GERD. Learning Objectives Differentiate between physiologic GER and gastroesophageal reflux disease...

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 extraesophageal 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


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


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


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


61%

N=668 pts in 13 case series

Effect of Antireflux Pharmacotherapy in Children

with Asthma


Clinical improvement or reduced dosages of antiasthmatic therapy in 63% of asthma patients with GER treated with:• Conservative management• Prokinetic monotherapy• H2RA monotherapy

A recent metanalysis found only 4 studies, one was DBPCT that did not show that omeprazole reduced symptoms of asthma.


Sopo, SM J Investig Allergol Clin Immunol. 2009

63%

Effect of Antireflux Surgery in Children With Asthma



•Clinical improvement or reduced dosages of

antiasthmatic therapy in 85% of children

•Persistent asthma requiring intensive steroid therapy before surgery

•GER most often confirmed by pH studies

•Failure of antireflux medical therapy did not preclude response to antireflux surgery

85%

Asthma: When to Treat for GERD

Persistent asthma and GER symptoms

Persistent asthma and no GER symptoms


Vigorous acid-suppressive therapy for 3 months, monitoring outcome variables

Consider esophageal pH monitoring or empiric treatment trial in children with

• recurrent pneumonia• nocturnal asthma > 1X weekly• corticosteroid dependence

If pH studies positive 3-month trial of antireflux medical therapy, monitoring outcome variables

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

GERD. Learning Objectives Differentiate between physiologic GER and gastroesophageal reflux disease...

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Transcript of GERD. Learning Objectives Differentiate between physiologic GER and gastroesophageal reflux disease...