Gastroesophageal Reflux in infants & Proton Pump InhibitorsBy:Khalil EbrahimManal Darwish Shihadeh, MD, FAAP

Clinical Cases

• 5 month old who effortlessly spits-up 6–10x/day, but seems comfortable and is growing well

• 4 month old who is losing weight is reported to vomit 2–3x/day, and seems increasingly fussy with feeds

• 15 year old who presents complaining of heartburn

Gastroesophagyeal Reflux GER without D

GER is a physiologic Phenomenon that occurs at all ages and it allows depressurization of the stomach

GER• Gastroesophageal Reflux

– The passage of gastric contents into the esophagus– Occurs with/without regurgitation and vomiting

• GER is a normal physiologic process – Several times/day in healthy infants, children, and adults

Physiology of GER

• GER occurs during transient relaxations of the lower esophageal sphincter (LES)– Relaxation of the LES that is unaccompanied by swallowing

permits gastric contents into the esophagus

• LES is not a “true” sphincter– Comprised of crural support, an intra abdominal segment, and ‑

the “angle of His”

• The main underlying mechanism that allows GER to occur across all ages

• Allows air to vent from the stomach

Composition of the LES

• Healthy adult – LES 3cm in length, at level of diaphragm

• Neonate – LES 1.5cm in length, above the diaphragm

Adult

Esophageal Capacity

• Shorter esophagus• Smaller capacity

GravityInfant

Most Episodes of GER

• Last < 3 minutes• Occur in the postprandial period• Cause few or no symptoms• GER can cause vomiting

– A coordinated autonomic and voluntary motor response with forceful expulsion of gastric contents

• Regurgitation (“spitting up”) is the most visible symptom of GER– Occurs daily in 50% of infants < 3 months of age– Resolves spontaneously in most by 12–14 months

Prevalence of Regurgitation in 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 SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux during infancy. A pediatric practice-based survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med. 1997;151(6):569–572

n=948

WHEN DOES GER “become” GERD

• Aberrance in normal physiology – Insufficient clearance and buffering of

refluxate– Decreased rate of gastric emptying– Abnormalities in efficacy of epithelial

repair– Decreased neural protective reflexes

Risk Factors for GERD

• Hiatal Hernia• Neurodevelopmental Delay• Anatomic Abnormalities: -TEF• Obesity• Delayed Gastric emptying??? -Pro-motility agents have not proven to

reduce bolus GER

Genetics of Reflux

• Cluster studies suggest inheritability of GER/GERD and their complications– Hiatal hernia– Erosive esophagitis– Barrett’s esophagus– Esophageal adenocarcinoma

• Swedish Twin Registry – Increased concordance in monozygotic vs. dizygotic

Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

How much reflux is too much?

Gastroesophageal Reflux, as Measured By 24-Hour pH Monitoring, in 509 Healthy InfantsScreened for Risk of Sudden InfantDeath Syndrome Pediatrics 1991

• Yvan Vandenplas, MD, PhD; Harry Goyvaerts, RN*; Rudy Helven, RN;• and Liliane Sacre, MD• From the Academisch Ziekenhuis Kinderen, Vrije Universiteit Brussel

and *Janssen• Pharmaceuticals, Belgium

Frequency of Reflux in 24hour among Infants

Percentile Reflux Index Number

1 0 1

5 0 6

10 1 9

25 2 16

50 4 27

75 7 41

90 10 56

95 10 71.5

99 13.9 99.7

Physician beliefs, according to specialty, based on overall clinical impression.

Golski C A et al. Pediatrics 2010;125:96-104

©2010 by American Academy of Pediatrics

Acta Paediatr. 2011 October; 100(10): e178–e180. doi: 10.1111/j.1651-2227.2011.02315.x

PMCID: PMC3187871Gastroesophageal reflux disease at any cost: a dangerous paediatric attitude

Andrea Taddio,1 Chiara Bersanini,2 Lucio Basile,3 Massimo Fontana,2 and Alessandro Ventura1

1Department of Pediatrics, Institute of Child Health IRCCS Burlo Garofolo, University of Trieste, Trieste, Italy

CASES OF INFANTS WITH INFANTILE SPASMS MISDIAGNOSED AS GERD

A GLOBAL, EVIDENCE-BASED CONSENSUS ON THE DEFINITION OF

GASTROESOPHAGEAL REFLUX DISEASE IN THE PEDIATRIC POPULATION

• GERD is present when reflux of gastric contents causes troublesome symptoms and/or complications, but this definition is complicated by unreliable reporting of symptoms in children under the age of 8 years

Troublesome symptoms or complications of reflux

• Recurrent vomiting andpoor weight gain in infant

• Recurrent vomiting andirritability in infant

• Recurrent vomiting inolder child

• Heartburn in child/adolescent

• Esophagitis

• Dysphagia or feeding refusal

• Apnea or ALTE• Asthma• Recurrent pneumonia• Upper airway symptoms • Unusual arching or

seizure-like movements (Sandifer syndrome)

What about complications of GERD?

e.g. Is there a danger to not recognizing and treating it?

Complications of Reflux

Normal mid- anddistal esophagus

Erosive esophagitis:grade 2 and grade 4

Z-line

Erosions

Esophageal stricturesecondary to GERD:radiography andendoscopy

Barrett’s esophagus:endoscopy and histology

Normal

Barrett’s

Barrett’sNormal

Stricture

Complications of Reflux

Diagnostic ApproachUpper GI Radiography

• Cannot discriminate between physiologic and nonphysiologic GER episodes

Limitation

• Useful for detecting anatomic abnormalities

Advantage

Pyloric stenosis Malrotation

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

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

Advantages

Multiple Intraluminal Electrical Impedance Measurement

Advantages• Detects nonacidic GER episodes• Detects brief (< 15 s) acidic GER episodes• Useful for studying respiratory symptoms

and GER in infants

Limitations• Normal values in pediatric age groups not

yet defined• Analysis of tracings time-consuming• Portable device unavailable for outpatient

studies

pH channel

pH 4

Impedancechannels

Z 1

Z 4

Non-AcidReflux

History and Physical Exam

• Symptoms and signs associated with GER are non-specific– i.e. Not all children with GER have heartburn or irritability– Conversely, heartburn and irritability can be caused by

conditions other than GER

• Major roles of History/Physical Exam when evaluating GERD– To exclude other worrisome disorders that present with

vomiting– To recognize complications of GERD

Important to Obtain a Feeding and Vomiting HistoryFeeding and dietary history• Amount/frequency

(overfeeding)• Preparation of formula• Recent changes in feeding

type or technique• Position during feeding• Burping• Behavior during feeding:

choking, gagging, cough, arching, discomfort, refusal

Pattern of vomiting• Frequency/amount• Pain• Forceful or not• Blood or bile• Associated fever, lethargy,

diarrhea

History/Physical Examination

• Severity of reflux or esophagitis found on diagnostic testing does not directly correlate with symptom severity

• In infants and toddlers, there is no symptom or group

of symptoms that can reliably diagnose GERD or predict treatment response

• In older children and adolescents, history and

physical examination are generally sufficient to reliably diagnose GERD and initiate management

Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

Treatment with PPI’s

• >11 fold increase in new PPI prescriptions(2002-2009)• A liquid formulation of a PPI saw a 16-fold increase(1999-2004) despite the

fact that PPI are not FDA approved for use infants• 25% of extremely LBW infants discharged on antisecretory meds.• Drugs on which most advertising spent: PPI• In 2005, PPI sales grossed approx $13 billion in US alone.

Twenty-Four Hour Esophageal Impedance-pH Monitoring in Healthy Preterm Neonates: Rate and Characteristics of Acid, Weakly acidic, and weakly alkaline Gastroesophageal Reflux

Pediatrics 2006

21 Preterm neonate mean gestational age 32 weeks.• Non acid Reflux > acid• Median 70 events• Majority reached proximal esophagus• No difference between healthy and those with

cardio respiratory events

Esophageal pH-Impedance Monitoring in Patients With Therapy-Resistant Reflux

Symptoms: 'On' or 'Off' Proton Pump Inhibitor? Gerrit J.M. Hemmink, M.D., Albert J. Bredenoord, M.D., Ph.D., Bas L.A.M. Weusten,

M.D., Ph.D., Jan F. Monkelbaan, M.D., Robin Timmer, M.D., Ph.D., André J.P.M. Smout, M.D., Ph.D.

Disclosures Am J Gastroenterol. 2008;103(10):2446-2453.

• RESULTS: • The total number of reflux episodes and proximal

extent were not affected by PPI therapy. • On PPI, there were fewer acid reflux episodes while

more weakly acidic reflux episodes were identified.

Combined Esophageal Intraluminal Impedance, pH and Skin Conductance Monitoring to Detect Discomfort in GERD Infants

• Discomfort was significantly associated with reflux events and did not differ between weakly acidic and acid refluxes.

• The results may raise concerns about the over-prescription use of antacid drugs in the management of gastroesophageal reflux symptoms in infancy.

Proton pump inhibitor use in infants: FDA reviewer experience.

Division of Gastroenterology and Inborn Errors Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA.

• The Food and Drug Administration has completed its review of 4 clinical trials evaluating the use of proton pump inhibitors (PPIs) in infants (ages 1 month to <12 months) for the treatment of gastroesophageal reflux disease (GERD) in November 2010.

• Advisory Committee members agreed that PPIs should not be administered to treat the symptoms of GERD in the otherwise healthy infant without the evidence of acid-induced disease. Use of PPIs should be reserved for infants with an endoscopically documented acid-induced condition such as erosive esophagitis. The risk/benefit relation of administration of PPIs in infants with GER or GERD without a documented acid-induced condition is not favorable because no benefit can be attributed to the PPI. Furthermore, there may be risks associated with long-term PPI use that require further study in this young population

• PMID: 21946832 [PubMed - indexed for MEDLINE]

Efficacy of Proton-Pump Inhibitors in Children WithGastroesophageal Reflux Disease: A Systematic Review

• PPIs are not effective in reducing GERD symptoms in infants. • Placebo-controlled trials in older children are

lacking. • Although PPIs seem to be well tolerated

during short-term use, evidence supporting the safety of PPIs is lacking.

• Pediatrics 2011;127:925–935

PPI The Wolf in Sheep’s clothing

Reported Adverse Events of Acid suppression

• 1- C. difficile infection• 2- Community acquired pneumonia• Necrotizing enterocolitis• Osteopenia/ osteoporosis• Candidemia• Infant pneumonia• Bacterial Overgrowth• Vitamin B12 deficiency• Hypomagnesaemia• Interstitial nephritis

Pediatrics 2012;129;e40; originally published online December 12, 2011;Salvia, Laura Lega, Francesco Messina, Roberto Paludetto and Roberto Berni

Canani

• Ranitidine is Associated With Infections, Necrotizing Enterocolitis, and Fatal Outcome in Newborns

• FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs)

Safety Announcement [02-08-2012] The U.S. Food and Drug Administration (FDA) is

informing the public that the use of stomach acid drugs known as proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile–associated diarrhea (CDAD). A diagnosis of CDAD should be considered for patients taking PPIs who develop diarrhea that does not improve.

New Evidence: PPI Stomach Acid Drugs Cause Pneumonia Sunday, May 31, 2009 by: S. L. Baker, features writer

a new study just published in the Journal of the American Medical Association (JAMA) concludes that by disrupting the body's natural balance, PPIs may cause deadly pneumonia.

• Proton pump inhibitor side effects and drug interactions: Much ado about nothing?

Ryan D. Madanick, MD, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, CB #7080, Chapel Hill, NC 27599; e-mail madanick@med.unc.edu.

Available Prokinetic Agents Are Unproven or Ineffective• Cisapride: withdrawn• Bethanechol: only 1 randomized controlled trial (RCT)• Erythromycin: no RCT• Domperidone: available in Canada, no RCT• Metoclopramide:

– Esophageal pH improvement in 1 of 6 RCT– Clinical improvement in 1 of 4 RCT– High incidence (~30% prevalence) of adverse events

Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

Increasing Concern about Safety of ProkineticsProkinetic Adverse Events

Bethanechol Malaise, abdominal cramps, colicky, pain, nausea and belching, diarrhea, urinary urgency; contraindicated in

hyperthyroidism, bronchial asthma, and otherconditions

Domperidone Hyperprolactinemia, dry mouth, rash, headache,diarrhea, nervousness

Erythromycin Abdominal pain, nausea, vomiting, diarrhea, pyloricstenosis

Metoclopramide Restlessness, drowsiness, fatigue and lassitude(10%); insomnia, headache, confusion, dizziness,mental depression; extrapyramidal reactions includingparkinsonian-like symptoms, tardive dyskinesia, andmotor restlessness; galactorrhea, gynecomastia,cardiovascular effects, nausea, diarrhea

Prescribing Information for Reglan® and Urecholine®; Curry JI, Lander TD, Stringer MD. Erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15(5):595–603; Ramirez B, Richter JE. Review article: promotility drugs in the treatment of gastro-oesophageal reflux disease Aliment Pharmacol Ther. 1993;7(1):5–20

For Infants For Older Children

Conservative Therapy for GER

• Avoid large meals

• Do not lie down immediately after eating

• Lose weight, if obese

• Avoid caffeine, chocolate, and spicy foods that provoke symptoms

• Eliminate exposure to tobacco smoke

• Normalize feeding volumeand frequency

• Consider thickened formula

• Consider non-prone positioning during sleep

• Consider trial of hypoallergenic formula

Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux.

Orenstein SR, McGowan JD.Source

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

AbstractOBJECTIVE: To determine the efficacy of non-pharmacologic conservative therapy for infant gastroesophageal reflux disease (GERD).STUDY DESIGN: Consenting parents of the first 50 screened infants who met inclusion/exclusion criteria including abnormal (>16/42) scores on

the Infant Gastroesophageal Reflux Questionnaire-Revised (I-GERQ-R; n = 40) were taught conservative therapy measures by

each site's study nurse: feeding modifications, positioning, and tobacco smoke avoidance. We compared I-GERQ-R scores and symptom response details before and 2 weeks after institution of these measures with 2-tail Wilcoxon signed ranks test in the 37 infants (age range, 4-43 weeks; median age, 13 weeks) who completed the run-in.

RESULTS: The median initial and final scores were 23 (16-36) and 18 (7-34; P < .000001). The median score change was -5 (+6--16). Scores

of 78% improved at all; 59% improved at least the threshold of 5 points; 24% became normal. Scores for individual symptoms related to regurgitation, crying, and arching improved significantly.

CONCLUSIONS: Two weeks of conservative therapy measures taught in primary care

improved 59% beyond the 5-point threshold and normalized 24% of infants with symptom severity diagnostic for GERD, as substantiated with a responsiveness-validated instrument.

Thickened formula

Unthickened formula

Thickening a 20Kcal/oz infant formula with

• 1 Tbp/2oz-------------27kcal/oz• 1Tbp/1oz-------------34kcal/oz

Effect of Thickening Milk Formula Feedings With Rice Cereal

0.0

0.5

1.0

Adapted from Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy of gastroesophageal reflux. J Pediatr. 1987;110(2):181–186

Caloric Density(cal/cc)

Emesis(episodes/90 min)

Sleep Time(min asleep/90 min)

Crying Time(min crying/90 min)

Unthickened Thickened

p=.015 p=.026 p=.042

0

1

2

3

4

5

0

10

20

30

40

50

0

5

10

15

20

25

n=20

Positioning and GER

Sitting

Supine

Prone

60°

Adapted from Ramenofsky ML, Leape LL. Continuous upper esophageal pH monitoring in infants and children with gastroesophageal reflux, pneumonia, and apneic spells. J Pediatr Surg. 1981;16(3):374–378

Effect of Sleep Position on GER in Infants and Sudden Infant Death Syndrome (SIDS) Mortality

Reflux Index1

(% time pH <4)

Supine 15.3 0.05* 2.3 1.0

Left side 7.7 0.05* 1.1 3.5†

Right side 12.0 0.05* 1.8 3.5†

Prone 6.7 4.4 1.0 13.9

*Mortality rate for all non-prone positions combined†Combined odds ratio 1 Tobin JM, McCloud P, Cameron DJ. Posture and gastro-oesophageal reflux: a case for left lateral positioning. Arch Dis Child. 1997;76(3):254–3582 Skadberg BT, Morild I, Markestad T. Abandoning prone sleeping: Effect on the risk of sudden infant death syndrome. J Pediatr. 1998;132(2):340–3433 Oyen N, Markestad T, Skaerven R, et al. Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: the Nordic Epidemiological SIDS Study. Pediatrics. 1997;100(4):613–621

SIDS Mortality2

(per 1000 live births)Reflux IndexOdds Ratio

SIDS MortalityOdds Ratio3

Allergic gastroenteropathy in preterm infants.D'Netto MA, Herson VC, Hussain N, Ricci A Jr, Brown RT, Hyams JS, Justinich CJ.

Division of Neonatology, Department of Pediatrics, Connecticut Children's Medical Center, Hartford, CT 06106, USA.

AbstractOBJECTIVES: To determine the clinical presentation, histopathologic features, and outcome of biopsy-proven allergic gastroenteropathy (AGE) in preterm infants. We hypothesized that AGE is a more

frequent cause of gastrointestinal disease in this population than previously suspected.STUDY DESIGN: The retrospective portion of the study, from 1992 to 1997, included preterm infants <37 weeks' gestation who underwent biopsy because of suspected AGE. The prospective portion,

from January to December 1998, included 20 infants undergoing endoscopy and biopsy because of suspected AGE.RESULTS: Twenty-five infants (12 retrospective/13 prospective) with mean gestational age of 29 weeks at birth and mean postnatal age at diagnosis of 78 days were diagnosed with AGE. Three

clinical patterns of presentation were noted: group 1, gastroesophageal reflux disease (n = 5); group 2, non-specific feeding intolerance (n = 8); and group 3, lower gastrointestinal bleeding (n = 12). Ten patients had negative biopsy findings (3 retrospective/7 prospective) and had clinical features indistinguishable from those of groups 1 and 2. Patients in group 3 were most likely to have positive biopsy findings (12 of 12). Fifteen patients responded to a casein hydrolysate formula, and 10 patients required an amino acid-based formula. Patients with AGE who had eosinophilic infiltration and villous atrophy took longer to recover than those with eosinophilic infiltration alone (P <.03). Subsequently, most have tolerated formula challenges and are currently tolerating cow's milk.

CONCLUSIONS: AGE may be an under-recognized cause of

gastrointestinal symptoms in preterm infants. Confirmation with endoscopy and biopsy can be done safely and provides the basis for appropriate dietary management. J Pediatr. 2000 Oct;137(4):480-6

Cow’s Milk Allergy

-Symptoms may be identical to GERD -Atopic families -Eczema -History of crying when swallowing -2week trial with hydrolysate formula

Conclusions• It is important to clarify whether a pediatric patient

has physiologic GER or pathologic GERD

• There are guidelines for appropriate testing and treating of children with reflux disease…

Recommended Approach to the Infant With Recurrent Regurgitation and Vomiting

Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

Recommended Approach to the Infant With Recurrent Regurgitation and Weight Loss

Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

GERD in older Children

• Heartburn, epigastric pain, and regurgitation• Explore lifestyle in adolescents – cigarettes,

alcohol..• PPI if symptoms are typical and the child is old

enough to express the symptoms - 2,4 weeks and if symptoms resolve

continue and stop in 3 months - wean off PPI

Recommended Approach to the Older Child or Adolescent With Heartburn

Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

Thank you

Special thanks toDr. Manal Darwish