Post on 23-Dec-2015
GERD
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
DefinitionsGER Involuntary passage of gastric contents
into esophagus
GERD Symptoms or complications that may occur when gastric contents reflux into esophagus or oropharynx
Regurgitation Passage of refluxed gastric contents into oral pharynx
Vomiting Expulsion of refluxed gastric contents from mouth
Prevalence of Regurgitationin Infancy
0
10
20
30
40
50
60
70
0-3 4-6 7-9 10-12
Age (months)
% of Infants
1 time a day
4 times a day
Adapted from Nelson et al, Arch Pediatr Adolesc Med 1997;151:569
0
2
4
6
8
10
12
14
16
18
20
Prevalence of GERSymptoms in Children
Nelson et al, Arch Pediatr Adolesc Med 2000;154:150 and Locke et al, Gastroenterology 1997;112:1448
% of Children
Heartburn Epigastricpain
Regurgitation Heartburn and/oracid regurgitation
566 parents of children aged 3-9 yr
615 children aged 10-17 yr
2200 adults aged 25-74 years
The Antireflux Barrier
Transient LES Relaxations
Tracings reprinted from Kawahara et al, Gastroenterology 1997;113:399
Esophagus
LES
Cruraldiaphragm
Pylorus
Stomach
Angle of His
Pharynx
UES
Esophageal Capacitance
• Shorter esophagus• Smaller capacity
Gravity
Adult
Infant
Airway Protective Mechanisms
ESOPHAGEAL DISTENTION UES contracts
Vagal reflexesVocal cords closeCentral apnea occursUES relaxes
0.15 s
Refluxate enters pharynx0.3 s
Swallowing clears pharynx0.6 s
Small volume
1.0 sRespiration resumes
Large volume
Pathogenesis
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
Cruraldiaphragm
Pylorus
Stomach
Angle of His
Pharynx
UES
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
Sandifer Syndrome
Looking for reflux
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?
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
Upper GI Radiography
•Cannot discriminate between physiologic and
nonphysiologic GER episodes
Limitation
•Useful for detecting anatomic abnormalities
Advantage
Pyloric stenosis
Malrotation
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
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
Number of Eosinophils
Normal GER
BL, basal layer; EH, epithelial height; PL, papillary layerNormal: PL ~ 40% of epithelial height, BL ~ 15%GER: PL ~ 90% of epithelial height, BL ~ 30%
PLPL
BLBL
EH
EH
GER Eosinophilic esophagitisNormal esophagus
Eosinophil Count and Responseto Antireflux Therapy
Response toantireflux Rx
No response Response toantireflux Rx
Incomplete response
1.1
24.5
5
31
Mean Eosinophil Count ± SEM No. Eosinophils Per HPF
N=102p < .0025
N=28p = .009
Adapted from Ruchelli et al, Pediatr Dev Pathol 1999;2:15 and Walsh et al, Am J Surg Pathol 1999;23:390
Use of Eosinophilic Density to Guide Therapy?
No. of eosinophils per HPF
<5 5-20 >20
Consideraggressive
antireflux Rx?
Consider Rx for allergy or primary
eosinophilic esophagitis
• Identify and eliminate food allergen
• Steroids — systemic, topical
Eosinophilic Esophagitis
GER Complication
Normal mid- anddistal esophagus
Erosive esophagitis:grade 2 and grade 4
Z-line
Erosions
GER Complications
Esophageal stricturesecondary to GERD:radiography andendoscopy
Barrett’s esophagus:endoscopy and histology
Normal
Barrett’s
Barrett’s
Normal
Stricture
Capsule Endoscopy
Esophagitis Suspected Barrett’s
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
Intraluminal Electrical Impedance
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
Impedancechannels
Z
t
1
Z4
Management
EmpiricTherapy
DiagnosticWorkup
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 andphysical exam
Are there warning signals?
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 andphysical exam
Are therewarning signals?
Are there signsof complicated
GERD?
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 pediatricgastroenterologist
•Consider EGD and biopsy
•Consider nasogastric or nasojejunal tube feeding
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,
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/orelemental formula
pH studiesto correlatewith symptoms
1 2
•Based on expert opinion•Role of EGD and biopsy unclear
Management of Heartburn or Chest Pain
H2RA or PPI for 2-4 weeks
Lifestyle changes:• Weight loss if obese• No alcohol• No caffeine• No smoking
No change Improvement
EGD with biopsy
Rx for2-3 months
Symptoms recur
•Symptoms may occur in presence or absence of esophagitis
Pharmacotherapy
Adapted from Sanders SW, Clin Therapeutics 18, 2-34. Copyright 1996 by Excerpta Medica Inc.
Inhibition of Acid Secretionin Gastric Parietal Cell
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
H2RA Labeling for GERD
H2RA Indication in Important Pediatric InformationApproved Label in Approved Label
Famotidine Gastroesophageal Labeling for patients < 1 year of(Pepcid®) reflux age, including information on
dose, PK/PD, adverse events
Lower dose recommended inpatients <3 months of age
Ranitidine Gastroesophageal Age range includes 0-1 month;(Zantac®) reflux PK characterized in single and
continuous infusions
Recommended Oral H2RADosages for GERD
Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1
Infants and Children Adults
Cimetidine 40 mg/kg/day divided TID or QID 1600 mg/day
Famotidine 1 mg/kg/day divided BID 20 or 40 mg BID
Nizatidine 10 mg/kg/day divided BID 150 mg BID or 300 mg HS
Ranitidine 5-10 mg/kg/day divided TID 150 mg BID - QID
Recommended Oral H2RADosages for GERD
Rudolph et al, J Pediatr Gastroenterol Nutr 2001;32:S1
Infants and Children Adults
Cimetidine 40 mg/kg/day divided TID or QID 1600 mg/day
Famotidine 1 mg/kg/day divided BID 20 or 40 mg BID
Nizatidine 10 mg/kg/day divided BID 150 mg BID or 300 mg HS
Ranitidine 5-10 mg/kg/day divided TID 150 mg BID - QID
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
Esophagitis Healing
15%
71%
69%
“Vomiting” reduced in both treatment arms; significant improvement in other GERD symptoms only with nizatidine
Proton Pump Inhibition
Adapted from Sanders SW, Clin Therapeutics 18, 2-34. Copyright 1996 by Excerpta Medica Inc.
PPI Labeling for GERD
PPI Indication in Important Pediatric InformationApproved Label in Approved Label
Lansoprazole Gastroesophageal Safety and effectiveness established(Prevacid®) reflux and erosive in pediatric patients 1-11 years of age
esophagitisInformation on dose and adverse
events
Omeprazole Gastroesophageal Safety and effectiveness established(Prilosec®) reflux and erosive in pediatric patients 2-16 years of age
esophagitisInformation 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).
Omeprazole 10 mg QD (body weight < 20 kg)or 20 mg QD (> 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) or 30 mg QD (> 30 kg) [1]
15 or 30 mg QD
Pantoprazole Not available 40 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
Esomeprazole Capsule, IV
Lansoprazole Capsule, solutabs,Oral suspension, IV
Omeprazole Capsule, tabletsMUPS*
Pantoprazole Tablet, IV
Rabeprazole Tablet
PPI Formulations
* Multiple unit pellet system, available in Canada
Other PPI’s
Optimal Timing of PPI Dose
Single PPI dose:
Administer 1 half-hourbefore breakfast
If second PPI dose:
Administer 1 half-hourbefore evening meal
Safety Profiles of PPIsPPI Adverse Events
Esomeprazole Headache (~5%), diarrhea, nausea, abdominal pain,respiratory infection, flatulence, gastritis
Lansoprazole Headache (3%), constipation (5%), diarrhea,abdominal pain, nausea, elevated transaminase,
proteinuria, angina, hypotension
Omeprazole Headache (2.4%), diarrhea (1.9%), abdominal pain, nausea, rash (1.1%), constipation, vitamin
B12 deficiency
Pantoprazole Headache (6-9%), diarrhea (4-6%), abdominal pain (1-4%), nausea
Rabeprazole Headache (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®, ProtonixHassell, E et al. J Pediatr, March 2007. ®
Efficacy and safety of PPI studied up to 11 years duration .
0
20
40
60
80
Overall Heartburn Dysphagia Irritability Coughing
% of Patients*
Effect of Omeprazole onSymptoms in Children with Esophagitis
* % of patients with moderate to severe symptomsReprinted from Hassall et al, J Pediatr 2000; 137: 800
Pre-entry
5-14 days
3 months
N = 54100
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
0Healed with
< 3.5 mg/kg/day
95%
72%
44%
Healed with< 1.4 mg/kg/day
Healed with0.7 mg/kg/day
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
0Baseline Wk 2 Wk 12
100%
79%
20%
P<.01
Effect of Lansoprazole on Esophagitis
Tolia et al, J Pediatr Gastroenterol Nutr 2002 suppl (in press)
% Patients With
Esophagitis
100
80
60
40
20
0Baseline 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
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
Approaches toAcid-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
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
Respiratory Symptoms of GER
• Apnea/ALTE
• Stridor and hoarseness
• Cough
• Wheezing
• Recurrent pneumonia
Mechanisms of Respiratory Responses to GER
ALTE
Definition Frightening episode in infant that is characterized by:
- apnea- change in color- change in muscle tone- choking or gagging
and requires intervention by caretaker
Potential causes - Cardiac disorder - Upper airway obstruction - CNS disorder- Infection- GER- Intentional suffocation
•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
Association of GER with Apnea
Herbst et al, J Pediatr 1979;95:763
Time (sec)
EsophagealpH
NasalAirFlow
ChestWallMovement
GER Asthma
GER Asthma
GER Asthma
GER Asthma
Does GER Cause Asthma?
•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
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%
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%
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
Aspiration Syndromes
• Interstitial lung disease & pulmonary fibrosis
• Acid aspiration pneumonitis
• Aspiration pneumonia &pleural effusion
Aspiration From Swallowing or GER?
Lipid-Laden Macrophages
Normal Reflux laryngitis
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
Principles of Antireflux Surgery
Restore intra-abdominal segment
of esophagus
Approximatediaphagmatic
crurae
Reduce hiatal herniawhen present
Wrap fundus around LES to reinforce antireflux barrier
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