflux disease in childhood vary with age and underlying medical condition (13,38); however, the underlying pathophysiology of GERD is thought to be similar at all ages including the premature infant (23,39). In 1 study, regurgitation or vomiting, abdominal pain, and cough but not heartburn were the most frequently reported symptoms in children and adolescents with GERD. Cough and anorexia or feeding refusal were more common in children 1 to 5 years of age than in older children (40).
Symptoms and signs associated with reflux (Table 1) are nonspecific. For example, not all of the children with GER have heartburn or irritability. Conversely, heartburn and irritability can be caused by conditions other than GER. Regurgitation, irritability, and vomiting are common in infants with physiologic GER or GERD (14,18,41,42) but are indistinguishable from regurgitation, irritability, and vomiting caused by food allergy (43,44), colic (45,46), and other disorders. The severity of reflux or esophagitis found on diagnostic testing does not directly correlate with the severity of symptoms (47–49).
GERD is often diagnosed clinically in adults based on a history of heartburn, defined as substernal, burning chest pain, with or without regurgitation. Recent adult and pediatric consensus guidelines have applied the terms “typical reflux syndrome” or “reflux chest pain syndrome” to this presentation (13,50). Based on expert opinion, the diagnosis of GERD can be made in adolescents presenting with typical heartburn symptoms as in adults (49,51–55). However, a clinical diagnosis based on a history of heartburn cannot be used in infants, children, or nonverbal adolescents (eg, those with NI) because these individuals cannot reliably communicate the quality and quantity of their symptoms. The verbal child can communicate pain, but descriptions of quality, intensity, location, and severity generally are unreliable until at least 8 and possibly 12 years of age (56–60).
As in adults, individual symptoms in children generally are not highly predictive of findings of GERD by objective studies. For example, in a study of irritable infants younger than 9 months of age, regurgitation >5 times per day had a sensitivity of 54% and specificity of 71% for a reflux index (RI) >10% by esophageal pH testing, whereas feeding difficulties had a sensitivity of 75% and specificity of 46% (61). A similar poor correlation of symptoms and esophageal acid exposure was observed during an omeprazole treatment study in irritable infants; similar reductions in crying occurred in both treated and untreated infants, and the extent of reduction in crying did not correlate with extent of reduction of the RI in the treated patients (46).
Because individual symptoms do not consistently correlate with objective findings or response to medical treatment, parent- or patient-reported questionnaires based on clusters of symptoms have been developed. Orenstein et al (51,62) developed a diagnostic questionnaire for GERD in infants. A score of >7 (of 25 possible) on the initial instrument demonstrated a sensitivity of 0.74 and specificity of 0.94 during primary validation. The questionnaire has undergone several revisions (54). The questionnaire has been shown to be reliable for documentation and monitoring of reported symptoms. However, when applied to a population in India, it had a sensitivity and specificity of only 43% and 79%, respectively, compared with pH-monitoring results (52). In another study of infants referred for symptoms of reflux disease and controls, the questionnaire had a sensitivity and specificity of 47% and 81% for a RI >10% and 65% and 63% for a reflux index >5%. The questionnaire score failed to identify 26% of the infants with GERD. The score was positive in 17 of 22 infants with normal biopsies and pH studies and in 14 of 47 infants with normal pH studies. No single symptom was significantly associated with esophagitis (49). In another study, the questionnaire was unable to identify a group of infants responsive to proton pump inhibitor (PPI) therapy (9). Thus, no symptom or cluster of symptoms has been shown to reliably predict complications of reflux or to predict those infants likely to respond to therapy.
A 5-item questionnaire developed for children 7 to 16 years of age had a sensitivity of 75% and a specificity of 96% compared with pH monitoring during primary validation (63). No subsequent independent confirmatory validation has been performed. Other diagnostic questionnaires, such as the GERD symptom questionnaire (53), have not been compared with objective standards like endoscopy, pH monitoring, or esophageal multiple intraluminal impedance (MII) monitoring. Some researchers have used questionnaires to monitor symptoms of children during GERD therapy (64). Whether this method is preferable to monitoring individual symptoms is uncertain. Although daily symptom diaries are frequently used in adults to monitor the effects of therapy, these have not been validated in children.
Esophageal pH Monitoring
Intraluminal esophageal pH monitoring measures the frequency and duration of acid esophageal reflux episodes. Most commercially available systems include a catheter for nasal insertion with 1 or more pH electrodes (antimony, glass, or ion-sensitive field effect) arrayed along its length and a system for data capture, analysis, and reporting. Slow electrode response times (antimony being the slowest) do not alter the assessment of total reflux time substantially but may affect the accuracy of correlation between symptoms and reflux episodes (65). Esophageal pH monitoring is insensitive to weakly acid and nonacid reflux events. Recently, wireless sensors that can be clipped to the esophageal mucosa during endoscopy have allowed pH monitoring without a nasal cannula for up to 48 hours. Placement of wireless electrodes requires sedation or anesthesia, and comfort has been an issue in some studies (66–68). The size of current wireless electrodes precludes their use in small infants. Benefits, risks, and indications for wireless electrode monitoring have not been fully defined in children. Data on reproducibility of conventional and wireless pH studies are contradictory (68–72).
By convention, a drop in intraesophageal pH <4.0 is considered an acid reflux episode. This cutoff was initially chosen because heartburn induced by acid perfusion of the esophagus in adults generally occurs at pH <4.0 (73). Although interpretation of pH monitoring data is simplified by computerized analysis, visual inspection of the tracing is required to detect artifacts and evaluate possible clinical correlations. Common parameters obtained from pH monitoring include the total number of reflux episodes, the number of reflux episodes lasting >5 minutes, the duration of the longest reflux episode, and the RI (percentage of the entire record that esophageal pH is <4.0). GER events that occur while supine or upright or while awake or asleep are often discriminated by the automated software used in both adults and children, but the clinical value of such differentiation has not been established (74–80).
The RI is the most commonly used summary score. Several scoring systems for pH-monitoring studies have been developed (74,75,81), but no system is clearly superior to measuring the RI (82). Normal pediatric ranges are established for glass and antimony electrodes but not for ion-sensitive field effect or wireless technologies. The normal pediatric ranges previously in general use were obtained using glass electrodes (65,83), but such data poorly correlate with that obtained by the antimony electrodes now in common use (84). Moreover, normal data depend on the definition of a “normal population.” In the first study by Vandenplas et al (83), showing a low RI in young infants, the definition of “normal infant” was an infant who did not regurgitate or vomit. In the second study, a “normal population” was defined as an infant who had not been treated for reflux (65). Although the definition of the first study was biased toward a “too normal” population, the second study included all of the untreated infants, thus possibly some infants with GERD. A study by Sondheimer (85) showed a different range of normal values for infants. Most of the data, provided in previous sections, pertain to infants, in whom frequency of feeding and buffering of refluxate can confound findings between studies (76). For these reasons, specific “cutoff” values that discriminate between physiologic GER and pathologic GERD are suspect; rather, it is likely that a continuum exists such that normal ranges should be regarded as guidelines for interpretation rather than absolutes. In pH studies performed with antimony electrodes, an RI >7% is considered abnormal, an RI <3% is considered normal, and an RI between 3% and 7% is indeterminate.
Abnormal esophageal pH monitoring has not been shown to correlate with symptom severity in infants. In a study of infants with suspected GERD, an abnormal pH study (RI >10%) was associated only with pneumonia, apnea with fussing, defecation less than once per day, and constipation (49). An abnormal RI is more frequently observed in adults and children with erosive esophagitis than in normal adults and children or those with nonerosive reflux disease (NERD), but there is substantial overlap among groups (79,86,87). In childen with documented esophagitis, normal esophageal pH monitoring suggests a diagnosis other than GERD (88,89). The RI is often abnormal in children with difficult-to-control asthma and in otherwise healthy infants with daily wheezing (90). Esophageal pH monitoring may be abnormal in patients with conditions other than GERD, such as gastric outlet obstruction, motility disorders, and esophagitis due to other disorders, including eosinophilic esophagitis (EoE) (91–94). Although multiple case series report the use of esophageal pH monitoring to select the children reported to benefit from antireflux surgery (95–99), the reliability of such data to predict improvement following either medical or surgical antireflux therapy has not been established.
The application of various methods of analysis of esophageal pH-monitoring results, including the symptom index (SI), symptom sensitivity index (SSI), and symptom association probability (SAP), may help in correlating symptoms with acid reflux. A prospective study in adults found that when compared with symptom improvement following high-dose PPI therapy, the sensitivities of the SI, SSI, and SAP were 35%, 74%, and 65% and specificities were 80%, 73%, and 73%, respectively (100). The clinical utility of pH studies and their ability to determine a causal relation between specific symptoms (eg, pain, cough) and reflux remain controversial in adults (101), and are not validated in pediatric patients.
Esophageal pH monitoring provides a quantitative measure of esophageal acid exposure with established normal ranges, but the severity of pathologic acid reflux does not correlate consistently with symptom severity or demonstrable complications. In childen with documented esophagitis, normal esophageal pH monitoring suggests a diagnosis other than GERD (88,89). Esophageal pH monitoring is useful for evaluating the efficacy of antisecretory therapy. It may be useful to correlate symptoms (eg, cough, chest pain) with acid reflux episodes, and to select those children with wheezing or respiratory symptoms in which acid reflux may be an aggravating factor. The sensitivity and specificity of pH monitoring are not well established.
Combined Multiple Intraluminal Impedance and pH Monitoring
MII is a procedure for measuring the movement of fluids, solids, and air in the esophagus (102). It is a relatively new technology that provides a more detailed description of esophageal events with a more rapid response time than current pH-monitoring technology. MII measures changes in the electrical impedance (ie, resistance) between multiple electrodes located along an esophageal catheter. Esophageal impedance tracings are analyzed for the typical changes in impedance caused by the passage of liquid, solid, gas, or mixed boluses. If the impedance changes of a liquid bolus appear first in the distal channels and proceed sequentially to the proximal channels, they indicate retrograde bolus movement, which is GER. The direction and velocity of a bolus can be calculated using the defined distance between electrodes and the time between alterations in the impedance pattern of sequential electrode pairs. The upward extent of the bolus and the physical length of the bolus can also be evaluated (103). MII can detect extremely small bolus volumes (104).
MII and pH electrodes can and should be combined on a single catheter. The combined measurement of pH and impedance (pH/MII) provides additional information as to whether refluxed material is acidic, weakly acidic, or nonacidic (105–109). Recent studies have found variable reproducibility (110,111). Evaluation of MII recordings is aided by automated analysis tools (112), but until the currently available automatic analysis software has been validated, a visual reading of the data is required. Normal values for all of the age groups have not yet been established (113).
The risks and side effects of MII are low and the same as those of isolated pH monitoring. The combination of pH/MII with simultaneous monitoring of symptoms using video-polysomnography or manometry has proven useful for the evaluation of symptom correlations between reflux episodes and apnea, cough, other respiratory symptoms, and behavioral symptoms (23,24,114–116). The technology is especially useful in the postprandial period or at other times when gastric contents are nonacidic. The relation between weakly acid reflux and symptoms of GERD requires clarification. Measurement of other parameters such as SI or SAP may be of additional value to prove symptom association with reflux, especially when combined with MII (117). Whether combined esophageal pH and impedance monitoring will provide useful measurements that vary directly with disease severity, prognosis, and response to therapy in pediatric patients has yet to be determined.
Esophageal manometry measures esophageal peristalsis, upper and lower esophageal sphincter pressures, and the coordinated function of these structures during swallowing. Although esophageal manometry has been an important tool in studying the mechanisms of GERD, GERD cannot be diagnosed by esophageal manometry. Manometric studies were critical in identifying TLESR as a causative mechanism for GERD (21). A variety of nonspecific esophageal motor abnormalities have been found in children with developmental delay and NI, a group at high risk for severe GERD (118). Esophageal motor abnormalities are also common in patients with esophagitis (119,120). In these 2 situations esophageal motor dysfunction may be a secondary phenomenon related to esophagitis because it has been observed to resolve upon treatment of esophagitis (119). Recent studies indicate that there is no role for manometry in predicting outcome of fundoplication (121). Manometric studies are also important in confirming a diagnosis of achalasia or other motor disorders of the esophagus that may mimic GERD (122).
Esophageal manometry may be abnormal in patients with GERD, but the findings are not sufficiently sensitive or specific to confirm a diagnosis of GERD, nor to predict response to medical or surgical therapy. It may be useful in patients who have failed acid suppression and who have negative endoscopy to search for a possible motility disorder, or to determine the position of the LES to place a pH probe. Manometric studies are useful to confirm a diagnosis of achalasia or other motor disorders of the esophagus that may mimic GERD.
Endoscopy and Biopsy
Upper gastrointestinal (GI) endoscopy allows direct visual examination of the esophageal mucosa. Mucosal biopsies enable evaluation of the microscopic anatomy (123). Macroscopic lesions associated with GERD include esophagitis, erosions, exudate, ulcers, strictures, HH, areas of possible esophageal metaplasia, and polyps. Although endoscopy can detect strictures, subtle degrees of narrowing may be better shown on barium contrast study, during which the esophagus can be distended with various techniques, such as a radioopaque pill and barium-soaked bread or marshmallows. Malrotation and achalasia cannot be diagnosed by endoscopy. These and other anatomic and motility disorders of the esophagus are better evaluated by barium radiology or motility studies.
Recent global consensus guidelines define reflux esophagitis as the presence of endoscopically visible breaks in the esophageal mucosa at or immediately above the gastroesophageal junction (13,50,124). Evidence from adult studies indicates that visible breaks in the esophageal mucosa are the endoscopic signs of greatest interobserver reliability (125–127). Operator experience is an important component of interobserver reliability (128,129). Mucosal erythema or an irregular Z-line is not a reliable sign of reflux esophagitis (126,127). Grading the severity of esophagitis, using a recognized endoscopic classification system, is useful for evaluation of the severity of esophagitis and response to treatment. The Hetzel-Dent classification (125) has been used in several pediatric studies (29,130,131), whereas the Los Angeles classification (124) is generally used for adults, but it is suitable also for children. The presence of endoscopically normal esophageal mucosa does not exclude a diagnosis of NERD or esophagitis of other etiologies (93,132,133).
The diagnostic yield of endoscopy is generally greater if multiple samples of good size and orientation are obtained from biopsy sites that are identified relative to major esophageal landmarks (28,123,134). Several variables have an impact on the validity of histology as a diagnostic tool for reflux esophagitis (133,135). These include sampling error because of the patchy distribution of inflammatory changes and a lack in standardization of biopsy location, tissue processing, and interpretation of morphometric parameters. Histology may be normal or abnormal in NERD because GERD is an inherently patchy disease (133,136). Histologic findings of eosinophilia, elongation of papillae (rete pegs), basal hyperplasia, and dilated intercellular spaces (spongiosis) are neither sensitive nor specific for reflux esophagitis. They are nonspecific reactive changes that may be found in esophagitis of other causes or in healthy volunteers (49,89,132,133,135,137–141). Recent studies have shown considerable overlap between the histology of reflux esophagitis and EoE (93,94,132,142). Many histologic parameters are influenced by drugs used to treat esophagitis or other disorders.
GERD is likely the most common cause of esophagitis in children, but other disorders such as EoE, Crohn disease, and infections also cause esophagitis (Table 3) (132). EoE and GERD have similar symptoms and signs and can be best distinguished by endoscopy with biopsy. A key difference, endoscopically, is that EoE is generally not an erosive disease but has its own typical endoscopic features such as speckled exudates, trachealization of the esophagus, or linear furrowing. In up to 30% of cases, however, the esophageal mucosal appearance is normal (93). When EoE is considered as a part of the differential diagnosis, it is advisable to take esophageal biopsies from the proximal and distal esophagus (93). Mucosal eosinophilia may be present in the esophageal mucosa in asymptomatic infants younger than 1 year of age (143), and in symptomatic infants eosinophilic infiltrate may be because of milk-protein allergy (142).
There is insufficient evidence to support the use of histology to diagnose or exclude GERD. The primary role for esophageal histology is to rule out other conditions in the differential diagnosis, such as EoE, Crohn disease, BE, and infection. This conclusion concurs with that of a global pediatric consensus group that included some members of the present committee (E.H., Y.V., C.D.R.) (13). When symptoms suggestive of GERD are present in adolescents or adults in the absence of erosive esophagitis, the clinical entity is known as NERD. In NERD, there is no evidence that esophageal histology makes a difference to clinical care decisions; that is, patient treatment is guided by symptoms, whether or not reactive histologic changes are present on biopsy.
At endoscopy, accurate documentation of esophagogastric landmarks is necessary for the diagnosis of HH and endoscopically suspected esophageal metaplasia (ESEM) (123,134,144–147). This is of particular importance in children with severe esophagitis, in whom landmarks may be obscured by bleeding or exudate, or when landmarks are displaced by anatomic abnormalities or HH (28,123,134). In these circumstances, a course of high-dose PPIs for at least 12 weeks is advised, followed by a repeat endoscopy, to remove the exudative camouflage and better visualize the landmarks (134,148).
When biopsies from ESEM show columnar epithelium, the term BE should be applied and the presence or absence of intestinal metaplasia specified (13,50). Thus, BE may be diagnosed in the presence of only cardia-type mucosa (149,150). BE occurs with greatest frequency in children with underlying conditions putting them at high risk for GERD (see Section 7) (28,31).
Barium Contrast Radiography
The upper GI series is neither sensitive nor specific for diagnosing GERD. The sensitivity, specificity, and positive predictive value of the upper GI series range from 29% to 86%, 21% to 83%, and 80% to 82%, respectively, when compared with esophageal pH monitoring (151–157). The brief duration of the upper GI series produces false-negative results, whereas the frequent occurrence of nonpathological reflux during the examination produces false-positive results.
Therefore, routine performance of upper GI series to diagnose reflux or GERD is not justified (158). However, the upper GI series is useful to detect anatomic abnormalities such as esophageal stricture, HH, achalasia, tracheoesophageal fistula, intestinal malrotation, or pyloric stenosis, which may be considered in the differential diagnosis of infants and children with symptoms suggesting GERD.
In gastroesophageal scintigraphy, food or formula labeled with 99technetium is introduced into the stomach and areas of interest—stomach, esophagus, and lungs—are scanned for evidence of reflux and aspiration. The nuclear scan evaluates only postprandial reflux and demonstrates reflux independent of the gastric pH. Scintigraphy can provide information about gastric emptying, which may be delayed in children with GERD (159–161). A lack of standardized techniques and the absence of age-specific norms limit the value of this test. Sensitivity and specificity of a 1-hour scintigraphy for the diagnosis of GERD are 15% to 59% and 83% to 100%, respectively, when compared with 24-hour esophageal pH monitoring (162–165). Late postprandial acid exposure detected by pH monitoring may be missed with scintigraphy (166).
Gastroesophageal scintigraphy scanning can detect reflux episodes and aspiration occurring during or shortly after meals, but its reported sensitivity for microaspiration is relatively low (167–169). Evidence of pulmonary aspiration may be detected during a 1-hour scintigraphic study or on images obtained up to 24 hours after administration of the radionuclide (170). A negative test does not exclude the possibility of infrequently occurring aspiration (168). One study of children with refractory respiratory symptoms found that half had scintigraphic evidence of pulmonary aspiration (169). However, aspiration of both gastric contents and saliva also occurs in healthy adults during deep sleep (171,172).
Gastric emptying studies have shown prolonged half-emptying times in children with GER. Delayed gastric emptying may predispose to GERD. Tests of gastric emptying are not a part of the routine examination of patients with suspected GERD, but may be important when symptoms suggest gastric retention (173–176).
Nuclear scintigraphy is not recommended in the routine diagnosis and management of GERD in infants and children.
Esophageal and Gastric Ultrasonography
Ultrasonography is not recommended as a test for GERD but can provide information not available through other technology. Ultrasonography of the gastroesophageal junction can detect fluid movements over short periods of time and thereby can detect nonacid reflux events. It can also detect HH, length and position of the LES relative to the diaphragm, and magnitude of the gastroesophageal angle of His. Barium upper GI series can provide the same information. When compared with the results of 24-hour esophageal pH testing as a diagnostic test for GERD, the sensitivity of color Doppler ultrasound performed for 15 minutes postprandially is about 95% with a specificity of only 11%, and there is no correlation between reflux frequency detected by ultrasound and reflux index detected by pH monitoring (177,178). Intraluminal esophageal ultrasound is used in adults to evaluate esophageal wall thickness and muscle shortening, parameters that vary with inflammation, scarring, and malignancy (179). At present, there is no role for ultrasound as a routine diagnostic tool for GERD in children.
Tests on Ear, Lung, and Esophageal Fluids
Recent studies have suggested that finding pepsin, a gastric enzyme, in middle ear effusions of children with chronic otitis media, indicates that reflux is playing an etiologic role (180–183). One recent study showed no relation between the presence of pepsin in the middle ear and symptoms of GERD (184), and this relation has not been validated in controlled treatment trials. Similarly, the presence of lactose, glucose, pepsin, or lipid-filled macrophages in bronchoalveolar lavage fluids has been proposed to implicate aspiration secondary to reflux as a cause of some chronic pulmonary conditions (185–187). No controlled studies have proven that reflux is the only reason these compounds appear in bronchoalveolar lavage fluids or that reflux is the cause of pulmonary disease when they are present.
Continuous monitoring of bilirubin in the esophagus has been suggested as a means of detecting esophageal reflux of duodenal juice or duodenogastroesophageal reflux. Duodenal juice components appear to damage the esophagus in a pH-dependent manner (188). Two uncontrolled pediatric case series have suggested that duodenogastroesophageal reflux produced GERD that was refractory to therapy with PPIs (189,190). One study indicated that therapy with PPIs decreased the esophageal damage caused by duodenogastroesophageal reflux (190). At present, there is insufficient evidence to recommend continuous monitoring of the esophagus for bilirubin in the routine evaluation of GERD. The role of bile reflux in children resistant to PPI treatment has not been established.
Empiric Trial of Acid Suppression as a Diagnostic Test
In adults, empiric treatment with acid suppression, that is, without diagnostic testing, has been used for symptoms of heartburn (191), chronic cough (192,193), noncardiac chest pain (194), and dyspepsia (195). However, empiric therapy has only modest sensitivity and specificity as a diagnostic test for GERD, depending upon the comparative reference standard used (endoscopy, pH monitoring, symptom questionnaires) (196), and the appropriate duration of a “diagnostic trial” of acid suppression has not been determined. A meta-analysis evaluating pooled data from 3 large treatment trials among the adults with NERD showed that 85% of the patients who had symptom resolution after 1 week of PPI treatment remained well for the entire 4 weeks of PPI treatment, thus “confirming” the diagnosis of GERD (197). However, 22% of the patients who had no improvement after 1 week of treatment did improve by the fourth week of treatment. An uncontrolled trial of esomeprazole therapy in adolescents with heartburn, epigastric pain, and acid regurgitation showed complete resolution of symptoms in 30% to 43% by 1 week, but the responders increased to 65% following 8 weeks of treatment (55). Another uncontrolled treatment trial of pantoprazole in children ages 5 to 11 years reported greater symptom improvement at 1 week with one 40-mg dose compared with one 10-mg or 20-mg dose (64). After 8 weeks all of the treatment groups improved. Similar improvement in symptoms over time has been observed in adults with erosive esophagitis (198,199). One study of infants with symptoms suggestive of GERD who were treated empirically with a PPI showed no efficacy over placebo (9).
The treatment period required to achieve uniform therapeutic responses with PPI therapy probably varies with disease severity, treatment dose, and specific symptoms or complications (200). The 2-week “PPI test” lacks adequate specificity and sensitivity for use in clinical practice. In an older child or adolescent with symptoms suggesting GERD, an empiric PPI trial is justified for up to 4 weeks. Improvement following treatment does not confirm a diagnosis of GERD because symptoms may improve spontaneously or respond by a placebo effect. There is no evidence to support an empiric trial of pharmacologic treatment in infants and young children as a diagnostic test of GERD.
Management options for physiologic GER and for GERD discussed in this section include lifestyle changes, pharmacologic therapy, and surgery. Lifestyle changes in infants with physiologic GER include nutrition, feeding, and positional modifications. In older children and adolescents, lifestyle changes include modification of diet and sleeping position, weight reduction, and smoking cessation.
Medications for use in GERD include agents to buffer gastric contents or suppress acid secretion. Agents affecting GI motility are discussed. Surgical therapy includes fundoplication and other procedures to eliminate reflux.
Parental education, guidance, and support are always required and usually sufficient to manage healthy, thriving infants with symptoms likely because of physiologic GER.
Feeding Changes in Infants
About 50% of the healthy 3- to 4-month-old infants regurgitate at least once per day (16,18) and up to 20% of caregivers in the United States seek medical help for this normal behavior (16). Breast-fed and formula-fed infants have a similar frequency of physiologic GER, although the duration of reflux episodes measured by pH probe may be shorter in breast-fed infants (201–203).
A subset of infants with allergy to cow's milk protein experience regurgitation and vomiting indistinguishable from that associated with physiologic GER (9,69,142,204–206). In these infants, vomiting frequency decreases significantly (usually within 2 weeks) after the elimination of cow's milk protein from the diet, and reintroduction causes recurrence of symptoms (206,207). Studies support the use of extensively hydrolyzed or amino acid formula in formula-fed infants with bothersome regurgitation and vomiting for trials lasting up to 4 weeks (206–208). Cow's milk protein and other proteins pass into human breast milk in small quantities. Breast-fed infants with regurgitation and vomiting may therefore benefit from a trial of withdrawal of cow's milk and eggs from the maternal diet (209,210). The symptoms of infant reflux are almost never so severe that breast-feeding should be discontinued. There are no studies specifically evaluating soy protein allergy in infants with regurgitation and vomiting, or the role of soy protein–based formula in the treatment of infants with regurgitation. Moreover, there are no data on allergy to possible formula-thickening agents such as rice cereals.
One study in infants showed that large volume feedings promote regurgitation, probably by increasing the frequency of TLESR and reduced feeding volume and decreased reflux frequency (211). Severe reduction in feeding volume during an extended period may deprive the infant of needed energy and adversely affect weight gain. Infants with inadequate weight gain because of losses by regurgitation may benefit from increasing the energy density of formula when volume or frequency of feedings is decreased as a part of therapy.
Adding thickening agents such as rice cereal to formula does not decrease the time with pH <4 (reflux index) measured by esophageal pH studies, but it does decrease the frequency of overt regurgitation (211–215). Studies with combined pH/MII show that the height of reflux in the esophagus is decreased with thickened formula as well as the overt frequency of regurgitation, but not the frequency of reflux episodes (114). One study reported an improvement in esophageal pH parameters with cornstarch-thickened formula (216). Another study showed no change in esophageal impedance parameters of premature infants receiving cornstarch-thickened human milk (217).
In the United States, rice cereal is the most commonly used thickening agent for formula (214). Rice cereal–thickened formula produces a decrease in the volume of regurgitation but may increase coughing during feedings (218). Formula with added rice cereal may require a nipple with an enlarged hole to allow adequate flow. Excessive energy intake is a potential problem with long-term use of feedings thickened with rice cereal or cornstarch (219). Thickening a 20-kcal/oz infant formula with 1 tablespoon of rice cereal per ounce increases the energy density to ∼34 kcal/oz (∼1.1 kcal/mL). Thickening with 1 tablespoon per 2 oz of formula increases the energy density to ∼27 kcal/oz (∼0.95 kcal/mL).
Commercial antiregurgitant (AR) formulae containing processed rice, corn or potato starch, guar gum, or locust bean gum are available in Europe, Asia, and the United States. These formulae decrease overt regurgitation and vomiting frequency and volume compared with unthickened formulae (1,220,221) or formulae thickened with rice cereal (216,222–226). However, a natural history study showed only a nonsignificant decrease in episodes of regurgitation and no change in infant comfort among infants fed with a formula thickened with bean gum versus those fed with a formula thickened with rice cereal or regular formula (227). When ingested in normal volumes, AR formulae contain an energy density, osmolarity, protein, calcium, and fatty acid content appropriate to an infant's nutritional needs, whereas a formula with added thickener has a higher energy density, and in normal ingested volumes this may provide more energy than needed. A largely untested potential advantage of AR formulae is that they do not require a substantially increased sucking effort, obviating the need for use of a large-bore nipple hole. In vitro studies have shown a decrease in the absorption of minerals and micronutrients from formulae commercially thickened with indigestible but not digestible carbohydrates (228,229). The clinical significance of these findings is unclear because a 3-month follow-up study of children on formula thickened with indigestible carbohydrate showed normal growth and nutritional parameters (230).
The use of AR formulae and formulae with added thickener results in a decrease of observed regurgitation. Although the actual number of esophageal reflux episodes may not decrease, the reduction in regurgitation may be a welcome improvement in quality of life for caregivers. The impact of thickened formula on the natural history of physiologic GER or GERD has not been studied. The allergenicity of commercial thickening agents is uncertain, and the possible nutritional risks of long-term use require additional study.
Infants with GERD who are unable to gain weight despite conservative measures and in whom nasogastric or nasojejunal feeding may be beneficial are rare (231). Similarly, nasojejunal feeding is occasionally useful in infants with recurrent reflux-related pneumonia to prevent recurrent aspiration. Although these approaches to therapy are widely used, there are no controlled studies comparing them to pharmacologic or surgical treatments.
Positioning Therapy for Infants
Several studies in infants have demonstrated significantly decreased acid reflux in the flat prone position compared with flat supine position (232–236). There is conflicting evidence as to whether infants placed prone with the head elevated have less reflux than those kept prone but flat (232–234,237). The amount of reflux in supine infants with head elevated is equal to or greater than in infants supine and flat (232,234,238,239). The semisupine positioning as attained in an infant car seat exacerbates GER (240). Although the full upright position appears to decrease measured reflux, 1 study suggested that using formula thickened with rice cereal is more effective in decreasing the frequency of regurgitation than upright positioning after feeds (223).
In the 1980s, prone positioning was recommended for the treatment of GERD in infants because studies showed less reflux in this position. Prone sleep positioning is associated with longer uninterrupted sleep periods and supine sleep positioning with more frequent arousals and crying (241). However, concerns regarding the association between prone positioning and sudden infant death syndrome (SIDS) required a reassessment of the benefits and risks of prone positioning for reflux management. The Nordic Epidemiological SIDS Study demonstrated that the odds ratio of mortality from SIDS was more than 10 times higher in prone-sleeping infants and 3 times higher in side-sleeping infants than in supine-sleeping infants (242–244). Therefore, prone positioning is acceptable if the infant is observed and awake, particularly in the postprandial period, but prone positioning during sleep can only be considered in infants with certain upper airway disorders in which the risk of death from GERD may outweigh the risk of SIDS. Prone positioning may be beneficial in children older than 1 year of age with GER or GERD whose risk of SIDS is negligible.
Esophageal pH and combined pH/MII monitoring show that reflux is quantitatively similar in the left-side-down and prone positions. Measured reflux in these 2 positions is less than in the right-side-down and supine positions (234,245–247). Two impedance studies of preterm infants found that postprandial reflux was greater in the right-side-down than in the left-side-down position (173,235). Based on these findings, 1 study recommended that infants be placed right-side-down for the first hour after feeding to promote gastric emptying and then switched to left-side-down thereafter to decrease reflux (173). These findings notwithstanding, it is important to note that side-lying is an unstable position for an infant who may slip unobserved into the prone position. Bolstering an infant with pillows to maintain a side-lying position is not recommended (248).
Lifestyle Changes in Children and Adolescents
Lifestyle changes often recommended for children and adolescents with GER and GERD include dietary modification, avoidance of alcohol, weight loss, positioning changes, and cessation of smoking. Most studies investigating these recommendations have been performed in adults, thus their applicability to children of all ages is uncertain. A review of lifestyle changes in adults with GERD concluded that only weight loss improved pH profiles and symptoms (249). Although alcohol, chocolate, and high-fat meals reduce LES pressure, only a few studies have evaluated the impact of these factors on symptoms. Tobacco smoke exposure is associated with increased irritability in infants, yet neither tobacco nor alcohol cessation has been shown to improve esophageal pH profiles or symptoms. One uncontrolled study (250) found that a low-carbohydrate diet reduced distal esophageal acid exposure and improved symptoms in obese individuals with GERD. Gastric bypass surgery significantly improved symptoms of GERD in obese adults (251). Another study (252) detected more overnight reflux in adults eating a late evening meal than in adults eating an earlier evening meal. The difference was especially obvious in overweight adults.
Current evidence generally does not support (or refute) the use of specific dietary changes to treat reflux beyond infancy. Expert opinion suggests that children and adolescents with GERD should avoid caffeine, chocolate, alcohol, and spicy foods if they provoke symptoms (253–264). In an overweight individual, weight loss does decrease reflux, and is therefore recommended (250–252,265–267). Smoking should be avoided in those with GERD because it has been linked to adenocarcinoma of the esophagus in adults (268,269). Three studies have shown that chewing sugarless gum after a meal decreases reflux (270–272). It is not known whether any lifestyle changes have an additive benefit in children or adolescents receiving pharmacological therapy.
The effectiveness of positioning for treatment of GER and GERD in children older than 1 year of age has not been studied. It is unclear whether the benefits of positional therapy identified in adults and infants younger than 1 year can be extrapolated to children in general (215). Some studies have shown that adults who sleep with the head of the bed elevated have fewer and shorter episodes of reflux and fewer reflux symptoms (273–275). Other studies in adults have shown that reflux increases in the right lateral decubitus position (245,276). It is likely therefore that adolescents, like adults, may benefit from the left lateral decubitus sleeping position with elevation of the head of the bed.
The major pharmacologic agents currently used for treating GERD in children are gastric acid buffering agents, mucosal surface barriers, and gastric antisecretory agents. Since the withdrawal of cisapride from commercial availability in most countries, prokinetic agents have been less frequently used, although domperidone is commercially available in Canada and Europe.
Comparisons between pharmacologic agents for GERD in children have been impaired by small sample size, absence of controls, and use of unreliable endpoints such as esophageal histology (Section 3.4).
Histamine-2 Receptor Antagonists
Histamine-2 receptor antagonists (H2RAs) decrease acid secretion by inhibiting histamine-2 receptors on gastric parietal cells. In 1 study of infants, ranitidine (2 mg/kg per dose orally) reduced the time that gastric pH was <4.0 by 44% when given twice daily and by 90% when given 3 times per day (277). One dose of ranitidine (5 mg/kg) has been shown to increase gastric pH for 9 to 10 hours in infants (278). Pharmacokinetic studies in 4- to 11-year-old children suggest that peak plasma ranitidine concentration occurs 2.5 hours after dosing with a half-life of 2 hours. Gastric pH begins to increase within 30 minutes of administration and the effect lasts for 6 hours (279). Tachyphylaxis, or diminution of the response, to intravenous ranitidine and escape from its acid-inhibitory effect have been observed after 6 weeks (280), and tolerance to oral H2RAs in adults is well recognized (281,282). Numerous randomized controlled trials (RCTs) in adults have demonstrated that cimetidine, ranitidine, and famotidine are superior to placebo for relief of symptoms and healing of esophageal mucosa (283–285). However, the efficacy of H2RAs in achieving mucosal healing is much greater in mild esophagitis than in severe esophagitis (286). One randomized trial of infants and children with erosive esophagitis compared the efficacy of cimetidine (30–40 mg · kg−1 · day−1) to placebo (287). Significant improvement in clinical and histopathology scores occurred only in the cimetidine-treated group. Another randomized study in 24 children with mild to moderate esophagitis demonstrated that nizatidine (10 mg · kg−1 · day−1) was more effective than placebo for the healing of esophagitis and symptom relief (288). There are case series providing additional support for the efficacy of H2RAs in infants and children (289–294). Although no RCTs in children demonstrate the efficacy of ranitidine or famotidine for the treatment of esophagitis, expert opinion is that these agents are as effective as cimetidine and nizatidine. Extrapolation of the results of a large number of adult studies to older children and adolescents suggests that H2RAs may be used in these patients for the treatment of GERD symptoms and for healing esophagitis, although H2RAs are less effective than PPIs for both symptom relief and healing of esophagitis (283,295,296).
The fairly rapid tachyphylaxis that develops with H2RAs is a drawback to chronic use. In some infants, H2RA therapy causes irritability, head banging, headache, somnolence, and other side effects that, if interpreted as persistent symptoms of GERD, could result in an inappropriate increase in dosage (293). H2RAs, particularly cimetidine, are associated with an increased risk of liver disease (297,298) and cimetidine with gynecomastia (299). Other adverse effects of suppression of gastric acid are discussed in the section on PPIs.
Proton Pump Inhibitors
PPIs inhibit acid secretion by blocking Na+–K+-ATPase, the final common pathway of parietal cell acid secretion, often called the proton pump. Studies in adults have shown that PPIs produce higher and faster healing rates for erosive esophagitis than H2RAs, which in turn are better than placebo (122). The superior efficacy of PPIs is largely because of their ability to maintain intragastric pH at or above 4 for longer periods and to inhibit meal-induced acid secretion, a characteristic not shared by H2RAs. In contrast with H2RAs, the effect of PPIs does not diminish with chronic use. The potent suppression of acid secretion by PPIs also results in decrease of 24-hour intragastric volumes, thereby facilitating gastric emptying and decreasing volume reflux (300). Despite their efficacy in the management of acid-related disorders, PPIs have limitations as a consequence of their pharmacologic characteristics. They must be taken once per day before breakfast and must be protected from gastric acid by enteric coatings. Bioavailability of PPIs is decreased if they are not taken before meals. However, taking the medications before meals effectively delays absorption and onset of their antisecretory effect. Most available PPIs are therefore regarded as “delayed release” preparations. Achievement of maximal acid suppressant effect can take up to 4 days (301). However, a summary of adult data suggests that PPIs can also be used for “on-demand” treatment of symptoms (302). One commercially available “immediate-release” PPI is uncoated omeprazole with added bicarbonate (302). There are no data available concerning its use in children. Dexlansoprazole MR is said to be less dependent on being taken on an empty stomach. This new medication has 2 delayed-release mechanisms, and therefore a longer duration of acid suppression (303). The clinical importance of this modification has yet to be determined. There are no pediatric clinical trials and the drug is not approved for use in children.
PPIs currently approved for use in children in North America are omeprazole, lansoprazole, and esomeprazole. At this moment, in Europe, only omeprazole and esomeprazole are approved. No PPI has been approved for use in infants younger than 1 year of age. Most studies of PPIs in children are open-label and uncontrolled. In children, as in adults, PPIs are highly efficacious for the treatment of symptoms due to GERD and the healing of erosive disease. PPIs have greater efficacy than H2RAs. These data and recommendations regarding administration of PPIs are detailed in Section 6.3. Children 1 to 10 years of age appear to require a higher dose per kilogram for some PPIs than adolescents and adults. Young children require higher per kilogram doses to attain the same acid blocking effect or area under the curve (304–306). This may not apply to all of the PPIs (307). There are few pharmacokinetic data for PPIs in infants, but studies indicate that infants younger than 6 months may have a lower per-kilogram dose requirement than older children and adolescents (308,309).
The number of PPI prescriptions written for infants has increased manyfold in recent years despite the absence of evidence for acid-related disorders in the majority (6–8). Infant responses to many stimuli, including GER, are nonspecific (310). Double-blind randomized placebo-controlled trials of PPI efficacy in infants with GERD-like symptoms showed that PPI and placebo produced similar improvement in crying, despite the finding that acid suppression only occurred in the PPI group (9,46,308). In the largest double-blind randomized placebo-controlled trial of PPI in infants with symptoms purported to be due to GERD, response rates in those treated for 4 weeks with lansoprazole or placebo were identical (54%) (9). Thus, no placebo-controlled treatment trial, in which enrollment was based on “typical” GERD symptoms, has demonstrated symptom improvement in infants. This result may be because of a lack of specificity of symptom-based diagnosis of GERD, especially with esophagitis, in this age group (see above discussion on history). Double-blind randomized placebo-controlled trials show that PPI therapy is not beneficial for the treatment of infants with symptoms that previously were purported but not proven to be due to GERD.
There are potential risks associated with acid suppression resulting from PPI therapy in infants (9,46). There are 4 main categories of adverse effects related to PPIs: idiosyncratic reactions, drug–drug interactions, drug-induced hypergastrinemia, and drug-induced hypochlorhydria. Idiosyncratic side effects occur in up to 14% of children taking PPIs (28,311,312). The most common are headache, diarrhea, constipation, and nausea, each occurring in 2% to 7%. These may resolve with decreased dose or change to a different PPI. Parietal cell hyperplasia (313,314) and occasional fundic gland polyps (315) are benign changes resulting from PPI-induced acid suppression and hypergastrinemia. Enterochromaffin cell-like hyperplasia is also a result of acid suppression. A prospective study monitoring patients treated for up to 2 years (316) and retrospective studies of patients treated up to 11 years (28) have found only mild grades of enterochromaffin-like cell hyperplasia. A recent retrospective study using sensitive staining techniques (317) showed enterochromaffin cell-like hyperplasia in the gastric body of almost half of children receiving long-term PPI continuously for a median of 2.84 years (up to 10.8 years); the hyperplasia was of the lowest 2 grades (not clinically significant), and no patient developed atrophic gastritis or carcinoid tumors.
Increasing evidence suggests that hypochlorhydria, that is, acid suppression, associated with H2RAs or PPIs may increase rates of community-acquired pneumonia in adults and children, gastroenteritis in children, and candidemia and necrotizing enterocolitis in preterm infants (318–322). In 1 study, PPIs but not H2RAs were associated with bacterial enterocolitis in adults. Doubling of the PPI dose increased the risk (323). Infants treated with PPI in a study (9) had a significantly higher rate of all adverse effects compared with the placebo group. Lower respiratory tract infections were the most frequent among these adverse effects, although the difference in respiratory tract infection rate between treated and placebo groups did not achieve statistical significance. PPIs have been shown to alter the gastric and intestinal bacterial flora in adults (324). The effect of PPI therapy on the flora of infants and childen or the consequences of any alterations have not been evaluated.
Other adverse effects have been reported in elderly patients on chronic PPI therapy, such as deficiency of vitamin B12 and increased incidence of hip fractures (325,326), but these findings have not been corroborated by recent studies (327,328). In a retrospective case review, 18 cases of biopsy-proven PPI-induced acute interstitial nephritis causing acute renal failure were reported, and the authors suggest this entity may go unrecognized as “unclassified acute renal failure” (329). PPIs are considered to be the most common cause of acute interstitial nephritis in adults (330). This adverse effect is considered to be an idiosyncratic reaction, more frequent in elderly adults. No childhood cases have been described. Animal studies suggest that acid suppression may predispose to the development of food allergy (331), but this remains to be confirmed by human studies.
Cisapride is a mixed serotonergic agent that facilitates the release of acetylcholine at synapses in the myenteric plexus, thus increasing gastric emptying and improving esophageal and intestinal peristalsis. Clinical studies of cisapride in children with GERD showed significant reduction in the RI (332) but with less consistent reduction in symptoms (333,334). After cisapride was found to produce prolongation of the QTc interval on electrocardiogram, a finding increasing the risk of sudden death (335), its use was restricted to limited-access programs supervised by a pediatric gastroenterologist and to patients in clinical trials, safety studies, or registries.
Domperidone and metoclopramide are antidopaminergic agents that facilitate gastric emptying. Metoclopramide has cholinomimetic and mixed serotonergic effects. Metoclopramide and placebo equally reduced symptom scores of infants with reflux. Metoclopramide did reduce the RI on pH probe examination but did not normalize it (336). A meta-analysis of 7 RCTs of metoclopramide in developmentally healthy children 1 month to 2 years of age with symptoms of GER found that metoclopramide reduced daily symptoms and the RI but was associated with significant side effects (215). Metoclopramide commonly produces adverse side effects in infants and children, particularly lethargy, irritability, gynecomastia, galacctorhea, and extrapyramidal reactions and has caused permanent tardive dyskinesia (337–340). A recent systematic review of studies on domperidone (341) identified only 4 RCTs in children, none providing “robust evidence” for efficacy of domperidone in pediatric GERD. Domperidone occasionally causes extrapyramidal central nervous system side effects (342).
Bethanechol, a direct cholinergic agonist studied in a few controlled trials, has uncertain efficacy and a high incidence of side effects in children with GERD (338,343,344). Erythromycin, a dopamine-receptor antagonist, is sometimes used in patients with gastroparesis to hasten gastric emptying. Its role in the therapy of GER and GERD has not been investigated.
Baclofen is a γ-amino-butyric-acid receptor agonist that reduces both acid and nonacid reflux in healthy adults and in adults with GERD (345). In children, it was shown to accelerate gastric empyting for 2 hours after dosing, without any deleterious effect on LES resting pressure or esophageal peristalsis (346). In a small group of children with GERD and NI, it was reported to decrease the frequency of emesis (347). Although no side effects were noted in 1 study, baclofen is known to cause dyspeptic symptoms, drowsiness, dizziness, and fatigue, and to lower the threshold for seizures. Such side effects preclude its routine use (348).
Currently, there is insufficient evidence to justify the routine use of cisapride, metoclopramide, domperidone, bethanechol, erythromycin, or baclofen for GERD (215,333,341,349,350).
Antacids directly buffer gastric contents, thereby reducing heartburn and healing esophagitis. On-demand use of antacids may provide rapid symptom relief in some children and adolescents with NERD (351). Although this approach appears to carry little risk, it has not been formally studied in children. Intensive, high-dose antacid regimens (eg, magnesium hydroxide and aluminum hydroxide; 700 mmol/1.73 m2/day) are as effective as cimetidine for treating peptic esophagitis in children ages 2 to 42 months (352,353). No studies of antacids to date have used combined esophageal pH/MII to assess outcome. Prolonged treatment with aluminum-containing antacids significantly increases plasma aluminum in infants (354,355), and some studies report plasma aluminum concentrations close to those that have been associated with osteopenia, rickets, microcytic anemia, and neurotoxicity (356–358). Milk-alkali syndrome, a triad of hypercalcemia, alkalosis, and renal failure, can occur due to chronic or high-dose ingestion of calcium carbonate. Although these side effects are less common than they were in the era before acid-suppressive drugs (359), all of the antacid buffering agents should be used with particular caution in infants and young children. Because safe and convenient alternatives are available that are more acceptable to patients, chronic antacid therapy is generally not recommended for patients with GERD.
Most surface protective agents contain either alginate or sucralfate. Alginates are insoluble salts of alginic acid, a component of algal cell walls. In older studies of alginic acid therapy in pediatric patients with GERD, the liquid preparations used also contained buffering agents, making it difficult to isolate the effect of the surface protective agent itself (360–363). Efficacy in these studies has varied widely. In 1 clinical study, a commercial liquid preparation containing only sodium-magnesium alginate significantly decreased the mean frequency and severity of vomiting in infants compared with placebo (364). Another placebo-controlled study of this preparation in infants showed that although symptoms improved with therapy, the only objective change on combined pH/MII evaluation was a marginal decrease in the height of reflux in the esophagus (365). Alginate is also available as tablets and is useful for on-demand treatment of symptoms.
Sucralfate is a compound of sucrose, sulfate, and aluminum, which, in an acid environment, forms a gel that binds to the exposed mucosa of peptic erosions. In adults, sucralfate decreased symptoms and promoted healing of nonerosive esophagitis (366). The only randomized comparison study in children demonstrates that sucralfate was as effective as cimetidine for treatment of esophagitis (367). The available data are inadequate to determine the safety or efficacy of sucralfate in the treatment of GERD in infants and children, particularly the risk of aluminum toxicity with long-term use.
None of the surface agents is recommended as a sole treatment for severe symptoms or erosive esophagitis.
Fundoplication decreases reflux by increasing the LES baseline pressure, decreasing the number of TLESRs and the nadir pressure during swallow-induced relaxation, increasing the length of the esophagus that is intraabdominal, accentuating the angle of His, and reducing an HH if present (24,368). Fundoplication usually eliminates reflux, including physiologic reflux (369). Fundoplication does not correct underlying esophageal clearance, gastric emptying, or other GI dysmotility disorders (21,24,370–373).
Most of the literature on surgical therapy in children with GERD consists of retrospective case series in which documentation of the diagnosis of GERD and details of previous medical therapy are deficient, making it difficult to assess the indications for and responses to surgery (374–377). Children with underlying conditions predisposing to the most severe GERD (Section 5.1.1) comprise a large percentage of most of the surgical series, further confounding efforts to determine the benefits versus risks of surgical antireflux procedures in specific patient populations. The absence of systematic postoperative evaluation, including objective testing with pH or impedance studies and endoscopy, further complicates the assessment of surgical outcomes in most series (368,372,378).
In general, outcomes of antireflux surgery have been more carefully evaluated in adults than in children. In 1 study (379), at a mean of 20 (±10) months after surgery, 61% of the adults were satisfied with their outcome; 32% were taking medications for heartburn, 11% required esophageal dilatation, and 7% had repeat surgery. This study found that a substantial number of patients underwent fundoplication for questionable reasons. In another study of patients relieved of typical reflux symptoms postoperatively, up to two thirds developed new symptoms postoperatively, including excessive gas, abdominal bloating, increased flatus, dysphagia, difficulty with eructation, and vomiting (378–381). In a large multicenter controlled study, 62% of the adults were taking PPIs for reflux symptoms 7 years after antireflux surgery (381). In another study, 37% of adults were taking antireflux medications at a mean of 5.9 years following antireflux surgery (382). Another study showed a similarly high surgical failure rate (383).
A large open RCT compared the efficacy and safety of laparoscopic fundoplication versus esomeprazole (20 mg qd) for treatment of adults with GERD (384). Short-term outcomes were reported in an interim analysis of data at 3 years. More than 90% of both the surgically and medically treated adults showed good to excellent symptom control; 10% of the surgical group had dysphagia whereas dysphagia was uncommon in the medically treated group. Quality of life measures were similar in both groups (384). Death related to open or laparoscopic surgery occurs. In adults, the mortality of the first operation is reported to be between 1 in 1000 and 1 in 330 (385–387).
In children who were operated on, those with NI have more than twice the complication rate, 3 times the morbidity, and 4 times the reoperation rate of children without NI (388). Other studies show similar data (389–391). One case series with a follow-up period of 3.5 years reported that more than 30% of children with NI had major complications or died within 30 days of antireflux surgery (392). Twenty-five percent of those patients had operative failure and 71% had a return of 1 or more preoperative symptoms within 1 year of surgery.
Children with repaired EA also have a high rate of operative failure (393,394), although not as high as those with NI. Recurrence of pathologic reflux after antireflux surgery in children with NI or EA may not be obvious, and detection often requires a high index of suspicion, repeated evaluation over time, and use of more than 1 test (391,394).
In a recent retrospective review of 198 children, 74% of whom had underlying disorders, two thirds had GERD symptoms or required medical treatment for GERD within 2 months of antireflux surgery (374). Fundoplication in early infancy has a higher failure rate than fundoplication performed later in childhood (395,396), and appears to be more frequent in children with associated anomalies (396).
The impact of antireflux surgery on hospitalization for reflux-related events, especially adverse respiratory events, was reviewed using a large administrative database (397). A significant reduction in the number of adverse respiratory events was observed in the year following surgery in those operated at <4 years of age (1.95 vs 0.67 events per year). However, in older children, no benefit of surgery on the rate of hospitalization for adverse respiratory events was found. In fact, children with developmental delay were hospitalized more frequently in the year following antireflux surgery than before surgery (397). In a recent pediatric study, Nissen fundoplication did not decrease hospital admissions for pneumonia, respiratory distress or apnea, or failure to thrive, even in those with underlying neurological impairment (398).
Complications following antireflux surgery may be due to alterations in fundic capacity, altered gastric compliance and sensory responses that may persist from months to years. These include gas-bloat syndrome, early satiety, dumping syndrome, and postoperative retching and gagging. In a postoperative study of otherwise healthy children, that is, children with no underlying disorders, 36% had mild to moderate gas bloat symptoms, 32% were “very slow” to finish most meals, 28% were unable to burp or vomit, and 25% choked on some solids (399). Early and late operative failure may result from disruption of the wrap or slippage of the wrap into the chest (385,389–394,400–404). In otherwise healthy children evaluated at a mean of 10 months (1–35 months) following antireflux surgery, 67% had “no complaints,” but one third had objective evidence of operative failure (405). Operative complications include splenic or esophageal laceration, each of which occurs in about 0.2% of pediatric cases (406). Children with underlying disorders such as NI are at substantially greater risk for surgical mortality (388,400,406), as are those in early infancy (396). Mortality due to surgery in children without NI is difficult to assess because of the heterogeneous population in most surgical studies.
Laparoscopic Nissen fundoplication (LNF) has largely replaced open Nissen fundoplication (ONF) as the preferred antireflux surgery for adults and children, due to its decreased morbidity, shorter hospital stays, and fewer perioperative problems (124,377,378,386,387,395,401,407–409). However, LNF is attended by as high a failure rate as open surgery in adults (378,401). In a randomized study of ONF versus LNF in adults, patients who received LNF had a higher incidence of disabling dysphagia (410). In a series of 456 children undergoing surgery younger than 5 years of age, Diaz et al (395) reported that those with LNF had a higher reoperation rate than those with ONF. Average time to reoperation with LNF was 11 months versus 17 months for ONF. In children with 1 to 3 comorbidities the probability of reoperation was 18% to 24% after LNF, compared with 6% to 16% for ONF (395).
Total esophagogastric dissociation is an operative procedure that is useful in selected children with NI or other conditions causing life-threatening aspiration during oral feedings. The operation has been used either after failed fundoplication or as a primary procedure (411,412). The esophagogastric disconnection eliminates all of the reflux while allowing tube feedings or oral supplementation up to the patient's tolerance. This is a technically demanding operation, and because of the fragile nature of the children involved—most of whom have histories of aspiration and pulmonary compromise—it carries significant morbidity (411,412).
Endoluminal endoscopic gastroplication has been described in children as an alternative to surgical fundoplication. When a group of 16 children with GERD refractory to or dependent on medical therapy was evaluated after endoluminal gastroplication (413), 4 had recurrent symptoms requiring a repeat procedure 2 to 24 months postoperatively. Three years after surgery, 9 patients (56%) were taking no antireflux medication. Longer-term studies in adults have shown little or no difference in procedure time or failure rate between endoluminal and surgical antireflux procedures (414,415). In some studies, sham-operated patients have done as well as operated patients (416,417). Other endoscopic GERD treatments have not been studied in children (368).
The annual number of antireflux operations has been on the increase in the United States, especially in children younger than 2 years of age (375,406). In contrast, in adults, rates of fundoplication are declining in the United States and have dropped 30% from their peak in 1999 (378). The greatest decline is in teaching hospitals and in young adult patients.
Antireflux surgery may be of benefit in children with confirmed GERD who have failed optimal medical therapy, or who are dependent on medical therapy over a long period of time, or who are significantly nonadherent with medical therapy, or who have life-threatening complications of GERD. Children with respiratory complications including asthma or recurrent aspiration related to GERD are generally considered most likely to benefit from antireflux surgery when medical therapy fails, but additional study is required to confirm this. Children with underlying disorders predisposing to the most severe GERD are at the highest risk for operative morbidity and operative failure. Before surgery it is essential to rule out non-GERD causes of symptoms, and ensure that the diagnosis of chronic-relapsing GERD is firmly established. It is important to provide families with appropriate education and a realistic understanding of the potential complications of surgery, including symptom recurrence.
EVALUATION AND MANAGEMENT OF THE PEDIATRIC PATIENT WITH SUSPECTED GERD
The following sections describe the relation between reflux and several common signs, symptoms or symptom complexes of infants and children. The evaluations appropriate to establish a diagnosis of GERD and recommendations for management in each case are outlined. Recommendations are based on the available evidence and the consensus opinion of the members of the guideline committee.
Recurrent Regurgitation and Vomiting
The practitioner's challenge is to distinguish regurgitation and vomiting caused by reflux or reflux disease from vomiting caused by numerous other disorders (Table 4). This can be confusing because reflux episodes sometimes trigger vomiting, a coordinated autonomic and voluntary motor response causing forceful expulsion of gastric contents. Vomiting associated with reflux is probably a result of the stimulation of pharyngeal sensory afferents by refluxed gastric contents (418,419). Laboratory and radiographic investigation may be necessary to exclude other causes of vomiting.
The Infant With Uncomplicated Recurrent Regurgitation
In the infant with recurrent regurgitation or spitting, a thorough history (Table 5) and physical examination with attention to warning signals suggesting other diagnoses (Table 1) is generally sufficient to establish a clinical diagnosis of uncomplicated infant GER (Fig. 1). The typical presentation of uncomplicated infant GER is effortless, painless regurgitation in a healthy-appearing child with normal growth—the so-called happy spitter. Intermittently, an episode of vomiting, even forceful vomiting may occur. Irritability may accompany regurgitation and vomiting; however, in the absence of other warning symptoms, it is not an indication for extensive diagnostic testing. An upper GI series or other diagnostic tests are not required unless other diagnoses such as GI obstruction are suspected. Recurrent regurgitation due to GER generally decreases during the first year, resolving at 12 to 18 months of age (17,18). If “warning signs” for GERD or other diagnoses are present, or if regurgitation is not resolving by 12 to 18 months of age, consultation with a pediatric gastroenterologist is recommended.
Generally, only parental education, anticipatory guidance, and modification of feeding composition, frequency, and volume are necessary for the management of uncomplicated infant GER (208,420). Overfeeding exacerbates recurrent regurgitation and should be avoided (211). In some infants with persistent regurgitation, a thickened or commercial antiregurgitation formula may help control the frequency of regurgitation (Section 4.1.1). There is no evidence that antisecretory or promotility agents improve physiologic infant regurgitation. Prone positioning is not recommended because of its association with SIDS. Because regurgitation is sometimes the sole manifestation of cow's milk protein allergy in healthy-looking infants (420,421), a 2-week trial of protein hydrolysate– or amino acid–based formula or a trial of milk-free diet for the breast-feeding mother is appropriate in infants not responding to previous management.
The Infant With Recurrent Regurgitation and Poor Weight Gain
The infant with recurrent regurgitation and poor weight gain should not be confused with the “happy spitter” described in Section 6.1.1. Whereas the history and physical examination may be identical, poor weight gain is not typical of uncomplicated infant GER and is a crucial warning sign that alters clinical management.
Because there are no well-controlled studies evaluating diagnostic or therapeutic strategies for these infants, the following approach is based on expert opinion (Fig. 2). A feeding history should be obtained that includes an estimate of energy offered and ingested per day, an estimate of energy loss through regurgitation, a description of formula preparation and feeding schedule, an assessment of breast milk sufficiency, and a description of infant sucking and swallowing behavior. Parents should be advised not to reduce intake to the point of energy deprivation in the attempt to prevent regurgitation. If problems identified by history seem to explain the symptoms and can be addressed, close outpatient monitoring of weight gain will determine whether further evaluation is indicated.
If chronic regurgitation and inadequate weight gain persist after observation and despite adequate energy intake, evaluation for causes of failure to thrive compatible with the history is mandatory. Among possible etiologies in infancy are infections (especially urinary tract), food allergy, anatomic abnormalities, neurologic disorders, metabolic disease, and neglect or abuse (Table 4). A 2- to 4-week trial of extensively hydrolyzed or amino acid–based formula is appropriate. Depending on the results of investigations and response to dietary management, the infant should be referred to a pediatric specialist. Hospitalization for observation and testing is appropriate in some infants with persistent failure to thrive. Nasogastric or nasojejunal feeding is occasionally necessary to achieve weight gain in the infant with no other clear explanation for poor weight gain (231).
The Infant With Unexplained Crying and/or Distressed Behavior
Irritability and regurgitation are nonspecific symptoms that occur in healthy infants and are associated with a wide range of physiologic and pathologic conditions. For example, exposure to environmental factors, such as tobacco smoke may result in irritability in infants (422,423). Healthy young infants fuss or cry an average of 2 hours daily. There is substantial individual variation and some healthy infants cry as much as 6 hours per day. Likewise, there is variation in parental perceptions regarding the severity and duration of crying and its importance. The amount of daily crying typically peaks at 6 weeks of age (424,425). As with fussing, sleeping patterns of healthy infants show great individual and maturational variation as do parental expectations for sleep behavior (426).
The concept that infant irritability and sleep disturbances are manifestations of GER is largely extrapolated from adult descriptions of heartburn and sleep disturbances that improve with antacid therapy (50,427–429). Although 1 study in infants showed a correlation between infant grimacing and episodes of reflux (430), multiple other studies have shown no relation between crying and GERD determined by esophageal pH testing (61,84,140,431) or the presence of esophagitis (47,84). Some small descriptive studies have evaluated pH probe studies in infants with irritability and sleep disturbance. One compared infants with normal and abnormal pH probe studies and found a slight increase in nighttime waking, delayed onset of sleep, and greater daytime sleeping in those with abnormal pH probe studies (432). Another study found no increase in sleep disturbance in infants with abnormal esophageal pH tests (431). One dual pH probe study showed slightly poorer proximal acid clearance in colicky infants, but no abnormality in other parameters (433). Recently, a study of colicky infants found abnormal pH test results only in those with excessive regurgitation or feeding difficulties (61).
There are few studies addressing the appropriate management of infants with irritability and reflux symptoms. One study showed a greater decrease in crying time in infants treated with a 1-mg/kg dose of famotidine than in infants given 0.5 mg/kg. Although the authors concluded from this study that famotidine was effective in treating infant crying, differences in age between treatment groups, absence of placebo control, and a lack of difference between the treatment group and a group withdrawn from medications cast doubt on this conclusion (293). Placebo-controlled studies have evaluated acid-suppressive therapy in irritable infants. A study of infants with irritability and normal esophageal pH tests found that combined ranitidine and cisapride treatment was not superior to placebo or counselling for persistent crying (45). A double-blind placebo-controlled trial of omeprazole in irritable infants who either had esophagitis or an RI >5% found no difference in crying between treated and placebo groups despite highly effective acid suppression in the treated group (46). A large double-blind study of 162 infants randomized to 4 weeks of placebo or lansoprazole showed an identical 54% response rate in each group, using an endpoint of >50% reduction of measures of feeding-related symptoms (crying, irritability, arching) and other parameters of the I-GERQ questionnaire (9). Furthermore, this study showed a small but significant increase in the numbers of infants that experienced lower respiratory symptoms during the treatment trial.
The available evidence does not support an empiric trial of acid suppression in infants with unexplained crying, irritability, or sleep disturbance. A symptom diary (61,434) or hospital observation (45,435) may be useful to confirm the history, which is subjective to observation bias.
Disorders other than GERD that are likely to cause irritability include cow's milk protein allergy (142,436), infections (especially of the urinary tract), constipation, respiratory disorders, congenital or acquired neurologic abnormalities (437), metabolic disease, surgical emergencies (eg, intermittent volvulus, ovarian torsion), cardiac disease, corneal abrasion, bone fractures, hair tourniquet syndrome, tobacco smoke exposure, hunger, abuse, or neglect (438,439). Allergy to cow's milk protein or other formula intolerance may cause infant irritability, distress, and vomiting indistinguishable from GER. In 1 controlled study, an empiric trial of formula made with partially hydrolyzed whey proteins, prebiotic oligosaccharides, and a high β-palmitic acid content significantly decreased colic (440). Data on the efficacy of extensively hydrolyzed formulae in infants with unexplained crying and/or distressed behavior are limited (441,442). An empiric 2- to 4-week trial of an extensively hydrolyzed formula (1 that has been validated as being tolerated by at least 90% of infants with cow's milk protein allergy with 95% confidence) or amino acid–based formula may be indicated in irritable infants after diagnostic evaluations have been performed for other conditions causing irritability. Reflux is an uncommon cause of irritability or unexplained crying in otherwise healthy infants. However, if irritability persists with no explanation other than suspected GERD, expert opinion suggests the following options. The practitioner may continue anticipatory guidance and training of parents in the management of such infants with the expectation of improvement with time. Additional investigations to ascertain the relation between reflux episodes and symptoms or to diagnose reflux or other causes of esophagitis may be indicated (pH monitoring ± impedance monitoring, endoscopy). A time-limited (2-week) trial of antisecretory therapy may be considered, but there is potential risk of adverse effects, and clinical improvement following empiric therapy may be due to spontaneous symptom resolution or a placebo response. The risk/benefit ratio of these approaches is not clear.
The Child Older Than 18 Months of Age With Chronic Regurgitation or Vomiting
Physiologic regurgitation, episodic vomiting, or regurgitation followed by swallowing of refluxate in the mouth are frequent in infants. Whether of new onset or persisting from infancy, these symptoms are less common in children older than 18 months of age. Although these symptoms are not unique to GERD, evaluation to diagnose possible GERD and to rule out alternative diagnosis is recommended based on expert opinion. Testing may include upper GI endoscopy, and/or esophageal pH/MII, and/or barium upper GI series (Table 4).
Heartburn or substernal burning pain is a symptom of GERD with or without esophagitis (443). Recent consensus statements suggest that typical heartburn is a reliable indicator for GERD in adolescents and adults if it is the dominant symptom (13,50). One study in adults found that dominant heartburn had a positive predictive value of 81% for GERD determined by pH study (444), but other studies have not confirmed this close association between history and test results (378). Esophageal pH probe results are normal in one third of adults with chronic heartburn, even those whose heartburn is reproduced by esophageal acid perfusion and those who respond favorably to antacids. Some adults with heartburn and normal pH studies have endoscopically proven esophagitis (445). In older children and adolescents the description and localization of heartburn pain is probably reliable. In young children, however, symptom descriptions and localization may be unreliable (56–60,446).
No randomized placebo-controlled studies evaluate lifestyle changes or pharmacologic therapy of heartburn in children or adolescents. Case series have shown that PPI therapy relieves heartburn symptoms in adolescents (55,64,447). Expert opinion suggests using a management approach to heartburn in older children and adolescents similar to that used in adults (Fig. 3). Other causes of heartburn-like chest pain including cardiac, respiratory, musculoskeletal, medication-induced, or infectious etiologies should be considered. If GERD is suspected as the most likely cause of symptoms, lifestyle changes, avoidance of precipitating factors, and a 2- to 4-week trial of PPI are recommended (446,448–450). If there is no improvement following empiric therapy, the older child or adolescent should be referred to a pediatric gastroenterologist for diagnostic evaluation. If improvement follows PPI therapy and lifestyle changes, treatment can be continued for 2 to 3 months. In some patients, abrupt discontinuation of treatment may result in acid rebound that precipitates symptoms; therefore, it is recommended that antisecretory therapy be weaned slowly (451,452). If symptoms recur when therapy is weaned or discontinued, upper endoscopy may be helpful to determine the presence and severity of esophagitis and differentiate reflux-related esophagitis from nonreflux pathologies such as infection or EoE that may present with heartburn (40,453) Because chronic heartburn can have a substantial negative impact on quality of life, long-term therapy with PPIs may be required, even in the absence of esophagitis (454,455). Extrapolation from adult data suggests that in older children and adolescents, on-demand or intermittent therapy with antacids, H2RA, or PPIs may be used for occasional symptoms of heartburn (302,455,456).
In open-label studies of children with erosive esophagitis, PPIs produced healing in 78% to 95% with 8 weeks of therapy and in 94% to 100% with 12 weeks of therapy. Symptoms improved in 70% to 80% of the group treated for 12 weeks (130,312,447). Most patients in these studies had lower grades of erosive esophagitis, and the studies did not include patients with underlying conditions such as NI, repaired tracheoesophageal fistula, chronic lung disease, or HH. PPIs have been shown to heal higher grades of esophagitis (grades 3–4) in children with these underlying conditions, even in some when esophagitis had been refractory to treatment with H2RAs, prokinetic agents, and even antireflux surgery (28,29,131). However, in these selected cases resistant to standard management, high per-kilogram dose and long duration of therapy (up to 6 months) may be required for healing and symptom control (28,29,131).
In uncontrolled studies of children with erosive and nonerosive disease treated with PPIs, 70% experienced relief of “typical symptoms of GERD,” that is, heartburn (312,447). A significant percent of patients remained symptomatic, albeit at lower intensity. Suboptimal symptom relief may be due to large per-kilogram dosing variation. Studies in adults have shown generally poorer therapeutic response to PPI in patients with NERD compared with patients with erosive esophagitis (457,458).
With regard to maintenance therapy, in a prospective study of children whose erosive esophagitis had healed following 3 months of omeprazole therapy, only half maintained the remission of symptoms and endoscopic disease in a maintenance phase during which they received half the healing dose of PPI (316). In another study, patients whose erosive esophagitis healed after 3 months' omeprazole treatment (1.4 mg · kg−1 · day−1) underwent double-blind randomization into 3 groups, receiving either maintenance therapy with omeprazole at half the healing dose, ranitidine, or placebo for 6 months (130). In all 3 groups, few patients had a relapse of symptoms or of endoscopic esophagitis during or after maintenance therapy. There were important differences between these 2 studies. Specifically, in the first study, the mean grade of esophagitis was higher, and 41% of patients had an underlying disorder predisposing to GERD. In a retrospective study of 166 children with erosive esophagitis unable to withdraw from PPIs for up to 11 years (median 3.5 years), 79% had at least 1 underlying condition predisposing them to GERD and 39% had HH (28). Thus, patients with lower grades of erosive esophagitis and without an underlying high-risk condition may not require long-term PPI therapy after initial effective treatment. In a recent study of adults with long-term PPI use, 27% were able to discontinue drug without relapse (452).
PPIs are recommended as initial therapy in children with erosive esophagitis. Initial treatment for 3 months is advised. If adequate control of symptoms is not achieved within 4 weeks, the dose of PPI can be increased. Patients who require higher PPI dose to control symptoms and produce healing are those with conditions that predispose to severe-chronic GERD and those with higher grades of esophagitis or BE. In most cases, efficacy of therapy can be monitored by extent of symptom relief without routine endoscopic follow-up. Endoscopic monitoring of treatment efficacy may be useful in patients whose presenting signs and symptoms are atypical, who have persistent symptoms while taking adequate acid-suppressive drugs, or who had higher grades of esophagitis or esophageal stricture at presentation (see also Section 5.2.2). Follow-up endoscopy is not routinely indicated in patients with nonerosive disease, particularly if they are asymptomatic on medication.
Most patients require only 1 daily dose of PPI to obtain symptomatic relief and heal esophagitis (29,131,447,459). The optimum dosage regimen is to administer a once-daily dose 15 to 30 minutes before the first meal of the day. It is not necessary to make patients achlorhydric to relieve symptoms or heal esophagitis, and, in light of the data on infectious and other complications of acid suppression by H2RAs or PPIs, it is probably not desirable to do so.
Not all reflux esophagitis is chronic or relapsing (130), and therefore trials of reduction of dose and withdrawal of PPI therapy should be performed after the patient has been asymptomatic for some time, that is, after 3 to 6 months on treatment. This approach will minimize the number of children that unnecessarily receive long-term treatment. PPIs should not be stopped abruptly, because rebound acid secretion may cause recurrence of symptoms (451,452). Instead, PPI should be tapered for at least 4 weeks. Recurrence of symptoms and/or esophagitis after repeated trials of PPI withdrawal usually indicates that chronic-relapsing GERD is present, if other causes of esophagitis have been ruled out. At this point, therapeutic options include long-term PPI therapy or antireflux surgery.
The prevalence of BE is much lower in children than adults, but it does occur in children with severe-chronic GERD. In 1 group of children with severe-chronic GERD, columnar metaplasia was present in 5% and columnar metaplasia with goblet-cell metaplasia was present in another 5% (28). Accuracy of diagnosis has important implications for longevity and surveillance. The diagnosis of BE is both overlooked and overcalled in children (28,134). Therefore, the primary task of the gastroenterologist is accuracy of diagnosis, especially in light of the proposed new criteria for the diagnosis of BE in children and adults (13,50). If esophagogastric landmarks are obscured by bleeding and exudate, a course of high-dose PPI for at least 12 weeks before making a diagnosis is advised to allow for better visualization of anatomic landmarks and to remove the histologic changes of chronic inflammation that may confuse the diagnosis. After PPI therapy, multiple biopsies should be taken to characterize the type of BE and to rule out dysplasia (134,148).
Dysplasia is managed according to adult guidelines (146,460). If dysplasia is absent, follow-up endoscopy every 3 to 5 years should be performed, until 20 years of age, when adult guidelines for surveillance should be followed (134). The management of nondysplastic BE is the same as that of erosive esophagitis, that is, long-term PPI or antireflux surgery (134,460). BE per se is not an indication for antireflux surgery. In BE, symptoms are often a poor guide to adequacy of treatment, and some advocate more aggressive acid suppression, based on esophageal pH monitoring (460). Although it is unclear whether progression of dysplasia is slowed by acid control, higher doses of PPI may be considered in BE than in esophagitis without metaplasia (461).
Dysphagia, Odynophagia, and Food Refusal
Dysphagia, or difficulty in swallowing, occurs in association with oral and esophageal anatomic abnormalities, neurologic and motor disorders, oral and esophageal inflammatory diseases, and psychologic stressors or disorders. GERD is commonly cited as a cause of dysphagia or odynophagia, and although it may be causal in some patients, there are no pediatric data demonstrating this relation, nor has symptom improvement in infants and children been demonstrated with antireflux therapy. In a population-based Australian study, 16% of healthy adults reported having “dysphagia ever” (462). In this study, dysphagia correlated with anxiety and depression but also with GERD (odds ratio 2.96) (462). Another study found dysphagia in 11% of healthy adults and 28% of adults with GERD symptoms (463). In a meta-analysis of 11,945 adults with erosive esophagitis, 37% had dysphagia (464). However, in young adults presenting with dysphagia, radiographic evaluation demonstrated conditions other than GERD in 70% that were more likely causes of the symptoms (465). Dysphagia is a prominent symptom in up to 80% of adults and children with EoE (93,450,466).
Odynophagia, or pain caused by swallowing, must be distinguished from heartburn (substernal pain caused by esophageal acid exposure) and dysphagia. Although odynophagia may be a symptom of peptic esophagitis, it is more often associated with other conditions such as oropharyngeal inflammation, esophageal ulcer, EoE, infectious esophagitis (eg, infection with herpes simplex, candida, or cytomegalovirus), and esophageal motor disorders. A patient with odynophagia may in time develop behaviors around eating that resemble dysphagia. There are no pediatric studies on the relation between GERD and odynophagia.
Patients often find it difficult to distinguish between dysphagia and odynophagia. In the majority of patients with dysphagia, the dysphagia is not caused or related to reflux disease. The present literature indicates that dysphagia is frequent among patients with EoE. In those relatively uncommon patients in whom GERD causes dysphagia, esophagitis is often present. Expert opinion suggests that odynophagia may be associated with peptic esophagitis and esophagitis of other causes.
Feeding refusal and feeding difficulty are terms used mainly to describe the following infant symptoms: refusal to eat, uncoordinated sucking and swallowing, gagging, vomiting, and irritability during feeding. A relation between GER or GERD and feeding refusal has not been established. Although older case series suggest that reflux disease caused infant feeding difficulty, no prospective studies have proven causation and none have shown resolution with GERD therapy (467). One retrospective study found a higher incidence of poor intake, decreased feeding readiness, and food refusal in infants with abnormal pH probe tests than in normal case controls (468). Another study found no association between GERD diagnosed by pH probe and feeding difficulty, except in infants who also had excessive regurgitation (61). A double-blind placebo-controlled trial showed no improvement in feeding difficulties following lansoprazole therapy compared with placebo in infants with suspected GERD (9). A recent study found that anorexia or feeding refusal was occasionally a symptom of erosive esophagitis in children 1 to 5 years of age (40).
An upper GI contrast study is useful but not required for the infant with feeding refusal or difficulty or the older child reporting dysphagia. Its major use is to identify a non-GERD disorder such as achalasia or foreign body or to identify esophageal narrowing from a stricture. The upper GI contrast study or a more focused videofluoroscopic swallowing study that evaluates the mechanisms of feeding and swallowing may be helpful to identify nonesophageal causes of feeding difficulties, especially in infants and younger children. In children and adolescents who report dysphagia or odynophagia in combination with esophageal symptoms, endoscopy with biopsy is useful to distinguish among causes of esophagitis.
There is no evidence that supports a causal relation between infant feeding difficulties and GER or GERD. In the infant with feeding refusal, acid suppression without earlier diagnostic evaluation is not recommended. Direct observation focused on neurologic, behavioral, metabolic, and infectious disease is essential for the evaluation and diagnosis of this symptom complex (469). In the older child or adolescent empiric antisecretory therapy is only recommended if there are additional symptoms or findings suggesting GERD.
The Infant With Apnea or ALTE
The literature on the relation between apnea, respiratory pauses, apparent life-threatening events (ALTEs) or SIDS, and reflux is conflicting, in large part because of the different criteria used to define breath stoppage, the various methods used to measure reflux and respiratory pauses, and the different populations studied.
A recent study combining data from simultaneous esophageal pH/MII and cardiorespiratory monitoring in infants showed a temporal association between 30% of the nonpathologic, short episodes of central apnea and reflux (115). These findings cannot be extrapolated to pathologic infant apnea and may represent a normal protective cessation of breathing during regurgitation. Recent studies using combined pH/MII have generally detected little relation between apneic spells and reflux episodes (470,471). Some studies have found a relation between long episodes of apnea (>30 seconds) and acid reflux in premature infants (472). In 1 older study, short apnea or bradycardia spells were tightly tied to spells of vomiting or regurgitation, whereas the majority of prolonged apnea spells (>20 seconds) were not (473). In highly selected cases, reflux is clearly associated with pathological, central, and obstructive apnea (241). None of these studies has conclusively shown a cause and effect relation between reflux and pathologic apnea.
ALTEs are frightening episodes in infants characterized by a combination of apnea, color change (cyanosis, pallor, and plethora), abnormal muscle tone (limpness and stiffness), choking, and gagging that require intervention by the observer (474). The identification of a behavior as ALTE is observer dependent (475). The first event usually occurs at 1 to 2 months of age and rarely after 8 months. ALTEs may recur (476,477), and infants with an ALTE are at slightly increased risk for subsequent sudden death (477–482). ALTEs may be associated with infection, child abuse, upper airway obstruction, cardiac, respiratory, metabolic, and neurologic disorders. ALTEs associated with reflux may not be pathologic; some may be an exaggeration of normal protective reflexes that inhibit breathing while the infant retches or while the pharynx is filled with gastric contents.
In older studies, patients with ALTEs had a 60% to 70% prevalence of recurrent regurgitation or emesis (475,477), and abnormal esophageal pH tests were documented in 40% to 80% of patients with ALTEs (483,484). Case reports and series described ALTEs triggered by overt regurgitation into the oropharynx, by aspiration of refluxed gastric contents, and by reflux induced by positional change after feedings (485–488). In selected patients with ALTE, acid perfusion of the esophagus induces obstructive apnea (485) or oxygen desaturation (483), suggesting that 1 mechanism for ALTE is acid stimulation of laryngeal, pharyngeal, or esophageal chemoreceptors with subsequent laryngospasm. In selected infants, a clear temporal relation between apnea and ALTE can be demonstrated. However, large case series have not shown a consistent statistical relation between GER and pathologic apnea or ALTEs (489,490). Larger studies using combined esophageal pH/MII may clarify the extent of these temporal relations.
Poor quality of sleep characterized by irregular breathing patterns is associated with reflux (484,489–496). Although several studies have reported an occasional correlation of GER with short mixed central apneas (5–15 seconds) (492,493,495), all of the patients also had episodes of apnea unrelated to episodes of GER, suggesting a primary impairment in the regulation of respiration.
At present there is no evidence that the characteristics of the ALTE or the polysomnographic record can predict which infants with ALTE are at risk for future life-threatening episodes or sudden death. Although rare, SIDS has been reported to occur in patients with a previous ALTE and documented GER (241,491,497). In none of these patients was a correlation between esophageal acidification and a cardiopulmonary event ever recorded.
The available evidence suggests that in the vast majority of infants, GER is not related to pathologic apnea or to ALTE, although a clear temporal relation based on history, observation or testing occurs in individual infants. Impedance/pH recording in combination with polysomnographic recording is recommended to demonstrate this relation in these infants.
Medical therapy of ALTEs suspected of being GER-related has not been adequately studied. Approaches that decrease the frequency of regurgitation and the volume of reflux such as thickened feeding may theoretically be beneficial. Pharmacotherapy has not been shown to be effective. The occurrence of ALTEs diminishes significantly with age and without therapy in most cases, suggesting that no antireflux therapy is needed. The ALTEs most likely to improve with antireflux therapy are those obviously associated with vomiting or regurgitation, those that occur in the awake infant after feeding, and those characterized by obstructive apnea. Because medical therapy has not been shown to be effective, surgery may be a reasonable approach in the rare infant in whom ALTEs are truly life threatening and are shown to be clearly related to GER.
In some exceptional situations, prone sleeping (with cardiorespiratory monitoring) may be recommended because of a major risk of apnea or aspiration caused by refluxed material.
Reactive Airways Disease
An etiologic role for reflux in reactive airways disease (asthma) has not been established, although animal and human studies have suggested that reflux may exacerbate existing asthma. Proposed mechanisms by which reflux aggravates asthma are direct production of airway inflammation by aspirated gastric contents, airway hyperresponsiveness triggered by lower airway aspiration of minute amounts of acid, vagally mediated bronchial or laryngeal spasm, and neurally mediated inflammation (498–501). Esophageal acidification in healthy adults has minimal effect on pulmonary function (498); however, esophageal acidification in asthmatic patients can produce airway hyperresponsiveness and airflow obstruction (502).
Few studies have evaluated the impact of asthma on the severity of GERD. Chronic hyperinflation caused by asthma can flatten the diaphragms, alter crural function, and displace the lower esophageal sphincter into the negative atmosphere of the chest, effectively reducing resting LES pressure and causing disappearance of the acute esophagogastric angle of His. Lung hyperinflation and airflow obstruction may produce increased negative intrathoracic pressure, effectively increasing the pressure gradient across the diaphragm and promoting reflux. Although theophylline and β-receptor agonists cause a reduction of resting LES pressure, these drugs have not been linked to the development of GERD in treated asthmatics (503). Oral corticosteroids promote reflux in adults, but the mechanism is unclear (504).
Many studies have demonstrated an association between asthma and measurements of reflux by pH probe or pH/MII. These studies have shown that 60% to 80% of children with asthma have abnormal pH or pH/MII recordings (505). A study of 77 children 3 to 14 years old with difficult-to-control asthma found that 66% had abnormal RI on pH testing (90). In a study of 84 otherwise healthy infants with daily wheezing, 64% had abnormal 24-hour pH studies, and 44% of these had no overt symptoms of GERD (506). Nocturnal wheezing appears particularly related to GERD. One study used combined esophageal pH/MII monitoring and demonstrated a tighter association between reflux episodes and respiratory symptoms than pH monitoring alone (507), but no studies to date have shown that pH/MII studies are useful in identifying those patients whose asthma may respond to antireflux therapy.
One study found omeprazole treatment to be ineffective in improving asthma symptoms, quality of life, lung function, or use of β2 agonists in children with asthma and GERD (508). High-dose prolonged PPI therapy in adult asthmatics has shown minimal or no efficacy. In 1 large double-blind placebo-controlled study of esomeprazole in adult asthmatics, no improvement occurred in morning peak expiratory flow, but posthoc analysis indicated mild improvements in FEV1 among patients with nocturnal asthma symptoms (509). However, patients with known erosive esophagitis or moderate-to-severe GERD symptoms were excluded. Another study showed a 4% decrease in the number of asthma exacerbations and a 14% decrease in the use of oral corticosteroids in adult patients with moderate-to-severe asthma and heartburn treated with lanzoprazole for 24 weeks but no improvement in symptoms, pulmonary functions, or albuterol use (510). One uncontrolled study in children found that children with persistent moderate asthma and reflux who received antireflux treatment including PPI used significantly less medication to control their asthma (511). Another double-blind placebo-controlled study showed no reduction in wheezing among infants treated with lansoprazole versus placebo for 4 weeks, although wheezing was a secondary endpoint and not the primary focus of the study (9). A controlled trial in adults with reflux and asthma evaluated asthma outcomes after 2 years of continuous ranitidine therapy versus antireflux surgery; surgery led to a larger reduction in symptoms and improved overall clinical status, but neither therapy had a clinically meaningful impact on pulmonary function or pulmonary medication use (512). Some uncontrolled case series using nonobjective parameters have shown a dramatic improvement in asthma symptoms in children after antireflux surgery (95).
Although adult studies show only limited, if any, benefit from PPI or surgical therapy, it is possible that selected patients with heartburn, nocturnal asthma, or steroid-dependent, difficult-to-control asthma may derive some benefit. Symptom reporting is less reliable in infants and children than in adults. Therefore, a reasonable approach to evaluation of pediatric patients in whom GERD is suspected of being a contributing or aggravating factor causing wheezing or asthma is shown in Fig. 4. Other causes of wheezing should be ruled out. There is no strong evidence to support empiric PPI therapy in unselected pediatric patients with wheezing or asthma. Finding abnormal esophageal pH exposure by esophageal pH monitoring, with or without impedance, before considering a trial of long-term PPI therapy or surgery may be useful, although the predictive value of these studies for this purpose has not been established. The relative efficacy of medical versus surgical therapy for GERD in children with asthma is unknown.
Recurrent pneumonia and interstitial lung disease may be complications of reflux, presumably as a result of the failure of airway protective mechanisms to protect the lungs against aspirated gastric contents (513). Reflux causing recurrent pneumonia has been reported in otherwise healthy infants and children (96,514,515). In a retrospective series reviewing the causes of recurrent pneumonia in a heterogenous group of 238 children, the primary cause was aspiration during swallowing in 48%, immunologic disorders in 14%, congenital heart disease in 9%, asthma in 8%, respiratory tract anatomic abnormalities in 8%, unknown in 8%, and reflux in only 6% (516). Small case series suggest that reflux may cause or exacerbate interstitial lung disorders such as idiopathic pulmonary fibrosis (517,518), cystic fibrosis (CF) (519,520), or lung transplant (520,521).
No test can determine whether reflux is causing recurrent pneumonia. An abnormal esophageal pH test may increase the probability that reflux is a cause of recurrent pneumonia but is not proof thereof. A normal esophageal pH test cannot exclude reflux as a cause of pneumonia because if airway protection mechanisms are compromised, even brief reflux episodes that are within the normal range, may be associated with aspiration. Aspiration during swallowing is much more common than aspiration of refluxed material (522). Upper esophageal and pharyngeal pH recordings, and combined pH/MII studies have similar limitations and do not improve the ability to predict GER-related pneumonia (523).
Lipid-laden alveolar macrophages have been used as an indicator of aspiration but the sensitivity and specificity as an indicator of GER-related lung disease is poor (187,524–529). Pepsin content of pulmonary lavage fluid has also been used to document aspiration of gastric contents. Pepsin concentration is elevated in pulmonary lavage from patients with reflux (185,186) but there is substantial overlap with controls (187). Nuclear scintigraphy can detect aspirated gastric contents when images are obtained for 24 hours after enteral administration of a labelled meal. One study reporting that 50% of patients with a variety of respiratory symptoms had aspiration on scintigraphy (169) has not been replicated. It is important to recognize that aspiration also occurs in healthy subjects, especially during sleep (171,172) so the threshold for pathologic aspiration of saliva or gastric contents is not established.
No data are available regarding the predictive value of any diagnostic test for determining which patients will respond to either medical or surgical therapy for GERD. Both medical (530) and surgical (97,531) therapy of GERD have been reported to reduce pulmonary symptoms in certain populations of children with recurrent pneumonia. However, in 1 study of children older than 4 years of age, the number of hospitalizations for respiratory related events increased after antireflux surgery (397). Gastrojejunal feeding provides an alternative approach to prevent reflux-related pneumonia in children with severe NI (532). A recent review of children with severe NI and GERD reported that surgical therapy improved several complications but did not alter the risk of pneumonia (533). The potential benefits of antisecretory therapy for neurologically impaired children with recurrent pneumonia must be balanced against the risk that PPI therapy may increase the incidence of community-acquired pneumonia in these patients, as it does in well children (322). A large double-blind placebo-controlled study to determine the role of PPI therapy in the child with NI is lacking.
In many cases the clinician must make management decisions based on inconclusive diagnostic studies with no certainty regarding outcome. In patients with severely impaired lung function, it may be necessary to proceed with antireflux surgery in an attempt to prevent further pulmonary damage, despite lack of definitive proof that reflux is a cause of pulmonary disease. Alternatively, if minimal pulmonary disease is present, consideration of medical therapy with careful follow-up of pulmonary function may be instituted, although the potential benefits versus risks of PPI are unclear. The efficacy of therapies such as lifestyle changes and prokinetics has not been well studied. A trial of nasogastric feeding may be used to exclude aspiration during swallowing as a potential cause of recurrent disease (532). A trial of nasojejunal therapy may help determine whether surgical antireflux therapy is likely to be beneficial.
Upper Airway Symptoms
The data showing a relation between reflux and upper airway disease are weak, consisting mainly of case descriptions. Airway symptoms attributed to reflux in adults include hoarseness (534), chronic cough (535,536), and the sensation of a lump in the throat (globus sensation) (537,538). Affected adults rarely have typical reflux symptoms. Laryngoscopic findings said to be reflux related include erythema, edema, nodularity, ulceration, granuloma, and cobblestoning (539,540). The sensitivity and specificity of these findings to identify reflux-induced disease are poor (541,542), and a study in children showed poor correlation between laryngeal changes and reflux quantitated by pH probe (543). In a descriptive pediatric study, GERD was more prevalent in children with recurrent laryngotracheitis than in controls (544). In a retrospective study of children undergoing otolaryngologic procedures, an association between esophagitis diagnosed by biopsy and recurrent croup, cough, stridor, laryngomalacia, subglottic stenosis, posterior glottic erythema, and posterior arytenoid erythema was observed (545). Increased frequency of daytime reflux has been described in children with hoarseness (546). One study suggested that reflux contributed to the development of subglottic stenosis in children and to poor outcomes after reparative surgery (547). Increased pharyngeal reflux has been observed in children with laryngomalacia (548,549).
Uncontrolled reports in adults and children showed improved upper airway symptoms after antireflux therapy including fundoplication (193,550–554). However, data from several placebo-controlled studies and careful meta-analyses uniformly have shown no effect of antireflux therapy on upper airway symptoms or signs (555–559). One uncontrolled trial reported a reduction in cough following medical antireflux therapy in children (560). However, a double-blind placebo-controlled study showed no difference in the frequency of symptoms of cough or hoarseness among infants treated with lansoprazole versus those treated with placebo (9).
In summary, descriptive studies report detecting and treating reflux in children with chronic laryngeal signs and symptoms. Upper airway edema, erythema, cobblestoning, and granulomas are neither sensitive nor specific for the diagnosis of GERD. Criteria used for assessing laryngeal findings are variable as are the criteria for diagnosing GERD in published reports. Laryngoscopy is indicated in some of these children to rule out anatomic abnormalities such as laryngeal cleft and functional abnormalities such as vocal-fold dysfunction. Data are insufficient to allow recommending a standard approach to diagnosis, treatment, and follow-up. Extrapolation from adult studies suggests that PPIs will not benefit most children with upper airway symptoms.
Reflux has been suggested as a factor contributing to recurrent sinus disease, pharyngitis, and otitis media (561,562). One uncontrolled case series of children with chronic sinusitis suggested that antireflux treatment dramatically reduced the need for sinus surgery (563). Another series demonstrated more episodes during which pharyngeal pH was <6.0 in children with recurrent rhinopharyngitis compared with controls (564). Two epidemiologic surveys, however, found no difference in the number of ear and sinus infections in infants with and without reflux (17,565). Otalgia has been associated with reflux in children and reported to improve with treatment of reflux (566). There is no proven mechanism by which reflux should cause sinusitis, pharyngitis, and otitis, although direct irritation by refluxed material causing pharyngeal tissue edema has been suggested. The lack of controlled studies and animal models of mechanism makes these studies difficult to translate to pediatric practice.
Case reports and a recent systematic review report a causative association between GERD and dental erosion (414). The severity of dental erosions seems to be correlated with the presence of GERD symptoms and in adults with the severity of proximal esophageal or oral exposure to an acidic pH. Young children and children with NI appear to be at greatest risk. One study in adolescents showed that reflux was associated with an increased incidence of erosion of enamel on the lingual surfaces of the teeth (567). In contrast, another study reported no increased incidence of dental erosions in adolescents with abnormal esophageal pH monitoring (568). Factors other than reflux may also cause similar dental erosions; these include juice drinking, bulimia, and racial and genetic factors that affect the characteristics of enamel and saliva. The approach to evaluation and therapy—specifically, the choice of diagnostic tests, duration of therapy, and criteria for cessation of therapy—is unclear. Close consultation with a qualified pediatric dentist is required. The inspection of the oral cavity in search for dental erosions is advisable in patients with known GERD.
Dystonic Head Posturing (Sandifer Syndrome)
Sandifer syndrome (spasmodic torsional dystonia with arching of the back and opisthotonic posturing, mainly involving the neck and back) is an uncommon but specific manifestation of GERD (13,569,570) that must be differentiated from other causes of abnormal movements including seizures, infantile spasms, and dystonia. The mechanisms underlying this disorder are unproven, but the disorder may be a vagally mediated reflex response to esophageal acid exposure. It resolves with antireflux treatment.
GROUPS AT INCREASED RISK FOR SEVERE, CHRONIC GERD
Children with certain underlying disorders are at high risk for developing severe-chronic GERD, compared with those who are otherwise healthy. Although the latter do develop GERD, which on occasion may be severe, the prevalence of severe-chronic GERD is much higher in children with certain underlying conditions, such as NI or anatomic abnormalities, such as repaired EA or HH. These children are more likely to require long-term treatment for healing and maintenance (28,372). Complications of severe GERD occur with greatest frequency in children with underlying GERD-provoking conditions (28,31). Performing studies of various GERD therapies in these groups has inherent difficulties because the populations are heterogeneous; many are unable to report symptoms, some have more than 1 condition, and some require medications to be given by feeding tube. These limit the data available to allow evidence-based recommendations on therapy. However, some studies with quantitative endpoints, for example, endoscopic healing, are available (28,29,131).
The increased frequency and severity of GERD among infants and children with NI including developmental delay are well documented (397,571,572). For example, children with cerebral palsy are at particularly high risk for GERD (571,573–575). Similarly, children with certain genetic syndromes such as Cornelia de Lange and Down syndrome are prone to GERD (576).
The high incidence of severe, chronic GERD is multifactorial in etiology. It is likely that in each child, factors unique to the specific diagnosis and clinical status are responsible. Contributing factors that increase reflux frequency and delay esophageal clearance are chronic supine positioning, abnormal swallowing, heightened gag reflex, abnormal sensory integration, delayed gastric emptying, constipation, obesity, skeletal abnormalities, abnormal muscle tone, and medication side effects. The severity of GERD may result from poor self-protective mechanisms and delayed diagnosis caused by difficulties in obtaining an accurate history of symptoms. Treatment should include lifestyle changes tailored to the unique risk factors of the patient. Changes in feeding volume, consistency, and frequency may be helpful, as may positional changes, control of muscular spasticity, and biofeedback. Antisecretory therapy should be optimized. Long-term treatment with PPIs is often effective for symptom control and maintenance of remission of esophagitis (28,577,578). Baclofen may be useful for reduction of vomiting, but care with regard to dosing and side effects is required (346,347). Elemental diet was shown to improve resistant GERD symptoms in 1 small uncontrolled study that did not differentiate EoE from GERD (579).
Descriptive studies suggest that placement of feeding gastrostomy in children with NI, either by open or laparoscopic surgery, increases the risk of subsequent GERD (580,581). Recent surgical studies comparing open and laparoscopic gastrostomy placement suggest that postoperative development of GERD is less common after laparoscopic and percutaneous endoscopic procedures than open surgical procedures (582–584).
Making a clinical diagnosis of GERD in children with NI is hampered by poor communication with the patient and the frequency of atypical presentations such as anxiety, self-injurious behavior, apparent seizures, and dystonia (585). Evaluation of the child with NI requires a high index of suspicion and must not only confirm the diagnosis but also rule out alternative diagnoses. Contrast GI radiographic studies, upper GI endoscopy and biopsy, metabolic and drug toxicity screening, and pH/impedance studies may be required.
Given the morbidity and high failure rates of antireflux surgery in this group, patients whose symptoms are well controlled on medical therapy may not derive additional benefit from antireflux surgery The relative risks versus benefit of antireflux surgery in children with persistent symptoms despite optimized medical therapy have not been clearly defined (397,586). Patients with respiratory complications of GERD appear to benefit most, but a cause-and-effect relation is difficult to establish, and therefore patient selection is difficult (Section 5.3).
Although pediatric data are scarce, in adults, obesity and/or incremental weight gain have been increasingly shown to be associated with a significantly higher prevalence and severity of GERD, BE, and esophageal adenocarcinoma (265–267).
Esophageal Anatomic Disorders and Achalasia
EA has an incidence of 1 in 3000 live births; thus it is an important cause of chronic-severe GERD in pediatric practice. The esophagus in EA is congenitally dysmotile; it is sometimes foreshortened as a result of surgery or stricture, and a HH is often present (28,29,587), especially in long-gap atresia (588). Significant heart disease, tracheomalacia, or gastric outlet obstruction occurs in up to 18% of these children (587).
Of children and young adults with repaired EA, 50% to 95% have GERD symptoms, including dysphagia and pulmonary symptoms (587,589,590). Esophagitis and BE or some form of metaplasia are prevalent (31,134,589,590), and esophageal adenocarcinoma and squamous cancer are reported in children and adults (589,591–594). A long-term study of 272 surviving children with EA observed no cases of esophageal cancer (595). However, the authors of that study and others (587,589) recommended that patients with EA undergo regular endoscopy to screen for BE and esophageal cancer, given the relatively normal longevity of most patients with EA. In the pre-PPI era, several case series demonstrated a benefit from antireflux surgery, but failure rates of fundoplication are high in children with repaired EA. Medical therapy with PPIs is highly effective in patients with EA and GERD (28).
Patients with achalasia are at increased risk for chronic GERD, esophagitis, and BE following treatment by either pneumatic dilation or myotomy (596,597). The benefit of antireflux therapy at the time of myotomy remains controversial (598). All of the patients with a history of achalasia or a history of EA repair require follow-up for possible complications of GERD, because even those who underwent antireflux surgery are at risk (596). The potential utility of endoscopic surveillance has not been evaluated in these patients.
Chronic Respiratory Disorders
A higher prevalence of GERD and its complications has been reported in patients with a variety of respiratory disorders including bronchopulmonary dysplasia, idiopathic interstitial fibrosis, and most commonly, CF (500,599,600). In 1 study, 27% of patients with CF younger than 5 years old reported GI symptoms suggestive of reflux (heartburn or regurgitation), compared with only 6% of their healthy siblings (519). However, intraesophageal pH studies in children with CF detect a much higher prevalence of pathologic GE reflux (500), that is, reflux is silent in the majority. Reflux may be silent because GI symptoms are truly absent, or symptoms may be relatively ignored by patients with CF because of their plethora of other problems. Some children with CF consider upper GI symptoms such as heartburn, chest pain, and occasional vomiting, to be part of CF, and therefore may not report them; this results in delayed diagnosis and presentation with complications of GERD (31). There are no trials formally evaluating the benefits and risks of GERD treatments in children with CF, but the high incidence of esophagitis and potential risk of adenocarcinoma makes aggressive treatment reasonable. A retrospective review of fundoplication outcome in patients with CF reported that complications requiring repeat surgery occurred in 12%, recurrent GERD symptoms developed in 48%, and only 28% discontinued GERD medications (601).
Bronchopulmonary dysplasia, a chronic lung disease of infancy with varying degrees of alveolar growth arrest, airway branching abnormalities, and peribronchiolar fibrosis, has been associated with GERD (602). However, more recent studies have not confirmed this association (603). Because most of the studies have been cross-sectional or case-control in design, a cause–effect relation remains to be defined.
Severe GERD is common in patients presenting for transplantation, and a high incidence of GERD occurs following lung transplantation in children and adults (521,604). Complications of GERD are a common source of morbidity in patients with transplantation (521). Pneumonectomy seems to contribute to esophageal and gastric motor dysfunction (605). It has been suggested that in the allograft lung, nonimmune-mediated injury because of reflux contributes to the development of bronchiolitis obliterans syndrome (606).
The Premature Infant
GERD treatment is frequently administered to premature infants (39,607,608). In a recent study, 25% of infants with birth weights <1000 g were discharged on medications to treat reflux (608). However, the true frequency of peptic esophagitis or pulmonary disease because of GERD is unknown. Most of the physiologic mechanisms that protect against reflux appear to be intact in the preterm infant (609,610). Although some suggest a relation between apnea or bradycardias of prematurity and reflux (472), most studies do not support reflux as a cause of pathologic apnea in premature infants (113,591,611,612). One retrospective study showed that GER-related apnea improved rapidly following commencement of gastrojejunal feeding, suggesting that in some cases reflux may cause apnea (613). Behaviors often interpreted as signs of reflux disease in the preterm infant are nonspecific and not predictive of esophagitis (614). One study in infants with chronic lung disease found that a variety of observed symptoms (respiratory, sensory, and movement) were associated with reflux into the proximal esophagus (610), but the clinical significance of these symptoms is not clear.
Although reflux episodes may be more common in infants with bronchopulmonary dysplasia, there is no evidence that GERD therapy affects the clinical course or outcome (603,615). GERD is frequently diagnosed by inadequate criteria in the preterm infant. The relative risks, benefits, and indications for GERD therapy are unclear in premature infants. The long-term risk of GERD in premature infants during adulthood is controversial.
One study (616) reported a greater than 11-fold increase in the incidence of esophageal adenocarcinoma in adults who were born preterm or small-for-gestational age. However, a subsequent nested case-control study did not confirm a strong association between risk of esophageal cancer and birth weight (617).
The committee is indebted to Sandy Fasold, Inge Sienaert, and Ilse Van Lier for facilitation of meetings and telephone conference arrangements.
1. Rudolph CD, Mazur LJ, Liptak GS, et al
. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001; 32(Suppl 2):S1–S31.
2. Vandenplas Y, Belli DC, Benatar A, et al
. The role of cisapride in the treatment of pediatric gastroesophageal reflux. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 1999; 28:518–528.
3. Vandenplas Y, Belli D, Benhamou P, et al
. A critical appraisal of current management practices for infant regurgitation–recommendations of a working party. Eur J Pediatr 1997; 156:343–357.
4. Fried M, Quigley EM, Hunt RH, et al
. Is an evidence-based approach to creating guidelines always the right one? Nat Clin Pract Gastroenterol Hepatol 2008; 5:60–61.
5. Fried M, Quigley EM, Hunt RH, et al
. Are global guidelines desirable, feasible and necessary? Nat Clin Pract Gastroenterol Hepatol 2008; 5:2–3.
6. Barron JJ, Tan H, Spalding J, et al
. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr 2007; 45:421–427.
7. Orenstein SR, Hassall E. Infants and proton pump inhibitors: tribulations, no trials. J Pediatr Gastroenterol Nutr 2007; 45:395–398.
8. Khoshoo V, Edell D, Thompson A, et al
. Are we overprescribing antireflux medications for infants with regurgitation? Pediatrics 2007; 120:946–949.
9. Orenstein SR, Hassall E, Furmaga-Jablonska W, et al
. Multicenter, double-blind, randomized, placebo-controlled trial assessing efficacy & safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr 2009; 154:514–520.
10. McMurray AR. Three decision-making aids: brainstorming, nominal group, and Delphi technique. J Nurs Staff Dev 1994; 10:62–65.
11. Phillips B. Towards evidence-based medicine for paediatricians. Arch Dis Child 2008; 93:628.
12. Shay S, Tutuian R, Sifrim D, et al
. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004; 99:1037–1043.
13. Sherman P, Hassall E, Fagundes-Neto U, et al
. A global evidence-based consensus on the definition of gastroesophageal reflux disease in children. Am J Gastroenterol 2009; 104:1278–1295.
14. Hegar B, Boediarso A, Firmansyah A, et al
. Investigation of regurgitation and other symptoms of gastroesophageal reflux in Indonesian infants. World J Gastroenterol 2004; 10:1795–1797.
15. Miyazawa R, Tomomasa T, Kaneko H, et al
. Prevalence of gastro-esophageal reflux-related symptoms in Japanese infants. Pediatr Int 2002; 44:513–516.
16. Nelson SP, Chen EH, Syniar GM, et al
. Prevalence of symptoms of gastroesophageal reflux during infancy. A pediatric practice-based survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med 1997; 151:569–572.
17. Nelson SP, Chen EH, Syniar GM, et al
. One-year follow-up of symptoms of gastroesophageal reflux during infancy. Pediatric Practice Research Group. Pediatrics 1998; 102:E67.
18. Martin AJ, Pratt N, Kennedy JD, et al
. Natural history and familial relationships of infant spilling to 9 years of age. Pediatrics 2002; 109:1061–1067.
19. Chial HJ, Camilleri M, Williams DE, et al
. Rumination syndrome in children and adolescents: diagnosis, treatment, and prognosis. Pediatrics 2003; 111:158–162.
20. Tutuian R, Castell DO. Rumination documented by using combined multichannel intraluminal impedance and manometry. Clin Gastroenterol Hepatol 2004; 2:340–343.
21. Kawahara H, Dent J, Davidson G. Mechanisms responsible for gastroesophageal reflux in children. Gastroenterology 1997; 113:399–408.
22. Werlin SL, Dodds WJ, Hogan WJ, et al
. Mechanisms of gastroesophageal reflux in children. J Pediatr 1980; 97:244–249.
23. Omari T. Gastro-oesophageal reflux disease in infants and children: new insights, developments and old chestnuts. J Pediatr Gastroenterol Nutr 2005; 41(Suppl 1):S21–S23.
24. Vandenplas Y, Hassall E. Mechanisms of gastroesophageal reflux and gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2002; 35:119–136.
25. Murray JA, Camilleri M. The fall and rise of the hiatal hernia. Gastroenterology 2000; 119:1779–1781.
26. Carre IJ, Johnston BT, Thomas PS, et al
. Familial hiatal hernia in a large five generation family confirming true autosomal dominant inheritance. Gut 1999; 45:649–652.
27. Cameron AJ, Higgins JA. Linear gastric erosion. A lesion associated with large diaphragmatic hernia and chronic blood loss anemia. Gastroenterology 1986; 91:338–342.
28. Hassall E, Kerr W, El-Serag HB. Characteristics of children receiving proton pump inhibitors continuously for up to 11 years duration. J Pediatr 2007; 150:262–267.
29. Gunasekaran TS, Hassall EG. Efficacy and safety of omeprazole for severe gastroesophageal reflux in children. J Pediatr 1993; 123:148–154.
30. Cameron AJ. Barrett's esophagus: prevalence and size of hiatal hernia. Am J Gastroenterol 1999; 94:2054–2059.
31. Hassall E. Co-morbidities in childhood Barrett's esophagus. J Pediatr Gastroenterol Nutr 1997; 25:255–260.
32. Jones MP, Sloan SS, Rabine JC, et al
. Hiatal hernia size is the dominant determinant of esophagitis presence and severity in gastroesophageal reflux disease. Am J Gastroenterol 2001; 96:1711–1717.
33. Cameron AJ, Lagergren J, Henriksson C, et al
. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology 2002; 122:55–59.
34. Chak A, Ochs-Balcom H, Falk G, et al
. Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev 2006; 15:1668–1673.
35. Mohammed I, Cherkas LF, Riley SA, et al
. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut 2003; 52:1085–1089.
36. Romero Y, Cameron AJ, Locke GR 3rd, et al
. Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology 1997; 113:1449–1456.
37. Trudgill N. Familial factors in the etiology of gastroesophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma. Chest Surg Clin N Am 2002; 12:15–24.
38. Salvatore S, Hauser B, Vandenplas Y. The natural course of gastro-oesophageal reflux. Acta Paediatr 2004; 93:1063–1069.
39. Jadcherla S, Rudolph C. Gastroesophageal reflux in the preterm neonate. Neoreviews 2005; 6:e87–e98.
40. Gupta SK, Hassall E, Chiu YL, et al
. Presenting symptoms of nonerosive and erosive esophagitis in pediatric patients. Dig Dis Sci 2006; 51:858–863.
41. Iacono G, Merolla R, D'Amico D, et al
. Gastrointestinal symptoms in infancy: a population-based prospective study. Dig Liver Dis 2005; 37:432–438.
42. Nelson SP, Chen EH, Syniar GM, et al
. Prevalence of symptoms of gastroesophageal reflux during childhood: a pediatric practice-based survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med 2000; 154:150–154.
43. Salvatore S, Vandenplas Y. Gastroesophageal reflux and cow milk allergy: is there a link? Pediatrics 2002; 110:972–984.
44. Venter C, Pereira B, Grundy J, et al
. Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life. J Allergy Clin Immunol 2006; 117:1118–1124.
45. Jordan B, Heine RG, Meehan M, et al
. Effect of antireflux medication, placebo and infant mental health intervention on persistent crying: a randomized clinical trial. J Paediatr Child Health 2006; 42:49–58.
46. Moore DJ, Tao BS, Lines DR, et al
. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr 2003; 143:219–223.
47. Chadwick LM, Kurinczuk JJ, Hallam LA, et al
. Clinical and endoscopic predictors of histological oesophagitis in infants. J Paediatr Child Health 1997; 33:388–393.
48. Hyams JS, Ricci A Jr, Leichtner AM. Clinical and laboratory correlates of esophagitis in young children. J Pediatr Gastroenterol Nutr 1988; 7:52–56.
49. Salvatore S, Hauser B, Vandemaele K, et al
. Gastroesophageal reflux disease in infants: how much is predictable with questionnaires, pH-metry, endoscopy and histology? J Pediatr Gastroenterol Nutr 2005; 40:210–215.
50. Vakil N, van Zanten SV, Kahrilas P, et al
. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900–1920.
51. Orenstein SR, Shalaby TM, Cohn JF. Reflux symptoms in 100 normal infants: diagnostic validity of the infant gastroesophageal reflux questionnaire. Clin Pediatr (Phila) 1996; 35:607–614.
52. Aggarwal S, Mittal SK, Kalra KK, et al
. Infant gastroesophageal reflux disease score: reproducibility and validity in a developing country. Trop Gastroenterol 2004; 25:96–98.
53. Deal L, Gold BD, Gremse DA, et al
. Age-specific questionnaires distinguish GERD symptom frequency and severity in infants and young children: development and initial validation. J Pediatr Gastroenterol Nutr 2005; 41:178–185.
54. Kleinman L, Rothman M, Strauss R, et al
. The infant gastroesophageal reflux questionnaire revised: development and validation as an evaluative instrument. Clin Gastroenterol Hepatol 2006; 4:588–596.
55. Gold BD, Gunasekaran T, Tolia V, et al
. Safety and symptom improvement with esomeprazole in adolescents with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007; 45:520–529.
56. von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children and adolescents aged 3 to 18 years. Pain 2007; 127:140–150.
57. Stanford EA, Chambers CT, Craig KD. The role of developmental factors in predicting young children's use of a self-report scale for pain. Pain 2006; 120:16–23.
58. Stanford EA, Chambers CT, Craig KD. A normative analysis of the development of pain-related vocabulary in children. Pain 2005; 114:278–284.
59. Beyer JE, McGrath PJ, Berde CB. Discordance between self-report and behavioral pain measures in children aged 3–7 years after surgery. J Pain Symptom Manage 1990; 5:350–356.
60. Shields BJ, Palermo TM, Powers JD, et al
. Predictors of a child's ability to use a visual analogue scale. Child Care Health Dev 2003; 29:281–290.
61. Heine RG, Jordan B, Lubitz L, et al
. Clinical predictors of pathological gastro-oesophageal reflux in infants with persistent distress. J Paediatr Child Health 2006; 42:134–139.
62. Orenstein SR, Cohn JF, Shalaby TM, et al
. Reliability and validity of an infant gastroesophageal reflux questionnaire. Clin Pediatr (Phila) 1993; 32:472–484.
63. Stordal K, Johannesdottir GB, Bentsen BS, et al
. Gastroesophageal reflux disease in children: association between symptoms and pH monitoring. Scand J Gastroenterol 2005; 40:636–640.
64. Tolia V, Bishop PR, Tsou VM, et al
. Multicenter, randomized, double-blind study comparing 10, 20 and 40 mg pantoprazole in children (5–11 years) with symptomatic gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2006; 42:384–391.
65. Vandenplas Y, Goyvaerts H, Helven R, et al
. Gastroesophageal reflux, as measured by 24-hour pH monitoring, in 509 healthy infants screened for risk of sudden infant death syndrome. Pediatrics 1991; 88:834–840.
66. Hochman JA, Favaloro-Sabatier J. Tolerance and reliability of wireless pH monitoring in children. J Pediatr Gastroenterol Nutr 2005; 41:411–415.
67. Croffie JM, Fitzgerald JF, Molleston JP, et al
. Accuracy and tolerability of the Bravo catheter-free pH capsule in patients between the ages of 4 and 18 years. J Pediatr Gastroenterol Nutr 2007; 45:559–563.
68. Gunnarsdottir A, Stenstrom P, Arnbjornsson E. 48-hour wireless oesophageal pH-monitoring in children: are two days better than one? Eur J Pediatr Surg 2007; 17:378–381.
69. Nielsen RG, Bindslev-Jensen C, Kruse-Andersen S, et al
. Severe gastroesophageal reflux disease and cow milk hypersensitivity in infants and children: disease association and evaluation of a new challenge procedure. J Pediatr Gastroenterol Nutr 2004; 39:383–391.
70. Friesen CA, Hodge C, Roberts CC. Accuracy and reproducibility of 12-h esophageal pH monitoring. J Pediatr Gastroenterol Nutr 1991; 12:166–168.
71. Mahajan L, Wyllie R, Oliva L, et al
. Reproducibility of 24-hour intraesophageal pH monitoring in pediatric patients. Pediatrics 1998; 101:260–263.
72. Vandenplas Y, Helven R, Goyvaerts H, et al
. Reproducibility of continuous 24 hour oesophageal pH monitoring in infants and children (see comments). Gut 1990; 31:374–377.
73. Tuttle SG, Grossman MI. Detection of gastro-esophageal reflux by simultaneous measurement of intraluminal pressure and pH. Proc Soc Exp Biol Med 1958; 98:225–227.
74. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974; 62:325–332.
75. Johnson LF, DeMeester TR. Development of the 24-hour intraesophageal pH monitoring composite scoring system. J Clin Gastroenterol 1986; 8(Suppl 1):S52–S58.
76. Berquist WE, Ament ME. Upper GI function in sleeping infants. Am Rev Respir Dis 1985; 131:S26–S29.
77. Branicki FJ, Evans DF, Ogilvie AL, et al
. Ambulatory monitoring of oesophageal pH in reflux oesophagitis using a portable radiotelemetry system. Gut 1982; 23:992–998.
78. Chen CL, Orr WC. Analysis of 24-hour esophageal pH monitoring: the effect of state of consciousness. Curr Gastroenterol Rep 2008; 10:258–262.
79. Cucchiara S, Staiano A, Gobio Casali L, et al
. Value of the 24 hour intraoesophageal pH monitoring in children. Gut 1990; 31:129–133.
80. de Caestecker JS, Blackwell JN, Pryde A, et al
. Daytime gastro-oesophageal reflux is important in oesophagitis. Gut 1987; 28:519–526.
81. Boix-Ochoa J, Lafuenta JM, Gil-Vernet JM. Twenty-four hour exophageal pH monitoring in gastroesophageal reflux. J Pediatr Surg 1980; 15:74–78.
82. Vandenplas Y, Derde MP, Piepsz A. Evaluation of reflux episodes during simultaneous esophageal pH monitoring and gastroesophageal reflux scintigraphy in children. J Pediatr Gastroenterol Nutr 1992; 14:256–260.
83. Vandenplas Y, Sacre-Smits L. Continuous 24-hour esophageal pH monitoring in 285 asymptomatic infants 0–15 months old. J Pediatr Gastroenterol Nutr 1987; 6:220–224.
84. Vandenplas Y, Badriul H, Verghote M, et al
. Oesophageal pH monitoring and reflux oesophagitis in irritable infants. Eur J Pediatr 2004; 163:300–304.
85. Sondheimer JM. Continuous monitoring of distal esophageal pH: a diagnostic test for gastroesophageal reflux in infants. J Pediatr 1980; 96:804–807.
86. Wenner J, Johansson J, Johnsson F, et al
. Optimal thresholds and discriminatory power of 48-h wireless esophageal pH monitoring in the diagnosisof GERD. Am J Gastroenterol 2007; 102:1862–1869.
87. Vandenplas Y, Franckx-Goossens A, Pipeleers-Marichal M, et al
. Area under pH 4: advantages of a new parameter in the interpretation of esophageal pH monitoring data in infants. J Pediatr Gastroenterol Nutr 1989; 9:34–39.
88. Sant'Anna AM, Rolland S, Fournet JC, et al
. Eosinophilic esophagitis in children: symptoms, histology and pH probe results. J Pediatr Gastroenterol Nutr 2004; 39:373–377.
89. Steiner SJ, Gupta SK, Croffie JM, et al
. Correlation between number of eosinophils and reflux index on same day esophageal biopsy and 24 hour esophageal pH monitoring. Am J Gastroenterol 2004; 99:801–805.
90. Cinquetti M, Micelli S, Voltolina C, et al
. The pattern of gastroesophageal reflux in asthmatic children. J Asthma 2002; 39:135–142.
91. Semeniuk J, Kaczmarski M. 24-hour esophageal pH monitoring in children with pathological acid gastroesophageal reflux: primary and secondary to food allergy. Part I. Intraesophageal pH values in distal channel; preliminary study and control studies–after 1, 2, 4 and 9 years of clinical observation as well as dietary and pharmacological treatment. Adv Med Sci 2007; 52:199–205.
92. Semeniuk J, Kaczmarski M. 24-hour esophageal pH monitoring in children with pathological acid gastroesophageal reflux: primary and secondary to food allergy. Part II. Intraesophageal pH values in proximal channel; preliminary study and control studies–after 1, 2, 4 and 9 years of clinical observation as well as dietary and pharmacological treatment. Adv Med Sci 2007; 52:206–212.
93. Furuta GT, Liacouras CA, Collins MH, et al
. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133:1342–1363.
94. Spechler SJ, Genta RM, Souza RF. Thoughts on the complex relationship between gastroesophageal reflux disease and eosinophilic esophagitis. Am J Gastroenterol 2007; 102:1301–1306.
95. Rothenberg SS, Bratton D, Larsen G, et al
. Laparoscopic fundoplication to enhance pulmonary function in children with severe reactive airway disease and gastroesophageal reflux disease. Surg Endosc 1997; 11:1088–1090.
96. Berquist WE, Rachelefsky GS, Kadden M, et al
. Gastroesophageal reflux-associated recurrent pneumonia and chronic asthma in children. Pediatrics 1981; 68:29–35.
97. Foglia RP, Fonkalsrud EW, Ament ME, et al
. Gastroesophageal fundoplication for the management of chronic pulmonary disease in children. Am J Surg 1980; 140:72–79.
98. Ahrens P, Heller K, Beyer P, et al
. Antireflux surgery in children suffering from reflux-associated respiratory diseases. Pediatr Pulmonol 1999; 28:89–93.
99. Andze GO, Brandt ML, St Vil D, et al
. Diagnosis and treatment of gastroesophageal reflux in 500 children with respiratory symptoms: the value of pH monitoring. J Pediatr Surg 1991; 26:295–299, discussion 299–300.
100. Taghavi SA, Ghasedi M, Saberi-Firoozi M, et al
. Symptom association probability and symptom sensitivity index: preferable but still suboptimal predictors of response to high dose omeprazole. Gut 2005; 54:1067–1071.
101. Hirano I, Richter JE. ACG practice guidelines: esophageal reflux testing. Am J Gastroenterol 2007; 102:668–685.
102. Silny J, Silny J. Intraluminal multiple electric impedance procedure for measurement of gastrointestinal motility. J Gastrointest Motil 1991; 3:151–162.
103. Wenzl TG. Invited review: investigating esophageal reflux with the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 2002; 34:261–268.
104. Peter CS, Wiechers C, Bohnhorst B, et al
. Detection of small bolus volumes using multiple intraluminal impedance in preterm infants. J Pediatr Gastroenterol Nutr 2003; 36:381–384.
105. Skopnik H, Silny J, Heiber O, et al
. Gastroesophageal reflux in infants: evaluation of a new intraluminal impedance technique. J Pediatr Gastroenterol Nutr 1996; 23:591–598.
106. Wenzl TG, Moroder C, Trachterna M, et al
. Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2002; 34:519–523.
107. Rosen R, Lord C, Nurko S. The sensitivity of multichannel intraluminal impedance and the pH probe in the evaluation of gastroesophageal reflux in children. Clin Gastroenterol Hepatol 2006; 4:167–172.
108. Woodley FW, Mousa H. Acid gastroesophageal reflux reports in infants: a comparison of esophageal pH monitoring and multichannel intraluminal impedance measurements. Dig Dis Sci 2006; 51:1910–1916.
109. Vandenplas Y, Salvatore S, Devreker T, et al
. Gastro-oesophageal reflux disease: oesophageal impedance versus pH monitoring. Acta Paediatr 2007; 96:956–962.
110. Peter CS, Sprodowski N, Ahlborn V, et al
. Inter- and intraobserver agreement for gastroesophageal reflux detection in infants using multiple intraluminal impedance. Biol Neonate 2004; 85:11–14.
111. Dalby K, Nielsen RG, Markoew S, et al
. Reproducibility of 24-hour combined multiple intraluminal impedance (MII) and pH measurements in infants and children. Evaluation of a diagnostic procedure for gastroesophageal reflux disease. Dig Dis Sci 2007; 52:2159–2165.
112. Trachterna M, Wenzl TG, Silny J, et al
. Procedure for the semi-automatic detection of gastro-oesophageal reflux patterns in intraluminal impedance measurements in infants. Med Eng Phys 1999; 21:195–201.
113. Lopez-Alonso M, Moya MJ, Cabo JA, et al
. Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics 2006; 118:e299–e308.
114. Wenzl TG. Evaluation of gastroesophageal reflux events in children using multichannel intraluminal electrical impedance. Am J Med 2003; 115(Suppl 3A):161S–165S.
115. Wenzl TG, Schenke S, Peschgens T, et al
. Association of apnea and nonacid gastroesophageal reflux in infants: investigations with the intraluminal impedance technique. Pediatr Pulmonol 2001; 31:144–149.
116. Wenzl TG, Silny J, Schenke S, et al
. Gastroesophageal reflux and respiratory phenomena in infants: status of the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 1999; 28:423–428.
117. Loots CM, Benninga MA, Davidson GP, et al
. Addition of pH-impedance monitoring to standard pH monitoring increases the yield of symptom association analysis in infants and children with gastroesophageal reflux. J Pediatr 2009; 154:248–252.
118. Staiano A, Cucchiara S, Del Giudice E, et al
. Disorders of oesophageal motility in children with psychomotor retardation and gastro-oesophageal reflux. Eur J Pediatr 1991; 150:638–641.
119. Cucchiara S, Campanozzi A, Greco L, et al
. Predictive value of esophageal manometry and gastroesophageal pH monitoring for responsiveness of reflux disease to medical therapy in children. Am J Gastroenterol 1996; 91:680–685.
120. Hillemeier AC, Grill BB, McCallum R, et al
. Esophageal and gastric motor abnormalities in gastroesophageal reflux during infancy. Gastroenterology 1983; 84:741–746.
121. Mattioli G, Sacco O, Repetto P, et al
. Necessity for surgery in children with gastrooesophageal reflux and supraoesophageal symptoms. Eur J Pediatr Surg 2004; 14:7–13.
122. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al
. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology 2008; 135:1383–1391, 1391 e1–5.
123. Gillett P, Hassall E. Pediatric gastrointestinal mucosal biopsy. Special considerations in children. Gastrointest Endosc Clin N Am 2000; 10:669–712, vi–vii.
124. Lundell LR, Dent J, Bennett JR, et al
. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999; 45:172–180.
125. Hetzel DJ, Dent J, Reed WD, et al
. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988; 95:903–912.
126. Vieth M, Haringsma J, Delarive J, et al
. Red streaks in the oesophagus in patients with reflux disease: is there a histomorphological correlate? Scand J Gastroenterol 2001; 36:1123–1127.
127. Bytzer P, Havelund T, Hansen JM. Interobserver variation in the endoscopic diagnosis of reflux esophagitis. Scand J Gastroenterol 1993; 28:119–125.
128. Pandolfino JE, Vakil NB, Kahrilas PJ. Comparison of inter- and intraobserver consistency for grading of esophagitis by expert and trainee endoscopists. Gastrointest Endosc 2002; 56:639–643.
129. Rath HC, Timmer A, Kunkel C, et al
. Comparison of interobserver agreement for different scoring systems for reflux esophagitis: impact of level of experience. Gastrointest Endosc 2004; 60:44–49.
130. Boccia G, Manguso F, Miele E, et al
. Maintenance therapy for erosive esophagitis in children after healing by omeprazole: is it advisable? Am J Gastroenterol 2007; 192:1291–1297.
131. Hassall E, Israel D, Shepherd R, et al
. Omeprazole for treatment of chronic erosive esophagitis in children: a multicenter study of efficacy, safety, tolerability and dose requirements. International Pediatric Omeprazole Study Group. J Pediatr 2000; 137:800–807.
132. Dahms BB. Reflux esophagitis: sequelae and differential diagnosis in infants and children including eosinophilic esophagitis. Pediatr Dev Pathol 2004; 7:5–16.
133. Dent J. Microscopic esophageal mucosal injury in nonerosive reflux disease. Clin Gastroenterol Hepatol 2007; 5:4–16.
134. Hassall E. Esophageal metaplasia: definition and prevalence in childhood. Gastrointest Endosc 2006; 64:676–677.
135. van Malenstein H, Farre R, Sifrim D. Esophageal dilated intercellular spaces (DIS) and nonerosive reflux disease. Am J Gastroenterol 2008; 103:1021–1028.
136. Pope C. Is it necessary to perform a biopsy in erosive esophagitis? In: Giuli R TG, DeMeester TR, Galmiche J-P, eds. The Esophageal Mucosa
. Amsterdam: Elsevier Press; 1994:303–8.
137. Behar J, Sheahan D. Histologic abnormalities in reflux esophagitis. Arch Pathol 1975; 99:387–391.
138. Ismail-Beigi F, Horton PF, Pope CE 2nd. Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970; 58:163–174.
139. Weinstein WM, Bogoch ER, Bowes KL. The normal human esophageal mucosa: a histological reappraisal. Gastroenterology 1975; 68:40–44.
140. Heine RG, Cameron DJ, Chow CW, et al
. Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic findings. J Pediatr 2002; 140:14–19.
141. Ravelli AM, Villanacci V, Ruzzenenti N, et al
. Dilated intercellular spaces: a major morphological feature of esophagitis. J Pediatr Gastroenterol Nutr 2006; 42:510–515.
142. Hill DJ, Heine RG, Cameron DJ, et al
. Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. J Pediatr 2000; 136:641–647.
143. Orenstein SR, Shalaby TM, Kelsey SF, et al
. Natural history of infant reflux esophagitis: symptoms and morphometric histology during one year without pharmacotherapy. Am J Gastroenterol 2006; 101:628–640.
144. Boyce HW. Endoscopic definitions of esophagogastric junction regional anatomy. Gastrointest Endosc 2000; 51:586–592.
145. McClave SA, Boyce HW Jr, Gottfried MR. Early diagnosis of columnar-lined esophagus: a new endoscopic diagnostic criterion. Gastrointest Endosc 1987; 33:413–416.
146. Ofman JJ, Shaheen NJ, Desai AA, et al
. The quality of care in Barrett's esophagus: endoscopist and pathologist practices. Am J Gastroenterol 2001; 96:876–881.
147. Gordon C, Kang JY, Neild PJ, et al
. The role of the hiatus hernia in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2004; 20:719–732.
148. Weinstein WM, Ippoliti AF. The diagnosis of Barrett's esophagus: goblets, goblets, goblets. Gastrointest Endosc 1996; 44:91–95.
149. Hassall E. Cardia-type mucosa as an esophageal metaplastic condition in children:“Barrett's esophagus, intestinal metaplasia-negative?”. J Pediatr Gastroenterol Nutr 2008; 47:102–106.
150. Peitz U, Vieth M, Pross M, et al
. Cardia-type metaplasia arising in the remnant esophagus after cardia resection. Gastrointest Endosc 2004; 59:810–817.
151. Siebert JJ, Byrne WJ, Euler AR, et al
. Gastroesophageal reflux - the acid test: scintigraphy or the pH probe? Am J Roentgenol 1983; 140:1087–1090.
152. Stephen TC, Younoszai MK, Massey MP, et al
. Diagnosis of gastroesophageal reflux in pediatrics. J Ky Med Assoc 1994; 92:188–191.
153. Meyers WF, Roberts CC, Johnson DG, et al
. Value of tests for evaluation of gastroesophageal reflux in children. J Pediatr Surg 1985; 20:515–520.
154. Thompson JK, Koehler RE, Richter JE. Detection of gastroesophageal reflux: value of barium studies compared with 24-hr pH monitoring. AJR Am J Roentgenol 1994; 162:621–626.
155. Gupta JP, Kumar A, Jain AK, et al
. Gastro-esophageal reflux disease (GERD): an appraisal of different tests for diagnosis. J Assoc Physicians India 1990; 38(Suppl 1):S699–S702.
156. Chen MY, Ott DJ, Sinclair JW, et al
. Gastroesophageal reflux disease: correlation of esophageal pH testing and radiographic findings. Radiology 1992; 185:483–486.
157. Aksglaede K, Pedersen JB, Lange A, et al
. Gastro-esophageal reflux demonstrated by radiography in infants less than 1 year of age. Comparison with pH monitoring. Acta Radiol 2003; 44:136–138.
158. Simanovsky N, Buonomo C, Nurko S. The infant with chronic vomiting: the value of the upper GI series. Pediatr Radiol 2002; 32:549–550, discussion 551.
159. Di Lorenzo C, Piepsz A, Ham H, et al
. Gastric emptying with gastro-oesophageal reflux. Arch Dis Child 1987; 62:449–453.
160. Papaila JG, Wilmot D, Grosfeld JL, et al
. Increased incidence of delayed gastric emptying in children with gastroesophageal reflux. A prospective evaluation. Arch Surg 1989; 124:933–936.
161. Hillemeier AC, Lange R, McCallum R, et al
. Delayed gastric emptying in infants with gastroesophageal reflux. J Pediatr 1981; 98:190–193.
162. Seibert JJ, Byrne WJ, Euler AR, et al
. Gastroesophageal reflux- the acid test: scintigraphy or the pH probe? AJR Am J Roentgenol 1983; 140:1087–1090.
163. Arasu TS, Wyllie R, Fitzgerald JF, et al
. Gastroesophageal reflux in infants and children comparative accuracy of diagnostic methods. J Pediatr 1980; 96:798–803.
164. Tolia V, Kauffman RE. Comparison of evaluation of gastroesophageal reflux in infants using different feedings during intraesophageal pH monitoring. J Pediatr Gastroenterol Nutr 1990; 10:426–429.
165. Balson BM, Kravitz EK, McGeady SJ. Diagnosis and treatment of gastroesophageal reflux in children and adolescents with severe asthma. Ann Allergy Asthma Immunol 1998; 81:159–164.
166. Vandenplas Y, Belli D, Boige N, et al
. A standardized protocol for the methodology of esophageal pH monitoring and interpretation of the data for the diagnosis of gastroesophageal reflux (ESPGAN statement). J Pediatr Gastroenterol Nutr 1992; 14:467–471.
167. Ghaed N, Stein MR. Assessment of a technique for scintigraphic monitoring of pulmonary aspiration of gastric contents in asthmatics with gastroesophageal reflux. Ann Allergy 1979; 42:306–308.
168. Fawcett HD, Hayden CK, Adams JC, et al
. How useful is gastroesophageal reflux scintigraphy in suspected childhood aspiration? Pediatr Radiol 1988; 18:311–313.
169. Ravelli AM, Panarotto MB, Verdoni L, et al
. Pulmonary aspiration shown by scintigraphy in gastroesophageal reflux-related respiratory disease. Chest 2006; 130:1520–1526.
170. McVeagh P, Howman-Giles R, Kemp A. Pulmonary aspiration studied by radionuclide milk scanning and barium swallow roentgenography. Am J Dis Child 1987; 141:917–921.
171. Gleeson K, Eggli DF, Maxwell SL. Quantitative aspiration during sleep in normal subjects. Chest 1997; 111:1266–1272.
172. Huxley EJ, Viroslav J, Gray WR, et al
. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978; 64:564–568.
173. van Wijk MP, Benninga MA, Dent J, et al
. Effect of body position changes on postprandial gastroesophageal reflux and gastric emptying in the healthy premature neonate. J Pediatr 2007; 151:585–590, 590 e1–2.
174. Gatti C, di Abriola FF, Dall'Oglio L, et al
. Is the 13C-acetate breath test a valid procedure to analyse gastric emptying in children? J Pediatr Surg 2000; 35:62–65.
175. Van Den Driessche M, Peeters K, Marien P, et al
. Gastric emptying in formula-fed and breast-fed infants measured with the 13C-octanoic acid breath test. J Pediatr Gastroenterol Nutr 1999; 29:46–51.
176. Van Den Driessche M. Study of gastro-intestinal motility in infants and children using 13
C breath tests. In: Faculty of Medicine
. Leuven: Catholic University Leuven; 2001:129.
177. Westra SJ, Wolf BH, Staalman CR. Ultrasound diagnosis of gastroesophageal reflux and hiatal hernia in infants and young children. J Clin Ultrasound 1990; 18:477–485.
178. Jang HS, Lee JS, Lim GY, et al
. Correlation of color Doppler sonographic findings with pH measurements in gastroesophageal reflux in children. J Clin Ultrasound 2001; 29:212–217.
179. Tipnis NA, Liu J, Puckett JL, et al
. Common cavity pressure during gastroesophageal reflux: reassessment using simultaneous pressure, impedance, and ultrasound imaging. Am J Physiol Gastrointest Liver Physiol 2006; 290:G1149–G1156.
180. Tack J. Review article: the role of bile and pepsin in the pathophysiology and treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2006; 24(Suppl 2):S10–S16.
181. Abd El-Fattah AM, Abdul Maksoud GA, Ramadan AS, et al
. Pepsin assay: a marker for reflux in pediatric glue ear. Otolaryngol Head Neck Surg 2007; 136:464–470.
182. He Z, O'Reilly RC, Bolling L, et al
. Detection of gastric pepsin in middle ear fluid of children with otitis media. Otolaryngol Head Neck Surg 2007; 137:59–64.
183. Crapko M, Kerschner JE, Syring M, et al
. Role of extra-esophageal reflux in chronic otitis media with effusion. Laryngoscope 2007; 117:1419–1423.
184. O'Reilly RC, He Z, Bloedon E, et al
. The role of extraesophageal reflux in otitis media in infants and children. Laryngoscope 2008; 118:1–9.
185. Farhath S, Aghai ZH, Nakhla T, et al
. Pepsin, a reliable marker of gastric aspiration, is frequently detected in tracheal aspirates from premature ventilated neonates: relationship with feeding and methylxanthine therapy. J Pediatr Gastroenterol Nutr 2006; 43:336–341.
186. Farrell S, McMaster C, Gibson D, et al
. Pepsin in bronchoalveolar lavage fluid: a specific and sensitive method of diagnosing gastro-oesophageal reflux-related pulmonary aspiration. J Pediatr Surg 2006; 41:289–293.
187. Starosta V, Kitz R, Hartl D, et al
. Bronchoalveolar pepsin, bile acids, oxidation, and inflammation in children with gastroesophageal reflux disease. Chest 2007; 132:1557–1564.
188. Orel R, Vidmar G. Do acid and bile reflux into the esophagus simultaneously? Temporal relationship between duodenogastro-esophageal reflux and esophageal pH. Pediatr Int 2007; 49:226–231.
189. Hoffman I, Tertychnyy A, Ectors N, et al
. Duodenogastro-esophageal reflux in children with refractory gastro-esophageal reflux disease. J Pediatr 2007; 151:307–311.
190. Orel R, Brecelj J, Homan M, et al
. Treatment of oesophageal bile reflux in children: the results of a prospective study with omeprazole. J Pediatr Gastroenterol Nutr 2006; 42:376–383.
191. Armstrong D, Marshall JK, Chiba N, et al
. Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults - update 2004. Can J Gastroenterol 2005; 19:15–35.
192. Irwin RS. Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines. Chest 2006; 129:80S–94S.
193. Ours TM, Kavuru MS, Schilz RJ, et al
. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999; 94:3131–3138.
194. Cremonini F, Wise J, Moayyedi P, et al
. Diagnostic and therapeutic use of proton pump inhibitors in non-cardiac chest pain: a metaanalysis. Am J Gastroenterol 2005; 100:1226–1232.
195. Talley NJ, Vakil N. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005; 100:2324–2337.
196. Numans ME, Lau J, de Wit NJ, et al
. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease: a meta-analysis of diagnostic test characteristics. Ann Intern Med 2004; 140:518–527.
197. Talley NJ, Armstrong D, Junghard O, et al
. Predictors of treatment response in patients with non-erosive reflux disease. Aliment Pharmacol Ther 2006; 24:371–376.
198. Kahrilas PJ, Falk GW, Johnson DA, et al
. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. The Esomeprazole Study Investigators. Aliment Pharmacol Ther 2000; 14:1249–1258.
199. Richter JE, Kahrilas PJ, Johanson J, et al
. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001; 96:656–665.
200. Vakil N. Review article: how valuable are proton-pump inhibitors in establishing a diagnosis of gastro-oesophageal reflux disease? Aliment Pharmacol Ther 2005; 22(Suppl 1):S64–S69.
201. Heacock HJ, Jeffery HE, Baker JL, et al
. Influence of breast versus formula milk on physiological gastroesophageal reflux in healthy, newborn infants. J Pediatr Gastroenterol Nutr 1992; 14:41–46.
202. Osatakul S, Sriplung H, Puetpaiboon A, et al
. Prevalence and natural course of gastroesophageal reflux symptoms: a 1-year cohort study in Thai infants. J Pediatr Gastroenterol Nutr 2002; 34:63–67.
203. Barak M, Lahav S, Mimouni FB, et al
. The prevalence of regurgitations in the first 2 days of life in human milk- and formula-fed term infants. Breastfeed Med 2006; 1:168–171.
204. Forget P, Arends JW. Cow's milk protein allergy and gastro-oesophageal reflux. Eur J Pediatr 1985; 144:298–300.
205. Semeniuk J, Kaczmarski M. Gastroesophageal reflux in children and adolescents. Clinical aspects with special respect to food hypersensitivity. Adv Med Sci 2006; 51:327–335.
206. Iacono G, Carroccio A, Cavataio F, et al
. Gastroesophageal reflux and cow's milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996; 97:822–827.
207. Hill DJ, Cameron DJ, Francis DE, et al
. Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. J Allergy Clin Immunol 1995; 96:386–394.
208. Orenstein S, McGowan J. Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux. J Pediatr 2008; 152:310–314.
209. Isolauri E, Tahvanainen A, Peltola T, et al
. Breast-feeding of allergic infants. J Pediatr 1999; 134:27–32.
210. Vance GH, Lewis SA, Grimshaw KE, et al
. Exposure of the fetus and infant to hens' egg ovalbumin via the placenta and breast milk in relation to maternal intake of dietary egg. Clin Exp Allergy 2005; 35:1318–1326.
211. Khoshoo V, Ross G, Brown S, et al
. Smaller volume, thickened formulas in the management of gastroesophageal reflux in thriving infants. J Pediatr Gastroenterol Nutr 2000; 31:554–556.
212. Vandenplas Y, Sacre L. Milk-thickening agents as a treatment for gastroesophageal reflux [published erratum appears in Clin Pediatr (Phila)
. 1987; 26:148]. Clin Pediatr (Phila)
213. Bailey DJ, Andres JM, Danek GD, et al
. Lack of efficacy of thickened feeding as treatment for gastroesophageal reflux. J Pediatr 1987; 110:187–189.
214. Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy of gastroesophageal reflux. J Pediatr 1987; 110:181–186.
215. Craig WR, Hanlon-Dearman A, Sinclair C, Taback S, Moffatt M. Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years. Cochrane Database Syst Rev
216. Xinias I, Mouane N, Le Luyer B, et al
. Cornstarch thickened formula reduces oesophageal acid exposure time in infants. Dig Liver Dis 2005; 37:23–27.
217. Corvaglia L, Ferlini M, Rotatori R, et al
. Starch thickening of human milk is ineffective in reducing the gastroesophageal reflux in preterm infants: a crossover study using intraluminal impedance. J Pediatr 2006; 148:265–268.
218. Orenstein SR, Shalaby TM, Putnam PE. Thickened feedings as a cause of increased coughing when used as therapy for gastroesophageal reflux in infants. J Pediatr 1992; 121:913–915.
219. Chao HC, Vandenplas Y. Comparison of the effect of a cornstarch thickened formula and strengthened regular formula on regurgitation, gastric emptying and weight gain in infantile regurgitation. Dis Esophagus 2007; 20:155–160.
220. Vandenplas Y, Hachimi-Idrissi S, Casteels A, et al
. A clinical trial with an “anti-regurgitation” formula. Eur J Pediatr 1994; 153:419–423.
221. Moukarzel AA, Abdelnour H, Akatcherian C. Effects of a prethickened formula on esophageal pH and gastric emptying of infants with GER. J Clin Gastroenterol 2007; 41:823–829.
222. Borrelli O, Salvia G, Campanozzi A, et al
. Use of a new thickened formula for treatment of symptomatic gastrooesophageal reflux in infants. Ital J Gastroenterol Hepatol 1997; 29:237–242.
223. Chao HC, Vandenplas Y. Effect of cereal-thickened formula and upright positioning on regurgitation, gastric emptying, and weight gain in infants with regurgitation. Nutrition 2007; 23:23–28.
224. Miyazawa R, Tomomasa T, Kaneko H, et al
. Effects of pectin liquid on gastroesophageal reflux disease in children with cerebral palsy. BMC Gastroenterol 2008; 8:11.
225. Miyazawa R, Tomomasa T, Kaneko H, et al
. Effect of formula thickened with reduced concentration of locust bean gum on gastroesophageal reflux. Acta Paediatr 2007; 96:910–914.
226. Vanderhoof JA, Moran JR, Harris CL, et al
. Efficacy of a pre-thickened infant formula: a multicenter, double-blind, randomized, placebo-controlled parallel group trial in 104 infants with symptomatic gastroesophageal reflux. Clin Pediatr (Phila) 2003; 42:483–495.
227. Hegar B, Rantos R, Firmansyah A, et al
. Natural evolution of infantile regurgitation versus the efficacy of thickened formula. J Pediatr Gastroenterol Nutr 2008; 47:26–30.
228. Bosscher D, Van Caillie-Bertrand M, Deelstra H. Do thickening properties of locust bean gum affect the amount of calcium, iron and zinc available for absorption from infant formula? In vitro studies. Int J Food Sci Nutr 2003; 54:261–268.
229. Bosscher D, Van Caillie-Bertrand M, Van Dyck K, et al
. Thickening infant formula with digestible and indigestible carbohydrate: availability of calcium, iron, and zinc in vitro. J Pediatr Gastroenterol Nutr 2000; 30:373–378.
230. Levtchenko E, Hauser B, Vandenplas Y. Nutritional value of an “anti-regurgitation” formula. Acta Gastroenterol Belg 1998; 61:285–287.
231. Ferry GD, Selby M, Pietro TJ. Clinical response to short-term nasogastric feeding in infants with gastroesophageal reflux and growth failure. J Pediatr Gastroenterol Nutr 1983; 2:57–61.
232. Meyers WF, Herbst JJ. Effectiveness of positioning therapy for gastroesophageal reflux. Pediatrics 1982; 69:768–772.
233. Vandenplas Y, Sacre-Smits L. Seventeen-hour continuous esophageal pH monitoring in the newborn: evaluation of the influence of position in asymptomatic and symptomatic babies. J Pediatr Gastroenterol Nutr 1985; 4:356–361.
234. Tobin JM, McCloud P, Cameron DJ. Posture and gastro-oesophageal reflux: a case for left lateral positioning. Arch Dis Child 1997; 76:254–258.
235. Corvaglia L, Rotatori R, Ferlini M, et al
. The effect of body positioning on gastroesophageal reflux in premature infants: evaluation by combined impedance and pH monitoring. J Pediatr 2007; 151:591–596, 596 e1.
236. Bhat RY, Rafferty GF, Hannam S, et al
. Acid gastroesophageal reflux in convalescent preterm infants: effect of posture and relationship to apnea. Pediatr Res 2007; 62:620–623.
237. Orenstein SR. Prone positioning in infant gastroesophageal reflux: is elevation of the head worth the trouble? J Pediatr 1990; 117:184–187.
238. Jeske HC, Borovicka J, von Goedecke A, et al
. The influence of postural changes on gastroesophageal reflux and barrier pressure in nonfasting individuals. Anesth Analg 2005; 101:597–600. Table of contents.
239. Bagucka B, DeSchepper J, Peelman M, et al
. Acid gastroesophageal reflux in the 10°-reverse-Trendelenburg position in supine sleeping infants. Acta Pediatri Taiwan 1999; 40:298–301.
240. Orenstein SR, Whitington PF, Orenstein DM. The infant seat as treatment for gastroesophageal reflux. N Engl J Med 1983; 309:760–763.
241. Vandenplas Y, Hauser B. Gastro-oesophageal reflux, sleep pattern, apparent life threatening event and sudden infant death. The point of view of a gastro-enterologist. Eur J Pediatr 2000; 159:726–729.
242. Oyen N, Markestad T, Skaerven R, et al
. Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: the Nordic Epidemiological SIDS Study. Pediatrics 1997; 100:613–621.
243. Skadberg BT, Morild I, Markestad T. Abandoning prone sleeping: effect on the risk of sudden infant death syndrome. J Pediatr 1998; 132:340–343.
244. Adams EJ, Chavez GF, Steen D, et al
. Changes in the epidemiologic profile of sudden infant death syndrome as rates decline among California infants: 1990–1995. Pediatrics 1998; 102:1445–1451.
245. Katz LC, Just R, Castell DO. Body position affects recumbent postprandial reflux. J Clin Gastroenterol 1994; 18:280–283.
246. Khoury RM, Camacho-Lobato L, Katz PO, et al
. Influence of spontaneous sleep positions on nighttime recumbent reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol 1999; 94:2069–2073.
247. Omari TI, Rommel N, Staunton E, et al
. Paradoxical impact of body positioning on gastroesophageal reflux and gastric emptying in the premature neonate. J Pediatr 2004; 145:194–200.
248. American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome. The changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics
249. Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med 2006; 166:965–971.
250. Austin GL, Thiny MT, Westman EC, et al
. A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms. Dig Dis Sci 2006; 51:1307–1312.
251. Peluso L, Vanek VW. Efficacy of gastric bypass in the treatment of obesity-related comorbidities. Nutr Clin Pract 2007; 22:22–28.
252. Piesman M, Hwang I, Maydonovitch C, et al
. Nocturnal reflux episodes following the administration of a standardized meal. Does timing matter? Am J Gastroenterol 2007; 102:2128–2134.
253. Vandenplas Y, De Wolf D, Sacre L. Influence of xanthines on gastroesophageal reflux in infants at risk for sudden infant death syndrome. Pediatrics 1986; 77:807–810.
254. Pehl C, Pfeiffer A, Wendl B, et al
. The effect of decaffeination of coffee on gastro-oesophageal reflux in patients with reflux disease. Aliment Pharmacol Ther 1997; 11:483–486.
255. Wendl B, Pfeiffer A, Pehl C, et al
. Effect of decaffeination of coffee or tea on gastro-oesophageal reflux. Aliment Pharmacol Ther 1994; 8:283–287.
256. Brazer SR, Onken JE, Dalton CB, et al
. Effect of different coffees on esophageal acid contact time and symptoms in coffee-sensitive subjects. Physiol Behav 1995; 57:563–567.
257. Chang CS, Poon SK, Lien HC, et al
. The incidence of reflux esophagitis among the Chinese. Am J Gastroenterol 1997; 92:668–671.
258. Castiglione F, Emde C, Armstrong D, et al
. Oesophageal pH-metry: should meals be standardized? Scand J Gastroenterol 1992; 27:350–354.
259. Murphy DW, Castell DO. Chocolate and heartburn: evidence of increased esophageal acid exposure after chocolate ingestion. Am J Gastroenterol 1988; 83:633–636.
260. Wright LE, Castell DO. The adverse effect of chocolate on lower esophageal sphincter pressure. Am J Dig Dis 1975; 20:703–707.
261. Bartlett DW, Evans DF, Smith BG. Oral regurgitation after reflux provoking meals: a possible cause of dental erosion? J Oral Rehabil 1997; 24:102–108.
262. Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976; 21:953–956.
263. Allen ML, Mellow MH, Robinson MG, et al
. The effect of raw onions on acid reflux and reflux symptoms. Am J Gastroenterol 1990; 85:377–380.
264. Bulat R, Fachnie E, Chauhan U, et al
. Lack of effect of spearmint on lower oesophageal sphincter function and acid reflux in healthy volunteers. Aliment Pharmacol Ther 1999; 13:805–812.
265. Jacobson BC, Somers SC, Fuchs CS, et al
. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006; 354:2340–2348.
266. El-Serag H. Role of obesity in GORD-related disorders. Gut 2008; 57:281–284.
267. Gerson LB. A little weight gain, how much gastroesophageal reflux disease? Gastroenterology 2006; 131:1644–1646, discussion 1646.
268. Veugelers PJ, Porter GA, Guernsey DL, et al
. Obesity and lifestyle risk factors for gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma. Dis Esophagus 2006; 19:321–328.
269. Whiteman DC, Sadeghi S, Pandeya N, et al
. Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus. Gut 2008; 57:173–180.
270. Avidan B, Sonnenberg A, Schnell TG, et al
. Walking and chewing reduce postprandial acid reflux. Aliment Pharmacol Ther 2001; 15:151–155.
271. Moazzez R, Bartlett D, Anggiansah A. The effect of chewing sugar-free gum on gastro-esophageal reflux. J Dent Res 2005; 84:1062–1065.
272. Smoak BR, Koufman JA. Effects of gum chewing on pharyngeal and esophageal pH. Ann Otol Rhinol Laryngol 2001; 110:1117–1119.
273. Stanciu C, Bennett JR. Effects of posture on gastro-oesophageal reflux. Digestion 1977; 15:104–109.
274. Hamilton JW, Boisen RJ, Yamamoto DT, et al
. Sleeping on a wedge diminishes exposure of the esophagus to refluxed acid. Dig Dis Sci 1988; 33:518–522.
275. Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid form tablets on gastroesophageal reflux. Dig Dis Sci 1981; 26:673–680.
276. Meining A, Classen M. The role of diet and lifestyle measures in the pathogenesis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2000; 95:2692–2697.
277. Sutphen JL, Dillard VL. Effect of ranitidine on twenty-four-hour gastric acidity in infants. J Pediatr 1989; 114:472–474.
278. Mallet E, Mouterde O, Dubois F, et al
. Use of ranitidine in young infants with gastro-oesophageal reflux. Eur J Clin Pharmacol 1989; 36:641–642.
279. Orenstein SR, Blumer JL, Faessel HM, et al
. Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux. Aliment Pharmacol Ther 2002; 16:899–907.
280. Hyman PE, Garvey TQ 3rd, Abrams CE. Tolerance to intravenous ranitidine. J Pediatr 1987; 110:794–796.
281. Nwokolo CU, Smith JT, Gavey C, et al
. Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine. Aliment Pharmacol Ther 1990; 4(Suppl 1):S29–S45.
282. Wilder-Smith CH, Ernst T, Gennoni M, et al
. Tolerance to oral H2-receptor antagonists. Dig Dis Sci 1990; 35:976–983.
283. Chiba N, De Gara CJ, Wilkinson JM, et al
. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997; 112:1798–1810.
284. McCarty-Dawson D, Sue SO, Morrill B, et al
. Ranitidine versus cimetidine in the healing of erosive esophagitis. Clin Ther 1996; 18:1150–1160.
285. Stacey JH, Miocevich ML, Sacks GE. The effect of ranitidine (as effervescent tablets) on the quality of life of GORD patients. Br J Clin Pract 1996; 50:190–194, 196.
286. Sabesin SM, Berlin RG, Humphries TJ, et al
. Famotidine relieves symptoms of gastroesophageal reflux disease and heals erosions and ulcerations. Results of a multicenter, placebo-controlled, dose-ranging study. USA Merck Gastroesophageal Reflux Disease Study Group. Arch Intern Med 1991; 151:2394–2400.
287. Cucchiara S, Gobio-Casali L, Balli F, et al
. Cimetidine treatment of reflux esophagitis in children: an Italian multicentric study. J Pediatr Gastroenterol Nutr 1989; 8:150–156.
288. Simeone D, Caria MC, Miele E, et al
. Treatment of childhood peptic esophagitis: a double-blind placebo-controlled trial of nizatidine. J Pediatr Gastroenterol Nutr 1997; 25:51–55.
289. Kelly DA. Do H2 receptor antagonists have a therapeutic role in childhood? J Pediatr Gastroenterol Nutr 1994; 19:270–276.
290. Berezin S, Medow MS, Glassman M, et al
. Use of the intraesophageal acid perfusion test in provoking nonspecific chest pain in children. J Pediatr 1989; 115:709–712.
291. Cucchiara S, Minella R, Iervolino C, et al
. Omeprazole and high dose ranitidine in the treatment of refractory reflux oesophagitis. Arch Dis Child 1993; 69:655–659.
292. DeAngelis G, Banchini G. Ranitidine in paediatric patients, a personal experience. Clin Trials 1989; 26:370–375.
293. Orenstein SR, Shalaby TM, Devandry SN, et al
. Famotidine for infant gastro-oesophageal reflux: a multi-centre, randomized, placebo-controlled, withdrawal trial. Aliment Pharmacol Ther 2003; 17:1097–1107.
294. Orenstein SR, Gremse DA, Pantaleon CD, et al
. Nizatidine for the treatment of pediatric gastroesophageal reflux symptoms: an open-label, multiple-dose, randomized, multicenter clinical trial in 210 children. Clin Ther 2005; 27:472–483.
295. van Pinxteren B, Numans ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H2
-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev
296. Khan M, Santana J, Donnellan C, Preston C, Moayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev
297. Garcia Rodriguez LA, Wallander MA, Stricker BH. The risk of acute liver injury associated with cimetidine and other acid-suppressing anti-ulcer drugs. Br J Clin Pharmacol 1997; 43:183–188.
298. Ribeiro JM, Lucas M, Baptista A, et al
. Fatal hepatitis associated with ranitidine. Am J Gastroenterol 2000; 95:559–560.
299. Garcia Rodriguez LA, Jick H. Risk of gynaecomastia associated with cimetidine, omeprazole, and other antiulcer drugs. BMJ 1994; 308:503–506.
300. Champion G, Richter JE, Vaezi MF, et al
. Duodenogastroesophageal reflux: relationship to pH and importance in Barrett's esophagus. Gastroenterology 1994; 107:747–754.
301. Hunt RH. Review article: the unmet needs in delayed-release proton-pump inhibitor therapy in 2005. Aliment Pharmacol Ther 2005; 22(Suppl 3):S10–S19.
302. Metz DC, Inadomi JM, Howden CW, et al
. On-demand therapy for gastroesophageal reflux disease. Am J Gastroenterol 2007; 102:642–653.
303. Metz DC, Howden CW, Perez MC, Larsen L, et al
. Clinical Trial. Dexlansoprazole MR, a proton pump inhibitor with Dual Delayed Release technology, effectively controls symptoms and prevents relapse in patients with healed erosive esophagitis. Aliment Pharmacol Ther 2009; 29:742–754.
304. Andersson T, Hassall E, Lundborg P, et al
. Pharmacokinetics of orally administered omeprazole in children. International Pediatric Omeprazole Pharmacokinetic Group. Am J Gastroenterol 2000; 95:3101–3106.
305. Litalien C, Théorêt Y, Faure C. Pharmacokinetics of proton pump inhibitors in children. Clin Pharmacokinet 2005; 44:441–466.
306. Zhao J, Li J, Hamer-Maansson JE, et al
. Pharmacokinetic properties of esomeprazole in children aged 1 to 11 years with symptoms of gastroesophageal reflux disease: a randomized, open-label study. Clin Ther 2006; 28:1868–1876.
307. Gremse D, Winter H, Tolia V, et al
. Pharmacokinetics and pharmacodynamics of lansoprazole in children with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2002; 35(Suppl 4):S319–S326.
308. Omari TI, Haslam RR, Lundborg P, et al
. Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pediatr Gastroenterol Nutr 2007; 44:41–44.
309. Zhang W, Kukulka M, Witt G, et al
. Age-dependent pharmacokinetics of lansoprazole in neonates and infants. Paediatr Drugs 2008; 10:265–274.
310. Hassall E. Talk is cheap, often effective: symptoms in infants often respond to non-pharmacologic measures. J Pediatr 2008; 152:301–303.
311. Li J, Zhao J, Hamer-Maansson JE, et al
. Pharmacokinetic properties of esomeprazole in adolescent patients aged 12 to 17 years with symptoms of gastroesophageal reflux disease: a randomized, open-label study. Clin Ther 2006; 28:419–427.
312. Tolia V, Fitzgerald J, Hassall E, et al
. Safety of lansoprazole in the treatment of gastroesophageal reflux disease in children. J Pediatr Gastroenterol Nutr 2002; 35(Suppl 4):S300–S307.
313. Drut R, Altamirano E, Cueto Rua E. Omeprazole-associated changes in the gastric mucosa of children. J Clin Pathol
314. Hassall E, Dimmick JE, Israel DM. Parietal cell hyperplasia in children receiving omeprazole. Gastroenterology 1995; 108:A110.
315. Pashankar DS, Israel DM. Gastric polyps and nodules in children receiving long-term omeprazole therapy. J Pediatr Gastroenterol Nutr 2002; 35:658–662.
316. Hassall E, for the International Pediatric Omeprazole Study Group. Omeprazole for maintenance therapy of erosive esophagitis in children. Gastroenterology 2000; 118:A658.
317. Hassall E, Owen D, Kerr W, et al
. Gastric histology in children treated with proton pump inhibitors (PPIs) long-term. Gastroenterology 2008; 134:A174.
318. Canani RB, Cirillo P, Roggero P, et al
. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics 2006; 117:e817–e820.
319. Guillet R, Stoll BJ, Cotten CM, et al
. Association of H2
-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006; 117:e137–e142.
320. Saiman L, Ludington E, Dawson JD, et al
. Risk factors for Candida species colonization of neonatal intensive care unit patients. Pediatr Infect Dis J 2001; 20:1119–1124.
321. Dial S, Delaney JA, Barkun AN, et al
. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005; 294:2989–2995.
322. Laheij RJ, Sturkenboom MC, Hassing RJ, et al
. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004; 292:1955–1960.
323. Garcia Rodriguez LA, Ruigomez A, Panes J. Use of acid-suppressing drugs and the risk of bacterial gastroenteritis. Clin Gastroenterol Hepatol 2007; 5:1418–1423.
324. Williams C, McColl KE. Review article: proton pump inhibitors and bacterial overgrowth. Aliment Pharmacol Ther 2006; 23:3–10.
325. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004; 57:422–428.
326. Yang YX, Lewis JD, Epstein S, et al
. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296:2947–2953.
327. den Elzen WP, Groeneveld Y, de Ruijter W, et al
. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther 2008; 27:491–497.
328. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008; 28:951–959.
329. Geevasinga N, Coleman PL, Webster AC, et al
. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol 2006; 4:597–604.
330. Brewster UC, Perazella MA. Proton pump inhibitors and the kidney: critical review. Clin Nephrol 2007; 68:65–72.
331. Untersmayr E, Jensen-Jarolim E. The role of protein digestibility and antacids on food allergy outcomes. J Allergy Clin Immunol 2008; 121:1301–1308, quiz 1309–10.
332. Rode H, Stunden RJ, Millar AJ, et al
. Esophageal pH assessment of gastroesophageal reflux in 18 patients and the effect of two prokinetic agents: cisapride and metoclopramide. J Pediatr Surg 1987; 22:931–934.
333. Augood C, MacLennan S, Gilbert R, Logan S. Cisapride treatment for gastro-oesophageal reflux in children. Cochrane Database Syst Rev
334. Dalby-Payne JR, Morris AM, Craig JC. Meta-analysis of randomized controlled trials on the benefits and risks of using cisapride for the treatment of gastroesophageal reflux in children. J Gastroenterol Hepatol 2003; 18:196–202.
335. Perrio M, Voss S, Shakir SA. Application of the bradford hill criteria to assess the causality of cisapride-induced arrhythmia: a model for assessing causal association in pharmacovigilance. Drug Saf 2007; 30:333–346.
336. Tolia V, Calhoun J, Kuhns L, et al
. Randomized, prospective double-blind trial of metoclopramide and placebo for gastroesophageal reflux in infants. J Pediatr 1989; 115:141–145.
337. Machida HM, Forbes DA, Gall DG, et al
. Metoclopramide in gastroesophageal reflux of infancy. J Pediatr 1988; 112:483–487.
338. Shafrir Y, Levy Y, Beharab A, et al
. Acute dystonic reaction to bethanechol–a direct acetylcholine receptor agonist. Dev Med Child Neurol 1986; 28:646–648.
339. Madani S, Tolia V. Gynecomastia with metoclopramide use in pediatric patients. J Clin Gastroenterol 1997; 24:79–81.
340. Putnam PE, Orenstein SR, Wessel HB, et al
. Tardive dyskinesia associated with use of metoclopramide in a child. J Pediatr 1992; 121:983–985.
341. Pritchard DS, Baber N, Stephenson T. Should domperidone be used for the treatment of gastro-oesophageal reflux in children? Systematic review of randomized controlled trials in children aged 1 month to 11 years old. Br J Clin Pharmacol 2005; 59:725–729.
342. Djeddi D, Kongolo G, Lefaix C, et al
. Effect of domperidone on QT interval in neonates. J Pediatr 2008; 153:663–666.
343. Euler AR. Use of bethanechol for the treatment of gastroesophageal reflux. J Pediatr 1980; 96:321–324.
344. Levi P, Marmo F, Saluzzo C, et al
. Bethanechol versus antiacids in the treatment of gastroesophageal reflux. Helv Paediatr Acta 1985; 40:349–359.
345. Vela MF, Tutuian R, Katz PO, et al
. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther 2003; 17:243–251.
346. Omari TI, Benninga MA, Sansom L, et al
. Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: a randomized controlled trial. J Pediatr 2006; 149:468–474.
347. Kawai M, Kawahara H, Hirayama S, et al
. Effect of baclofen on emesis and 24-hour esophageal pH in neurologically impaired children with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2004; 38:317–323.
348. Di Lorenzo C. Gastroesophageal reflux: not a time to “relax”. J Pediatr 2006; 149:436–438.
349. Rocha CM, Barbosa MM. QT interval prolongation associated with the oral use of domperidone in an infant. Pediatr Cardiol 2005; 26:720–723.
350. Hibbs AM, Lorch SA. Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review. Pediatrics 2006; 118:746–752.
351. Tran TT, Quandalle P. Long term results of treatment by simple surgical closure of perforated gastroduodenal ulcer followed by eradication of Helicobacter pylori. Ann Chir 2006; 131:502–503.
352. Cucchiara S, Staiano A, Romaniello G, et al
. Antacids and cimetidine treatment for gastro-oesophageal reflux and peptic oesophagitis. Arch Dis Child 1984; 59:842–847.
353. Iacono G, Carroccio A, Montalto G, et al
. Magnesium hydroxide and aluminum hydroxide in the treatment of gastroesophageal reflux. Minerva Pediatr 1991; 43:797–800.
354. Tsou VM, Young RM, Hart MH, et al
. Elevated plasma aluminum levels in normal infants receiving antacids containing aluminum. Pediatrics 1991; 87:148–151.
355. Woodard-Knight L, Fudge A, Teubner J, et al
. Aluminium absorption and antacid therapy in infancy. J Paediatr Child Health 1992; 28:257–259.
356. Sedman A. Aluminum toxicity in childhood. Pediatr Nephrol 1992; 6:383–393.
357. American Academy of Pediatrics Committee on Nutrition. Aluminum toxicity in infants and children. Pediatrics
358. Friedman JA, Carroll JC, Bergstrom WH. Antacid-induced hypophosphatemic rickets. Drug Nutr Interact 1985; 3:197–199.
359. Beall DP, Henslee HB, Webb HR, et al
. Milk-alkali syndrome: a historical review and description of the modern version of the syndrome. Am J Med Sci 2006; 331:233–242.
360. Greally P, Hampton FJ, MacFadyen UM, et al
. Gaviscon and Carobel compared with cisapride in gastro-oesophageal reflux. Arch Dis Child 1992; 67:618–621.
361. Forbes D, Hodgson M, Hill R. The effects of gaviscon and metoclopramide in gastroesophageal reflux in children. J Pediatr Gastroenterol Nutr 1986; 5:556–559.
362. Le Luyer B, Mougenot JF, Mashako L, et al
. Multicenter study of sodium alginate in the treatment of regurgitation in infants. Ann Pediatr (Paris) 1992; 39:635–640.
363. Buts JP, Barudi C, Otte JB. Double-blind controlled study on the efficacy of sodium alginate (Gaviscon) in reducing gastroesophageal reflux assessed by 24 h continuous pH monitoring in infants and children. Eur J Pediatr 1987; 146:156–158.
364. Miller S. Comparison of the efficacy and safety of a new aluminium-free paediatric alginate preparation and placebo in infants with recurrent gastro-oesophageal reflux. Curr Med Res Opin 1999; 15:160–168.
365. Del Buono R, Wenzl TG, Ball G, et al
. Effect of Gaviscon Infant on gastro-oesophageal reflux in infants assessed by combined intraluminal impedance/pH. Arch Dis Child 2005; 90:460–463.
366. Simon B, Ravelli GP, Goffin H. Sucralfate gel versus placebo in patients with non-erosive gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1996; 10:441–446.
367. Arguelles-Martin F, Gonzalez-Fernandez F, Gentles MG. Sucralfate versus cimetidine in the treatment of reflux esophagitis in children. Am J Med 1989; 86:73–76.
368. Lobe TE. The current role of laparoscopic surgery for gastroesophageal reflux disease in infants and children. Surg Endosc 2007; 21:167–174.
369. Berquist WE, Fonkalsrud EW, Ament ME. Effectiveness of Nissen fundoplication for gastroesophageal reflux in children as measured by 24-hour intraesophageal pH monitoring. J Pediatr Surg 1981; 16:872–875.
370. Di Lorenzo C, Flores A, Hyman PE. Intestinal motility in symptomatic children with fundoplication. J Pediatr Gastroenterol Nutr 1991; 12:169–173.
371. Di Lorenzo C, Orenstein S. Fundoplication: friend or foe? J Pediatr Gastroenterol Nutr 2002; 34:117–124.
372. Hassall E. Outcomes of fundoplication: causes for concern, newer options. Arch Dis Child 2005; 90:1047–1052.
373. Kawahara H, Nakajima K, Yagi M, et al
. Mechanisms responsible for recurrent gastroesophageal reflux in neurologically impaired children who underwent laparoscopic Nissen fundoplication. Surg Endosc 2002; 16:767–771.
374. Gilger MA, Yeh C, Chiang J, et al
. Outcomes of surgical fundoplication in children. Clin Gastroenterol Hepatol 2004; 2:978–984.
375. Gibbons TE, Stockwell JA, Kreh RP, et al
. Population-based epidemiological survey of gastroesophageal reflux disease in hospitalized US children. Gastroenterology 2001; 120:A419.
376. Fonkalsrud EW, Ashcraft KW, Coran AG, et al
. Surgical treatment of gastroesophageal reflux in children: a combined hospital study of 7467 patients. Pediatrics 1998; 101:419–422.
377. Mathei J, Coosemans W, Nafteux P, et al
. Laparoscopic Nissen fundoplication in infants and children: analysis of 106 consecutive patients with special emphasis in neurologically impaired vs. neurologically normal patients. Surg Endosc 2008; 22:1054–1059.
378. Vakil N. Review article: the role of surgery in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2007; 25:1365–1372.
379. Vakil N, Shaw M, Kirby R. Clinical effectiveness of laparoscopic fundoplication in a U.S. community. Am J Med 2003; 114:1–5.
380. Jackson PG, Gleiber MA, Askari R, et al
. Predictors of outcome in 100 consecutive laparoscopic antireflux procedures. Am J Surg 2001; 181:231–235.
381. Spechler SJ, Lee E, Ahnen D, et al
. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001; 285:2331–2338.
382. Wijnhoven BP, Lally CJ, Kelly JJ, et al
. Use of antireflux medication after antireflux surgery. J Gastrointest Surg 2008; 12:510–517.
383. Sullivan EM, Pelletier EM, Richter JE. Use of acid reduction therapy and medical costs among medically vs surgically managed GERD patients. Am J Gastroenterol 2002; 97:S239.
384. Lundell L, Attwood S, Ell C, et al
. Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the LOTUS trial. Gut 2008; 57:1207–1213.
385. Lundell L. Complications after anti-reflux surgery. Best Pract Res Clin Gastroenterol 2004; 18:935–945.
386. Perdikis G, Hinder RA, Lund RJ, et al
. Laparoscopic Nissen fundoplication: where do we stand? Surg Laparosc Endosc 1997; 7:17–21.
387. Rantanen TK, Salo JA, Sipponen JT. Fatal and life-threatening complications in antireflux surgery: analysis of 5,502 operations. Br J Surg 1999; 86:1573–1577.
388. Pearl RH, Robie DK, Ein SH, et al
. Complications of gastroesophageal antireflux surgery in neurologically impaired versus neurologically normal children. J Pediatr Surg 1990; 25:1169–1173.
389. Smith CD, Othersen HB Jr, Gogan NJ, et al
. Nissen fundoplication in children with profound neurologic disability. High risks and unmet goals. Ann Surg 1992; 215:654–658, discussion 658–9.
390. Spitz L, Roth K, Kiely EM, et al
. Operation for gastro-oesophageal reflux associated with severe mental retardation. Arch Dis Child 1993; 68:347–351.
391. Martinez DA, Ginn-Pease ME, Caniano DA. Recognition of recurrent gastroesophageal reflux following antireflux surgery in the neurologically disabled child: high index of suspicion and definitive evaluation. J Pediatr Surg 1992; 27:983–988, discussion 988–90.
392. Martinez DA, Ginn-Pease ME, Caniano DA. Sequelae of antireflux surgery in profoundly disabled children. J Pediatr Surg 1992; 27:267–271, discussion 271–3.
393. Curci MR, Dibbins AW. Problems associated with a Nissen fundoplication following tracheoesophageal fistula and esophageal atresia repair. Arch Surg 1988; 123:618–620.
394. Wheatley MJ, Coran AG, Wesley JR. Efficacy of the Nissen fundoplication in the management of gastroesophageal reflux following esophageal atresia repair. J Pediatr Surg 1993; 28:53–55.
395. Diaz DM, Gibbons TE, Heiss K, et al
. Antireflux surgery outcomes in pediatric gastroesophageal reflux disease. Am J Gastroenterol 2005; 100:1844–1852.
396. Kubiak R, Spitz L, Kiely EM, et al
. Effectiveness of fundoplication in early infancy. J Pediatr Surg 1999; 34:295–299.
397. Goldin AB, Sawin R, Seidel KD, et al
. Do antireflux operations decrease the rate of reflux-related hospitalizations in children? Pediatrics 2006; 118:2326–2333.
398. Lee SL, Shabatian H, Hsu JW, et al
. Hospital admissions for respiratory symptoms and failure to thrive before and after Nissen fundoplication. J Pediatr Surg 2008; 43:59–63, discussion 63–5.
399. Harnsberger JK, Corey JJ, Johnson DG, et al
. Long-term follow-up of surgery for gastroesophageal reflux in infants and children. J Pediatr 1983; 102:505–508.
400. Caniano DA, Ginn-Pease ME, King DR. The failed antireflux procedure: analysis of risk factors and morbidity. J Pediatr Surg 1990; 25:1022–1025, discussion 1025–6.
401. Carlson MA, Frantzides CT. Complications and results of primary minimally invasive antireflux procedures: a review of 10,735 reported cases. J Am Coll Surg 2001; 193:428–439.
402. Dalla Vecchia LK, Grosfeld JL, West KW, et al
. Reoperation after Nissen fundoplication in children with gastroesophageal reflux: experience with 130 patients. Ann Surg 1997; 226:315–321, discussion 321–3.
403. Lindahl H, Rintala R, Louhimo I. Failure of the Nissen fundoplication to control gastroesophageal reflux in esophageal atresia patients. J Pediatr Surg 1989; 24:985–987.
404. Taylor LA, Weiner T, Lacey SR, et al
. Chronic lung disease is the leading risk factor correlating with the failure (wrap disruption) of antireflux procedures in children. J Pediatr Surg 1994; 29:161–164, discussion 164–6.
405. van der Zee DC, Arends NJ, Bax NM. The value of 24-h pH study in evaluating the results of laparoscopic antireflux surgery in children. Surg Endosc 1999; 13:918–921.
406. Lasser MS, Liao JG, Burd RS. National trends in the use of antireflux procedures for children. Pediatrics 2006; 118:1828–1835.
407. Capito C, Leclair MD, Piloquet H, et al
. Long-term outcome of laparoscopic Nissen-Rossetti fundoplication for neurologically impaired and normal children. Surg Endosc 2008; 22:875–880.
408. Luostarinen ME, Isolauri JO. Surgical experience improves the long-term results of Nissen fundoplication. Scand J Gastroenterol 1999; 34:117–120.
409. Watson DI, Baigrie RJ, Jamieson GG. A learning curve for laparoscopic fundoplication. Definable, avoidable, or a waste of time? Ann Surg 1996; 224:198–203.
410. Bais JE, Bartelsman JF, Bonjer HJ, et al
. Laparoscopic or conventional Nissen fundoplication for gastro-oesophageal reflux disease: randomised clinical trial. The Netherlands Antireflux Surgery Study Group. Lancet 2000; 355:170–174.
411. Lall A, Morabito A, Dall'Oglio L, et al
. Total oesophagogastric dissociation: experience in 2 centres. J Pediatr Surg 2006; 41:342–346.
412. Morabito A, Lall A, Lo Piccolo R, et al
. Total esophagogastric dissociation: 10 years' review. J Pediatr Surg 2006; 41:919–922.
413. Thomson M, Antao B, Hall S, et al
. Medium-term outcome of endoluminal gastroplication with the EndoCinch device in children. J Pediatr Gastroenterol Nutr 2008; 46:172–177.
414. Pace F, Costamagna G, Penagini R, et al
. Review article: endoscopic antireflux procedures - an unfulfilled promise? Aliment Pharmacol Ther 2008; 27:375–384.
415. Rothstein RI. Endoscopic therapy of gastroesophageal reflux disease: outcomes of the randomized-controlled trials done to date. J Clin Gastroenterol 2008; 42:594–602.
416. Hogan WJ. Clinical trials evaluating endoscopic GERD treatments: is it time for a moratorium on the clinical use of these procedures? Am J Gastroenterol 2006; 101:437–439.
417. Corley DA, Katz P, Wo JM, et al
. Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial. Gastroenterology 2003; 125:668–676.
418. Wang SC, Borison HL. A new concept of organization of the central emetic mechanism: recent studies on the sites of action of apomorphine, copper sulfate and cardiac glycosides. Gastroenterology 1952; 22:1–12.
419. Orenstein SR, Peters JM. Vomiting and regurgitation. In: Kleigman RM, Greenbaum LA, Lye PS, editors. Practical Strategies in Pediatric Diagnosis and Therapy. 2nd ed. Philadelphia: WB Saunders Company; 2004.
420. Shalaby TM, Orenstein SR. Efficacy of telephone teaching of conservative therapy for infants with symptomatic gastroesophageal reflux referred by pediatricians to pediatric gastroenterologists. J Pediatr 2003; 142:57–61.
421. Cavataio F, Carroccio A, Iacono G. Milk-induced reflux in infants less than one year of age. J Pediatr Gastroenterol Nutr 2000; 30(Suppl):S36–S44.
422. Reijneveld SA, Lanting CI, Crone MR, et al
. Exposure to tobacco smoke and infant crying. Acta Paediatr 2005; 94:217–221.
423. Shenassa ED, Brown MJ. Maternal smoking and infantile gastrointestinal dysregulation: the case of colic. Pediatrics 2004; 114:e497–e505.
424. Hunziker UA, Barr RG. Increased carrying reduces infant crying: a randomized controlled trial. Pediatrics 1986; 77:641–648.
425. Barr RG. The normal crying curve: what do we really know? Dev Med Child Neurol 1990; 32:356–362.
426. Armstrong KL, Quinn RA, Dadds MR. The sleep patterns of normal children. Med J Aust 1994; 161:202–206.
427. Singh S, Richter JE, Bradley LA, et al
. The symptom index. Differential usefulness in suspected acid-related complaints of heartburn and chest pain. Dig Dis Sci 1993; 38:1402–1408.
428. Richter JE. A critical review of current medical therapy for gastroesophageal reflux disease. J Clin Gastroenterol 1986; 8(Suppl 1):S72–80.
429. Vakil N. Proton pump inhibitors for dyspepsia. Dig Dis 2008; 26:215–217.
430. Feranchak AP, Orenstein SR, Cohn JF. Behaviors associated with onset of gastroesophageal reflux episodes in infants. Prospective study using split-screen video and pH probe. Clin Pediatr (Phila) 1994; 33:654–662.
431. Heine RG, Jaquiery A, Lubitz L, et al
. Role of gastro-oesophageal reflux in infant irritability. Arch Dis Child 1995; 73:121–125.
432. Ghaem M, Armstrong KL, Trocki O, et al
. The sleep patterns of infants and young children with gastro-oesophageal reflux. J Paediatr Child Health 1998; 34:160–163.
433. Arana A, Bagucka B, Hauser B, et al
. pH monitoring in the distal and proximal esophagus in symptomatic infants. J Pediatr Gastroenterol Nutr 2001; 32:259–264.
434. Barr RG, Rotman A, Yaremko J, et al
. The crying of infants with colic: a controlled empirical description. Pediatrics 1992; 90:14–21.
435. Zwart P, Vellema-Goud MG, Brand PL. Characteristics of infants admitted to hospital for persistent colic, and comparison with healthy infants. Acta Paediatr 2007; 96:401–405.
436. Vandenplas Y, Koletzko S, Isolauri E, et al
. Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child 2007; 92:902–908.
437. Rao MR, Brenner RA, Schisterman EF, et al
. Long term cognitive development in children with prolonged crying. Arch Dis Child 2004; 89:989–992.
438. Poole SR. The infant with acute, unexplained, excessive crying. Pediatrics 1991; 88:450–455.
439. Barr RG. Colic and crying syndromes in infants. Pediatrics 1998; 102:1282–1286.
440. Savino F, Palumeri E, Castagno E, et al
. Reduction of crying episodes owing to infantile colic: a randomized controlled study on the efficacy of a new infant formula. Eur J Clin Nutr 2006; 60:1304–1310.
441. Lucassen PL, Assendelft WJ, Gubbels JW, et al
. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind, randomized, placebo-controlled trial. Pediatrics 2000; 106:1349–1354.
442. Hill DJ, Hudson IL, Sheffield LJ, et al
. A low allergen diet is a significant intervention in infantile colic: results of a community-based study. J Allergy Clin Immunol 1995; 96:886–892.
443. Klauser AG, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet 1990; 335:205–208.
444. Shi G, Bruley des Varannes S, Scarpignato C, et al
. Reflux related symptoms in patients with normal oesophageal exposure to acid. Gut 1995; 37:457–464.
445. Dent J, Brun J, Fendrick AM, et al
. An evidence-based appraisal of reflux disease management - the Genval workshop report. Gut 1999; 44(Suppl 2):S1–S16.
446. Venables TL, Newland RD, Patel AC, et al
. Omeprazole 10 milligrams once daily, omeprazole 20 milligrams once daily, or ranitidine 150 milligrams twice daily, evaluated as initial therapy for the relief of symptoms of gastro-oesophageal reflux disease in general practice. Scand J Gastroenterol 1997; 32:965–973.
447. Fiedorek S, Tolia V, Gold BD, et al
. Efficacy and safety of lansoprazole in adolescents with symptomatic erosive and non-erosive gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2005; 40:319–327.
448. Richter JE, Kovacs TO, Greski-Rose PA, et al
. Lansoprazole in the treatment of heartburn in patients without erosive oesophagitis. Aliment Pharmacol Ther 1999; 13:795–804.
449. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999; 94:1434–1442.
450. Muller S, Puhl S, Vieth M, et al
. Analysis of symptoms and endoscopic findings in 117 patients with histological diagnoses of eosinophilic esophagitis. Endoscopy 2007; 39:339–344.
451. Fossmark R, Johnsen G, Johanessen E, et al
. Rebound acid hypersecretion after long-term inhibition of gastric acid secretion. Aliment Pharmacol Ther 2005; 21:149–154.
452. Bjornsson E, Abrahamsson H, Simren M, et al
. Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial. Aliment Pharmacol Ther 2006; 24:945–954.
453. Havelund T, Lind T, Wiklund I, et al
. Quality of life in patients with heartburn but without esophagitis: effects of treatment with omeprazole. Am J Gastroenterol 1999; 94:1782–1789.
454. Revicki DA, Crawley JA, Zodet MW, et al
. Complete resolution of heartburn symptoms and health-related quality of life in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1999; 13:1621–1630.
455. Pappa KA, Williams BO, Payne JE, et al
. A double-blind, placebo-controlled study of the efficacy and safety of non-prescription ranitidine 75 mg in the prevention of meal-induced heartburn. Aliment Pharmacol Ther 1999; 13:467–473.
456. Pace F, Tonini M, Pallotta S, et al
. Systematic review: maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken ‘on-demand’. Aliment Pharmacol Ther 2007; 26:195–204.
457. DeVault KR. Review article: the role of acid suppression in patients with non-erosive reflux disease or functional heartburn. Aliment Pharmacol Ther 2006; 23(Suppl 1):33–39.
458. Fass R. Erosive esophagitis and nonerosive reflux disease (NERD): comparison of epidemiologic, physiologic, and therapeutic characteristics. J Clin Gastroenterol 2007; 41:131–137.
459. Tolia V, Ferry G, Gunasekaran T, et al
. Efficacy of lansoprazole in the treatment of gastroesophageal reflux disease in children. J Pediatr Gastroenterol Nutr 2002; 35:S308–S318.
460. Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 2008; 103:788–797.
461. Sharma P, McQuaid K, Dent J, et al
. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology 2004; 127:310–330.
462. Eslick GD, Talley NJ. Dysphagia: epidemiology, risk factors and impact on quality of life–a population-based study. Aliment Pharmacol Ther 2008; 27:971–979.
463. Bollschweiler E, Knoppe K, Wolfgarten E, et al
. Prevalence of Dysphagia in patients with gastroesophageal reflux in Germany. Dysphagia 2008; 23:172–176.
464. Vakil NB, Traxler B, Levine D. Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment. Clin Gastroenterol Hepatol 2004; 2:665–668.
465. Lundquist A, Olsson R, Ekberg O. Clinical and radiologic evaluation reveals high prevalence of abnormalities in young adults with dysphagia. Dysphagia 1998; 13:202–207.
466. Pasha SF, DiBaise JK, Kim HJ, et al
. Patient characteristics, clinical, endoscopic, and histologic findings in adult eosinophilic esophagitis: a case series and systematic review of the medical literature. Dis Esophagus 2007; 20:311–319.
467. Dellert SF, Hyams JS, Treem WR, et al
. Feeding resistance and gastroesophageal reflux in infancy. J Pediatr Gastroenterol Nutr 1993; 17:66–71.
468. Mathisen B, Worrall L, Masel J, et al
. Feeding problems in infants with gastro-oesophageal reflux disease: a controlled study. J Paediatr Child Health 1999; 35:163–169.
469. Rommel N, De Meyer AM, Feenstra L, et al
. The complexity of feeding problems in 700 infants and young children presenting to a tertiary care institution. J Pediatr Gastroenterol Nutr 2003; 37:75–84.
470. Mousa H, Woodley FW, Metheney M, et al
. Testing the association between gastroesophageal reflux and apnea in infants. J Pediatr Gastroenterol Nutr 2005; 41:169–177.
471. Peter CS, Sprodowski N, Bohnhorst B, et al
. Gastroesophageal reflux and apnea of prematurity: no temporal relationship. Pediatrics 2002; 109:8–11.
472. Magista AM, Indrio F, Baldassarre M, et al
. Multichannel intraluminal impedance to detect relationship between gastroesophageal reflux and apnoea of prematurity. Dig Liver Dis 2007; 39:216–221.
473. Menon AP, Schefft GL, Thach BT. Apnea associated with regurgitation in infants. J Pediatr 1985; 106:625–629.
474. National Institutes of Health Consensus Development Conference. Infantile apnea and home monitoring: consensus statement. Pediatrics
475. Tirosh E, Kessel A, Jaffe M, et al
. Outcome of idiopathic apparent life-threatening events: infant and mother perspectives. Pediatr Pulmonol 1999; 28:47–52.
476. Cote A, Hum C, Brouillette RT, et al
. Frequency and timing of recurrent events in infants using home cardiorespiratory monitors. J Pediatr 1998; 132:783–789.
477. Rosen CL, Frost JD Jr, Harrison GM. Infant apnea: polygraphic studies and follow-up monitoring. Pediatrics 1983; 71:731–736.
478. Burchfield DJ, Rawlings DJ. Sudden deaths and apparent life-threatening events in hospitalized neonates presumed to be healthy. Am J Dis Child 1991; 145:1319–1322.
479. Kahn A, Blum D, Rebuffat E, et al
. Polysomnographic studies of infants who subsequently died of sudden infant death syndrome. Pediatrics 1988; 82:721–727.
480. Kelly DH, Golub H, Carley D, et al
. Pneumograms in infants who subsequently died of sudden infant death syndrome. J Pediatr 1986; 109:249–254.
481. Kelly DH, Shannon DC, O'Connell K. Care of infants with near-miss sudden infant death syndrome. Pediatrics 1978; 61:511–514.
482. Oren J, Kelly D, Shannon DC. Identification of a high-risk group for sudden infant death syndrome among infants who were resuscitated for sleep apnea. Pediatrics 1986; 77:495–499.
483. Friesen CA, Streed CJ, Carney LA, et al
. Esophagitis and modified Bernstein tests in infants with apparent life-threatening events. Pediatrics 1994; 94:541–544.
484. Newman LJ, Russe J, Glassman MS, et al
. Patterns of gastroesophageal reflux (GER) in patients with apparent life-threatening events. J Pediatr Gastroenterol Nutr 1989; 8:157–160.
485. Herbst JJ, Minton SD, Book LS. Gastroesophageal reflux causing respiratory distress and apnea in newborn infants. J Pediatr 1979; 95:763–768.
486. Leape LL, Holder TM, Franklin JD, et al
. Respiratory arrest in infants secondary to gastroesophageal reflux. Pediatrics 1977; 60:924–928.
487. Herbst JJ, Book LS, Bray PF. Gastroesophageal reflux in the “near miss” sudden infant death syndrome. J Pediatr 1978; 92:73–75.
488. Spitzer AR, Boyle JT, Tuchman DN, et al
. Awake apnea associated with gastroesophageal reflux: a specific clinical syndrome. J Pediatr 1984; 104:200–205.
489. Ariagno RL. Evaluation and management of infantile apnea. Pediatr Ann 1984; 13:210–213, 216–217.
490. Kahn A, Rebuffat E, Sottiaux M, et al
. Lack of temporal relation between acid reflux in the proximal oesophagus and cardiorespiratory events in sleeping infants. Eur J Pediatr 1992; 151:208–212.
491. Veereman-Wauters G, Bochner A, Van Caillie-Bertrand M. Gastroesophageal reflux in infants with a history of near-miss sudden infant death. J Pediatr Gastroenterol Nutr 1991; 12:319–323.
492. Sacre L, Vandenplas Y. Gastroesophageal reflux associated with respiratory abnormalities during sleep. J Pediatr Gastroenterol Nutr 1989; 9:28–33.
493. Paton JY, Nanayakkara CS, Simpson H. Observations on gastro-oesophageal reflux, central apnoea and heart rate in infants. Eur J Pediatr 1990; 149:608–612.
494. Paton JY, Macfadyen U, Williams A, et al
. Gastro-oesophageal reflux and apnoeic pauses during sleep in infancy - no direct relation. Eur J Pediatr 1990; 149:680–686.
495. Walsh JK, Farrell MK, Keenan WJ, et al
. Gastroesophageal reflux in infants: relation to apnea. J Pediatr 1981; 99:197–201.
496. Suys B, De Wolf D, Hauser B, et al
. Bradycardia and gastroesophageal reflux in term and preterm infants: is there any relation? J Pediatr Gastroenterol Nutr 1994; 19:187–190.
497. Jolley SG, Halpern LM, Tunell WP, et al
. The risk of sudden infant death from gastroesophageal reflux. J Pediatr Surg 1991; 26:691–696.
498. Field SK. A critical review of the studies of the effects of simulated or real gastroesophageal reflux on pulmonary function in asthmatic adults. Chest 1999; 115:848–856.
499. Boyle JT, Tuchman DN, Altschuler SM, et al
. Mechanisms for the association of gastroesophageal reflux and bronchospasm. Am Rev Respir Dis 1985; 131:S16–S20.
500. Malfroot A, Dab I. Pathophysiology and mechanisms of gastroesophageal reflux in childhood asthma. Pediatr Pulmonol Suppl 1995; 11:55–56.
501. Hamamoto J, Kohrogi H, Kawano O, et al
. Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs. J Appl Physiol 1997; 82:738–745.
502. Herve P, Denjean A, Jian R, et al
. Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects. Am Rev Respir Dis 1986; 134:986–989.
503. Sontag SJ, O'Connell S, Khandelwal S, et al
. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613–620.
504. Lazenby JP, Guzzo MR, Harding SM, et al
. Oral corticosteroids increase esophageal acid contact times in patients with stable asthma. Chest 2002; 121:625–634.
505. Scarupa MD, Mori N, Canning BJ. Gastroesophageal reflux disease in children with asthma: treatment implications. Paediatr Drugs 2005; 7:177–186.
506. Sheikh S, Stephen T, Howell L, et al
. Gastroesophageal reflux in infants with wheezing. Pediatr Pulmonol 1999; 28:181–186.
507. Condino AA, Sondheimer J, Pan Z, et al
. Evaluation of gastroesophageal reflux in pediatric patients with asthma using impedance-pH monitoring. J Pediatr 2006; 149:216–219.
508. Stordal K, Johannesdottir GB, Bentsen BS, et al
. Acid suppression does not change respiratory symptoms in children with asthma and gastro-oesophageal reflux disease. Arch Dis Child 2005; 90:956–960.
509. Kiljander TO, Harding SM, Field SK, et al
. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006; 173:1091–1097.
510. Littner MR, Leung FW, Ballard ED 2nd, et al
. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128:1128–1135.
511. Khoshoo V, Le T, Haydel RM Jr, et al
. Role of gastroesophageal reflux in older children with persistent asthma. Chest 2003; 123:1008–1013.
512. Sontag SJ, O'Connell S, Khandelwal S, et al
. Asthmatics with gastroesophageal reflux: long term results of a randomized trial of medical and surgical antireflux therapies. Am J Gastroenterol 2003; 98:987–999.
513. Boesch RP, Daines C, Willging JP, et al
. Advances in the diagnosis and management of chronic pulmonary aspiration in children. Eur Respir J 2006; 28:847–861.
514. Euler AR, Byrne WJ, Ament ME, et al
. Recurrent pulmonary disease in children: a complication of gastroesophageal reflux. Pediatrics 1979; 63:47–51.
515. Carre IJ. Pulmonary infections in children with a partial thoracic stomach (‘hiatus hernia’). Arch Dis Child 1960; 35:481–483.
516. Owayed AF, Campbell DM, Wang EE. Underlying causes of recurrent pneumonia in children. Arch Pediatr Adolesc Med 2000; 154:190–194.
517. Raghu G, Yang ST, Spada C, et al
. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest 2006; 129:794–800.
518. Tobin RW, Pope CE 2nd, Pellegrini CA, et al
. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158:1804–1808.
519. Scott RB, O'Loughlin EV, Gall DG. Gastroesophageal reflux in patients with cystic fibrosis. J Pediatr 1985; 106:223–227.
520. Button BM, Roberts S, Kotsimbos TC, et al
. Gastroesophageal reflux (symptomatic and silent): a potentially significant problem in patients with cystic fibrosis before and after lung transplantation. J Heart Lung Transplant 2005; 24:1522–1529.
521. Benden C, Aurora P, Curry J, et al
. High prevalence of gastroesophageal reflux in children after lung transplantation. Pediatr Pulmonol 2005; 40:68–71.
522. Sheikh S, Allen E, Shell R, et al
. Chronic aspiration without gastroesophageal reflux as a cause of chronic respiratory symptoms in neurologically normal infants. Chest 2001; 120:1190–1195.
523. Cucchiara S, Santamaria F, Minella R, et al
. Simultaneous prolonged recordings of proximal and distal intraesophageal pH in children with gastroesophageal reflux disease and respiratory symptoms. Am J Gastroenterol 1995; 90:1791–1796.
524. Knauer-Fischer S, Ratjen F. Lipid-laden macrophages in bronchoalveolar lavage fluid as a marker for pulmonary aspiration. Pediatr Pulmonol 1999; 27:419–422.
525. Ahrens P, Noll C, Kitz R, et al
. Lipid-laden alveolar macrophages (LLAM): a useful marker of silent aspiration in children. Pediatr Pulmonol 1999; 28:83–88.
526. Bauer ML, Lyrene RK. Chronic aspiration in children: evaluation of the lipid-laden macrophage index. Pediatr Pulmonol 1999; 28:94–100.
527. Staugas R, Martin AJ, Binns G, et al
. The significance of fat-filled macrophages in the diagnosis of aspiration associated with gastro-oesophageal reflux. Aust Paediatr J 1985; 21:275–277.
528. Nussbaum E, Maggi JC, Mathis R, et al
. Association of lipid-laden alveolar macrophages and gastroesophageal reflux in children. J Pediatr 1987; 110:190–194.
529. Rosen R, Fritz J, Nurko A, et al
. Lipid-laden macrophage index is not an indicator of gastroesophageal reflux-related respiratory disease in children. Pediatrics 2008; 121:e879–e884.
530. Bohmer CJ, Niezen-de Boer RC, Klinkenberg-Knol EC, et al
. Omeprazole: therapy of choice in intellectually disabled children. Arch Pediatr Adolesc Med 1998; 152:1113–1118.
531. Wilkinson JD, Dudgeon DL, Sondheimer JM. A comparison of medical and surgical treatment of gastroesophageal reflux in severely retarded children. J Pediatr 1981; 99:202–205.
532. Wales PW, Diamond IR, Dutta S, et al
. Fundoplication and gastrostomy versus image-guided gastrojejunal tube for enteral feeding in neurologically impaired children with gastroesophageal reflux. J Pediatr Surg 2002; 37:407–412.
533. Cheung KM, Tse HW, Tse PW, et al
. Nissen fundoplication and gastrostomy in severely neurologically impaired children with gastroesophageal reflux. Hong Kong Med J 2006; 12:282–288.
534. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991; 101:1–78.
535. Fitzgerald JM, Allen CJ, Craven MA, et al
. Chronic cough and gastroesophageal reflux. CMAJ 1989; 140:520–524.
536. Ing AJ, Ngu MC, Breslin AB. Chronic persistent cough and gastro-oesophageal reflux. Thorax 1991; 46:479–483.
537. Curran AJ, Barry MK, Callanan V, et al
. A prospective study of acid reflux and globus pharyngeus using a modified symptom index. Clin Otolaryngol Allied Sci 1995; 20:552–554.
538. Woo P, Noordzij P, Ross JA. Association of esophageal reflux and globus symptom: comparison of laryngoscopy and 24-hour pH manometry. Otolaryngol Head Neck Surg 1996; 115:502–507.
539. Wilson JA, White A, von Haacke NP, et al
. Gastroesophageal reflux and posterior laryngitis. Ann Otol Rhinol Laryngol 1989; 98:405–410.
540. Shaw GY, Searl JP. Laryngeal manifestations of gastroesophageal reflux before and after treatment with omeprazole. South Med J 1997; 90:1115–1122.
541. Branski RC, Bhattacharyya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal findings associated with laryngopharyngeal reflux disease. Laryngoscope 2002; 112:1019–1024.
542. Hicks DM, Ours TM, Abelson TI, et al
. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice 2002; 16:564–579.
543. McMurray JS, Gerber M, Stern Y, et al
. Role of laryngoscopy, dual pH probe monitoring, and laryngeal mucosal biopsy in the diagnosis of pharyngoesophageal reflux. Ann Otol Rhinol Laryngol 2001; 110:299–304.
544. Contencin P, Narcy P. Gastropharyngeal reflux in infants and children. A pharyngeal pH monitoring study. Arch Otolaryngol Head Neck Surg 1992; 118:1028–1030.
545. Yellon RF, Coticchia J, Dixit S. Esophageal biopsy for the diagnosis of gastroesophageal reflux-associated otolaryngologic problems in children. Am J Med 2000; 108(Suppl 4a):131S–138S.
546. Gumpert L, Kalach N, Dupont C, et al
. Hoarseness and gastroesophageal reflux in children. J Laryngol Otol 1998; 112:49–54.
547. Halstead LA. Gastroesophageal reflux: a critical factor in pediatric subglottic stenosis. Otolaryngol Head Neck Surg 1999; 120:683–688.
548. Conley SF, Werlin SL, Beste DJ. Proximal pH-metry for diagnosis of upper airway complications of gastroesophageal reflux. J Otolaryngol 1995; 24:295–298.
549. Matthews BL, Little JP, McGuirt WF Jr, et al
. Reflux in infants with laryngomalacia: results of 24-hour double-probe pH monitoring. Otolaryngol Head Neck Surg 1999; 120:860–864.
550. Suskind DL, Zeringue GP 3rd, Kluka EA, et al
. Gastroesophageal reflux and pediatric otolaryngologic disease: the role of antireflux surgery. Arch Otolaryngol Head Neck Surg 2001; 127:511–514.
551. Allen CJ, Anvari M. Does laparoscopic fundoplication provide long-term control of gastroesophageal reflux related cough? Surg Endosc 2004; 18:633–637.
552. Wo JM, Grist WJ, Gussack G, et al
. Empiric trial of high-dose omeprazole in patients with posterior laryngitis: a prospective study. Am J Gastroenterol 1997; 92:2160–2165.
553. Kamel PL, Hanson D, Kahrilas PJ. Omeprazole for the treatment of posterior laryngitis [see comments]. Am J Med 1994; 96:321–326.
554. Hanson DG, Kamel PL, Kahrilas PJ. Outcomes of antireflux therapy for the treatment of chronic laryngitis. Ann Otol Rhinol Laryngol 1995; 104:550–555.
555. Vaezi MF, Richter JE, Stasney CR, et al
. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope 2006; 116:254–260.
556. Wo JM, Koopman J, Harrell SP, et al
. Double-blind, placebo-controlled trial with single-dose pantoprazole for laryngopharyngeal reflux. Am J Gastroenterol 2006; 101:1972–1978, quiz 2169.
557. Karkos PD, Wilson JA. Empiric treatment of laryngopharyngeal reflux with proton pump inhibitors: a systematic review. Laryngoscope 2006; 116:144–148.
558. Qadeer MA, Phillips CO, Lopez AR, et al
. Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006; 101:2646–2654.
559. Williams RB, Szczesniak MM, Maclean JC, et al
. Predictors of outcome in an open label, therapeutic trial of high-dose omeprazole in laryngitis. Am J Gastroenterol 2004; 99:777–785.
560. Corrado G, D'Eufemia P, Pacchiarotti C, et al
. Irritable oesophagus syndrome as cause of chronic cough. Ital J Gastroenterol 1996; 28:526–530.
561. Tasker A, Dettmar PW, Panetti M, et al
. Reflux of gastric juice and glue ear in children. Lancet 2002; 359:493.
562. Weaver EM. Association between gastroesophageal reflux and sinusitis, otitis media, and laryngeal malignancy: a systematic review of the evidence. Am J Med 2003; 115:81S–89S.
563. Bothwell MR, Parsons DS, Talbot A, et al
. Outcome of reflux therapy on pediatric chronic sinusitis. Otolaryngol Head Neck Surg 1999; 121:255–262.
564. Contencin P, Narcy P. Nasopharyngeal pH monitoring in infants and children with chronic rhinopharyngitis. Int J Pediatr Otorhinolaryngol 1991; 22:249–256.
565. El-Serag HB, Gilger M, Kuebeler M, et al
. Extraesophageal associations of gastroesophageal reflux disease in children without neurologic defects. Gastroenterology 2001; 121:1294–1299.
566. Gibson WS Jr, Cochran W. Otalgia in infants and children - a manifestation of gastroesophageal reflux. Int J Pediatr Otorhinolaryngol 1994; 28:213–218.
567. Bartlett DW, Coward PY, Nikkah C, et al
. The prevalence of tooth wear in a cluster sample of adolescent schoolchildren and its relationship with potential explanatory factors. Br Dent J 1998; 184:125–129.
568. O'Sullivan EA, Curzon ME, Roberts GJ, et al
. Gastroesophageal reflux in children and its relationship to erosion of primary and permanent teeth. Eur J Oral Sci 1998; 106:765–769.
569. Cerimagic D, Ivkic G, Bilic E. Neuroanatomical basis of Sandifer's syndrome: a new vagal reflex? Med Hypotheses 2008; 70:957–961.
570. Kinsbourne M. Hiatus Hernia with contortions of the neck. Lancet 1964; 13:1058–1061.
571. Del Giudice E, Staiano A, Capano G, et al
. Gastrointestinal manifestations in children with cerebral palsy. Brain Dev 1999; 21:307–311.
572. Bohmer CJ, Klinkenberg-Knol EC, Niezen-de Boer MC, et al
. Gastroesophageal reflux disease in intellectually disabled individuals: how often, how serious, how manageable? Am J Gastroenterol 2000; 95:1868–1872.
573. Reyes AL, Cash AJ, Green SH, et al
. Gastrooesophageal reflux in children with cerebral palsy. Child Care Health Dev 1993; 19:109–118.
574. Bozkurt M, Tutuncuoglu S, Serdaroglu G, et al
. Gastroesophageal reflux in children with cerebral palsy: efficacy of cisapride. J Child Neurol 2004; 19:973–976.
575. Pensabene L, Miele E, Giudice ED, et al
. Mechanisms of gastroesophageal reflux in children with sequelae of birth asphyxia. Brain Dev 2008; 30:563–571.
576. Luzzani S, Macchini F, Valade A, et al
. Gastroesophageal reflux and Cornelia de Lange syndrome: typical and atypical symptoms. Am J Med Genet A 2003; 119:283–287.
577. Cheung KM, Tse PW, Ko CH, et al
. Clinical efficacy of proton pump inhibitor therapy in neurologically impaired children with gastroesophageal reflux: prospective study. Hong Kong Med J 2001; 7:356–359.
578. Bohmer CJ, Klinkenberg-Knol EC, Niezen-de Boer RC, et al
. The prevalence of gastro-oesophageal reflux disease based on non-specific symptoms in institutionalized, intellectually disabled individuals. Eur J Gastroenterol Hepatol 1997; 9:187–190.
579. Miele E, Staiano A, Tozzi A, et al
. Clinical response to amino acid-based formula in neurologically impaired children with refractory esophagitis. J Pediatr Gastroenterol Nutr 2002; 35:314–319.
580. Sleigh G, Brocklehurst P. Gastrostomy feeding in cerebral palsy: a systematic review. Arch Dis Child 2004; 89:534–539.
581. Sleigh G, Sullivan PB, Thomas AG. Gastrostomy feeding versus oral feeding alone for children with cerebral palsy. Cochrane Database Syst Rev
582. Razeghi S, Lang T, Behrens R. Influence of percutaneous endoscopic gastrostomy on gastroesophageal reflux: a prospective study in 68 children. J Pediatr Gastroenterol Nutr 2002; 35:27–30.
583. Catto-Smith AG, Jimenez S. Morbidity and mortality after percutaneous endoscopic gastrostomy in children with neurological disability. J Gastroenterol Hepatol 2006; 21:734–738.
584. Samuel M, Holmes K. Quantitative and qualitative analysis of gastroesophageal reflux after percutaneous endoscopic gastrostomy. J Pediatr Surg 2002; 37:256–261.
585. Gossler A, Schalamon J, Huber-Zeyringer A, et al
. Gastroesophageal reflux and behavior in neurologically impaired children. J Pediatr Surg 2007; 42:1486–1490.
586. Vernon-Roberts A, Sullivan PB. Fundoplication versus post-operative medication for gastro-oesophageal reflux in children with neurological impairment undergoing gastrostomy. Cochrane Database Syst Rev
587. Koivusalo A, Pakarinen MP, Rintala RJ. The cumulative incidence of significant gastrooesophageal reflux in patients with oesophageal atresia with a distal fistula–a systematic clinical, pH-metric, and endoscopic follow-up study. J Pediatr Surg 2007; 42:370–374.
588. Bagolan P, Iacobelli Bd B, De Angelis P, et al
. Long gap esophageal atresia and esophageal replacement: moving toward a separation? J Pediatr Surg 2004; 39:1084–1090.
589. Taylor AC, Breen KJ, Auldist A, et al
. Gastroesophageal reflux and related pathology in adults who were born with esophageal atresia: a long-term follow-up study. Clin Gastroenterol Hepatol 2007; 5:702–706.
590. Deurloo JA, Ekkelkamp S, Bartelsman JF, et al
. Gastroesophageal reflux: prevalence in adults older than 28 years after correction of esophageal atresia. Ann Surg 2003; 238:686–689.
591. Pultrum BB, Bijleveld CM, de Langen ZJ, et al
. Development of an adenocarcinoma of the esophagus 22 years after primary repair of a congenital atresia. J Pediatr Surg 2005; 40:e1–e4.
592. Krug E, Bergmeijer JH, Dees J, et al
. Gastroesophageal reflux and Barrett's esophagus in adults born with esophageal atresia. Am J Gastroenterol 1999; 94:2825–2828.
593. Konkin DE, O'Hali WA, Webber EM, et al
. Outcomes in esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2003; 38:1726–1729.
594. Adzick NS, Fisher JH, Winter HS, et al
. Esophageal adenocarcinoma 20 years after esophageal atresia repair. J Pediatr Surg 1989; 24:741–744.
595. Sistonen SJ, Koivusalo A, Lindahl H, et al
. Cancer after repair of esophageal atresia: population-based long-term follow-up. J Pediatr Surg 2008; 43:602–605.
596. Leeuwenburgh I, Van Dekken H, Scholten P, et al
. Oesophagitis is common in patients with achalasia after pneumatic dilatation. Aliment Pharmacol Ther 2006; 23:1197–1203.
597. Jaakkola A, Reinikainen P, Ovaska J, et al
. Barrett's esophagus after cardiomyotomy for esophageal achalasia. Am J Gastroenterol 1994; 89:165–169.
598. Roberts KE, Duffy AJ, Bell RL. Controversies in the treatment of gastroesophageal reflux and achalasia. World J Gastroenterol 2006; 12:3155–3161.
599. Hassall E, Israel DM, Davidson AG, et al
. Barrett's esophagus in children with cystic fibrosis: not a coincidental association. Am J Gastroenterol 1993; 88:1934–1938.
600. Malfroot A, Vandenplas Y, Verlinden M, et al
. Gastroesophageal reflux and unexplained chronic respiratory disease in infants and children. Pediatr Pulmonol 1987; 3:208–213.
601. Boesch RP, Acton JD. Outcomes of fundoplication in children with cystic fibrosis. J Pediatr Surg 2007; 42:1341–1344.
602. Radford PJ, Stillwell PC, Blue B, et al
. Aspiration complicating bronchopulmonary dysplasia. Chest 1995; 107:185–188.
603. Akinola E, Rosenkrantz TS, Pappagallo M, et al
. Gastroesophageal reflux in infants <32 weeks gestational age at birth: lack of relationship to chronic lung disease. Am J Perinatol 2004; 21:57–62.
604. Young LR, Hadjiliadis D, Davis RD, et al
. Lung transplantation exacerbates gastroesophageal reflux disease. Chest 2003; 124:1689–1693.
605. Suen HC, Hendrix H, Patterson GA. Special article: physiologic consequences of pneumonectomy. Consequences on the esophageal function. 1999. Chest Surg Clin N Am 2002; 12:587–595.
606. Palmer SM, Miralles AP, Howell DN, et al
. Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation. Chest 2000; 118:1214–1217.
607. Dhillon AS, Ewer AK. Diagnosis and management of gastro-oesophageal reflux in preterm infants in neonatal intensive care units. Acta Paediatr 2004; 93:88–93.
608. Malcolm WF, Gantz M, Martin RJ, et al
. Use of medications for gastroesophageal reflux at discharge among extremely low birth weight infants. Pediatrics 2008; 121:22–27.
609. Jadcherla SR. Manometric evaluation of esophageal-protective reflexes in infants and children. Am J Med 2003; 115(Suppl 3A):157S–160S.
610. Jadcherla SR, Gupta A, Fernandez S, et al
. Spatiotemporal characteristics of acid refluxate and relationship to symptoms in premature and term infants with chronic lung disease. Am J Gastroenterol 2008; 103:720–728.
611. Finer NN, Higgins R, Kattwinkel J, et al
. Summary proceedings from the apnea-of-prematurity group. Pediatrics 2006; 117:S47–51.
612. Poets CF. Gastroesophageal reflux: a critical review of its role in preterm infants. Pediatrics 2004; 113:e128–e132.
613. Misra S, Macwan K, Albert V. Transpyloric feeding in gastroesophageal-reflux-associated apnea in premature infants. Acta Paediatr 2007; 96:1426–1429.
614. Snel A, Barnett CP, Cresp TL, et al
. Behavior and gastroesophageal reflux in the premature neonate. J Pediatr Gastroenterol Nutr 2000; 30:18–21.
615. Fuloria M, Hiatt D, Dillard RG, et al
. Gastroesophageal reflux in very low birth weight infants: association with chronic lung disease and outcomes through 1 year of age. J Perinatol 2000; 20:235–239.
616. Kaijser M, Akre O, Cnattingius S, et al
. Preterm birth, low birth weight, and risk for esophageal adenocarcinoma. Gastroenterology 2005; 128:607–609.
617. Akre O, Forssell L, Kaijser M, et al
. Perinatal risk factors for cancer of the esophagus and gastric cardia: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2006; 15:867–871.
This article has been cited 48 time(s).
Computer Methods and Programs in BiomedicineSoftware for symptom association analysis in pediatric gastroesophageal reflux diseaseComputer Methods and Programs in Biomedicine
European Archives of Oto-Rhino-LaryngologyAre contrast swallows a relevant investigation for paediatric stridor?European Archives of Oto-Rhino-Laryngology
American Journal of Physiology-Gastrointestinal and Liver PhysiologyPhysiology of esophageal sensorimotor malfunctions in neonatal neurological illnessAmerican Journal of Physiology-Gastrointestinal and Liver Physiology
Journal of Parenteral and Enteral NutritionThe Incidence of Oropharyngeal Dysphagia in Infants With GERD-Like SymptomsJournal of Parenteral and Enteral Nutrition
Gastroesophageal reflux in pediatrics; (patho)physiology and new insights in diagnostics and treatment
Minerva Pediatrica, 64(1):
Journal of Pediatric SurgeryGastric emptying in children with gastroesophageal reflux and in healthy childrenJournal of Pediatric Surgery
PediatricsCLINICAL REPORT Gastroesophageal Reflux: Management Guidance for the PediatricianPediatrics
PediatricsInfluence of "GERD" Label on Parents' Decision to Medicate InfantsPediatrics
PediatricsThe Hazards of Medicalizing Variants of NormalPediatrics
Journal of PediatricsAcid Suppression and the Risk of Clostridium difficile InfectionJournal of Pediatrics
Journal of PediatricsEfficacy and Safety of Once-Daily Esomeprazole for the Treatment of Gastroesophageal Reflux Disease in Neonatal PatientsJournal of Pediatrics
Current Allergy & Clinical Immunology
Gastro-Oesophageal Reflux and Asthma in Children - Comorbidity or Coincidence?
Current Allergy & Clinical Immunology, 25(2):
World Journal of Surgical OncologyThe role of the 5-hydroxytryptamine pathway in reflux-induced esophageal mucosal injury in ratsWorld Journal of Surgical Oncology
Diseases of the EsophagusAnti-reflux surgery for patients with esophageal atresiaDiseases of the Esophagus
Biological conditions affecting chronic inflammation in upper airways in children
Jornal De PediatriaDigestive tract neural control and gastrointestinal disorders in cerebral palsyJornal De Pediatria
Journal of PediatricsDiagnostic Accuracy of Tests in Pediatric Gastroesophageal Reflux DiseaseJournal of Pediatrics
Journal of Gastrointestinal SurgeryComplete Versus Partial Fundoplication in Children with Gastroesophageal Reflux Disease: Results of a Systematic Review and Meta-analysisJournal of Gastrointestinal Surgery
NutritionPractical algorithms for managing common gastrointestinal symptoms in infantsNutrition
Neurogastroenterology and MotilityThe binomial symptom index: toward an optimal method for the evaluation of symptom association in gastroesophageal refluxNeurogastroenterology and Motility
Journal of Paediatrics and Child HealthDiagnosing gastro-oesophageal reflux disease or lactose intolerance in babies who cry a lot in the first few months overlooks feeding problemsJournal of Paediatrics and Child Health
Journal of Paediatrics and Child HealthMewling and puking: Infantile gastroesophageal reflux in the 21st centuryJournal of Paediatrics and Child Health
Pediatric DrugsGastroesophageal Reflux Disease in Neonates and Infants When and How to TreatPediatric Drugs
Turkish Journal of GastroenterologyWhat is the diagnostic utility of endoscopic scoring systems in children?Turkish Journal of Gastroenterology
ChestA Multicenter Study on Chronic Cough in Children Burden and Etiologies Based on a Standardized Management PathwayChest
Neurogastroenterology and MotilityEvaluation of esophageal motor function in clinical practiceNeurogastroenterology and Motility
Journal of PediatricsGastroesophageal Reflux, Esophageal Function, Gastric Emptying, and the Relationship to Dysphagia before and after Antireflux Surgery in ChildrenJournal of Pediatrics
Diseases of the EsophagusSymptom index P-value and symptom sensitivity index P-value to determine symptom association between apnea and reflux in premature infants at termDiseases of the Esophagus
Diseases of the EsophagusBaseline esophageal impedance according to different time intervalsDiseases of the Esophagus
Canadian Veterinary Journal-Revue Veterinaire Canadienne
Prospective medical evaluation of 7 dogs presented with fly biting
Canadian Veterinary Journal-Revue Veterinaire Canadienne, 53():
Physical & Occupational Therapy in PediatricsOral-Motor Function and Feeding InterventionPhysical & Occupational Therapy in Pediatrics
Canadian Family Physician
Proton pump inhibitors for irritable infants
Canadian Family Physician, 59(2):
Journal of PediatricsManagement of Apparent Life-Threatening Events in Infants: A Systematic ReviewJournal of Pediatrics
Neurogastroenterology and MotilityEffect of lateral positioning on gastroesophageal reflux (GER) and underlying mechanisms in GER disease (GERD) patients and healthy controlsNeurogastroenterology and Motility
World Journal of PediatricsEffect of proton pump inhibition on acid, weakly acid and weakly alkaline gastro-esophageal reflux in childrenWorld Journal of Pediatrics
Journal of PediatricsPrognostic Values of Multichannel Intraluminal Impedance and pH Monitoring in Newborns with Symptoms of Gastroesophageal Reflux DiseaseJournal of Pediatrics
Biomed Research InternationalNonpharmacological Management of Gastroesophageal Reflux in Preterm InfantsBiomed Research International
Scandinavian Journal of GastroenterologyThe role of baseline impedance as a marker of mucosal integrity in children with gastro esophageal reflux diseaseScandinavian Journal of Gastroenterology
Diagnostic testing and management of gastroesophageal reflux disease (GERD) in children
Minerva Pediatrica, 64(6):
Pediatric AnnalsDysphagia and Gastroesophageal Reflux Disease: Dilemmas in Diagnosis and Management in Children with Neurological ImpairmentPediatric Annals
Monatsschrift KinderheilkundeGastroesophageal reflux disease. International evidence-based consensus on the definition of GERD in children and adolescentsMonatsschrift Kinderheilkunde
Bmc PediatricsGastroesophageal reflux symptoms in infants in a rural population: longitudinal data over the first six monthsBmc Pediatrics
Annals of PharmacotherapyEffectiveness and Safety of Proton Pump Inhibitors in Infantile Gastroesophageal Reflux DiseaseAnnals of Pharmacotherapy
Diagnosis and Management of Gastroesophageal Reflux Disease (GERD): An Indian Perspective
Indian Pediatrics, 50(1):
Pediatric Surgery InternationalAnastomotic strictures and endoscopic dilatations following esophageal atresia repairPediatric Surgery International
European Journal of Pediatric SurgeryGastroesophageal Reflux after Repair of Esophageal AtresiaEuropean Journal of Pediatric Surgery
Gastroenterology Research and PracticePharmacological Therapy of Gastroesophageal Reflux in Preterm InfantsGastroenterology Research and Practice
Journal of Pediatric Gastroenterology and NutritionData Analysis and Interpretation in Impedance Outcome StudiesJournal of Pediatric Gastroenterology and Nutrition
Clinical practice guidelines; Diagnostic tests; Gastroesophageal reflux (GER); Gastroesophageal reflux disease (GERD); Therapeutic modalities
© 2009 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read