Gastroesophageal reflux in children

1. Gastroesophageal reflux in children 浙江大学医学院附属儿童医院 江米足

2. Definition of GER or GERD • GER: means involuntary passage of gastric contents into the esophagus and is often physiological. • GERD: means symptoms or complications associated with pathological GER. Hassall E. Arch Dis Child 2005

3. Prevalence • USA: • 3-9 y:566 cases, 1.8% • 10-17 y:615 cases, 3.5% • Adults (＞18 y):22% • The prevalence of GERD slowly increases with age during childhood and becomes quite frequent among young adults. Nelson SP, et al. Arch Pediatr Adolesc Med 2000

4. Prevalence • India:602 infants • 1-6m(55%) • 7-12m(15%) • 12-24m(10%) • Italy:2642 infants • 0-12m (12%) • Australia:863 infants • 3-4m(41%) • 13-14m(＜5%) Martin AJ, et al. Pediatrics 2002 Campanozzi A et al. Pediatrics 2009 De S, et al. Trop Gastroenterol 2001

5. Prevalence • GER is frequently seen in early infancy and it almost disappears by one year of age. • Persistence or appearance of regurgitation beyond 18 months of age is suggestive of pathological condition. • The prevalence of GERD in infancy is 5%-9% of all infants with regurgitation. Poddar U. Indian Pediatr 2013

6. Risk factors of GER • Poor function of LES (pressure and length) • Esophageal dysmotility resulting in reduced clearance • Abnormal anatomy-including congenital malformation (short intra-abdominal esophagus) or acquired disease (esophageal atresia repair) • Higher intra-gastric pressure and delayed gastric emptying Liu XL, et al. Hong Kong Med J 2012

7. Mechanisms • Closing mechanisms • The diaphragm creates a pinch cork action and functions to increase the pressure • The intra-abdominal portion of the esophagus • The angle of His between the stomach and the esophagus • Opening mechanisms • Increased intra-abdominal pressure (from abdominal tumours, coughing, and constipation) increases intra-gastric pressure Liu XL, et al. Hong Kong Med J 2012

8. TLESR TLESR is the predominant mechanism of GER triggering, accounting for 50-100% (median 91.5%) of all GER episodes. Omari TI, et al. Gut 2002

9. Clinical symptoms of GER • Clinical features of GER vary in children of different ages. • Typical symptoms • Regurgitation • Vomiting • Heartburn • Chest pain • Atypical symptoms • Feeding difficulties/anorexia • Failure to thrive • Postural defect • Stridor • Chronic cough • Laryngitis, otitis • Asthma • sinusitis Martigne L, et al. Eur J Pediatr 2012

10. Yuksel ES, et al. Eur J Med Sci 2010

11. Presenting symptoms • Regurgitation or vomiting • Healthy: no failure to thrive or other associated symptoms • Infants with GERD • Growth failure or indirect symptoms of pain due to esophagitis like irritability, feeding difficulty, sleeping difficulties, crying episodes, anemia • Rarely apnea or ALTE • Chronic respiratory diseases and upper airway problems like sinusitis, otitis media, laryngitis, dental erosion • In children and adolescents, symptoms and complications of GERD are heartburn or substernal pain

12. Diagnostic test • Esophageal pH monitoring • Multichannel intraluminal impedance (MII) measurement • High resolution manometry (HRM) • Endoscopy • Confocal laser endomicroscopy • Barium UGI series • Nuclear scintigraphy • GER questionnaire • Rome III criteria

13. Esophageal pH monitoring • To establish the presence of acidic reflux (pH<4) • To quantify reflux in patients with mainly extra-esophageal symptoms • To assess the efficacy of medical therapy • To measure GER in patients not responding to antireflux treatment and in research

14. 24 hr ambularoty pH-metry

15. Parameters of pH monitoring • Percent total time with a pH<4.0 (reflux index, RI) • Percent upright time with a pH<4.0 • Percent supine time with a pH<4.0 • Number of reflux episodes • Number of reflux episodes lasting≥5 min • Longest reflux episode (min) • The scoring system • Boix-Ochoa score • Demeester score

16. Diagnostic criteria of pathological GER • RI is the main parameter in diagnosing GERD. • RI 10%（<1 year）, 5% （>1 year ） • RI 10%（<1 year), 4.2%（>1 year） • USA: RI≥12% (<1 year)，≥6% (>1 year) • RI>7% as abnormal, <3% as normal, 3-7% as indeterminate (ESPGHN, NASPGHN) • Boix-Ochoa score >11.99 • Demeester score >14.72 Van der Pol RJ, et al. J Pediatrics 2012 Vandenplas Y, et al. J Pediatr Gastroenterol Nutr 2009 Mattioli G, et al. Dig Dis Sci 2006 Aggarwal S, et al.Trop Gastroenterol 2004 Wenzl TG. J Pediatr Gastroenterol Nutr 2011

17. Esophageal pH monitoring • Advantages • Be done in any age • Be relatively non-invasive • Disadvantage • Does not measure non-acid or weakly acidic reflux

18. Multichannel intraluminal-impedance (MII) measurement • To detect the change in electrical resistance (or impedance) when substances pass through the esophagus using a series of impedance sensors lying 1 cm apart on a probe • Impedance is inversely proportional to electrical conductivity • Since the conductivity of liquid (high) and air (low) is different, MII can easily differentiate liquid from gas reflux

19. Wenzl TG, et al. J Pediatr Gastroenterol Nutr 2012

20. Wenzl TG, et al. J Pediatr Gastroenterol Nutr 2012

21. Advantages of MII-pH monitoring • Be superior to pH-study alone for evaluation of GER-related symptom association • Picking up acid, non-acid or weakly acid reflux, • the direction of reflux • To distinguish between liquid, solid and gas reflux in all age groups

22. Limitations of MII-pH study • High cost • Limited availability • Limited therapeutic implications (clinical relevance of measuring non-acidic reflux remains doubtful) • The lack of evidence-based parameters for assessment of GER

23. High resolution manometry (HRM) • Conventional manometry assemblies detect pressure using a catheter with several water-perfused sideholes by gaps between the pressure sensors which are several centimeters long. • HRM catheters are equipped with intraluminal pressure transducers • Simultaneously measure from hypopharynx to stomach • Assign color to specific pressure levels which are than presented in a spatiotemporal plot • Pressure topography plots are more intuitive and easier learned by clinicians Kessing BF, et al. Curr Gastroenterol Rep 2012

24. Clinical application of HRM • HRM is superior to other diagnostic tools for the evaluation of achalasia and contributes to a more specific classification of esophageal disorders in patients with non-obstructive dysphagia Kessing BF, et al. Curr Gastroenterol Rep 2012

25. Endoscopy • Upper gastrointestinal endoscopy is the best method of detecting esophagitis as a consequence of GERD. • Normal endoscopy (found in 60%-80% cases of GERD in children) does not rule out GERD and this type of GERD is called Non-erosive reflux disease (NERD). • Endoscopy needs to be combined with a biopsy to increase the diagnostic yield (especially in NERD) and to rule out other causes of esophagitis (like eosinophilic esophagitis, Crohn’s disease).

26. Indications of endoscopy • Persistence of symptoms despite therapy • Dysphagia or odynophagia • Evidence of GI bleeding or iron deficiency anemia • Stricture or ulcer on barium study • Long duration GERD to detect Barrett’s esophagus.

27. Advantages of endoscopy • Gives a direct information about the presence and severity of esophagitis • Detects complications like ulcer, stricture, Barrett’s esophagus • Documents healing of erosive esophagitis after therapy. • Exclude other causes of esophagits by endoscopic esophageal biopsy.

28. Los Angeles classification • A One or more mucosal breaks, each ≤ 5 mm in length • B At least one mucosal break > 5 mm long, but not continuous between the tops of adjacent mucosal folds • C At least one mucosal break that is continuous between the tops of adjacent mucosal folds, but which is not circumferential (< 75% of luminal circumference) • D Mucosal break that involves at least 75% of the luminal circumference

29. Kamal A, et al. Best Practice Res Clin Gastroenterol 2010

30. The evidence of histology • Histology is more sensitive than endoscopy in the early stage (non-erosive stage). • Erosive esophagitis is the most definite evidence of GERD on endoscopy. • Biopsy (2 cm proximal to gastroesophageal junction) helps to establish the diagnosis of GERD if there is no erosion or mucosal break on endoscopy.

31. Esophageal histological features of GERD • Basal zone hyperplasia (>20% of total thickness) • Elongation of papillae (>50% of total thickness) • Infiltration with neutrophils or eosinophils (<15/high power field) • The presence of dilated intercellular spaces • Growing of blood vessels in papilla • Histological changes are neither sensitive nor specific for reflux disease in NERD cases and should not be used alone to diagnose or exclude GERD Poddar U. Indian Pediatr 2013 Tobey NA, et al. Gastroenterology 1996 Boccia G, et al. Am J Gastroenterol 2007 Vandenplas Y, et al. J Pediatr Gastroenterol Nutr 2009

32. Barium UGI series • Be useful to detect anatomical anomalies such as the angle of His, esophageal dysmotility, mucosal irregularity, stricture, and hiatus hernia, but not useful in diagnosing GERD. • The sensitivity and specificity to diagnose GERD is less than 50%. • Cannot differentiate physiological from pathological reflux. • Most useful in ruling out underlying obstruction such as that due to achalasia

33. Nuclear scintigraphy • Be a non-invasive test but has poor sensitivity and specificity. • To confirm silent aspiration in patients with recurrent pneumonia due to aspiration of gastric contents. • Be a useful tool in evaluation of delayed gastric emptying • Not recommended for the routine evaluation of pediatric patients with suspected GERD.

34. Infant GER questionnaire (I-GERQ) Orenstein SR, et al. Clin Pediatr 1996

35. I-GERQ • Maximum total score:25 • Score＞7, for diagnosing GERD in infants • Sensitivity 74% • Specificity 94% • Can be used to segregate those infants who needs empirical therapy or further investigation because of its simplicity (take just 20 minutes to complete) and reproducibility.

36. Rome III criteria • Must include all of the following in otherwise healthy infants 3 weeks to 12 months of age • Regurgitation 2 or more times per day for 3 or more weeks • No retching, hematemesis, aspiration, apnea, failure to thrive, feeding or swallowing difficulties, or abnormal posturing

37. Diagnostic test • When symptoms are not classical and in cases with complicated GERD • Endoscopy,pH study, barium upper GI series • In a patient with classical symptoms of GERD • No need to confirm the presence of GER by pH study or by endoscopy • In patients with extra-esophageal symptoms like respiratory symptoms without any GER symptoms • pH study is required to document reflux • When esophagitis is suspected (pain or blood loss) • Upper gastrointestinal endoscopy with esophageal biopsy is recommended • Any suggestion of an anatomical abnormality like intestinal obstruction or dysphagia • Barium upper GI series is indicated

38. Diagnostic approach to GERD • There is no gold standard for the diagnosis of GERD. • The choice of investigation depends on the clinical situation for which the investigation is asked for.

39. Management---GER in infants • Counseling-the most important part • Explain the natural history of GER in infants to parents or care-givers • Other measures • Feeding advice • Avoid overfeeding, forceful feeding • Try to give small but frequent feeds • positioning • Prone position-not recommended (the risk of SIDS) • Left lateral position (age>13m)-the best in preventing reflux • feed thickening • Adding rice, corn or potato starch • decrease the number regurgitation of vomiting • does not decreases the acid exposure of esophagus • Feed thickener has only cosmetic value but no therapeutic benefit.

40. Proton pump inhibitors (PPIs) • PPIs are not recommended in this subset of patient • Only a few of the infants are likely to have acid-related cause for their symptoms • The largest randomized, controlled trial in infants showed that for symptoms, presumably to be related to reflux disease, a PPI was not better than placebo. Orenstein SR, et al. J Pediatr 2009

41. Management---GERD in children • Besides medication, life-style modification in terms of weight reduction, avoiding caffeine, chocolate, abstinence from alcohol, tobacco helps in children. • Adolescents, like in adults, may benefit from the left lateral decubitus sleeping position with head-end elevation

42. Pharmacological therapy • Acid suppressants • Histamin-2 receptor antagonists (H2RA) • Ranitidine: 6-8mg/kg/day, bid or tid • Famotidine:1mg/kg/day, bid • PPIs • Omeprazole:0.7 to 3.5 mg/kg/day, qd • Neutralizing or surface protective agents (antacids or sucralfate) • Prokinetics

43. H2RA • Rapid onset of action (in 30 min) • Short acting (6 hr) acid suppressants • used for on-demand therapy (SOS therapy) • A lack of post-prandial acid suppressant effect • Develop tachyphylaxis on long-term use (in 6 weeks) • Cannot be used for long term therapy • H2RA are less effective than PPI

44. PPIs • Inhibit acid secretion by irreversibly blocking Na+-K+-ATPase in the apical membrane of parietal cells • Be taken 30 min before breakfast as parietal cells get activated in response to a meal. • Require a higher per kilogram dose than adults to obtain a similar degree of acid suppression due to higher metabolism of the drug. • Omeprazole, 2-2.5mg/kg/day • Lansoprazole, 1.4mg/kg/day

45. Side effect of PPIs • Mild side effects have been reported in up to 14% of children • Most common side effects • headache • diarrhea • constipation • nausea

46. Prokinetics • metoclopramide, domperidone, erythromycin, baclofen or itopride in the management of GERD • prokinetics may be of some use is GERD with associated gastroparesis Vandenplas Y, et al. J Pediatr Gastroenterol Nutr 2009 Poddar U. Indian Pediatr 2013

47. Duration of medical therapy • GERD needs profound acid suppression for a longer duration of time • PPI therapy is recommended for at least 12 weeks and then to taper over 2 to 3 months as rebound hyperacidity after sudden stoppage of PPI • No symptomatic improvement in 4 weeks then the dose of PPI needs to be increased • A relapse on withdrawal of PPI, medication needs to be restarted • Frequent relapses or continuous symptoms are indications for prolonged PPI therapy or surgery

48. Repeat endoscopy to document healing is indicated at the end of 12 weeks course in erosive esophagitis • Prolonged PPI therapy (median 3 years and up to 12 years) is safe • Full healing dose is superior to half dose in PPI maintenance therapy

49. Surgery • Nissen fundoplication (open or laparoscopic) may be of benefit in children with confirmed GERD • Who have failed optimal medical therapy • Who are dependent on medical therapy for a long time • Who are significantly noncompliant to medical therapy • Who have life threatening complication of GERD • Point: who need surgery most, develop surgery related complications and surgical failure most • Fundoplication in early infancy has a higher failure rate than in late childhood Hassall E. Arch Dis Child 2005 Vandenplas Y, et al. J Pediatr Gastroenterol Nutr 2009 Poddar U. Indian Pediatr 2013

50. Conclusion • GER is common in infants but GERD is not so common in early childhood • Most infants have physiological reflux and need minimal intervention as their symptoms resolve by 18 months of age • There is no gold standard diagnostic test for GERD and investigation should be tailored to the clinical concern for a given child • For extraesophageal manifestations, pH-metry with or without impedance is the best investigations • For esophagitis, endoscopy is the best investigations • Empirical PPI therapy for 4 weeks is justified in older children and adolescents with classical symptoms • Medical therapy with PPI is very effective and safe. • Surgical therapy is not a panacea as it carries significant morbidity and often fails in those who need it most.