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Differentiating GER from GERD: To "D" or not to "D"

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Presentation on theme: "Differentiating GER from GERD: To "D" or not to "D""— Presentation transcript:

1 Differentiating GER from GERD: To "D" or not to "D"
Jenifer R. Lightdale, MD, MPH Gastroenterology and Nutrition Boston Children’s Hospital Harvard Medical School Prepared for your next patient. Children’s Hospital Boston

2 Disclaimers I have no relevant financial relationships with the manufacturers of any commercial products and/or provider of commercial services discussed in this presentation. I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation. Statements and opinions expressed are those of the authors and not necessarily those of the American Academy of Pediatrics. Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter’s comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label. Session agenda

3 AAP PCO Webinar Objectives
Clarify terms related to reflux disease in children Review options for testing and treating reflux disorders Discuss guidelines for appropriately managing children with reflux disease

4 Practice Change “As a result of participating in this webinar, attendees will be aware of a guideline based approach for identifying which patients will benefit from treatment for gastroesophgeal reflux disease (GERD), as well as which patients should be reassured their gastroesophgeal reflux (GER) is physiologic and not harmful.”

5 Jenifer R. Lightdale, MD, MPH
Pediatric Gastroenterologist Children’s Hospital Boston Endoscopy Colic/fussy babies Quality of care

6 Lay Reports on GERD in Infants
Increased in past decade Describe inconsolable newborns who improved dramatically on proton pump inhibitors (PPIs) Discussed “colic” as poorly understood Have contributed to 750% rise in use of PPIs in infants Evokes questions of previous misdiagnosis vs. current overuse

7

8 WSJ Provocative Health Reporting:
“Even the terminology is confusing…most babies have reflux [and] it usually doesn’t hurt…” “GER becomes more-serious GERD if the infant won’t eat and stops gaining weight, vomits blood and is extremely irritable…”

9 GOOD NEWS! There is a pediatric global definition of GER vs. GERD
To define reflux disease and its manifestations in infants, toddlers, children, and adolescents A primary objective of the definition is to clarify terms related to reflux-related symptoms and signs in children Sherman PM, Hassall E, Fagundes-Neto U, et al. A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population. Am J Gastroenterol. 2009;104(5):1278–1295

10 More Good News! There are Pediatric Gastroesophageal Reflux Clinical Practice Guidelines Endorsed by the North American and European Societies for Pediatric Gastroenterology, Hepatology, and Nutrition Basis of a 2013 Clinical Report from the American Academy of Pediatrics (AAP) Intended to be used in daily practice of all practitioners when evaluating and managing children with reflux disease Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557. Lightdale JR, Gremse DA. Section on Gastroenterology, Hepatology and Nutrition. Gastroenterology Reflux: Management Guidance for the Pediatriatrician. Pediatrics. 2013: 131(5): e

11 Global consensus especially useful because physiologic GER is now recognized to be relatively common in babies and kids… (Mean upper limit of normal) Infants (N=509) Children (N=48) Adults (N=432) # daily reflux episodes 73 25 45 # reflux episodes lasting > 5 min 9.7 6.8 3.2 Reflux index (% of time pH < 4)* *over approx 24 hours 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 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(supplement 2):S1–S31 11

12 Clarification via Global Consensus
GERD is defined to be present when reflux of gastric contents causes either troublesome symptoms or complications

13 Troublesome symptoms or complications of reflux
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 Unusual arching or seizure-like movements (Sandifer syndrome) GER in infants most often manifests as vomiting. A small minority of infants develop GERD, with symptoms including weight loss or poor weight gain (failure to thrive), irritability, dysphagia, odynophagia, and arching of the back during feedings. In infants, GER may cause apparent life-threatening events (ALTE) and has been associated with chronic respiratory disorders such as reactive airways disease, recurrent stridor, chronic cough, and recurrent pneumonia. In preschool-aged children, GER may present as intermittent vomiting. Older children are more likely to have an adult-type pattern of chronic heartburn or regurgitation with reswallowing. Esophagitis in older children may present as dysphagia or food impaction. Rarely, esophageal pain causes stereotypical repetitive stretching and arching movements that are mistaken for atypical seizures or dystonia (Sandifer syndrome). More severe inflammation may cause chronic blood loss with anemia and hematemesis. Chronic inflammation may result rarely in Barrett’s esophagus. 13

14 Example of Sandifer Syndrome
Sandifer syndrome is a rare complication of GER, in which esophageal pain causes stereotypical repetitive stretching and arching movements that are mistaken for atypical seizures or dystonia [1, 2]. It is often seen in children who are otherwise neurologically normal. The differential diagnosis includes neurologic disorders and an adverse reaction to medications, including metoclopramide. Photos courtesy of Harland S. Winter, MD. References 1. Werlin SL, D’Souza BJ, Hogan WJ, Dodds WJ, Arndorfer RC. Sandifer syndrome: an unappreciated clinical entity. Dev Med Child Neurol 1980;22:374-8. 2. Gorrotxategi P, Reguilon MJ, Arana J, et al. Gastroesophageal reflux in association with the Sandifer syndrome. Eur J Pediatr Surg 1995;5:203-5. Photos courtesy of Harland Winter, MD. Werlin SL, D'Souza BJ, Hogan WJ, et al. Sandifer syndrome: an unappreciated clinical entity. Dev Med Child Neurol. 1980;22(3):374–378 14

15 What about complications of GERD?
e.g. Is there a danger to not recognizing and treating it?

16 Complications of Reflux
Normal mid- and distal esophagus Z-line EGD and biopsy can determine the presence and severity of esophagitis and other GER complications. This slide contrasts endoscopic views of the normal esophagus and erosive esophagitis. A normal appearance of the esophagus on endoscopy does not exclude histopathologic esophagitis. Because there is a poor correlation between endoscopic appearance and histopathology, esophageal biopsy is recommended when diagnostic endoscopy is performed [1]. In a single-center review of children with GERD who underwent EGD, 34.6% (139/402) had erosive esophagitis [2]. Mean age was 9.7 years (range, 1.5 to 25 years); only 3/402 patients were older than 18. The children were neurologically normal and without congenital esophageal anomalies. The prevalence of erosive esophagitis increased with age in this pediatric population. Normal mid- and distal esophagus and Hetzel-Dent grades 2 and 4 erosive esophagitis; endoscopic views courtesy of Benjamin D. Gold, 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, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32:S1-31. 2. El-Serag HB, Bailey NR, Gilger M, Rabeneck L. Endoscopic manifestations of gastroesophageal reflux disease in patients between 18 months and 25 years without neurological deficits. Am J Gastroenterol 2002;97: Erosive esophagitis: grade 2 and grade 4 Erosions 16

17 Complications of Reflux
Esophageal stricture secondary to GERD: radiography and endoscopy Stricture Barrett’s esophagus: endoscopy and histology Barrett’s If esophageal inflammation caused by GER is untreated, strictures may form. In this slide at top, an esophagram and an endoscopic view show an esophageal stricture secondary to GERD. Chronic inflammation may also result in replacement of distal esophageal mucosa with a metaplastic, potentially malignant specialized epithelium known as a Barrett’s esophagus. In this slide at bottom, both endoscopic and histologic views contrast Barrett’s epithelium and normal epithelium. In the single-center review of 402 children with GERD who underwent EGD, esophageal stricture was reported in 1.5% and Barrett’s esophagus was suspected in 2.7% (due to a finding of columnar-lined esophagus) [1]. However, intestinal metaplasia was seen in no biopsy samples. In a review of the published literature, Barrett’s esophagus was estimated in 0.02% of children undergoing endoscopy, most of whom had risk factors for severe GERD (e.g., congenital esophageal anomalies, cerebral palsy) [2]. Esophageal stricture and Barrett’s esophagus; images courtesy of Benjamin D. Gold, MD. References 1. El-Serag HB, Bailey NR, Gilger M, Rabeneck L. Endoscopic manifestations of gastroesophageal reflux disease in patients between 18 months and 25 years without neurological deficits. Am J Gastroenterol 2002;97: 2. Hassall E. Co-morbidities in childhood Barrett’s esophagus. J Pediatr Gastroenterol Nutr 1997;25: Barrett’s Normal Normal 17

18 Endoscopic Biopsies Useful to evaluate for a variety conditions, but are not required for diagnosis of GERD Possible findings on biopsy: 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. 18

19 Pathologic esophagitis
EH EH PL PL BL Histologic views of normal esophagus (left) and GER with no eosinophils (right); courtesy of Susan R. Orenstein, MD. Traditionally, intraepithelial eosinophils in the esophagus have been considered a marker for injury from acid reflux [1]. The presence of eosinophils correlates with abnormal esophageal acid clearance. However, eosinophilia is not a sensitive measure for GER, and biopsy samples from GER patients may show no eosinophils. In addition to eosinophilic infiltration, other histologic criteria for reflux esophagitis were defined in a study of 35 infants aged 2 weeks to 24 months with symptomatic GER [2]. Normal values were obtained from autopsy specimens. Seventy-seven percent of patients had at least one abnormal histologic parameter and were thus considered to have esophagitis. The four parameters (basal cell thickness, papillary height, intraepithelial eosinophils, intraepithelial neutrophils) correlated well with each other. Ninety-three percent of patients with histologic esophagitis had significant reflux as determined by pH monitoring. References 1. Winter HS, Madara JL, Stafford RJ, Grand RJ, Quinlan JE, Goldman H. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology 1982;83: 2. Black DD, Haggitt RC, Orenstein SR, Whitington PF. Esophagitis in infants: morphometric histological diagnosis and correlation with measures of gastroesophageal reflux. Gastroenterology 1990;98: BL Normal Esophagitis EH, epithelial height; PL, papillary layer; BL, basal layer Normal: PL ~ 40% of epithelial height; BL ~ 15% GERD: PL ~ 90% of epithelial height; BL ~ 30% 19

20 Eosinophilic esophagitis
The esophageal biopsy specimen at center, from a patient with GER, shows a small number of intraepithelial eosinophils. Basal cell thickening of the esophageal mucosal epithelium and lengthening of stromal papillae, also depicted, are additional markers of GER. If biopsy reveals extensive eosinophilia, for example, >20 intraepithelial eosinophils per high-power microscopic field (HPF), an allergic condition or idiopathic esophagitis, rather than GER, should be considered. The histologic picture at right is of primary eosinophilic esophagitis, showing clusters of eosinophils and papillary and basal increases; this patient had dysphagia and food allergies that responded to an elimination diet. Normal esophagus (left); GER (center), with approximately 5 eosinophils per HPF; and primary eosinophilic esophagitis (right); endoscopic views courtesy of Susan R. Orenstein, MD. Normal esophagus Peptic esophagitis Eosinophilic esophagitis 20

21 Eosinophilic Esophagitis
A subtle macroscopic indication of eosinophilic esophagitis is a furrowed, occasionally ringed appearance of the esophageal mucosa, without erosions or other mucosal breaks [1, 2]. This appearance of the esophagus, also called felinization, may also occur in otherwise normal individuals. Ringed esophagus (left); endoscopic view courtesy of Harland S. Winter, MD. Eosinophilic esophagitis showing furrowing and granularity (right); endoscopic view courtesy of Seema Khan, MD. References 1. Bousvaros A, Antonioli DA, Winter HS. Ringed esophagus: an association with esophagitis. Am J Gastroenterol 1992;87: 2. Orenstein SR, Mousa H, Di Lorenzo C, Kocoshis S, Putnam P, del Rosario J, Sigurdsson L, Shalaby T. The spectrum of eosinophilic esophagitis in children, abstr G1019. Gastroenterology 1998;114(4):A248. 21

22 Clinical Cases 5 month old who effortlessly spits-up 6–10x/day, but seems comfortable and is growing well 4 month old who is losing weight is reported to vomit 2–3x/day, and seems increasingly fussy with feeds 15 year old who presents complaining of heartburn

23 So What is GER??? And What is GERD???
Understanding the difference May help to avoid overclassifying patients with GERD vs. physiologic GER May avoid overtesting May avoid overtreatment May help identify when to refer patients to specialists

24 GER Gastroesophageal Reflux GER is a normal physiologic process
The passage of gastric contents into the esophagus Occurs with/without regurgitation and vomiting GER is a normal physiologic process Several times/day in healthy infants, children, and adults

25 Most Episodes of GER Last < 3 minutes
Occur in the postprandial period Cause few or no symptoms GER can cause vomiting A coordinated autonomic and voluntary motor response with forceful expulsion of gastric contents Regurgitation (“spitting up”) is the most visible symptom of GER Occurs daily in 50% of infants < 3 months of age Resolves spontaneously in most by 12–14 months

26 Prevalence of Regurgitation in Infancy
 1 time a day  4 times a day % of Infants Age (months) n=948 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 Adapted from 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(6):569–572 26

27 Physiology of GER GER occurs during transient relaxations of the lower esophageal sphincter (LES) Relaxation of the LES that is unaccompanied by swallowing permits gastric contents into the esophagus LES is not a “true” sphincter Comprised of crural support, an intra‑abdominal segment, and the “angle of His”

28 Composition of the LES The lower esophageal sphincter (LES) constitutes the major barrier to GER. The LES is a specialized region of smooth muscle that is tonically contracted. In the healthy adult, this region is about 3 cm in length and located at the level of the diaphragm. In the neonate, the sphincter length is about 1.5 cm and it is located about 2 cm above the level of the diaphragm. In the older child and adult, the crus of the diaphragm (skeletal muscle) contracts during inspiration and increases the high-pressure barrier in the region of the LES. Other anatomic components of the antireflux barrier include the phrenoesophageal ligament, which anchors the distal esophagus to the crural diaphragm [1], and the angle of His [2]. References 1. Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med 1997;336: 2. Bardaji C, Boix-Ochoa J. Contribution of the His angle to the gastroesophageal antireflux mechanism: an experimental study in dogs. Pediatr Surg Int 1986;1:172-6. Healthy adult – LES 3cm in length, at level of diaphragm Neonate – LES 1.5cm in length, above the diaphragm 28

29 Esophageal Capacity Shorter esophagus Smaller capacity Gravity Infant
A number of factors contribute to the frequency of regurgitation in infants. A shorter esophagus, the small capacity of the esophagus, and recumbent posture (lack of gravity) make it more likely that refluxed material in the infant will fill the esophagus and pass into the pharynx. The infant is thus more likely to regurgitate than the adult when gastric contents empty into the esophagus. The esophagus is approximately 11 cm at birth, with a diameter of 5 mm. By adulthood, the esophagus is cm long, with lateral and anteroposterior diameters of 30 and 19 mm, respectively [1]. Reference 1. Weaver TL. Anatomy and embryology. In: Walker WA, Durie PR, Hamilton JR, et al, eds. Pediatric Gastrointestinal Disease, 1st ed. Philadelphia: BC Decker; 1991: Infant Adult 29

30 WHEN DOES GER “become” GERD
Aberrance in normal physiology Insufficient clearance and buffering of refluxate Decreased rate of gastric emptying Abnormalities in efficacy of epithelial repair Decreased neural protective reflexes Development of erosive esophagitis causes esophageal shortening May result in hiatal herniation

31 Esophagitis can cause shortening of the stomach, leading to hiatal hernia.
© Copyright 2003 New England Minimally Invasive Surgeons

32 Genetics of Reflux Cluster studies suggest inheritability of GER/GERD and their complications Hiatal hernia Erosive esophagitis Barrett’s esophagus Esophageal adenocarcinoma Swedish Twin Registry Increased concordance in monozygotic vs. dizygotic Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

33 High Risk Populations Several pediatric patient populations appear to be at higher risk of GERD Neurologically impaired Obese infants, children, and adolescents Certain genetic syndromes Esophageal atresia Chronic lung diseases History of prematurity Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

34 Testing for Reflux Disorders
No one test can be used to diagnose reflux, and instead must be matched to a clinical question Reflux tests are useful To document the presence of GER(D) To detect complications To establish a causal relationship between GER and symptoms To evaluate therapy To exclude other conditions Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

35 Diagnostic Approach Depends on symptoms and signs
History and physical examination Upper gastrointestinal (GI) series Esophageal pH monitoring Esophagogastroduodenoscopy and biopsy Empirical medical therapy In most infants with vomiting, and in most children with regurgitation or heartburn, a history and physical examination are sufficient to reliably diagnose GER. Three types of tests are frequently considered: (1) surrogate tests to quantify reflux, such as esophageal pH monitoring, scintigraphy, and intraluminal esophageal impedance; (2) tests for inflammation; and (3) tests of symptoms, that is, symptom assessment questionnaires. Esophageal pH monitoring is used clinically to assess the relationship between symptoms and GER, whereas intraluminal esophageal impedance is currently being validated as a clinical tool that can document acidic and non-acidic reflux. Scintigraphy to assess gastric emptying may explain a contributing pathogenic factor, but it is not helpful in determining the presence of GERD. Scintigraphy can document aspiration. Esophageal manometry usually is not helpful in the evaluation of infants and children with GERD. Esophagogastroduodenoscopy and biopsy provide information about the severity of GERD. The presence of inflammation in the esophagus suggests significant peptic injury, whereas inflammation in the stomach or duodenum may support other conditions, such as food allergy. Empiric medical therapy, i.e., a trial of time-limited medical treatment, is useful for determining if GER is causing a specific symptom. 35

36 Upper GI Radiography Advantage
Useful for detecting anatomic abnormalities Limitation Cannot discriminate between physiologic and nonphysiologic GER episodes Upper GI (or barium contrast) radiography cannot discriminate between physiologic and nonphysiologic GER episodes. The brief duration of the upper GI series results in false-negative findings, while the frequent occurrence of non-pathologic reflux results in false-positive findings. Therefore, it is not a reliable diagnostic test for GERD. An upper GI series is useful for ruling out anatomic disorders that may present similarly to GERD. In the vomiting infant, for example, contrast radiography can detect an anatomic abnormality such as an esophageal or antral web, malrotation, or pyloric stenosis. Disorders of esophageal motility, such as achalasia, may also be detected. In the infant or child with recurrent pneumonia, aspiration during swallowing or a tracheoesophageal fistula may be detected. Complications of GER occasionally are detected by barium contrast radiography, such as esophageal stricture or severe esophagitis with thickening of the esophageal mucosa. Barium flowing retrograde from stomach into esophagus; x-ray courtesy of APHS Inc. 36

37 Pyloric stenosis Malrotation
An upper GI series is useful for detecting anatomic abnormalities such as a malrotation or pyloric stenosis. In this slide, the upper GI series at left revealed pyloric stenosis (shown by arrow) in a 10-week-old boy with an 8-week history of non-bilious vomiting. The upper GI series at right was obtained from an 8-year-old child with chronic vomiting and heartburn. The ligament of Treitz does not cross the midline, a picture consistent with intestinal malrotation. Pyloric stenosis (left) and malrotation (right); x-rays courtesy of Harland S. Winter, MD. Pyloric stenosis Malrotation 37

38 Esophagogastroduodenoscopy (EGD)
Advantages Enables visualization and biopsy of esophageal epithelium Determines presence of esophagitis, other complications Discriminates between reflux and non-reflux esophagitis Limitations Need for sedation or anesthesia Endoscopic grading systems not yet validated for pediatrics Poor correlation between endoscopic appearance and histopathology Generally not useful for extra-esophageal GERD Esophagogastroduodenoscopy (EGD) enables visualization and biopsy of the esophageal epithelium. EGD and biopsy can determine the presence and severity of esophagitis, stricture, and Barrett’s esophagus, as well as exclude other disorders, such as eosinophilic or infectious esophagitis. Limitations include the need for sedation or anesthesia. Grading systems for the severity of erosive esophagitis, such as the Los Angeles classification [1], have not yet been validated in pediatric patients. There is a poor correlation between endoscopic appearance and histopathology. Therefore, esophageal biopsy is recommended when diagnostic endoscopy is performed. In general, EGD is not useful for extraesophageal manifestations of GERD. Hetzel-Dent grade 4 erosive esophagitis; endoscopic view courtesy of Benjamin D. Gold, MD. Reference 1. 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: 38

39 Esophageal pH Monitoring
Advantages Detects episodes of reflux Determines temporal association between acid GER and symptoms 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. 39

40 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 40

41 Impedance Sensors Pediatric Catheter pH Sensors Infant Catheter 41

42 Non-Acid Reflux 42

43 History and Physical Exam
Symptoms and signs associated with GER are non-specific i.e. Not all children with GER have heartburn or irritability Conversely, heartburn and irritability can be caused by conditions other than GER Major roles of History/Physical Exam when evaluating GERD To exclude other worrisome disorders that present with vomiting To recognize complications of GERD

44 Symptoms and Signs of GER/GERD
Recurrent regurgitation with/without vomiting Weight loss or poor weight gain Irritability in infants Heartburn or chest pain Hematemesis Dysphagia, Odynophagia, Feeding refusal Apnea spells Wheezing Stridor Cough Hoarseness Dystonic neck posturing (Sandifer syndrome) Signs Esophagitis Esophageal stricture Barrett Esophagus Laryngeal/pharyngeal inflammation Recurrent pneumonia Anemia Dental erosion

45 Indications for Further Evaluation in Infants With Vomiting
Bilious vomiting GI bleeding Hematemesis Hematochezia Consistently forceful vomiting Onset of vomiting after 6 months of life Severe failure to thrive Diarrhea Constipation Fever Lethargy Hepatosplenomegaly Bulging fontanelle Macro/microcephaly Seizures Abdominal tenderness or distension Documented or suspected genetic/metabolic syndrome Associated chronic disease

46 Differential Diagnosis of Vomiting in Infants and Children – GI
Gastrointestinal obstruction Pyloric stenosis Malrotation with intermittent volvulus Intestinal duplication Hirschsprung disease Antral/duodenal web Foreign body Incarcerated hernia Other GI disorders Achalasia Gastroparesis Gastroenteritis Peptic ulcer Eosinophilic esophagitis/gastroenteritis Food allergy Inflammatory bowel disease Pancreatitis Appendicitis

47 Differential Diagnosis of Vomiting in Infants and Children – Non-GI
Neurologic Hydrocephalus Subdural hematoma Intracranial hemorrhage Intracranial mass Infant migraine Infectious Sepsis Meningitis Urinary tract infection Pneumonia Otitis media Hepatitis Metabolic/endocrine Galactosemia Hereditary fructose intolerance Urea cycle defects Amino and organic acidemias Congenital adrenal hyperplasia Renal Obstructive uropathy Renal insufficiency Toxic Lead Iron Vitamin A and D Medications: ipecac, digoxin, theophylline, etc. Cardiac Congestive heart failure Vascular ring Psychiatric Munchausen syndrome by proxy Child neglect or abuse Self induced vomiting

48 Important to Obtain a Feeding and Vomiting History
Feeding and dietary history Amount/frequency (overfeeding) Preparation of formula Recent changes in feeding type or technique Position during feeding Burping Behavior during feeding: choking, gagging, cough, arching, discomfort, refusal Pattern of vomiting Frequency/amount Pain Forceful or not Blood or bile Associated fever, lethargy, diarrhea

49 Other Histories in the Infant/Child With Suspected GERD
Family medical history Significant illnesses Family history of GI disorders Family history of atopy Growth chart Height Weight Head circumference Past medical history Prematurity Growth and development Past surgery and hospitalizations Newborn screen results Recurrent illnesses (croup, pneumonia, asthma) Symptoms of hoarseness, fussiness, hiccups Apnea Previous weight and height gain Medications Current vs. Recent Prescription Non-prescription Family psycho-social history Sources of stress Maternal or paternal drug use Post partum depression

50 History/Physical Examination
Severity of reflux or esophagitis found on diagnostic testing does not directly correlate with symptom severity In infants and toddlers, there is no symptom or group of symptoms that can reliably diagnose GERD or predict treatment response In older children and adolescents, history and physical examination are generally sufficient to reliably diagnose GERD and initiate management Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

51 Conservative Therapy for GER
For Infants For Older Children Normalize feeding volume and frequency Consider thickened formula Consider non-prone positioning during sleep Consider trial of hypoallergenic formula Avoid large meals Do not lie down immediately after eating Lose weight, if obese Avoid caffeine, chocolate, and spicy foods that provoke symptoms Eliminate exposure to tobacco smoke Conservative therapy, or lifestyle changes, is recommended for all infants and children with GER irrespective of disease severity. A complete history can reveal provocative aspects of lifestyle, such as huge feedings at infrequent intervals in infants. It is important to normalize feeding volume and frequency. Thickened feedings may be beneficial when regurgitation has resulted in poor weight gain. Prethickened formula may be purchased, or infant formula may be thickened by adding rice cereal. Frequent, smaller feedings are encouraged. There is evidence to support a 1- or 2-week trial of a hypoallergenic formula in formula-fed infants with vomiting. Positioning therapy is a traditional part of antireflux management. Supine positioning confers the lowest risk for SIDS, and non-prone positioning during sleep is recommended. For older children, conservative therapy is similar to recommendations for adults: Avoid large meals, and do not lie down immediately after eating. Lose weight if obese; a recent study confirmed that obesity is a strong risk factor for reflux disease [1]. Avoid caffeine, chocolate, and spicy foods that provoke symptoms. Eliminate exposure to tobacco smoke. Reference 1. Locke GR III, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ III. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106:642-9. 51

52 Treating physiologic GER in infants
Once the diagnosis of GER is established Parental education, reassurance, and anticipatory guidance are recommended Dietary changes and thickening of formula can be considered In general no other intervention is necessary If symptoms worsen or do not resolve by 12 to 18 months of age or “warning signs” develop, referral to a pediatric gastroenterologist is recommended Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

53 Treatment of GER in infants
Evidence supports 2–4 week trial of an extensive protein hydrolysate in formula fed infants with vomiting Thickening of formula which may decrease visible reflux (regurgitation) Supine position for sleeping If no improvement, referral to a pediatric gastroenterologist may be appropriate Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

54 Effect of Thickening Milk Formula Feedings With Rice Cereal
Unthickened Thickened n=20 p=.015 p=.026 p=.042 Infants with regurgitation may benefit from thickening of milk formula with rice cereal. This slide summarizes a study in 20 infants with GER who were observed after a pair of feedings, once with radiolabeled infant formula and once with radiolabeled formula thickened with dry rice cereal [1]. Thickening resulted in a decrease in the number of episodes of emesis, an increase in sleep time, and reduction in crying time. Reports of the effect of thickened feedings on the incidence of reflux and other esophageal acid parameters have been inconsistent [2, 3]. References 1. Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy of gastroesophageal reflux. J Pediatr 1987;110:181-6. 2. Bailey DJ, Andres JM, Danek GD, Pineiro-Carrero VM. Lack of efficacy of thickened feeding as treatment for gastroesophageal reflux. J Pediatr 1987;110:187-9. 3. Vandenplas Y, Belli D, Cadranel S, Cucchiara S, Dupont C, Heymans H, Polanco I. Dietary treatment for regurgitation—recommendations from a working party. Acta Paediatr 1998;87:462-8. Caloric Density (cal/cc) Emesis (episodes/90 min) Sleep Time (min asleep/90 min) Crying Time (min crying/90 min) Adapted from Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy of gastroesophageal reflux. J Pediatr. 1987;110(2):181–186 54

55 Thickened formula Unthickened formula
In the USA, thickening is usually achieved with the addition of rice cereal to formula. If an infant formula has a caloric density of 20 kcal per ounce, the addition of 1 tablespoonful of rice cereal per ounce of formula increases the caloric density to about 34 kcal per ounce [1]. This slide contrasts ready-to-use milk-based infant formula and the same formula thickened with dry rice cereal (1 tablespoonful per fluid ounce of formula). 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. Unthickened formula 55

56 Pre-thickened Formulas Change Viscosity With Acidification
rice cereal Newer formulas that contain carob flour or locust bean gum as thickening agents are available in Europe. A formula with added rice starch is available in the USA and Canada. The formula with added rice starch thickens on acidification, such as may occur in an acidic stomach. This slide depicts an increase in the viscosity of a prethickened preparation as pH decreases. The effect on viscosity of the prethickened preparation contrasts with effects on regular (unthickened) infant formula and formula to which rice cereal was added. Effect of pH on viscosity of Enfamil AR®, unthickened infant formula, and formula mixed with dry rice cereal. Reprinted with permission from Mead Johnson Nutritionals. Unthickened formula Enfamil AR Reprinted with permission from Mead Johnson Nutrition 56

57 Positioning and GER Sitting Supine Prone 60°
The effects of prone and supine positioning, as well as sitting, on the air-fluid interface in an infant’s stomach are illustrated in this slide [1]. The propensity to reflux is greatest when the gastroesophageal junction is below the air-fluid interface. Reference 1. Ramenofsky ML, Leape LL. Continuous upper esophageal pH monitoring in infants and children with gastroesophageal reflux, pneumonia, and apneic spells. J Pediatr Surg 1981;16:374-8. Supine Adapted from Ramenofsky ML, Leape LL. Continuous upper esophageal pH monitoring in infants and children with gastroesophageal reflux, pneumonia, and apneic spells. J Pediatr Surg. 1981;16(3):374–378 Prone 57

58 Effect of Sleep Position on GER in Infants and Sudden Infant Death Syndrome (SIDS) Mortality
Reflux Index1 (% time pH <4) SIDS Mortality2 (per 1000 live births) Reflux Index Odds Ratio SIDS Mortality Odds Ratio3 Supine * Left side * † Right side * † Prone Clinicians must decide whether the benefits of strategies to reduce the risk of GER are outweighed by the potential for an increased risk of SIDS. In most cases, the risk of SIDS outweighs the benefits of prone positioning. The effects of sleep position on GER in infants and mortality from SIDS have been quantified. In a study of 24 infants younger than 5 months of age [1], the prone and left-side (left lateral) positions were most effective in reducing the reflux index (percent of time esophageal pH <4). However, based on an analysis of data from a population-based case reference study [2], the SIDS mortality rate associated with sleeping prone was 4.4 per 1000 live births, compared with 0.05 per 1000 live births for supine and lateral sleeping positions combined. In terms of odds ratios, sleeping supine was 2.3 times more likely than sleeping prone to induce GER, while a right-sided sleep position was 1.8 times more likely than a prone position to induce GER [1]. These effects must be weighed, however, against odds ratios for SIDS mortality of 13.9 with prone positioning and 3.5 for side-sleeping, when compared with supine positioning [3]. Other studies have supported the avoidance of prone positioning during sleep. In a trial from New Zealand [4], the relative risk for SIDS with sheepskin use was significantly increased in infants placed prone to sleep (odds ratio, 1.70) but not in infants placed supine or laterally (odds ratio, 0.82). In California, the SIDS rate declined from 1.2 to 0.7 per 1000 live births in the first five years after a public health campaign (“Back to Sleep”) to reduce prone sleeping [5]. Data suggest that airway protection is compromised in the prone position during active sleep [6]. References 1. Tobin JM, McCloud P, Cameron DJS. Posture and gastro-oesophageal reflux: a case for left lateral positioning. Arch Dis Child 1997;76:254-8. 2. Skadberg BT, Morild I, Markestad T. Abandoning prone sleeping: effect on the risk of sudden infant death syndrome. J Pediatr 1998;132:340-3. 3. Oyen N, Markestad T, Skjaerven R, Irgens LM, Helweg-Larsen K, Alm B, Norvenius G, Wennergren G. Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: the Nordic Epidemiologic SIDS Study. Pediatrics 1997;100: 4. Mitchell EA, Thompson JMD, Ford RPK, Taylor BJ. Sheepskin bedding and the sudden infant death syndrome. J Pediatr 1998;133:701-4. 5. Adams EJ, Chavez GF, Steen D, Shah R, Iyasu S, Krous HF. Changes in the epidemiologic profile of sudden infant death syndrome as rates decline among California infants: Pediatrics 1998;102: 6. Jeffery HE, Megevand A, Page M. Why the prone position is a risk factor for sudden infant death syndrome. Pediatrics 1999;104:263-9. *Mortality rate for all non-prone positions combined †Combined odds ratio 1 Tobin JM, McCloud P, Cameron DJ. Posture and gastro-oesophageal reflux: a case for left lateral positioning. Arch Dis Child. 1997;76(3):254–358 2 Skadberg BT, Morild I, Markestad T. Abandoning prone sleeping: Effect on the risk of sudden infant death syndrome. J Pediatr. 1998;132(2):340–343 3 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(4):613–621 58

59 Positioning Therapy for GERD
For Infants For Older Children Non-prone positioning during sleep is recommended Supine positioning confers lowest risk for SIDS and is preferred Prone positioning may be considered in cases where risk of death from GER complications outweighs potential increased risk of SIDS If prone positioning is recommended, discuss rationale with parents Avoid soft bedding, pillows, loose sheets near infant Left side positioning during sleep may be beneficial Elevate head of bed Avoid lying down immediately after eating In infants with GER, the risk of SIDS generally outweighs the potential benefits of prone sleeping. Therefore, consistent with the recommendations of the American Academy of Pediatrics [1], the NASPGHAN guidelines recommended non-prone positioning of infants during sleep [2]. Supine positioning confers the lowest risk for SIDS and is preferred. Prone positioning during sleep may be considered only in unusual cases where the risk of death from complications of GER outweighs the potential increased risk of SIDS. If prone positioning is recommended for an infant with GER, it is important to discuss the rationale with the parents. Awareness of the detriments of prone positioning, through the “Back to Sleep” campaign, through family members, and through the media, is high. A factor in SIDS deaths associated with sleeping prone may be suffocation or the re-breathing of carbon dioxide due to “puffy” bed materials. Thus, it is important to avoid placing soft bedding, quilts, or loose sheets near a sleeping infant. The efficacy of positioning therapy in children older than 1 year has not been studied. As in adults, it is likely that there is a benefit to left side positioning during sleep [3] and elevation of the head of the bed [4]. References 1. Changing concepts of sudden infant death syndrome: implications for infant sleeping environment and sleep position. American Academy of Pediatrics. Task Force on Infant Sleep Position and Sudden Infant Death Syndrome. Pediatrics 2000;105:650-6. 2. 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. 3. Khoury RM, Camacho-Lobato L, Katz PO, Mohiuddin MA, Castell DO. Influence of spontaneous sleep positions on nighttime recumbent reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol 1999;94: 4. Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid foam tablets on gastroesophageal reflux. Dig Dis Sci 1981;26: American Academy of Pediatrics, Task Force on Infant Sleep Position and Sudden Infant Death Syndrome. Changing concepts of sudden infant death syndrome: implications for infant sleeping environment and sleep position. Pediatrics. 2000;105(3 Pt 1):650–656; 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(supplement 2):S1–S31 59

60 Treatment of GERD in Older Children
A left sided sleeping position with elevation of the head of the bed may decrease symptoms and GER In adults, obesity and late night eating are associated with increased reflux To date, no evidence to support specific dietary restrictions to decrease symptoms of GER in pediatric populations Appropriate to trial acid suppression

61 Goals of Pharmacotherapy
Control symptoms Promote healing Prevent complications Improve health-related quality of life Avoid adverse effects of treatment The goals of antireflux pharmacotherapy are to control symptoms, promote healing of esophagitis if present, and prevent complications by reducing exposure of the esophagus or respiratory tract to acid refluxate. In addition, pharmacotherapy aims to improve the patient’s health-related quality of life and to avoid adverse events of treatment. 61

62 Medical Treatment of GERD
Both Histamine-2 receptor antagonists (H2RAs) and PPIs Produce relief of symptoms and mucosal healing of GERD Are superior to buffering agents, alginates, and sucralfate PPIs are superior to H2RAs in relieving symptoms and healing esophagitis. Potential side effects of each currently available prokinetic agent outweigh the potential benefits No evidence for routine use of metoclopramide, erythromycin, bethanechol, or domperidone for GERD Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

63 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. Copyright 1996 by Excerpta Medica Inc. Adapted from Sanders SW. Pathogenesis and treatment of acid peptic disorders: comparison of proton pump inhibitors with other antiulcer agents. Clin Ther. 1996;18(1):2–34 63

64 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 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(2):150–156 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 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(1):51–55 64

65 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. Copyright 1996 by Excerpta Medica Inc. Adapted from Sanders SW. Pathogenesis and treatment of acid peptic disorders: comparison of proton pump inhibitors with other antiulcer agents. Clin Ther. 1996;18(1):2–34 65

66 PPIs in Adults With GERD
Most potent inhibitors of acid secretion Both pharmacolic and numerous randomized controlled trials Superior to H2RAs in relieving reflux symptoms and healing esophagitis Effective in patients unresponsive to high-dose H2RA Superior to H2RAs in maintaining remission of esophagitis Demonstrated safety in patients treated for 1.4 to 11.2 years (N=230 patients) PPIs are the most potent inhibitors of gastric acid secretion. In general, PPIs produce a greater reduction in acid secretion and have a longer duration of action than H2RAs. Five PPIs are currently marketed in the USA: esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. Numerous randomized controlled trials have demonstrated the superiority of PPIs over H2RAs in relieving reflux symptoms and healing esophagitis [1]. Symptomatic relief can be expected in about 83% of PPI-treated adults, and healing of esophagitis in 78% of PPI-treated adults [2]. PPIs are effective in patients unresponsive to high-dose H2RA therapy [3] and are more effective than H2RAs in maintaining remission of esophagitis [4]. Long-term studies support the safety of omeprazole in adults with esophagitis treated for 1.4 to 11.2 years [5]. Issues of hypergastrinemia and bacterial overgrowth with longer-term PPI use remain to be resolved. References 1. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997;112: 2. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 1999;94: 3. Klinkenberg-Knol EC, Jansen JM, Festen HP, Meuwissen SG, Lamers CB. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1987;1: 4. Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995;333: 5. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2000;118:661-9. 66

67 PPIs in Infants and Children With GERD
Pharmacologic studies with omeprazole and lansoprazole No randomized placebo-controlled trials have demonstrated improvement of GERD in children 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. 67

68 Case Series of Esophagitis Patients Treated With Omeprazole
Authors N Results Gunasekaran, et al, 1993 15 children < 3.3 mg/kg/day x 12.2 mo (mean) Symptoms and endoscopic assessment improved in all De Giacomo, et al, 1997 10 children 20 or 40 mg QD x 3 mo Clinical, endoscopic, and pH improvements in all; no change in biopsy findings Alliet, et al, 1998 12 infants 0.5 mg/kg/day x 6 wk Endoscopic and histologic improvement or resolution in all Strauss, et al, 1999 18 children mg/kg/day x 8–12 wk 13/17 asymptomatic Hassall, et al, 2000 57 children mg/kg/day x 3 mo Esophagitis healed in 54/57; symptomatic improvement in 93% Numerous case series have evaluated the effectiveness of omeprazole in infants and children with reflux esophagitis. In 15 children aged 0.8 to 17 years with reflux esophagitis who failed H2RA and prokinetic therapy, reflux symptoms and endoscopic assessment improved with omeprazole treatment for 5.5 to 26 months (mean, 12.2 months) [1]. Eight children were neurologically impaired. The omeprazole dose was initially mg/day, escalating up to 40 mg ( mg/kg/day). De Giacomo et al. [2] reported results of omeprazole treatment in 10 children aged 25 to 109 months with severe esophagitis. After 3 months of omeprazole 20 mg/day (weight <30 kg) or 40 mg/day (>30 kg), all 10 improved on clinical, endoscopic, and pH-metry assessment, but there was no change in esophageal biopsy findings. Omeprazole 0.5 mg/kg/day for 6 weeks was evaluated in 12 neurologically normal infants with grade 2 esophagitis unresponsive to cimetidine, cisapride, and alginic acid [3]. After 6 weeks, all patients reported symptom improvement and endoscopic and histologic improvement or resolution. Eighteen children aged 2 to 17 years with histologic evidence of esophagitis and recurrent symptoms refractory to H2RA and prokinetic therapy were treated with omeprazole mg/kg/day (dosed by gastric pH studies) for 8-12 weeks [4]. A total of 13/17 became asymptomatic, while the remaining 4 reported symptom improvement. In the largest study to date, 65 children aged 1-16 years with esophagitis were treated with omeprazole for 3 months; 57 completed the study [5]. Esophagitis healed in 54/57 patients with omeprazole mg/kg/day. Another 3 patients healed with a second course of omeprazole treatment. At 3 months, 93% had absent or mild reflux symptoms overall. These and other studies [6] demonstrate that omeprazole is effective in the treatment of reflux esophagitis in infants and children. References 1. Gunasekaran TS, Hassall EG. Efficacy and safety of omeprazole for severe gastroesophageal reflux in children. J Pediatr 1993;123: 2. De Giacomo C, Bawa P, Franceschi M, Luinetti O, Fiocca R. Omeprazole for severe reflux esophagitis in children. J Pediatr Gastroenterol Nutr 1997;24: 3. Alliet P, Raes M, Bruneel E, Gillis P. Omeprazole in infants with cimetidine-resistant peptic esophagitis. J Pediatr 1998;132:352-4. 4. Strauss RS, Calenda KA, Dayal K, Mobassaleh M. Histological esophagitis: clinical and histological response to omeprazole in children. Dig Dis Sci 1999;44:134-9. 5. 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. 6. Kato S, Ebina K, Fujii K, Chiba H, Nakagawa H. Effect of omeprazole in the treatment of refractory acid-related diseases in childhood: endoscopic healing and 24-hour intragastric acidity. J Pediatr 1996;128: 68

69 Effect of Omeprazole on Esophagitis
N = 65 children with erosive esophagitis % of Patients Healed with < 3.5 mg/kg/day 95% 72% 44% Healed with < 1.4 mg/kg/day Healed with 0.7 mg/kg/day In a multinational open-labeled study, 65 children aged 1-16 years with erosive esophagitis were treated with omeprazole for 3 months [1]. At study entry, two-thirds of the 57 children had grade 3 or 4 esophagitis; about 50% had neurologic impairment or repaired esophageal atresia. The initial omeprazole dosage was 0.7 mg/kg/day, which was then adjusted to a “healing” dose that controlled acid reflux (esophageal pH <4 for <6% of a 24-hour period). At 3 months, esophagitis healed in 44% of patients treated with 0.7 mg/kg/day, in 72% treated with at least 1.4 mg/kg/day, and in 95% treated with at least 3.5 mg/kg/day. The healing dose correlated with the grade of esophagitis. 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. 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(6):800–807 69

70 Optimal Timing of PPI Dose
Single PPI dose: Administer half-hour before breakfast If second PPI dose: Administer 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. 70

71 Available Prokinetic Agents Are Unproven or Ineffective
Cisapride: withdrawn Bethanechol: only 1 randomized controlled trial (RCT) Erythromycin: no RCT Domperidone: available in Canada, no RCT Metoclopramide: Esophageal pH improvement in 1 of 6 RCT Clinical improvement in 1 of 4 RCT High incidence (~30% prevalence) of adverse events The rationale for prokinetic therapy in the treatment of GERD is based on evidence that such medications enhance esophageal peristalsis and accelerates gastric emptying [1]. The only prokinetic agent that has been shown to reduce esophageal acid exposure in children is cisapride, a mixed serotonergic agonist. However, cisapride has been withdrawn and is available in the USA only through a limited-access program to patients for whom other antireflux therapies are ineffective. Studies evaluating bethanechol, a direct cholinergic agonist, and domperidone, a dopamine antagonist available in Canada, have been few and have reported mixed results [1]. Only one randomized controlled trial (RCT) has evaluated bethanechol [2] and no RCTs have evaluated domperidone in pediatric patients with gastroesophageal reflux. Studies with erythromycin have suggested prokinetic effects on the GI tract at doses lower than antimicrobial doses [3]. Erythromycin has been evaluated in various pediatric populations, but no RCT in children with GER has been performed. RCTs have evaluated the efficacy of metoclopramide, an antidopaminergic agent, in children with GER. Esophageal pH improvement was reported in 1 of 6 RCTs; clinical improvement in 1 of 4 RCTs. Use of metoclopramide has been hampered by a high incidence of adverse events, including central nervous system (CNS) effects. 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-S31. 2. Euler AR. Use of bethanechol for the treatment of gastroesophageal reflux. J Pediatr 1980;96:321-4. 3. Curry JI, Lander TD, Stringer MD. Review article: erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15: Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557 71

72 Increasing Concern about Safety of Prokinetics
Prokinetic Adverse Events Bethanechol Malaise, abdominal cramps, colicky, pain, nausea and belching, diarrhea, urinary urgency; contraindicated in hyperthyroidism, bronchial asthma, and other conditions Domperidone Hyperprolactinemia, dry mouth, rash, headache, diarrhea, nervousness Erythromycin Abdominal pain, nausea, vomiting, diarrhea, pyloric stenosis Metoclopramide Restlessness, drowsiness, fatigue and lassitude (10%); insomnia, headache, confusion, dizziness, mental depression; extrapyramidal reactions including parkinsonian-like symptoms, tardive dyskinesia, and motor restlessness; galactorrhea, gynecomastia, cardiovascular effects, nausea, diarrhea The safety profiles of bethanechol and metoclopramide have limited their use for the treatment of GERD in adults [1]. Bethanechol 25 mg QID has been associated with significant abdominal cramping, blurred vision, fatigue, and urinary urgency [1]. This slide lists adverse reactions reported in the Prescribing Information (PI) for Urecholine® [2]. Bethanechol is contraindicated in hyperthyroidism, bronchial asthma, and other conditions [2]. In adult studies, adverse effects with domperidone, such as prolactinemia, occurred in 10% to 15% of patients [1]. Occasionally, dry mouth, skin rash, headache, diarrhea, and restlessness have been reported [1]. The clinical experience with erythromycin as a prokinetic agent in pediatric patients was recently reviewed [3]. Associated GI side effects include abdominal pain, nausea and vomiting, and diarrhea. Apart from GI side effects, erythromycin is a well-tolerated antibiotic, with few adverse effects in children [3]. Pyloric stenosis has been reported in neonates given antimicrobial doses of erythromycin [3]. No serious adverse effects have been reported in children in association with low-dose erythromycin used for prokinetic effects [3]. Adverse effects associated with metoclopramide include CNS complications, such as parkinsonian reactions and tardive dyskinesia, which may be irreversible. This slide summarizes adverse reactions listed in the Reglan® PI [4]. Strict limitation of dosage is important to prevent extrapyramidal reactions. Irritability and sleep disturbances may result from being administered even a relatively low dose of metoclopramide (0.1 mg/kg QID). References 1. Ramirez B, Richter JE. Review article: promotility drugs in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1993;7:5-20. 2. Prescribing Information for Urecholine® (bethanechol chloride). Odyssey Pharmaceuticals Inc, East Hanover, NJ, revised November 2000. 3. Curry JI, Lander TD, Stringer MD. Review article: erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15: 4. Prescribing Information for Reglan® (metoclopramide). AH Robins Company, Richmond, VA, May 17, 2001. Prescribing Information for Reglan® and Urecholine®; Curry JI, Lander TD, Stringer MD. Erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15(5):595–603; Ramirez B, Richter JE. Review article: promotility drugs in the treatment of gastro-oesophageal reflux disease Aliment Pharmacol Ther. 1993;7(1):5–20 72

73 Treatment of GERD in Older Children
Lifestyle changes with a 4-week PPI trial are recommended. If symptoms resolve, continue PPI for 3 months If symptoms persist or recur after treatment, child should be referred to a pediatric gastroenterologist

74 Conclusions It is important to clarify whether a pediatric patient has physiologic GER or pathologic GERD There are guidelines for appropriate testing and treating of children with reflux disease… Also useful for deciding when to refer to subspecialists

75 Recommended Approach to the Infant With Recurrent Regurgitation and Vomiting
Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

76 Recommended Approach to the Infant With Recurrent Regurgitation and Weight Loss
Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

77 Recommended Approach to the Older Child or Adolescent With Heartburn
Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

78 Thank you!

79 Acknowledgements AAP EQIPP Staff and Co-Faculty NASPGHAN
NASPGHAN Foundation (CDHNF)

80 References Lightdale JR, Gremse DA. Section on Gastroenterology, Hepatology and Nutrition. Gastroenterology Reflux: Management Guidance for the Pediatriatrician. Pediatrics. 2013;131(5):e1684–1695 Sherman PM, Hassall E, Fagundes-Neto U, Gold BD, Kato S, Koletzko S, Orenstein S, Rudolph C, Vakil N, Vandenplas Y. A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population. Am J Gastroenterol. 2009;104(5):1278–1295 Orenstein SR, McGowan JD. Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux. J Pediatr. 2008;152:310–314 Nelson SP, Chen EH, Syniar GM, Christoffel KK. 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 Vandenplas Y, Rudolph C, Di Lorenzo C, Hassall E, Liptak G, Mazur L, Sondheimer J, Staiano A, Thomson M, Veereman-Wauters G, Wenz T. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN) and the European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). J Ped Gastr Nutr. 2009;49:548–557

81 Don’t have a subscription to PCO?
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