Gastroesophageal Reflux PEDIATRIC EVALUATION AND MANAGEMENT

Gastroesophageal Reflux PEDIATRIC EVALUATION AND MANAGEMENT
This slide set provides an overview of pediatric gastroesophageal reflux (GER). Information on the epidemiology, pathophysiology, and clinical manifestations of gastroesophageal reflux disease (GERD) are reviewed. Recommendations for the evaluation and management of infants and children with GER are presented, based on the clinical practice guidelines of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) [1]. The NASPGHAN guidelines, which are evidence based, were published in 2001 in the Journal of Pediatric Gastroenterology and Nutrition and are also available on (click on “Medical Professionals” and then “Position Papers”). Reference 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. Evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32:S1-31. Craig A. Friesen Children’s Mercy Hospital Kansas City, MO

Definitions GER Passage of gastric contents into esophagus GERD
Symptoms or complications that may occur when gastric contents reflux into esophagus or oropharynx Regurgitation Passage of refluxed gastric contents into oral pharynx Vomiting Expulsion of refluxed gastric contents from mouth Gastroesophageal reflux (GER) is defined as passage of gastric contents into the esophagus. GER is a normal physiologic process that occurs throughout the day in healthy infants, children, and adults. Gastroesophageal reflux disease (GERD) occurs when gastric contents reflux into the esophagus or oropharynx and produce symptoms. Regurgitation is defined as passage of refluxed gastric contents into the oral pharynx. Vomiting is defined as expulsion of the refluxed gastric contents from the mouth. During infancy, GER is common and most often manifests as vomiting. Vomiting resolves spontaneously in nearly all healthy infants within the first 18 months of life.

Warning Signals Suggestive of a Non-GER Diagnosis
Bilious or forceful vomiting Hematemesis or hematochezia Abdominal tenderness or distention Onset of vomiting after 6 months of life Fever, lethargy, hepatosplenomegaly Macrocephaly, microcephaly, seizures Recurrent vomiting History and physical exam During the history-taking and physical examination of an infant with recurrent vomiting, a number of warning signals, listed in this slide, can suggest a diagnosis other than GER. Are there warning signals? Adapted from Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Signs of Complicated GERD
Recurrent vomiting Poor weight gain Excessive crying or irritability Feeding problems Respiratory problems, including: wheezing stridor recurrent pneumonia History and physical exam Are there warning signals? During the history-taking and physical examination of an infant with recurrent vomiting, it is also important to determine whether any signs of complicated GERD are present. Are there signs of complicated GERD? Adapted from Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Clinical Predictors of GERD
Subjective symptom descriptions are unreliable in infants and children No symptoms or symptom clusters predict GERD complications No symptoms/clusters predict infants likely to respond to treatment ?diagnosis can be made in adolescents with typical heartburn symptoms

Cry Fuss Time in Response to Omeperazole in Infants with Esophagitis and /or Abnormal PH Study
(Mins/24 Hours) Moore, Et al: J Pediatr, 2003

Open Label Omeperazole in Adolescents with Heartburn, Epigastria Pain, and Acid Regurgitation
Moderate Severe Symptoms Gold, et al: JPGN, 2007

Esophageal pH Monitoring
Advantages Detects episodes of acid reflux Determines temporal association between acid GER and symptoms Assesses adequacy of H2RA or PPI dosage in unresponsive patients Limitations Cannot detect nonacidic reflux Cannot detect GER complications associated with “normal” range of GER Not useful in detecting association between GER and apnea unless combined with other techniques Esophageal pH monitoring measures the frequency and duration of acid reflux episodes and is used widely as an index of esophageal acid exposure. It is useful for establishing the presence of abnormal acid reflux, for determining whether there is a temporal association between acid reflux and frequently occurring symptoms, and for assessing the adequacy of dosage of histamine-2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) in unresponsive patients. It may be used to determine if a patient is at increased risk for airway complications of GER. This test cannot detect non-acidic reflux episodes, such as occur postprandially in infants, or GER complications such as an apparently life-threatening event (ALTE) or aspiration pneumonia when they are associated with brief reflux episodes that are within the range of “normal” GER. Esophageal pH monitoring is useful for detecting apnea only if performed simultaneously with measurement of respiration and chest wall movement.

Non-Acid Reflux in Relation to Meals in Infants (N=34)
% of Total GER Episodes Time After Meal Condino, et al; JPGN, 2006

Physiologic Gastroesophageal Reflux (Mean upper limit of normal)
Infants (N=509) Children (N=48) Adults (N=432) No. of daily reflux episodes 73 25 45 No. of reflux episodes > 5 min 9.7 6.8 3.2 Reflux index (% of time pH < 4) 11.7% 5.4% 6% GER is a physiologic process that is more common in infants than it is in older children and adults. In separate pH studies, the number of daily asymptomatic acid reflux episodes, the number of daily episodes lasting >5 minutes, and the reflux index (percent of total time that esophageal pH is <4) were all higher in healthy infants than in the two older age groups [1-6]. References 1. Vandenplas Y, Goyvaerts H, Helven R, Sacre L. Gastroesophageal reflux, as measured by 24-hour pH monitoring, in 509 healthy infants screened for risk of sudden infant death syndrome. Pediatrics 1991;88: 2. Euler AR, Byrne WJ. Twenty-four-hour esophageal intraluminal pH probe testing: a comparative analysis. Gastroenterology 1981;80: 3. Sondheimer JM. Continuous monitoring of distal esophageal pH: a diagnostic test for gastroesophageal reflux in infants. J Pediatr 1980;96:804-7. 4. Boix-Ochoa J, Lafuenta JM, Gil-Vernet JM. Twenty-four-hour esophageal pH monitoring in Twenty-four-hour. J Pediatr Surg 1980;15:74-8. 5. Jamieson JR, Stein HJ, DeMeester TR, et al. Ambulatory 24-h esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity, and reproducibility. Am J Gastroenterol 1992;87: 6. Quigley EM. 24-h pH monitoring for gastroesophageal reflux disease: already standard but not yet gold? Am J Gastroenterol 1992;87: Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Difficulties in Interpreting pH Studies
Normal ranges were determined with equipment and electrodes no longer in use ? Reproducibility Sensitivity and specificity not well established ? Correlation with severity and/or complications

Infant Gastroesophageal Reflux
45-90% OF GER EPISODES ARE NON-ACIDIC

Multiple Intraluminal Electrical Impedance Measurement
Advantages Detects nonacidic GER episodes Detects brief (<15 s) acidic GER episodes Useful for studying respiratory symptoms and GER in infants Limitations Normal values in pediatric age groups not yet defined Analysis of tracings time-consuming Portable device unavailable for outpatient studies pH channel pH 4 Z 1 Impedance channels Multiple intraluminal electrical impedance measurement (IMP) is a research tool developed in the late 1980s. IMP is pH independent, capable of detecting nonacidic as well as acidic GER episodes [1]. Thus, the technique is useful for investigating clinical situations of gastric hypoacidity. IMP may also be useful for describing the physiology of reflux clearance and swallowing. Unlike pH monitoring, IMP can detect postprandial GER episodes, which have a pH>4 because of neutralization by ingested food. IMP also can identify acidic reflux episodes that are too brief (<15 seconds) to be detected on pH monitoring. In infants, nonacidic GER has been documented in association with respiratory symptoms. Studies using IMP have documented a strong temporal association between GER episodes and irregular breathing [2]. Such findings have led investigators to hypothesize that apneic episodes in infants may be caused by “overreaction” of a protective neurorespiratory reflex. There are current limitations to its use [1]: Normal values in pediatric age groups remain to be defined. Software for the analysis of IMP tracings is needed, as manual and visual interpretation is time consuming. A portable recording device is currently unavailable for outpatient studies. Nonacidic GER depicted on IMP tracing. Arrow indicates bolus passage from distal (Z6) to proximal (Z1). Reprinted with permission from Wenzl, 2002 [1]. References 1. Wenzl TG. Investigating esophageal reflux with the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 2002;34:261-8. 2. Wenzl TG, Silny J, Schenke S, Peschgens T, Heimann G, Skopnik H. Gastroesophageal reflux and respiratory phenomena in infants: status of the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 1999;28:423-8. Z 4 t

PH Study Vs. Impedance for Correlating GER with Respiratory Symptoms in Children
33.3% % Positive Symptom Indices 5.6% Rosen & Nurko; Am J Gastro, 2004

Presenting Symptoms and Signs of GERD
Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next slides discuss recurrent vomiting in infants. Adapted from Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Prevalence of Regurgitation in Infancy
 1 time a day  4 times a day % of Infants Regurgitation is the most common manifestation of GER in childhood. A cross-sectional survey completed by 948 parents showed that the prevalence rate of regurgitation (at least 1 episode daily) was 50% in 0- to 3-month-old infants, reached a peak of 67% at 4 months, and dropped dramatically to 5% in 10- to 12-month-old infants [1]. A similar pattern was reported for regurgitation of at least 4 episodes daily. Many subjects in this survey “outgrew” GER by 7 months and most by 1 year. At 1-year follow-up, infants with previously reported daily regurgitation no longer were symptomatic—not one of their parents described spitting up as a current problem [2]. These findings support the concept that GER in most infants and children is a physiologic, self-limited condition. References 1. Nelson SP, Chen EH, Syniar GM, Christoffel KK. Prevalence of symptoms of gastroesophageal reflux during infancy. Arch Pediatr Adolesc Med 1997;151: 2. Nelson SP, Chen EH, Syniar GM, Christoffel KK. One-year follow-up of symptoms of gastroesophageal reflux during infancy. Pediatrics 1998;102(6):1470. Abstr e67. 0-3 4-6 7-9 10-12 Age (months) Adapted from Nelson et al, Arch Pediatr Adolesc Med 1997;151:569

Management of Infants With Recurrent Vomiting
History & physical exam generally sufficient Parental education warning signals reassurance Consider thickened formula hypoallergenic formula Pharmacotherapy not recommended If no resolution by months consider upper GI series or other test consider pediatric GI referral The classical presentation of uncomplicated GER is effortless, painless vomiting in a well-appearing child with normal growth, often referred to as a “happy spitter.” In general, the diagnosis of uncomplicated GER can be established by a thorough history and physical examination, with attention to warning signals that suggest other diagnoses. An upper GI series or other diagnostic test is not required unless GI obstruction is suspected. In the infant with uncomplicated GER, parental education, reassurance, and anticipatory guidance are recommended. Treatment options include thickening of formula and possibly a 1- or 2-week trial of a hypoallergenic formula. Generally pharmacotherapy is not recommended. If symptoms worsen or do not improve by months, further reevaluation is recommended, including an upper GI series or other test. Consultation with a pediatric gastroenterologist should be considered. Photo courtesy of Alejandro F. Flores, MD. No warning signals or signs of complicated GER Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next slides discuss recurrent vomiting and poor weight gain in infants.

Infant With Recurrent Vomiting and Poor Weight Gain
If warning signals present Consider other diagnoses If inadequate calories offered Educate and follow up closely If adequate calories offered Consider other causes of vomiting Metabolic disease Malabsorption Structural abnormalities In the infant with recurrent vomiting, a finding of growth failure alters clinical management. No well-controlled studies of diagnostic or treatment approaches are available. If warning signals are present, other causes of poor weight gain are to be considered. Expert opinion suggests assessment of the adequacy of calories being offered and ingested. If there is inadequate caloric intake, parents may need to be instructed to not limit formula intake. Close follow-up is warranted to determine if further evaluation is needed. If there is poor weight gain despite adequate caloric intake, further diagnostic evaluation is generally indicated to uncover other causes of vomiting, such as complete blood count (CBC), electrolytes, blood-urea-nitrogen (BUN), and review of newborn screening for galactosemia and maple sugar urine disease. An upper GI series is recommended to evaluate anatomy, and testing to assess the effectiveness of swallowing. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Management of Recurrent Vomiting and Poor Weight Gain
Rule out other causes Optimize medical management Consider: thickened feedings hypoallergenic formula Follow up closely Consider EGD and biopsy Consider nasogastric or nasojejunal tube feeding Management recommendations for the infant with recurrent vomiting and poor weight gain include the following: Rule out non-GER causes of vomiting. Optimize medical management. Consider formula thickening (to increase caloric density), a trial of a hypoallergenic formula, acid-suppressive therapy, prokinetic therapy, and prone positioning. Observation of the parent-child interaction may be warranted. Careful follow-up is warranted to ensure adequate weight gain. EGD with biopsy may be useful to determine if esophagitis is present and to delineate other causes of vomiting or poor weight gain. Finally, options to improve caloric intake include nasogastric (NG) or transpyloric (nasojejunal, or NJ) tube feedings. Surgery is rarely indicated. If weight gain is sustained, the patient can be expected to have decreasing requirements for interventions as the amount of vomiting and regurgitation decreases with age. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next slides discuss recurrent vomiting and irritability in infants.

Irritable Infant With Recurrent Vomiting
Minimal and conflicting evidence supports the contention that GER may cause irritability in infants Variations in parental perception of excessive crying/sleep disturbance complicate interpretation There is minimal and conflicting evidence to support the contention that GER may cause irritability in infants. Furthermore, variations in parental perception of excessive crying or sleep disturbance may complicate interpretation. The NASPGHAN guidelines summarized the very few pediatric studies that address this issue [1]. For example, using simultaneous video and esophageal pH monitoring, one study showed an association between grimacing and reflux episodes [2]. However, another pediatric study showed no correlation between excessive crying and esophagitis [3], while another noted no increase in irritability or back arching in infants with pathologic reflux [4]. Photo courtesy of Susan R. Orenstein, MD. References 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31. 2. 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: 3. Chadwick LM, Kurinczuk JJ, Hallam LA, et al. Clinical and endoscopic predictors of histological oesophagitis in infants. J Paediatr Child Health 1997;33: 4. Heine RG, Jaquiery A, Lubitz L, Cameron DJ, Catto-Smith AG. Role of gastro-oesophageal reflux in infant irritability. Arch Dis Child 1995;73:121-5.

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next topic is recurrent vomiting in the older child.

Older Child With Recurrent Vomiting
No published studies on management of child who has vomiting Diagnostic approach? No data available Expert opinion suggests upper GI series No consensus regarding utility of endoscopy Treatment approach? Consider prokinetic No published studies have described the management of a group of otherwise normal children who have recurrent vomiting after the age of 2 years. These children usually vomit, or regurgitate and reswallow, between once daily and once weekly. The vomiting is not associated with pain or discomfort, is not post-tussive, and is non-bloody and non-bilious. Often the vomiting occurs postprandially or with exertion. Expert opinion suggests that in most patients an upper GI series be performed to exclude an anatomic abnormality. Some experts also recommend EGD with biopsy, although in many cases there will be no abnormalities. If the vomiting persists and the child remains otherwise asymptomatic, a therapeutic trial of a prokinetic agent may be considered. If a good response to the prokinetic agent occurs, long-term therapy is an option. The small risks must be balanced with the potential improved quality of life in the individual and the family. In very unusual circumstances where the vomiting does not improve with pharmacotherapy and adversely affects the patient's lifestyle, surgical therapy is a consideration.

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next topic is heartburn in the older child and adolescent.

Management of Heartburn or Chest Pain
H2RA or PPI for 2-4 weeks Lifestyle changes: Weight loss if obese No alcohol No caffeine No smoking No change Improvement Heartburn or substernal burning pain may be caused by GER in the presence or absence of esophagitis. In older children and adolescents, the description and localization of esophageal pain is similar to that in adults, but in younger children, symptom description and localization may be atypical. Regurgitation of sour fluid into the mouth may be present. No randomized, placebo-controlled studies have been published evaluating the efficacy of either lifestyle or pharmacotherapy for the treatment of heartburn in children or adolescents. Expert opinion suggests the adoption of management approaches similar to those described for adult patients. Initial interventions of lifestyle changes, accompanied by a 2- to 4-week therapeutic trial of an H2RA or PPI, are recommended. If no improvement occurs, the child can be referred to a pediatric gastroenterologist for EGD with biopsy. If the child improves, therapy may be administered for 2 to 3 months. If symptoms recur as therapy is discontinued, referral for EGD is recommended to determine the presence and severity of esophagitis. Because persistent heartburn may have a substantial negative impact on a patient’s quality of life, long-term therapy can be continued with either a PPI or H2RA to provide symptom relief even in the absence of esophagitis. Episodic meal-induced heartburn in older children may be treated with antacids or an H2RA, as in adults. Symptoms recur EGD with biopsy Rx for 2-3 months Symptoms may occur in presence or absence of esophagitis

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next topic is dysphagia or feeding refusal.

Evaluation and Management of Dysphagia or Odynophagia
Infant GER not demonstrated to cause feeding difficulties Antireflux treatment not demonstrated to improve feeding Empiric therapy for GER not recommended If other symptoms suggest GERD  time-limited medical therapy Older Child/Adolescent Barium esophagram to identify: - anatomic abnormality - motility disorder Upper endoscopy with biopsy Treatment without diagnostic evaluation not recommended Esophagitis may cause discomfort or pain (odynophagia) or difficulty (dysphagia) with eating in infants and children. The older child is able to describe sensations that aid in discriminating between oropharyngeal and esophageal disorders. Complaints of chest pain or food being stuck in the chest generally indicate an esophageal disorder. In the older child or adolescent with symptoms suggestive of an esophageal cause of dysphagia or odynophagia, diagnostic evaluation usually begins with a radiographic contrast study (barium esophagram) to identify anatomic abnormalities, such as stricture or vascular rings, and motility disorders, such as achalasia. Upper endoscopy with biopsy is useful to determine the presence of esophagitis. If esophagitis is found, treatment of the underlying cause (e.g., reflux esophagitis, eosinophilic esophagitis, infectious esophagitis, or pill esophagitis) generally leads to symptom resolution. If the initial history suggests esophagitis, upper endoscopy may be performed as the initial diagnostic test. Treatment without prior diagnostic evaluation is not recommended. In the infant with feeding refusal, no studies have demonstrated that GER is causally related to the feeding difficulties. Nor has antireflux treatment been shown to improve feeding. Empiric therapy for GER is generally not recommended because a large variety of disorders may contribute to feeding problems. However, if there are other signs or symptoms to suggest GER, a time-limited course of antireflux medical therapy may be considered.

Differential Diagnosis of Esophagitis
Gastroesophageal reflux Food allergy or intolerance Primary eosinophilic esophagitis Drug induced Infection Candida herpes simplex cytomegalovirus In addition to GER, the differential diagnosis of esophagitis includes food allergy or intolerance. In patients with reflux symptoms unresponsive to even aggressive antireflux pharmacotherapy, the presence of intraepithelial eosinophils may be due to the ingestion of certain foods [1] or an allergy [2, 3]. In addition, esophageal inflammation may be idiopathic (primary), drug induced, or the result of or fungal or viral infections. References 1. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995;109: 2. Iacono G, Carroccio A, Cavataio F, Montalto G, Kazmierska I, Lorello D, Soresi M, Notarbartolo A. Gastroesophageal reflux and cow’s milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996;97:822-7. 3. Walsh SV, Antonioli DA, Goldman H, Fox VL, Bousvaros A, Leichtner AM, Furuta GT. Allergic esophagitis in children: a clinicopathological entity. Am J Surg Pathol 1999;23:390-6.

Respiratory Symptoms of GER
Apnea/ALTE Stridor and hoarseness Cough Wheezing Recurrent pneumonia Respiratory symptoms (such as apnea, apparently life-threatening events [ALTE], and hoarseness) and respiratory disorders (such as recurrent pneumonia) are well recognized as atypical manifestations of GER. However, the relationship between these conditions and GER can be difficult to establish. The confirmed presence of GER does not necessarily mean that it is the cause of a respiratory problem. GER may present solely as respiratory symptoms. In 39 neonates and infants with respiratory symptoms that warranted antireflux surgery, 64% had apnea, 31% pneumonia, 28% cyanosis, 18% cough, and 15% stridor [1]. A total of 38% reported coughing during feeding plus choking and wheezing. Most patients in this study received at least one incorrect, non-GER diagnosis to explain these symptoms. Reference 1. Krishnamoorthy M, Mintz A, Liem T, Applebaum H. Diagnosis and treatment of respiratory symptoms of initially unsuspected gastroesophageal reflux in infants. Am Surg 1994;60:783-5.

Prevalence of Gastroesophageal Reflux in Children With Pulmonary Disease
% of Patients A review of the published literature showed that the prevalence of GER in children with pulmonary disease ranged from 47% to 64% [1-7]. In these seven studies, the patient population ranged in number from 19 [4] to 82 [5]. Three studies evaluated just patients with asthma [1, 4, 6]; two evaluated patients with asthma or recurrent pneumonia [3, 5]; and one study evaluated patients with recurrent bronchitis [2]. In another study, patients had a diagnosis of asthma, bronchitis, nocturnal cough, pneumonia, pharyngitis, and/or laryngitis [7]. These studies suggest that GER may be a contributing factor in children with asthma and other pulmonary disorders. Slide courtesy of Stephen J. Sontag, MD. References 1. Friedland GW, Yamate M, Marinkovich VA. Hiatal hernia and chronic unremitting asthma. Pediatr Radiol 1973;1: 2. Danus O, Casar C, Larrain A, Pope CE II. Esophageal reflux—an unrecognized cause of recurrent obstructive bronchitis in children. J Pediatr 1976;89:220-4. 3. Euler AR, Byrne WJ, Ament ME, Fonkalsrud EW, Strobel CT, Siegel SC, Katz RM, Rachelefsy GS. Recurrent pulmonary disease in children: a complication of gastroesophageal reflux. Pediatrics 1979;63:47-51. 4. Shapiro GG, Christie DL. Gastroesophageal reflux in steroid-dependent asthma youths. Pediatrics 1979;63: 5. Berquist WE, Rachelefsky GS, Kadden M, Siegel SC, Katz RM, Fonkalsrud EW, et al. Gastroesophageal reflux-associated recurrent pneumonia and chronic asthma in children. Pediatrics 1981;68:29-35. 6. Martin ME, Grunstein MM, Larsen GL. The relationship of gastroesophageal reflux to nocturnal wheezing in children with asthma. Ann Allergy 1982;49: 7. Buts JP, Barudi C, Moulin D, Claus D, Cornu J, Otte JB. Prevalence and treatment of silent gastro-oesophageal reflux in children with recurrent respiratory disorders. Eur J Pediatr 1986;145: Shapiro et al, 1979 Friedland et al, 1973 Berquist et al, 1981 Danus et al, 1976 Buts et al, 1986 Euler et al, 1979 Martin et al, 1982

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next slides discuss apnea and ALTE.

ALTE Definition Frightening episode in infant that is characterized by: - apnea - change in color - change in muscle tone - choking or gagging and requires intervention by caretaker Potential causes - Cardiac disorder - Upper airway obstruction CNS disorder - Infection - GER - Intentional suffocation ALTE is defined as an episode in an infant that is frightening to the observer and characterized by a combination of apnea, change in color (cyanosis, pallor, rubor, etc), change in muscle tone (limpness, stiffness), or choking and gagging that requires intervention by the caregiver [1]. ALTEs can be caused by the conditions listed on this slide. It can be due to upper airway obstruction or central apnea as well as GER. Reference 1. National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, Sept 29 to Oct 1, Pediatrics 1987;79:292-9.

GER and ALTE Recurrent regurgitation in 60% to 70% of infants with ALTE Abnormal esophageal pH studies in 40% to 80% Relationship between GER and obstructive or mixed apnea most convincing when infant was: awake supine fed within past hour The prevalence of recurrent regurgitation or emesis in infants with ALTE is 60% to 70% [1]. About 40% to 80% of infants have abnormal esophageal pH studies. Investigations in unselected patients with ALTE have not demonstrated a convincing temporal relationship between esophageal acidification and apnea or bradycardia. Patients usually had apneic episodes unrelated to GER episodes. The relationship between GER and episodes of obstructive or mixed apnea was most convincing when the infant was awake, supine, and fed within the past hour [1]. Reference 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Association of GER with Apnea
Chest Wall Movement Nasal Air Flow Reflux may be the underlying cause in up to 20% of cases of infantile apnea [1]. A finding of greater than normal reflux, however, does not necessarily indicate a causal association in infants with apnea [2, 3]. Apnea related to reflux usually occurs when the infant is awake, supine, and fed within the past hour. It appears to be obstructive (with persistence of respiratory effort) rather than central (absence of respiratory effort), and may occur in infants with no history of regurgitation [4]. The tracings in this slide show obstructive apnea provoked by GER [5]. Obstructive apnea was characterized by a cessation of air flow (second channel from the top) during persisting chest wall movement (top channel). The apnea lasted about 24 seconds and occurred immediately after an episode of spontaneous acidic reflux, indicated by the decline in distal esophageal pH to <4. Obstructive apnea provoked by spontaneous GER. Tracings are from (top to bottom) impedance pneumotachography, which depicts chest wall movement; a nasal thermistor, which measures air flow at the nostril; and distal esophageal pH monitoring. Reprinted with permission from Herbst et al, 1979 [5]. References 1. Kahn A, Rebuffat E, Franco P, N’Duwimama M, Blum D. Apparently life-threatening events and apnea of infancy. In: Beckerman R, Brouilette R, Hunt C, eds. Respiratory Control Disorders in Infants and Children. Baltimore, Md; Williams & Wilkins: 1992; 2. Walsh JK, Farrell MK, Keenan WJ, Lucas M, Kramer M. Gastroesophageal reflux in infants: relation to apnea. J Pediatr 1981;99: 3. de Ajuriaguerra M, Radvanyl-Bouvet M, Huon C, Moriette G. Gastroesophageal reflux and apnea in prematurely born infants during wakefulness and sleep. Am J Dis Child 1991;145: 4. Colletti RB, Christie DL, Orenstein DR. Indications for pediatric esophageal pH monitoring: a medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1995;21: 5. Herbst JJ, Minton SD, Book LS. Gastroesophageal reflux causing respiratory distress and apnea in newborn infants. J Pediatr 1979;95:763-8. Esophageal pH Time (sec) Herbst et al, J Pediatr 1979;95:763

Management of GER-Associated ALTE
Esophageal pH monitoring is useful only if performed simultaneously with measurement of respiration and chest wall movement Infant is more likely to respond to antireflux therapy if: emesis or regurgitation is present at time of ALTE infant is awake obstructive apnea is present Therapeutic options include: thickened feedings acid suppression Antireflux surgery is considered only in severe cases No randomized studies have assessed the usefulness of esophageal pH monitoring in infants with ALTE [1]. Esophageal pH monitoring is useful to determine a temporal association between acid reflux and ALTE only if performed simultaneously with measurement of respiration and chest wall movement. The evidence suggests that infants with ALTE and GER are more likely to respond to antireflux therapy when gross emesis or oral regurgitation is present at the time of the ALTE, episodes occur in the awake infant, or ALTE is characterized by obstructive apnea. The effectiveness of medical therapy for GER-associated ALTE has not been adequately studied. Therapeutic options include thickened feedings, prokinetic therapy, and acid suppression. Since most infants improve with medical management, antireflux surgery is to be considered only in severe cases. Reference 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next series of slides discusses asthma.

Does GER Cause Asthma? GER Asthma
Patients with asthma are likely a heterogeneous group. Bronchospasm may have identifiable precipitants, which differ among patient subgroups: some may wheeze in response to inhaled or ingested allergens, others in response to GER, and still others during viral infections. GER is not a primary cause of asthma, although up to 50% of asthmatic children have esophagitis [1, 2]. GER likely exacerbates asthma by increasing airway hyperreactivity. Two mechanisms have been postulated: microaspiration of acidic refluxate into the bronchial tree and a vagally mediated esophagobronchial reflex. References 1. Shapiro GG, Christie DL. Gastroesophageal reflux in steroid-dependent asthmatic youths. Pediatrics 1979;63: 2. Baer M, Markku M, Nurminen J, Turjanmaa J, Pukander J, Vesikari T. Esophagitis and findings of long-term esophageal pH recording in children with repeated lower respiratory tract symptoms. J Pediatr Gastroenterol Nutr 1986;5:

Effect of Antireflux Pharmacotherapy in Children with Asthma
Clinical improvement or reduced dosages of antiasthmatic therapy in 63% of asthma patients with GER treated with: Conservative management Prokinetic monotherapy H2RA monotherapy 63% The NASPGHAN guidelines reviewed the published efficacy of antireflux pharmacotherapy in children with asthma [1]. From four case series reporting on 168 patients, clinical improvement or reduced dosages of bronchodilator and anti-inflammatory medications occurred in 63% of asthmatic patients treated with conservative management (positional therapy and thickened formula), cisapride, and ranitidine [2-5]. Adult studies suggested that the duration of therapy is important and aggressive acid suppression for at least 3 months may be necessary to reduce respiratory symptoms. References 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31. 2. Andze GO, Brandt ML, St Vil D, et al. Diagnosis and treatment of gastroesophageal reflux in 500 patients with respiratory symptoms: the value of pH monitoring. J Pediatr Surg 1991;26:295-9. 3. Berquist WE, Rachelefsky GS, Kadden M, et al. Gastroesophageal reflux-associated recurrent pneumonia and chronic asthma in children. Pediatrics 1981;68:29-35. 4. Tucci F, Resti M, Fontana R, et al. Gastroesophageal reflux and bronchial asthma: prevalence and effect of cisapride therapy. J Pediatr Gastroenterol Nutr 1993;17: 5. Gustafsson PM, Kjellman NI, Tibbling L. A trial of ranitidine in asthmatic children and adolescents with or without pathological gastro-oesophageal reflux. Eur Respir J 1992;5:201-6. Duration of therapy (>3 months) important (adult studies) N=168 pts in 4 case series Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Effect of Antireflux Surgery in Children With Asthma
Clinical improvement or reduced dosages of antiasthmatic therapy in 85% of children Persistent asthma requiring intensive steroid therapy before surgery GER most often confirmed by pH studies Failure of antireflux medical therapy did not preclude response to antireflux surgery 85% Striking results have been reported in asthmatic children following antireflux surgery [1]. In 6 case series, clinical improvement (decreased frequency and severity of asthmatic attacks) and reduced dosages of bronchodilator and anti-inflammatory medications occurred in 85% of 258 children who underwent antireflux surgery. It appears that the children all have severe persistent asthma requiring intensive steroid therapy before surgery. The diagnosis of GER was most often confirmed by esophageal pH studies. Failure of antireflux medical therapy did not preclude a favorable response to antireflux surgery. Reference 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31. N=258 pts in 6 case series Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Asthma: When to Treat for GERD
Persistent asthma and GER symptoms Persistent asthma and no GER symptoms Vigorous acid-suppressive therapy for 3 months, monitoring outcome variables Consider esophageal pH monitoring or empiric treatment trial in children with recurrent pneumonia nocturnal asthma > 1X weekly corticosteroid dependence If pH studies positive  3-month trial of antireflux medical therapy, monitoring outcome variables In children in whom symptoms of asthma and GER coexist, and in infants and toddlers with chronic vomiting or regurgitation and recurrent episodes of cough and wheezing, the NASPGHAN guidelines recommended a 3-month trial of vigorous acid-suppressive therapy. It was recommended that outcome variables (e.g., frequency of GER or asthma symptoms, symptom scores, changes in spirometry measurements) be determined prior to initiating therapy and then monitored during therapy. In patients with persistent asthma in whom GER symptoms are absent, esophageal pH monitoring was recommended in selected patients who are more likely to benefit from antireflux therapy. These included patients with radiographic evidence of recurrent pneumonia, patients with nocturnal asthma more than once a week, and patients requiring continuous oral corticosteroids or high-dose inhaled corticosteroids. If pH studies show an increased frequency or duration of esophageal acid exposure, a trial of prolonged antireflux medical therapy was recommended. Again, it was recommended that outcome variables be determined prior to initiating therapy and then monitored during therapy. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Aspiration Syndromes Interstitial lung disease & pulmonary fibrosis
Acid aspiration pneumonitis Aspiration pneumonia & pleural effusion Chronic pulmonary aspiration occurs when airway protective mechanisms are defective or overwhelmed and the lungs are contaminated with pharyngeal and/or gastric contents. The extent of pulmonary injury depends on multiple factors, including frequency, quantity, and composition of aspirate. The sequelae of aspiration include interstitial lung disease and pulmonary fibrosis, acid aspiration pneumonitis, and aspiration pneumonia with pleural effusion. This slide shows interstitial lung disease and pulmonary fibrosis secondary to GER with recurrent aspiration. Aspiration is more common in children with neurologic disorders, who often have impaired airway protective mechanisms, than in other children with GER symptoms. These children may also aspirate during swallowing. Generally, aspiration pneumonitis resolves spontaneously. There is an occasional bacterial superinfection, with new or progressive infiltrates after initial improvement. In about 10% of cases, a fulminant course ensues, with progressive respiratory failure in 24 to 48 hours. Bacterial pneumonia occurs in about 20% to 45% of patients who aspirate gastric contents. This may occur as early as 2 days and usually within 1 week of aspiration. The likely infecting organisms reflect mouth flora. Anaerobes outnumber aerobes by fivefold to tenfold. Gram-negative bacilli predominate in hospital-acquired aspiration pneumonia. About 40% of bacterial pneumonias are complicated by effusions and empyema. Interstitial lung disease and pulmonary fibrosis secondary to GER with recurrent aspiration; chest x-ray courtesy of Colin Rudolph, MD, PhD.

Aspiration From Swallowing or GER?
The underlying causes of recurrent pneumonia include aspiration from GER, aspiration during swallowing, anatomic abnormalities, foreign body, cystic fibrosis, and immunodeficiency [1]. Specific tests to detect aspiration are limited in sensitivity and may be difficult to interpret because small amounts of aspiration may occur without ill effect. One test consists of obtaining macrophages by pulmonary lavage during flexible bronchoscopy and staining for milk-derived lipid. Lipid-filled vacuoles can be observed in the cytoplasm, and the presence of large numbers of lipid-laden macrophages is suggestive of pulmonary aspiration [2]. However, considerable overlap in lipid content exists between normal controls, patients with other causes of pulmonary disease, and those with a history consistent with aspiration [3]. In addition, bronchoscopy with pulmonary lavage cannot distinguish between aspiration due to GER and aspiration during swallowing. The quantity of lipid-laden macrophages is thought to be important in making a diagnosis, but to date no system of measuring the extent of lipid infiltration has been found to be clinically useful. The higher the value on a lipid-laden alveolar macrophage (LLAM) score [4] or lipid-laden macrophage index (LLMI) [5], the greater the likelihood of chronic pulmonary aspiration, but studies have shown considerable overlap in results between patients with and without aspiration. Lipid-laden alveolar macrophages on pulmonary lavage; courtesy of Colin Rudolph, MD, PhD. References 1. Regelmann WE. Diagnosing the cause of recurrent and persistent pneumonia in children. Pediatr Ann 1993;22:561-8. 2. Nussbaum E, Maggi C, Mathis R, Galant SP. Association of lipid-laden alveolar macrophages and gastroesophageal reflux in children. J Pediatr 1987;110:190-4. 3. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31. 4. Ahrens P, Noll C, Kitz R, Willigens P, Zielen S, Hofmann D. Lipid-laden alveolar macrophages (LLAM): a useful marker of silent aspiration in children. Pediatr Pulmonol 1999;28:83-8. 5. Bauer ML, Lyrene RK. Chronic aspiration in children: evaluation of the lipid-laden macrophage index. Pediatr Pulmonol 1999;28: Lipid-Laden Macrophages

Aspiration From Swallowing or GER?
A barium esophagram and upper GI series may be ordered when respiratory complications of GER are suspected. Although not as sensitive or specific as other tests, they can rule out potential anatomic causes, such as an antral web or malrotation. These procedures also can demonstrate aspiration of stomach refluxate into the airway, supporting a diagnosis of GER. Nuclear scintigraphy offers some advantages over contrast radiography as a diagnostic tool. However, its value in predicting when GER is the cause of airway symptoms in infants and children has not been evaluated prospectively. The salivagram in this slide demonstrates radiolabeled saliva entering the tracheobronchial tree. Barium swallow (left) courtesy of Colin Rudolph, MD, PhD. Technetium-99m salivagram (anteroposterior view, right) courtesy of Harland S. Winter, MD. Barium Swallow Technetium-99m Salivagram

Causes of Recurrent Pneumonia in Children
Causes Frequency Aspiration 48 % Immune disorder 10 Congenital heart disease 9 Asthma 8 Respiratory tract anomaly 8 GER 5 Other/unknown 12 A retrospective review of medical records over a 10-year period at a tertiary care pediatric hospital determined the relative frequency of causes of recurrent pneumonia [1]. In this study, recurrent pneumonia was defined as 2 or more pneumonia episodes in a 1-year period or at least 3 during a lifetime. A total of 238 children hospitalized with pneumonia met the criteria for recurrent pneumonia. In order of frequency, underlying causes were oropharyngeal incoordination with aspiration syndrome (48%), immune disorder (10%), congenital heart disease (9%), asthma (8%), respiratory tract anomalies (8%), and GER (5%). Reference 1. Owayed AF, Campbell DM, Wang EE. Underlying causes of recurrent pneumonia in children. Arch Pediatr Adolesc Med 2000;154:190-4. N = 238 children hospitalized with pneumonia Owayed et al, Arch Pediatr Adolesc Med 2000;154:190

Recurrent Pneumonia and GER
GER can cause recurrent pneumonia in absence of esophagitis Normal esophageal pH studies do not exclude GER as a cause Before considering GER, rule out other causes neuromuscular disease or esophageal or laryngeal anatomic abnormalities Incidence of GER-related recurrent aspiration in otherwise healthy infants and children is rare GER can cause recurrent pneumonia in the absence of esophagitis. Nor do normal findings on esophageal pH studies exclude GER as a cause. Before considering GER as a cause of recurrent pneumonia, it is important to rule out other potential causes, such as an anatomic abnormality, aspiration during swallowing, foreign body, cystic fibrosis, or immunodeficiency [1]. Certain patient populations are prone to aspiration during swallowing and following GER episodes, including those with neuromuscular disease or a history of esophageal or laryngeal anatomic abnormalities. The incidence of GER-related recurrent aspiration in otherwise healthy infants and children is unknown but appears to be rare. Reference 1. Regelmann WE. Diagnosing the cause of recurrent and persistent pneumonia in children. Pediatr Ann 1993;22:561-8. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Management of Recurrent Pneumonia and GER
Combination of tests may aid in diagnosis flexible bronchoscopy with pulmonary lavage nuclear scintigraphy swallowing assessment (VSS, FEES) Severely impaired lung function  consider antireflux surgery balance potential benefits with potential complications Minimal pulmonary disease  consider medical therapy There is insufficient evidence to provide recommendations for a uniform approach to diagnosis and treatment. A combination of diagnostic tests may aid in diagnostic evaluation, including flexible bronchoscopy with pulmonary lavage (for lipid-laden macrophages), nuclear scintigraphy, and swallowing assessment. A videofluoroscopic swallowing study (VSS) or fiberendoscopic swallowing evaluation (FEES) may help identify at-risk patients. Often the clinician must make management decisions based on inconclusive information. If the patient has severely impaired lung function, it may be necessary to proceed with antireflux surgery to prevent further pulmonary damage. The potential benefits of surgery are balanced by the recognition of potential complications. If minimal pulmonary disease is present, medical therapy may be considered, with careful follow-up of pulmonary function. No controlled studies demonstrate the benefit of any medical therapy in preventing progression of chronic pulmonary disease caused by GER in children, but lifestyle and pharmacotherapy are options.

Recurrent vomiting in infant Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms The NASPGHAN guidelines reviewed various symptoms and signs associated with GER and presented recommendations for the evaluation and management of specific presentations in different pediatric age groups. The next slides discuss upper airway symptoms.

Normal Reflux laryngitis
Laryngeal inflammation can be a sequela of GER. Because abnormalities can present with very minimal subglottic acid exposure (even low levels of acid exposure can lead to airway narrowing), a fiberoptic laryngoscopic evaluation is preferable to dual-level esophageal pH monitoring and can distinguish posterior laryngeal inflammation from isolated laryngomalacia or other airway abnormalities. Laryngitis is manifested by hoarseness in verbal children and by a hoarse cry in nonverbal children. There are limited data on the association between GER and chronic laryngeal symptoms, such as cough and hoarseness. In a study of 21 children (aged 2 to 14 years) with chronic hoarseness (>3 months) and signs of posterior acid laryngitis, 13 (62%) had GER based on dual-channel esophageal pH monitoring [1]. In 7 (33%), the GER was severe (more than 3 times the upper limit of normal). Normal larynx (left) and reflux laryngitis with posterior laryngeal edema and erythema (right); endoscopic views courtesy of Colin Rudolph, MD, PhD. Reference 1. Gumpert L, Kalach N, Dupont C, Contencin P. Hoarseness and gastroesophageal reflux in children. J Laryngol Otol 1998;112:49-54. Normal Reflux laryngitis

Evaluation and Management of GER-Related Laryngeal Symptoms
Laryngoscopy generally indicated to rule out anatomic abnormalities of airway protection No randomized controlled trials of antireflux therapy in adults or children with laryngeal symptoms Adult studies suggest that therapeutic trial must last >3 months to adequately assess efficacy Clinical improvement followed by recurrence off treatment  association with GER There is insufficient evidence and experience to provide recommendations for a uniform approach to diagnosis and treatment. Evaluation of suspected GER-related laryngeal symptoms is complicated by a lack of uniform interpretation or laryngeal findings. Nonetheless, laryngoscopy is generally indicated to rule out potential anatomic abnormalities of airway protection, such as a laryngeal cleft. No randomized placebo-controlled treatment trials have assessed antireflux therapy in adults or children with GER-related laryngeal symptoms. Uncontrolled case series in children described symptomatic improvement. Adult studies suggest that a therapeutic trial must be prolonged (longer than 3 months) to adequately assess efficacy. If there is clinical improvement, followed by recurrence off treatment, it is reasonable to suspect a pathogenic role for GER. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Pharmacotherapy Antacids Histamine-2 receptor antagonists
Proton pump inhibitors Prokinetic agents Surface agents The two major pharmacotherapies for GERD, acid suppressants and prokinetic agents, reduce the amount of acid refluxate to which the esophagus or respiratory tract is exposed, thereby preventing symptoms and promoting healing. Antacids neutralize gastric acid and are commonly used for the short-term relief of intermittent GER symptoms in children and adolescents. Although there appears to be little risk to this approach, it has not been formally studied. In infants, treatment with aluminum-containing antacids significantly increases plasma aluminum levels [1]. Because more convenient and safe alternatives are available, chronic antacid therapy is generally not recommended. Surface agents include sodium alginate and sucralfate gel. Sucralfate adheres to lesions and protects the esophageal mucosal surface. Sucralfate is an aluminum complex, and potential adverse effects of aluminum in infants and children need to be considered. Available data are inadequate for determining sucralfate safety or efficacy in children. Reference 1. Tsou VM, Young RM, Hart MH, et al. Elevated plasma aluminum levels in normal infants receiving antacids containing aluminum. Pediatrics 1991;87:

Inhibition of Acid Secretion in Gastric Parietal Cell
Histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) suppress gastric acid secretion via different actions on the parietal cell [1]. The former inhibits the binding of histamine to specific (histamine-2) receptors on the luminal surface. Activation of these receptors by histamine stimulates the parietal cell to secrete acid, by triggering a sequence of intracellular events that lead to activation of an enzyme called hydrogen/potassium adenosine triphosphatase (H+,K+-ATPase). H+,K+-ATPase is the final step in acid production and is also known as the proton pump. H+,K+-ATPase inhibitors, or proton pump inhibitors, cross the membrane of parietal cells and accumulate in the secretory canaliculus, where they bind to and inhibit active proton pumps. As this diagram shows, the parietal cell may be stimulated to secrete acid by substances other than histamine, such as acetylcholine and gastrin. Inactivation of the proton pump also blocks the effects of histamine and other stimuli. Diagram adapted from Sanders SW: “Pathogenesis and treatment of acid peptic disorders: comparison of proton pump inhibitors with other antiulcer agents.” Clin Therapeutics, vol 18, pp Copyright 1996 by Excerpta Medica Inc. Reference 1. Robinson M. Innovations in acid suppression therapy: review of the proton pump inhibitors rabeprazole and pantoprazole. Pract Gastroenterol 1999;23(August suppl):1-20. Adapted from Sanders SW, Clin Therapeutics 18, Copyright 1996 by Excerpta Medica Inc.

Effect of H2RAs on Healing of Esophagitis
N = 32 children with esophagitis treated with cimetidine mg/kg/d or placebo for 12 weeks Cimetidine Placebo 71% Esophagitis Healing 20% Significant symptom improvement with cimetidine, not placebo Cucchiara et al, J Pediatr Gastroenterol Nutr 1989;8:150 N = 26 children with esophagitis treated with nizatidine 10 mg/kg/d or placebo for 8 weeks Nizatidine Placebo 69% Esophagitis Healing Two randomized placebo-controlled trials have evaluated H2RAs in children with reflux esophagitis. In 32 children treated with placebo or cimetidine mg/kg per day for 12 weeks, the esophagitis healed in 12/17 (71%) cimetidine-treated patients, compared with 3/15 (20%) placebo-treated patients (p<.01) [1]. The active treatment arm showed significant improvements in clinical and histopathology scores, while there was no improvement with placebo. In 26 children with mild to moderate esophagitis, nizatidine 10 mg/kg per day (in divided doses) for 8 weeks was more effective than placebo for healing of esophagitis (9/13, or 69%, versus 2/13, or 15%, p<.007) [2]. “Vomiting” was reduced in both treatment arms. Significant improvement in other GERD symptoms was reported only with nizatidine. References 1. 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;8:150-6. 2. Simeone D, Caria MC, Miele E, Staiano A. Treatment of childhood peptic esophagitis: a double-blind placebo-controlled trial of nizatidine. J Pediatr Gastroenterol Nutr 1997;25:51-5. 15% “Vomiting” reduced in both treatment arms; significant improvement in other GERD symptoms only with nizatidine Simeone et al, J Pediatr Gastroenterol Nutr 1997;25:51

Recommended Oral H2RA Dosages for GERD
Infants and Children Adults Cimetidine 40 mg/kg/day divided TID or QID 1600 mg/day Famotidine 1 mg/kg/day divided BID 20 or 40 mg BID Nizatidine 10 mg/kg/day divided BID 150 mg BID or 300 mg HS Ranitidine 5-10 mg/kg/day divided TID 150 mg BID - QID The NASPGHAN guidelines recommended these dosages of histamine-2 receptor antagonists (H2RAs) for use in infants and children [1]. Recommended dosages in adults with GERD are also listed. Reference 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

Proton Pump Inhibition
The enzyme H+,K+-ATPase, or proton pump, is present in the canalicular membrane of gastric parietal cells, where it secretes hydrochloric acid and hydrogen ion (H+) is exchanged for potassium ion (K+) [1]. H+,K+-ATPase inhibitors, or proton pump inhibitors (PPIs), cross the membrane of parietal cells and accumulate in the secretory canaliculus. In an acidic environment, PPIs are converted to an activated form (sulfenamides). The activated PPIs bind to and inhibit active proton pumps [2]. PPIs are most effective when the parietal cell is stimulated to secrete acid in response to a meal [3]. Diagram adapted from Sanders SW: “Pathogenesis and treatment of acid peptic disorders: comparison of proton pump inhibitors with other antiulcer agents.” Clin Therapeutics, vol 18, pp Copyright 1996 by Excerpta Medica Inc. References 1. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors: pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998;56: 2. Robinson M. Innovations in acid suppression therapy: review of the proton pump inhibitors rabeprazole and pantoprazole. Pract Gastroenterol 1999;23(August suppl):1-20. 3. Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology 2000;118:S9-31. Adapted from Sanders SW, Clin Therapeutics 18, Copyright 1996 by Excerpta Medica Inc.

PPIs in Infants and Children With GERD
Pharmacologic studies with omeprazole and lansoprazole No randomized placebo-controlled trials Multiple case series of children refractory to H2RA Data are limited on PPI pharmacology in infants and children. The pharmacokinetic and pharmacodynamic properties of lansoprazole and omeprazole have been studied [1-6]. No randomized placebo-controlled trials of PPI in infants or children have been reported to date. A randomized controlled study comparing omeprazole and high-dose ranitidine demonstrated comparable effectiveness in reducing symptoms and improving histopathology in 25 infants and children with esophagitis [7]. It should be noted that this study used a relatively low omeprazole dose (40 mg/1.73 m2) and a very high ranitidine dose (20 mg/kg). Case series of children with esophagitis refractory to H2RA and other treatments have reported responses to omeprazole and lansoprazole. The efficacy of other PPIs (esomeprazole, pantoprazole, rabeprazole) in the pediatric population has not yet been reported. References 1. Andersson T, Hassall E, Lundborg P, et al. Pharmacokinetics of orally administered omeprazole in children. Am J Gastroenterol 2000;95: 2. 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. J Pediatr 2000;137:800-7. 3. Faure C, Michaud L, Shaghaghi EK, et al. Lansoprazole in children: pharmacokinetics and efficacy in reflux oesophagitis. Aliment Pharmacol Ther 2001;15: 4. Tran A, Rey E, Pons G, et al. Pharmacokinetic-pharmacodynamic study of oral lansoprazole in children. Clin Pharmacol Ther 2002;71: 5. Book L, Chiu YL, Pilmer B, Gremse D. Effect of lansoprazole on intraesophageal pH in children with pathologic acid reflux. Gastroenterology 2002;122(4 suppl):A Abstr S1276. 6. Gremse D, Winter H, Tolia V, et al. Pharmacokinetic and pharmacodynamic lansoprazole in children with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2002 suppl (in press). 7. Cucchiara S, Minella R, Iervolino MR, et al. Omeprazole and high dose ranitidine in the treatment of refractory reflux oesophagitis. Arch Dis Child 1993;69:655-9.

Pharmacology of Omeprazole in Children
Pharmacokinetic (PK) values are generally within range previously reported for adults Children achieved these values with higher doses on per-kilogram basis than in adults Esophageal pH <4 for <6% of 24 h was achieved in 72% of 57 children with esophagitis with 0.7 or 1.4 mg/kg/day The pharmacokinetics of orally administered omeprazole was examined in 25 children aged 1-16 years with erosive esophagitis and abnormal esophageal pH studies after receiving healing doses of omeprazole for >7 days [1]. It is important to recognize that many factors determining drug disposition differ not only between children and adults but also between children of different ages [1]. Drug metabolism appears to be influenced by continuous changes up to puberty. In general, pharmacokinetic (PK) values for omeprazole in children 1 year of age and older are within the ranges previously reported for adults [1]. However, children achieved these values with considerably higher doses on a per-kilogram basis than in adults. These PK values suggest that children overall have a higher metabolic capacity than do adults and that metabolic capacity in childhood is higher with decreasing age. Based on results of a multinational study [2], esophageal pH <4 for <6% of a 24-hour period was achieved in 72% of 57 children with erosive esophagitis with omeprazole 0.7 or 1.4 mg/kg/day. References 1. Andersson T, Hassall E, Lundborg P, et al. Pharmacokinetics or orally administered omeprazole in children. Am J Gastroenterol 2000;95: 2. 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. J Pediatr 2000;137:800-7. Andersson et al, Am J Gastroenterol 2000;95:3101; Hassall et al, J Pediatr 2000;137:800

Effect of Omeprazole on Symptoms in Children with Esophagitis
100 Pre-entry 5-14 days 3 months N = 54 80 % of Patients* 60 40 In a multinational open-labeled study, 82% of 54 children with healed esophagitis were assessed by their parents or investigators at the pre-entry visit as having moderate or severe GERD symptoms overall [1]. By the healing visit (3 months), only 7% still had moderate or severe symptoms overall. This slide also depicts the percent of patients with specific symptoms at the pre-entry visit, at visit 2 (5 to 14 days), and at the healing visit (3 months). Reference 1. 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. J Pediatr 2000;137:800-7. 20 Overall Heartburn Dysphagia Irritability Coughing * % of patients with moderate to severe symptoms Reprinted from Hassall et al, J Pediatr 2000; 137: 800

Effect of Lansoprazole on GERD Symptoms
100 80 60 40 20 N = 66 children with GERD symptoms treated with lansoprazole mg QD-BID for 8-12 weeks 100% Median % of Days With GERD Symptoms 79% In a Phase I/II USA multicenter study, 66 children aged 1-11 years with GERD symptoms were treated with lansoprazole 15 mg QD (weight <30 kg) or 30 mg QD (>30 kg) for 8-12 weeks [1]. If patients remained symptomatic after 2 weeks, the regimen was increased to BID dosage. At the final visit, overall GERD symptoms resolved or improved in 45/64 (70%) by investigator assessment and in 47/62 (76%) by patient assessment (diary data). This slide shows the reduction in median percentage of days the children had GERD symptoms. Reference 1. Tolia V, Ferry G, Gunasekaran T, Huang B, Keith R, Book L. Efficacy of lansoprazole in the treatment of gastroesophageal reflux disease in children. J Pediatr Gastroenterol Nutr 2002 suppl (in press). 20% Baseline Wk Wk 12 Tolia et al, J Pediatr Gastroenterol Nutr 2002 suppl (in press)

Optimal Timing of PPI Dose
Single PPI dose: Administer 1 half-hour before breakfast If second PPI dose: Administer 1 half-hour before evening meal Optimal effectiveness is achieved when the PPI is administered one half-hour before breakfast so that peak plasma concentrations coincide with the meal time [1]. If there is a second daily dose, it is best administered one half-hour before the evening meal. Reference 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. 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:S1-31.

Complications of Hypochlorhydria
⁭ community acquired pneumonia ⁭ gastroenteritis ⁭ Candidemia ⁭ necrotizing enterocolitis ⁭ food allergy?

Gastroesophageal Reflux PEDIATRIC EVALUATION AND MANAGEMENT

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Gastroesophageal Reflux PEDIATRIC EVALUATION AND MANAGEMENT

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