1. GERD

2. Learning Objectives Differentiate between physiologic GER and gastroesophageal reflux disease (GERD) in children Review the natural history of GERD Explore pathophysiology and symptoms of GERD Review the extraesophageal manifestations of GERD Discuss the management and treatment options of Pediatric GERD

3. Definitions GERInvoluntary passage of gastric contents into esophagus GERDSymptoms or complications that may occur when gastric contents reflux into esophagus or oropharynx RegurgitationPassage of refluxed gastric contents into oral pharynx VomitingExpulsion of refluxed gastric contents from mouth

4. Prevalence of Regurgitation in Infancy 0-34-67-910-12 Age (months) % of Infants  1 time a day  4 times a day Adapted from Nelson et al, Arch Pediatr Adolesc Med 1997;151:569

5. 0 2 4 6 8 10 12 14 16 18 20 Prevalence of GER Symptoms in Children Nelson et al, Arch Pediatr Adolesc Med 2000;154:150 and Locke et al, Gastroenterology 1997;112:1448 % of Children Heartburn Epigastric pain RegurgitationHeartburn and/or acid regurgitation 566 parents of children aged 3-9 yr 615 children aged 10-17 yr 2200 adults aged 25-74 years

6. The Antireflux Barrier

7. Transient LES Relaxations Tracings reprinted from Kawahara et al, Gastroenterology 1997;113:399 Esophagus LES Crural diaphragm Pylorus Stomach Angle of His Pharynx UES

8. Esophageal Capacitance Shorter esophagus Smaller capacity Gravity Adult Infant

9. Airway Protective Mechanisms ESOPHAGEAL DISTENTION UES contracts Vagal reflexes Vocal cords close Central apnea occurs UES relaxes 0.15 s Refluxate enters pharynx 0.3 s Swallowing clears pharynx 0.6 s Small volume 1.0 s Respiration resumes Large volume

10. Pathogenesis

11. Pathogenic Factors in GERD Mechanisms of GER Transient LES relaxation Intra-abdominal pressure Reduced esophageal capacitance Gastric compliance Delayed gastric emptying Mechanisms of Esophageal Complications Impaired esophageal clearance Defective tissue resistance Noxious composition of refluxate Mechanisms of Airway Complications Vagal reflexes Impaired airway protection Esophagus LES Crural diaphragm Pylorus Stomach Angle of His Pharynx UES

12. 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 Epigastric pain Sandifers syndrome Heartburn in child/adolescent Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms Belching/eructation Hiccups

13. Sandifer Syndrome

14. Looking for reflux

15. Testing for GERD Is there a single test for GERD? What question does each test answer? How reproducible or reliable is the test? Does it guide our management and when is it useful?

16. Diagnostic approach in suspected GERD depends on presenting symptoms and signs History and physical examination Upper GI series Esophageal pH monitoring, and impedance Esophagogastroduodenoscopy and biopsy, capsule endoscopy () Nuclear medicine (gastric emptying scan) Empirical medical therapy

17. Upper GI Radiography Cannot discriminate between physiologic and nonphysiologic GER episodes Limitation Useful for detecting anatomic abnormalities Advantage

18. Pyloric stenosis Malrotation

19. Esophageal pH Monitoring 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 Limitations Detects episodes of reflux Determines temporal association between acid GER and symptoms Determines effectiveness of esophageal clearance mechanisms Assesses adequacy of H2RA or PPI dosage in unresponsive patients Advantages

20. Esophagogastroduodenoscopy (EGD) 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 Limitations Enables visualization and biopsy of esophageal epithelium Determines presence of esophagitis, other complications Discriminates between reflux and non- reflux esophagitis Advantages

21. Number of Eosinophils NormalGER BL, basal layer; EH, epithelial height; PL, papillary layer Normal: PL ~ 40% of epithelial height, BL ~ 15% GER: PL ~ 90% of epithelial height, BL ~ 30% PL BL EH

22. GEREosinophilic esophagitisNormal esophagus

23. Eosinophil Count and Response to Antireflux Therapy Response to antireflux Rx No responseResponse to antireflux Rx Incomplete response 1.1 24.5 5 31 Mean Eosinophil Count ± SEMNo. Eosinophils Per HPF N=102 p <.0025 N=28 p =.009 Adapted from Ruchelli et al, Pediatr Dev Pathol 1999;2:15 and Walsh et al, Am J Surg Pathol 1999;23:390

24. Use of Eosinophilic Density to Guide Therapy? No. of eosinophils per HPF <55-20>20 Consider aggressive antireflux Rx ? Consider Rx for allergy or primary eosinophilic esophagitis Identify and eliminate food allergen Steroids — systemic, topical

25. Eosinophilic Esophagitis

26. GER Complication Normal mid- and distal esophagus Erosive esophagitis: grade 2 and grade 4 Z-line Erosions

27. GER Complications Esophageal stricture secondary to GERD: radiography and endoscopy Barrett’s esophagus: endoscopy and histology Normal Barrett’s Normal Stricture

28. Capsule Endoscopy EsophagitisSuspected Barrett’s

29. Scintigraphy Lack of standardized techniques Absence of age-specific normative data Period of observation limited to early postprandial period Limitations Detects acidic and non-acidic GER Evaluates gastric emptying May demonstrate aspiration Advantages

30. Intraluminal Electrical Impedance

31. Multiple Intraluminal Electrical Impedance Measurement Advantages Detects weakly acidic, nonacidic and weakly alkaline GER episodes Useful for studying efficacy of therapy Useful for studying respiratory symptoms and GER Air swallowing, rumination, postsurgical Portable device Limitations Normal values in pediatric age groups not yet defined Analysis of tracings time-consuming pH channel pH 4 Impedance channels Z t 1 Z 4

32. Management Empiric Therapy Diagnostic Workup

33. Warning Signals Suggestive of a Non-GER Diagnosis Adapted from Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 Bilious or forceful vomiting Hematemesis or hematochezia Vomiting or diarrhea Abdominal tenderness or distention Onset of vomiting after 6 months of life Fever, lethargy, hepatosplenomegaly Macrocephaly, microcephaly, seizures Recurrent vomiting History and physical exam Are there warning signals?

34. Signs of Complicated GERD Adapted from Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 Poor weight gain Excessive crying or irritability Feeding problems Respiratory problems, including: –wheezing –stridor –recurrent pneumonia Recurrent vomiting History and physical exam Are there warning signals? Are there signs of complicated GERD?

35. Management of Recurrent Vomiting and Poor Weight Gain Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 Rule out other causes Optimize medical management Consider: –Nonpharmacological therapies Observe parent-child interaction Follow up closely Consult pediatric gastroenterologist Consider EGD and biopsy Consider nasogastric or nasojejunal tube feeding

36. Non-Pharmacologic Therapies Careful observation of feedings Careful handling of child during/after feeds Positioning - intragastric pressure Lower Osmolality + volumes - lesser TLESRs Feed thickeners - increase osmolality Thickeners relieve regurgitation, not reflux Huang RC, et al. Cochrane Database Rev 2002. et al,

37. Management of Irritable Infant with Recurrent Vomiting Symptom diary to determine extent of crying/irritability Adequate feeding? Is the infant hungry? Empiric therapy: acid suppression and/or elemental formula pH studies to correlate with symptoms 12 Based on expert opinion Role of EGD and biopsy unclear

38. 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 changeImprovement EGD with biopsy Rx for 2-3 months Symptoms recur Symptoms may occur in presence or absence of esophagitis

39. Pharmacotherapy

40. Adapted from Sanders SW, Clin Therapeutics 18, 2-34. Copyright 1996 by Excerpta Medica Inc. Inhibition of Acid Secretion in Gastric Parietal Cell

41. Mucosal Protectors Sucralfate –Forms a polymer to adhere selectively to ulcer or erosions –Barrier to pepsin, acid and bile salts. –Adverse effects: constipation, bezoars –Not effective in GERD

42. H2RA Labeling for GERD H2RAIndication inImportant Pediatric Information Approved Labelin Approved Label FamotidineGastroesophagealLabeling for patients < 1 year of (Pepcid®)refluxage, including information on dose, PK/PD, adverse events Lower dose recommended in patients <3 months of age RanitidineGastroesophagealAge range includes 0-1 month; (Zantac®) refluxPK characterized in single and continuous infusions

43. Recommended Oral H2RA Dosages for GERD Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 Infants and ChildrenAdults Cimetidine40 mg/kg/day divided TID or QID1600 mg/day Famotidine1 mg/kg/day divided BID20 or 40 mg BID Nizatidine10 mg/kg/day divided BID150 mg BID or 300 mg HS Ranitidine5-10 mg/kg/day divided TID150 mg BID - QID

44. Recommended Oral H2RA Dosages for GERD Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 Infants and ChildrenAdults Cimetidine40 mg/kg/day divided TID or QID1600 mg/day Famotidine1 mg/kg/day divided BID20 or 40 mg BID Nizatidine10 mg/kg/day divided BID150 mg BID or 300 mg HS Ranitidine5-10 mg/kg/day divided TID150 mg BID - QID

45. Effect of H2RAs on Healing of Esophagitis Cucchiara et al, J Pediatr Gastroenterol Nutr 1989;8:150 N = 32 children with esophagitis treated with cimetidine 30-40 mg/kg/d or placebo for 12 weeks Cimetidine Placebo 20% Significant symptom improvement with cimetidine, not placebo Simeone et al, J Pediatr Gastroenterol Nutr 1997;25:51 N = 26 children with esophagitis treated with nizatidine 10 mg/kg/d or placebo for 8 weeks Nizatidine Placebo Esophagitis Healing 15% 71% 69% “Vomiting” reduced in both treatment arms; significant improvement in other GERD symptoms only with nizatidine

46. Proton Pump Inhibition Adapted from Sanders SW, Clin Therapeutics 18, 2-34. Copyright 1996 by Excerpta Medica Inc.

47. PPI Labeling for GERD PPIIndication inImportant Pediatric Information Approved Labelin Approved Label LansoprazoleGastroesophagealSafety and effectiveness established (Prevacid®)reflux and erosivein pediatric patients 1-11 years of age esophagitis Information on dose and adverse events OmeprazoleGastroesophagealSafety and effectiveness established (Prilosec®)reflux and erosivein pediatric patients 2-16 years of age esophagitis Information on dose, PK, exposure/ response, and adverse events Note: Important pediatric information in approved label does not necessarily address approved indication (spelled out in second column above). PK, pharmacokinetics. Source: US Food and Drug Administration, Pediatric exclusivity labeling changes as of 9/10/02 and Prescribing Information for Prevacid (revised 8/02).

48. Omeprazole10 mg QD (body weight 20 kg) [2] 20 mg QD 1.0 mg/kg/day QD or divided BID [3] Oral PPI Dosages for GERD Infants and Children Adults Lansoprazole 15 mg QD (body weight 30 kg) [1] 15 or 30 mg QD PantoprazoleNot available40 mg QD Rabeprazole Not available 20 mg QD Esomeprazole Not available 20 or 40 mg QD 1 Prescribing Information for Prevacid (revised 8/02); 2 Prescribing Information for Prilosec (revised 7/02); 3 Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

49. EsomeprazoleCapsule, IV LansoprazoleCapsule, solutabs, Oral suspension, IV OmeprazoleCapsule, tablets MUPS* PantoprazoleTablet, IV RabeprazoleTablet PPI Formulations * Multiple unit pellet system, available in Canada

50. Other PPI’s

51. 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

52. Safety Profiles of PPIs PPIAdverse Events EsomeprazoleHeadache (~5%), diarrhea, nausea, abdominal pain, respiratory infection, flatulence, gastritis LansoprazoleHeadache (3%), constipation (5%), diarrhea, abdominal pain, nausea, elevated transaminase, proteinuria, angina, hypotension OmeprazoleHeadache (2.4%), diarrhea (1.9%), abdominal pain, nausea, rash (1.1%), constipation, vitamin B12 deficiency PantoprazoleHeadache (6-9%), diarrhea (4-6%), abdominal pain (1-4%), nausea RabeprazoleHeadache (2.4%), diarrhea, abdominal pain, nausea Rudolph et al, J Pediatr Gastroenteraol Nutr 2001;32:S1 and Scott et al, Drugs 2002;62:1503; prevalence rates from Prescribing Information for Aciphex®, Nexium™, Prevacid®, Prilosec®, Protonix Hassell, E et al. J Pediatr, March 2007. ® Efficacy and safety of PPI studied up to 11 years duration.

53. 0 20 40 60 80 OverallHeartburnDysphagiaIrritabilityCoughing % of Patients* Effect of Omeprazole on Symptoms in Children with Esophagitis * % of patients with moderate to severe symptoms Reprinted from Hassall et al, J Pediatr 2000; 137: 800 Pre-entry 5-14 days 3 months N = 54 100

54. Effect of Omeprazole on Esophagitis Hassall et al, J Pediatr 2000;137:800 N = 65 children with erosive esophagitis % of Patients 100 80 60 40 20 0 Healed with < 3.5 mg/kg/day 95% 72% 44% Healed with < 1.4 mg/kg/day Healed with 0.7 mg/kg/day

55. Effect of Lansoprazole on GERD Symptoms Tolia et al, J Pediatr Gastroenterol Nutr 2002 supl N = 66 children with GERD symptoms treated with lansoprazole 15-30 mg QD-BID for 8-12 weeks Median % of Days With GERD Symptoms 100 80 60 40 20 0 Baseline Wk 2 Wk 12 100% 79% 20% P<.01

56. Effect of Lansoprazole on Esophagitis Tolia et al, J Pediatr Gastroenterol Nutr 2002 suppl (in press) % Patients With Esophagitis 100 80 60 40 20 0 Baseline Wk 8 Wk 12 100% 22% 0% N = 28 children with grade > 2 erosive esophagitis treated with lansoprazole 15-30 mg QD-BID for 8-12 weeks

57. Available Prokinetic Agents Are Unproven or Ineffective Cisapride: withdrawn Bethanechol: only 1 randomized controlled trial (RCT) Erythromycin: Efficacy in gastric emptying, HPS risk Domperidone: available in Canada, no RCT Metoclopramide –Esophageal pH improvement in 1 of 6 RCT –Clinical improvement in 1 of 4 RCT –High incidence of CNS reactions(>20%) Adapted from J Pediatr Gastroenterol Nutr 2001;32:S1

58. Approaches to Acid-Reducing Therapy Step Down Begin treatment with PPI Maintain improvement with PPI Switch to H2RA Step Up Begin treatment with H2RA Inadequate response  PPI Inadequate response  ↑ PPI dose

59. Management of Infants and Children With Esophagitis Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 Initial treatment - Lifestyle changes - H2RA or PPI Optimize medical treatment - Add PPI or  PPI dose Repeat endoscopy Consider: - Esophageal pH monitoring on treatment - Prokinetic treatment - Fundoplication

60. Respiratory Symptoms of GER Apnea/ALTE Stridor and hoarseness Cough Wheezing Recurrent pneumonia

61. Mechanisms of Respiratory Responses to GER

62. ALTE DefinitionFrightening 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

63. 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 GER and ALTE Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1

64. Association of GER with Apnea Herbst et al, J Pediatr 1979;95:763 Time (sec) Esophageal pH Nasal Air Flow Chest Wall Movement

65. GER Asthma Does GER Cause Asthma?

66. GER (abnormal esophageal pH studies) in 61% of infants and children with asthma GER symptoms absent or mild in about 50% of those with persistent asthma and abnormal esophageal pH studies Prevalence of GER in Infants and Children with Asthma Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 61% N=668 pts in 13 case series

67. Effect of Antireflux Pharmacotherapy in Children with Asthma N=168 pts in 4 case series Clinical improvement or reduced dosages of antiasthmatic therapy in 63% of asthma patients with GER treated with: Conservative management Prokinetic monotherapy H2RA monotherapy A recent metanalysis found only 4 studies, one was DBPCT that did not show that omeprazole reduced symptoms of asthma. Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 Sopo, SM J Investig Allergol Clin Immunol. 2009 63%

68. Effect of Antireflux Surgery in Children With Asthma Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 N=258 pts in 6 case series 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%

69. Asthma: When to Treat for GERD Persistent asthma and GER symptoms Persistent asthma and no GER symptoms Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1 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

70. Aspiration Syndromes Interstitial lung disease & pulmonary fibrosis Acid aspiration pneumonitis Aspiration pneumonia & pleural effusion

71. Aspiration From Swallowing or GER? Lipid-Laden Macrophages

72. NormalReflux laryngitis

73. Candidate for Antireflux Surgery in Childhood Child Who: Fails medical therapy due to GERD Is dependent on aggressive or prolonged medical therapy Has persistent asthma or recurrent pneumonia due to GERD

74. Principles of Antireflux Surgery Restore intra- abdominal segment of esophagus Approximate diaphagmatic crurae Reduce hiatal hernia when present Wrap fundus around LES to reinforce antireflux barrier

75. Summary GER is common in healthy infants and usually resolves by 18 months of age Pediatric GER can present with variable symptoms Approach to diagnosis and treatment depends on presenting symptoms and signs Currently available tests often do not conclusively demonstrate a relationship between GER and specific symptoms Good history and clinical judgment are important for optimal evaluation and management