1. GERD in Infants
Focus on the efficacy and safety of PPIs
Joanna Yeh
Peds GI
Case Conference
Feb 2012

2. Objectives
• Review GERD, focusing on infants
• Review 2009 NASPGHAN and ESPGHAN Joint
Recommendations on GERD Clinical Practice
Guidelines
• Review PPI and H2 blocker physiology
• Discuss article “PPI Use in Infants: FDA
Reviewer Experience”

3. Case
• 11 month old refer for 2nd opinion
• Reason for consult: 2nd opinion for
recommended Nissen/pyloroplasty
• 7 months of age refer to Peds GI for FTT (<5%)
and emesis (Sept 2011)

4. Case
• BH: ex 36 wk, mom on bed-rest from 29-36 wks for
preterm labor, NSVD, no complications
• 1 DOL: “poky feeder”; episode of vomit, turn blue ->
NICU -> r/o sepsis
• 3 DOL: went home weighing 5 lbs 12 oz
• Breast fed x 3 months then Nestle Goodstart
• Fussy baby, lots of spitting up and back arching
• 3 months to 5 months: honeymoon phase
• 5 months: spit up returned; started solids at 6 months
of age (rice cereal, apple sauce, banana)
• He will vomit solids 2-3 hrs after being fed

5. Case
• Meds: s/p erythromycin 2 ml tid, reglan 1ml
qid, prevacid 1 solutab daily
• NKDA
• FH: 3 year old brother; mom history of reflux,
maternal grandfather with esophageal spasm,
unclear etiology. Dad with wheat/gluten
“allergy”
• SH: Lives with mom, dad, brother, 1 dog. No
smokers, no travel. Bakersfield.

6. Case
• Wt 8.1 kg (5-10%), Ht 70 cm (2%)
• BP 84/46 HR 164 Temp 36.6
• Exam
– General: NAD, happy
– HEENT: NCAT, EOMI, PERRL, anicteric, 2 teeth
– Heart: no murmurs
– Lungs: Clear
– Abd: soft, NTND, no masses, no HSM, +BS

7. Past workup
• Oct 2011: GES using 8 ounces of formula; t1/2 276
minutes, episode of reflux seen
• Oct 2011: UGI was normal
• Dec 2011: pH probe with impedance showed 18%
reflux while upright (nl <6.3%); longest reflux episode
6.7 minutes, composite score 28.1 (nl <14.7), 94%
correlation between symptoms and reflux; total of 103
reflux episodes (84 acidic and 19 nonacidic)
– Conclusion: moderate GERD
• Dec 2011: EGD showed “probable esophagitis just
above GE junction, obvious lack of peristalsis in the
antrum and in the pylorus of the stomach

8. Biopsy Results
• Duodenal mucosa : normal
• Antrum: normal
• MBGC: normal
• Esophagus: squamous epithelial hyperplasia
and rare eosinophils, c/w reflux esophagitis
– Basal layers appears mildly thickened in some
areas; within these areas can be found small
numbers of infiltrating eosinophils, usually
numbering no more than 2 per HPF

9. A B

10. Current status
• Mom put him on gluten free diet in December
and has gained nearly 2 lbs over the last 2
months, about 15-20 gm/day.
• 50% BF / 50% formula (Nestle GentleStart);
solids (veggies, fruits, chicken, avocado, egg)
• Spits up 3-5x/day (overall improved)
• Erythro, reglan, prevacid since 7 months, mom
stopped at about 9 months

11. Patient Summary
• 11 month old refer for 2nd opinion for
recommended Nissen/pyloroplasty for FTT,
GERD, delayed gastric emptying
• FTT improved per mom on gluten free diet
since 10 months of age, off medications since
9 months of age
What is the recommended approach to
diagnosing and treating GERD in infants?

12. GERD Basics
• GER: passage of gastric contents into esophagus
with or without regurgitation and vomiting
• GERD: above but with complications or
troublesome symptoms
• In infants, no symptom(s) is diagnostic
• Reflux is not a common cause of crying, irritability
• 50% of healthy 3-4 month old infants regurgitate
at least 1x/day and up to 20% of caregivers seek
help for this normal behavior

16. Potential Diagnostic Tools
• Esophageal pH monitoring
• Combined multiple intra-luminal impedance
(MII) and pH monitoring
• Motility
• Endoscopy
• (Upper GI)
• (GES)
• (Questionnaires)

17. Treatment Options
• Formula
– Thicken
– Hydrolyzed protein
– Smaller amounts, more frequent
• Position
• Medications
– Acid buffering agents
– Mucosal surface barriers
– Gastric antisecretory agents

18. Among infants <12 months old,
there was an 11 fold increase in
the number of PPI new
prescriptions dispensed between
2002 and 2009.

19. Calam J , Baron J H BMJ 2001;323:980-982
Stomach Physiology

20. Stomach Physiology
P

21. Histamine 2 Receptor Antagonists
• H2 blockers block action of histamine on parietal
cells of the stomach
• Can exhibit tachyphylaxis or tolerance (PPIs do
not), thus not ideal for chronic use
• Rapid onset of action (peak 2-3hr after dose,
gastric pH begins to increase within 30 min of
medication administration)
• Some infants with H2RA therapy have irritability,
head banging, headache, somnolence

23. Proton Pump Inhibitors
• Recognition that H-K-ATPase was the final step
of acid secretion resulted in development of
PPIs
• PPIs inhibit this enzyme
• Administer prior to breakfast
• Do not give at same time with H2 blockers

24. PPIs for Infants
• Approved in North America >1 year old
– Omeprazole (Prilosec)
– Lansoprazole (Prevacid)
– Esomeprazole (Nexium)
• No PPI has been approved for use in infants <1
year old
• Double blind randomized placebo controlled
trials shows that PPI tx is not beneficial in
infants with sx thought to be related to GERD

25. “Proton Pump Inhibitor Use in Infants:
FDA Reviewer Experience”
• Methods: Data from 4 FDA clinical reviews of
new drug applications including the RCTs
• Population:
– 1 to 12 months of age
– Otherwise healthy infants

26. RCT Study Design

27. PPI Dosing
• Esomeprazole (Nexium)
– 0.25 mg/kg/day
– 1 mg/kg/day
• Lansoprazole (Prevacid)
– 1 mg/kg/day
– 2mg/kg/day
• Pantoprazole (Protonix)
– 0.6 mg/kg/day
– 1.2 mg/kg/day

28. Results

29. Flaws
• PPI trials brief in duration (4 to 8 weeks)
• Can’t comment on safety profile for longer
time
• Primary endpoints
• “Symptom” based assessment
• Future suggestions: pediatric trials in infants
should be limited to acid-induced conditions
(i.e. erosive esophagitis)

30. Potential Adverse Effects
1. idiosyncratic reactions
– Headache, diarrhea, constipation, nausea (2-7%)
2. drug- drug interactions
3. drug induced hypergastrinemia
4. drug-induced hypochlorhydria
– Inc risk of community acquired pneumonias, gastroenteritis, candidemia,
NEC
In ELBW infants, acid suppression possibly linked to high rates of NEC.
In adults, deficiency of vitamin B12, hypomagnesemia, increased incidence of hip
fractures (osteoporosis), acute interstitial nephritis are possibilities.
Animal studies suggest predisposition to food allergies with acid suppression.
More studies needed.

31. Take Home Points
• Can not just assume GERD based on sx
• Tendency towards getting workup
• Be aware of warning signs
• Use of PPIs in infants is often from assumption
that acid reflux is the cause of their “GERD”
symptoms

32. References
• Chen et al, “Proton Pump Inhibitor Use in Infants: FDA
Reviewer Experience,” JPGN, Jan 2012.
• Pediatric GERD Clinical Practice Guidelines: Joint
Recommendations of NASPGHAN and ESPGHAN, JPGN,
2009.
• Salvatore et al, “GERD in Infants: How much is predictable
with questionnaires, ph-metry, endoscopy, and histology?”
JPGN, 2005.
• Van der Pol et al, “Efficacy of Proton Pump Inhibitors in
Children with Gastroesophageal Reflux Disease: A Systemic
Review,” Pediatrics, 2011.
• Shin, Sachs, “Pharmacology of Proton Pump Inhibitors,”
Curr Gastroenterol Rep, Dec 2008.