GERD in Infants Focus on the efficacy and safety of PPIs

Joanna Yeh

Peds GI

Case Conference

Feb 2012

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”

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)

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

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.

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

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

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

A B

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

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?

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

Potential Diagnostic Tools

• Esophageal pH monitoring

• Combined multiple intra-luminal impedance (MII) and pH monitoring

• Motility

• Endoscopy

• (Upper GI)

• (GES)

• (Questionnaires)

Treatment Options

• Formula – Thicken

– Hydrolyzed protein

– Smaller amounts, more frequent

• Position

• Medications – Acid buffering agents

– Mucosal surface barriers

– Gastric antisecretory agents

Among infants <12 months old, there was an 11 fold increase in

the number of PPI new prescriptions dispensed between

2002 and 2009.

Calam J , Baron J H BMJ 2001;323:980-982

Stomach Physiology

Stomach Physiology

P

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

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

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

“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

RCT Study Design

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

Results

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)

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.

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

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.