P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics: Effect on Design of Clinical Trials...

PPATHOLOGICATHOLOGIC GE GE RREFLUX IN EFLUX IN

CCHILDRENHILDRENAge-Related Characteristics:Age-Related Characteristics:

Effect on Design of Clinical TrialsEffect on Design of Clinical Trials

PPATHOLOGICATHOLOGIC GE GE RREFLUX IN EFLUX IN

CCHILDRENHILDRENAge-Related Characteristics:Age-Related Characteristics:

Effect on Design of Clinical TrialsEffect on Design of Clinical Trials

FDA / CDER Pediatric Advisory CommitteeFDA / CDER Pediatric Advisory Committee

Bethesda, MD Bethesda, MD

11 June ‘0211 June ‘02

FDA / CDER Pediatric Advisory CommitteeFDA / CDER Pediatric Advisory Committee

Bethesda, MD Bethesda, MD

11 June ‘0211 June ‘02

EERIC RIC HHASSALL MD ASSALL MD

Division of GastroenterologyDivision of GastroenterologyBC Children’s Hospital / BC Children’s Hospital /

University of British ColumbiaUniversity of British Columbia

Vancouver, BC, CANADAVancouver, BC, CANADA

EERIC RIC HHASSALL MD ASSALL MD

Division of GastroenterologyDivision of GastroenterologyBC Children’s Hospital / BC Children’s Hospital /

University of British ColumbiaUniversity of British Columbia

Vancouver, BC, CANADAVancouver, BC, CANADA

OOUTLINEUTLINE: F: FOCUSOCUS ON ON AAGEGE-R-RELATEDELATED D DIFFERENCESIFFERENCESOOUTLINEUTLINE: F: FOCUSOCUS ON ON AAGEGE-R-RELATEDELATED D DIFFERENCESIFFERENCES

BBACKGROUNDACKGROUND

Difficulties in ped studies,Difficulties in ped studies, Definitions, Complications, Goals of Definitions, Complications, Goals of

Rx, Rx,

Prevalence, Natural history, Available treatmentsPrevalence, Natural history, Available treatments

PPATHOPHYSIOLOGYATHOPHYSIOLOGY

Etiologies, Mechanisms, Acid secretion, Underlying diseasesEtiologies, Mechanisms, Acid secretion, Underlying diseases

PPHARMACOKINETICSHARMACOKINETICS

EENDPOINTS:NDPOINTS: P PRESENTINGRESENTING S SYMPTOMS YMPTOMS / S/ SIGNSIGNS

FFEASIBILITYEASIBILITY

RREQUIREMENTS FOR EQUIREMENTS FOR PPERFORMANCE OF ERFORMANCE OF SSUCCESSFUL UCCESSFUL SSTUDYTUDY


Difficulties in ped studies,Difficulties in ped studies, Definitions, Complications, Goals of Definitions, Complications, Goals of

Rx, Rx,








DDIFFICULTIES IN IFFICULTIES IN DDOING OING PPEDIATRIC EDIATRIC SSTUDIESTUDIES

Ethics: Placebo controls, etcEthics: Placebo controls, etc

Age-related differences in disease manifestationsAge-related differences in disease manifestations

Fears of parents / investigatorsFears of parents / investigators

Feasibilities: What’s practicable?Feasibilities: What’s practicable?

Time- and labor-intensivenessTime- and labor-intensiveness

Need for flexibility: Optional testsNeed for flexibility: Optional tests

Inexperience of centers: Uniformity of approachInexperience of centers: Uniformity of approach

DDIFFICULTIES IN IFFICULTIES IN DDOING OING PPEDIATRIC EDIATRIC SSTUDIESTUDIES

Ethics: Placebo controls, etcEthics: Placebo controls, etc

Age-related differences in disease manifestationsAge-related differences in disease manifestations

Fears of parents / investigatorsFears of parents / investigators

Feasibilities: What’s practicable?Feasibilities: What’s practicable?

Time- and labor-intensivenessTime- and labor-intensiveness

Need for flexibility: Optional testsNeed for flexibility: Optional tests

Inexperience of centers: Uniformity of approachInexperience of centers: Uniformity of approach

Gastroesophageal reflux [GER]Gastroesophageal reflux [GER]

vsvs

Gastroesophageal reflux disease [GERD]Gastroesophageal reflux disease [GERD]

Gastroesophageal reflux [GER]Gastroesophageal reflux [GER]

vsvs

Gastroesophageal reflux disease [GERD]Gastroesophageal reflux disease [GERD]

DEFINITIONSDEFINITIONSDEFINITIONSDEFINITIONS

CCOMPLICATIONSOMPLICATIONS OFOF GE R GE REFLUXEFLUXCCOMPLICATIONSOMPLICATIONS OFOF GE R GE REFLUXEFLUX

• EsophagitisEsophagitis• Peptic stricturePeptic stricture• Barrett’s esophagusBarrett’s esophagus• Failure to thriveFailure to thrive• Pulmonary / Pulmonary / ENT diseaseENT disease• Sandifer’s syndrome Sandifer’s syndrome

// torticollistorticollis

• EsophagitisEsophagitis• Peptic stricturePeptic stricture• Barrett’s esophagusBarrett’s esophagus• Failure to thriveFailure to thrive• Pulmonary / Pulmonary / ENT diseaseENT disease• Sandifer’s syndrome Sandifer’s syndrome

// torticollistorticollis

MANAGEMENT GOALSMANAGEMENT GOALSMANAGEMENT GOALSMANAGEMENT GOALS

• RRELIEVE SYMPTOMSELIEVE SYMPTOMS

• PPREVENT COMPLICATIONSREVENT COMPLICATIONS

• HHEAL ESOPHAGITISEAL ESOPHAGITIS

• MMAINTAIN REMISSIONAINTAIN REMISSION

• TTREAT COMPLICATIONSREAT COMPLICATIONS

• RRELIEVE SYMPTOMSELIEVE SYMPTOMS

• PPREVENT COMPLICATIONSREVENT COMPLICATIONS

• HHEAL ESOPHAGITISEAL ESOPHAGITIS

• MMAINTAIN REMISSIONAINTAIN REMISSION

• TTREAT COMPLICATIONSREAT COMPLICATIONS

Gastroesophageal Reflux Disease [GERD]Gastroesophageal Reflux Disease [GERD]Gastroesophageal Reflux Disease [GERD]Gastroesophageal Reflux Disease [GERD]



Difficulties in ped studies, Definitions, Complications, Goals of Difficulties in ped studies, Definitions, Complications, Goals of

Rx, Rx,

Prevalence, Natural history,Prevalence, Natural history, Available treatments Available treatments









Rx, Rx,

Prevalence, Natural history,Prevalence, Natural history, Available treatments Available treatments







PPREVALENCE, REVALENCE, NNATURAL ATURAL HHISTORYISTORY

Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151:569-72Arch Pediatr Adolesc Med 1997;151:569-72


Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151:569-72Arch Pediatr Adolesc Med 1997;151:569-72

* * Based on IGER, Orenstein SR, et al. Clin Pediatr 1993;32:472-84 [20min]Based on IGER, Orenstein SR, et al. Clin Pediatr 1993;32:472-84 [20min] * * Based on IGER, Orenstein SR, et al. Clin Pediatr 1993;32:472-84 [20min]Based on IGER, Orenstein SR, et al. Clin Pediatr 1993;32:472-84 [20min]

• X-sectional, community practice-basedX-sectional, community practice-based• 948 healthy children <13mo948 healthy children <13mo• Infant GER Questionnaire [IGER-SF], shortened, revised [5min] Infant GER Questionnaire [IGER-SF], shortened, revised [5min] **• Main outcome measure: Reported frequency of vomitingMain outcome measure: Reported frequency of vomiting

• X-sectional, community practice-basedX-sectional, community practice-based• 948 healthy children <13mo948 healthy children <13mo• Infant GER Questionnaire [IGER-SF], shortened, revised [5min] Infant GER Questionnaire [IGER-SF], shortened, revised [5min] **• Main outcome measure: Reported frequency of vomitingMain outcome measure: Reported frequency of vomiting

RESULTSRESULTS

• Vomiting at least 1/ day: 50% at 0-3moVomiting at least 1/ day: 50% at 0-3mo


• Peak frequency: 4moPeak frequency: 4mo

• Decrease from 61% to 21%: between 6-7moDecrease from 61% to 21%: between 6-7mo

• Peak frequency of vomiting reported as ‘problem’:Peak frequency of vomiting reported as ‘problem’: - 23% at 6mo to 14% at 7mo- 23% at 6mo to 14% at 7mo

RESULTSRESULTS



• Peak frequency: 4moPeak frequency: 4mo

• Decrease from 61% to 21%: between 6-7moDecrease from 61% to 21%: between 6-7mo

• Peak frequency of vomiting reported as ‘problem’:Peak frequency of vomiting reported as ‘problem’: - 23% at 6mo to 14% at 7mo- 23% at 6mo to 14% at 7mo

GE Reflux: Children v AdultsGE Reflux: Children v AdultsNatural HistoryNatural History

GE Reflux: Children v AdultsGE Reflux: Children v AdultsNatural HistoryNatural History

• Very often physiological, esp < 6moVery often physiological, esp < 6mo

• 90% resolve <12-18mo90% resolve <12-18mo

• Vomiting > 2yr age never Vomiting > 2yr age never physiologicalphysiological

• GERD usually a chronic relapsing GERD usually a chronic relapsing diseasedisease

• Very often physiological, esp < 6moVery often physiological, esp < 6mo

• 90% resolve <12-18mo90% resolve <12-18mo

• Vomiting > 2yr age never Vomiting > 2yr age never physiologicalphysiological

• GERD usually a chronic relapsing GERD usually a chronic relapsing diseasedisease

< 2yr age< 2yr age< 2yr age< 2yr age

> 2yr age -adulthood> 2yr age -adulthood> 2yr age -adulthood> 2yr age -adulthood

CarreCarreNelsonNelsonCarreCarreNelsonNelson

GE Reflux: Children v AdultsGE Reflux: Children v AdultsPresentationPresentation


2 - 4yr age2 - 4yr age2 - 4yr age2 - 4yr age

• Similar symptoms / Similar symptoms / signssigns to younger childrento younger children

• Heartburn very Heartburn very unusualunusual**

• Similar to adultsSimilar to adults

• Similar symptoms / Similar symptoms / signssigns to younger childrento younger children

• Heartburn very Heartburn very unusualunusual**

• Similar to adultsSimilar to adults

> 8 - 10yr age> 8 - 10yr age> 8 - 10yr age> 8 - 10yr age

* Nelson SP. Arch Ped & Adolesc Med, Feb 00* Nelson SP. Arch Ped & Adolesc Med, Feb 00* Nelson SP. Arch Ped & Adolesc Med, Feb 00* Nelson SP. Arch Ped & Adolesc Med, Feb 00

GE Reflux: Children v AdultsGE Reflux: Children v AdultsPresentation Presentation

GE Reflux: Children v AdultsGE Reflux: Children v AdultsPresentation Presentation

NATURE OF VOMITINGNATURE OF VOMITING

EffortlessEffortless vsvs

Forceful / ‘Projectile’Forceful / ‘Projectile’

DISPOSITION OF CHILDDISPOSITION OF CHILD

‘‘Fat happy spitters’ / thrivingFat happy spitters’ / thriving vsvs

Unhappy, irritable child / poor wt gainUnhappy, irritable child / poor wt gain

NATURE OF VOMITINGNATURE OF VOMITING

EffortlessEffortless vsvs

Forceful / ‘Projectile’Forceful / ‘Projectile’

DISPOSITION OF CHILDDISPOSITION OF CHILD

‘‘Fat happy spitters’ / thrivingFat happy spitters’ / thriving vsvs

Unhappy, irritable child / poor wt gainUnhappy, irritable child / poor wt gain




Rx, Rx,

Prevalence, Natural history, Prevalence, Natural history, Available treatmentsAvailable treatments









Rx, Rx,

Prevalence, Natural history, Prevalence, Natural history, Available treatmentsAvailable treatments







GE Reflux: Children & AdultsGE Reflux: Children & AdultsManaManaggement ement

GE Reflux: Children & AdultsGE Reflux: Children & AdultsManaManaggement ement

• Explanation, reassuranceExplanation, reassurance

• Diet, lifestyleDiet, lifestyle

• PositionPosition

• AntacidsAntacids

• Anticholinergics [e.g., Anticholinergics [e.g., XXbethanecolbethanecolXX]]

• Prokinetics [Prokinetics [XXmetoclopramidemetoclopramideXX, , XXcisapridecisaprideXX] ]

• HH22-Receptor Antagonists-Receptor Antagonists

• Prayer/Meditation/Vega therapy/‘Can-deeda’ Prayer/Meditation/Vega therapy/‘Can-deeda’

Rx Rx

• Explanation, reassuranceExplanation, reassurance

• Diet, lifestyleDiet, lifestyle

• PositionPosition

• AntacidsAntacids

• Anticholinergics [e.g., Anticholinergics [e.g., XXbethanecolbethanecolXX]]

• Prokinetics [Prokinetics [XXmetoclopramidemetoclopramideXX, , XXcisapridecisaprideXX] ]

• HH22-Receptor Antagonists-Receptor Antagonists

• Prayer/Meditation/Vega therapy/‘Can-deeda’ Prayer/Meditation/Vega therapy/‘Can-deeda’

Rx Rx

• Antireflux SurgeryAntireflux Surgery

• Proton Pump Proton Pump

InhibitorsInhibitors

• [Endoscopic Rx][Endoscopic Rx]

• Antireflux SurgeryAntireflux Surgery




GE Reflux: Children & AdultsGE Reflux: Children & Adults

Management of Management of SevereSevere GERDGERD

GE Reflux: Children & AdultsGE Reflux: Children & Adults

Management of Management of SevereSevere GERDGERD

AANTIREFLUX NTIREFLUX SSURGERY IN URGERY IN CCHILDRENHILDRENAANTIREFLUX NTIREFLUX SSURGERY IN URGERY IN CCHILDRENHILDREN

EXCLUDING ‘MINOR’ PROCEDURESEXCLUDING ‘MINOR’ PROCEDURES[Inguinal herniorrhaphy, central line placement][Inguinal herniorrhaphy, central line placement]

ANTIREFLUX SURGERY IS THE COMMONEST ANTIREFLUX SURGERY IS THE COMMONEST

OPERATION PERFORMED BY PEDIATRIC SURGEONSOPERATION PERFORMED BY PEDIATRIC SURGEONS

EXCLUDING ‘MINOR’ PROCEDURESEXCLUDING ‘MINOR’ PROCEDURES[Inguinal herniorrhaphy, central line placement][Inguinal herniorrhaphy, central line placement]

ANTIREFLUX SURGERY IS THE COMMONEST ANTIREFLUX SURGERY IS THE COMMONEST

OPERATION PERFORMED BY PEDIATRIC SURGEONSOPERATION PERFORMED BY PEDIATRIC SURGEONS




Rx, Rx,



Etiologies, Underlying diseases, Mechanisms,Etiologies, Underlying diseases, Mechanisms, Acid secretion, Acid secretion,







Rx, Rx,



Etiologies, Underlying diseases, Mechanisms,Etiologies, Underlying diseases, Mechanisms, Acid secretion, Acid secretion,





Conditions Predisposing to Conditions Predisposing to Severe Severe

GE Reflux in ChildrenGE Reflux in Children



• Neurologic impairment [NI]Neurologic impairment [NI]

• Repaired esophageal atresiaRepaired esophageal atresia

• Chronic lung disease [eg CF, Chronic lung disease [eg CF,

BPD]BPD]

• Hiatal herniaHiatal hernia

• Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR]sphincter relaxation [TLESR]




BPD]BPD]










BPD]BPD]






BPD]BPD]










BPD]BPD]






BPD]BPD]










BPD]BPD]






BPD]BPD]










BPD]BPD]






BPD]BPD]






Rx, Rx,



Etiologies, Underlying diseases, Mechanisms, Etiologies, Underlying diseases, Mechanisms, Acid secretion Acid secretion







Rx, Rx,



Etiologies, Underlying diseases, Mechanisms, Etiologies, Underlying diseases, Mechanisms, Acid secretion Acid secretion





AACIDCID S SECRETIONECRETIONAACIDCID S SECRETIONECRETION

Healthy term infantsHealthy term infants

• Relative hypochlorhydria for 0-5hrs age, nl by 6-8hrsRelative hypochlorhydria for 0-5hrs age, nl by 6-8hrs

[normal BAO 25+/-10 [normal BAO 25+/-10 mol/kg/hr mol/kg/hr in adults] in adults]

• Hypergastrinemia, despite nl acid secretionHypergastrinemia, despite nl acid secretion Euler, Gastro Euler, Gastro 19771977

• Enteral feedings necessary for nl oxyntic mucosal secretionEnteral feedings necessary for nl oxyntic mucosal secretion

- purely TPN-fed relatively hypochlorhydric- purely TPN-fed relatively hypochlorhydric Hyman, Gastro Hyman, Gastro 19831983

• Meal-stim secretion occurs, but weaker than older infants Meal-stim secretion occurs, but weaker than older infants

[>6mo][>6mo]Hyman, J Peds 1984Hyman, J Peds 1984

Healthy pre-term infantsHealthy pre-term infants

• BAO by 7days 12 BAO by 7days 12 mol/kg/hr, incr over 4wks to 30 [nl] mol/kg/hr, incr over 4wks to 30 [nl]

• A few infants are achlorhydric [pentagastrin-fast] in first wkA few infants are achlorhydric [pentagastrin-fast] in first wk

Hyman, J Peds Hyman, J Peds 19851985

Healthy term infantsHealthy term infants

• Relative hypochlorhydria for 0-5hrs age, nl by 6-8hrsRelative hypochlorhydria for 0-5hrs age, nl by 6-8hrs

[normal BAO 25+/-10 [normal BAO 25+/-10 mol/kg/hr mol/kg/hr in adults] in adults]

• Hypergastrinemia, despite nl acid secretionHypergastrinemia, despite nl acid secretion Euler, Gastro Euler, Gastro 19771977

• Enteral feedings necessary for nl oxyntic mucosal secretionEnteral feedings necessary for nl oxyntic mucosal secretion

- purely TPN-fed relatively hypochlorhydric- purely TPN-fed relatively hypochlorhydric Hyman, Gastro Hyman, Gastro 19831983

• Meal-stim secretion occurs, but weaker than older infants Meal-stim secretion occurs, but weaker than older infants

[>6mo][>6mo]Hyman, J Peds 1984Hyman, J Peds 1984

Healthy pre-term infantsHealthy pre-term infants

• BAO by 7days 12 BAO by 7days 12 mol/kg/hr, incr over 4wks to 30 [nl] mol/kg/hr, incr over 4wks to 30 [nl]

• A few infants are achlorhydric [pentagastrin-fast] in first wkA few infants are achlorhydric [pentagastrin-fast] in first wk

Hyman, J Peds Hyman, J Peds 19851985

AACIDCID S SECRETIONECRETION

SUMMARYSUMMARY

• Pre-term and term infants make acidPre-term and term infants make acid

• Acid secretion increases quickly to adult Acid secretion increases quickly to adult rangesranges [[mol/kg/hr]mol/kg/hr]

• Pentagastrin-responsive by 1-4wksPentagastrin-responsive by 1-4wks

• Increase in secretion depends on postnatal Increase in secretion depends on postnatal

ageage not gestational agenot gestational age

• Require enteral feeds for nl acid outputRequire enteral feeds for nl acid output

AACIDCID S SECRETIONECRETION

SUMMARYSUMMARY

• Pre-term and term infants make acidPre-term and term infants make acid

• Acid secretion increases quickly to adult Acid secretion increases quickly to adult rangesranges [[mol/kg/hr]mol/kg/hr]

• Pentagastrin-responsive by 1-4wksPentagastrin-responsive by 1-4wks

• Increase in secretion depends on postnatal Increase in secretion depends on postnatal

ageage not gestational agenot gestational age

• Require enteral feeds for nl acid outputRequire enteral feeds for nl acid output




Rx, Rx,



Etiologies, Underlying diseases, Mechanisms, Acid secretionEtiologies, Underlying diseases, Mechanisms, Acid secretion







Rx, Rx,








PPHARMACOKINETICSHARMACOKINETICSPPHARMACOKINETICSHARMACOKINETICS

FOR OMEPRAZOLEFOR OMEPRAZOLE

• Ontogeny [Ontogeny [CY2C19CY2C19, 3A]: metabolic capacity, 3A]: metabolic capacity [AUC, AUC normalized, t-half, C[AUC, AUC normalized, t-half, Cmax, max, CCmax max nl-ized]nl-ized]

- highest 1-6yrs, - highest 1-6yrs, - gradual decline with increasing age- gradual decline with increasing age

• NL adult values by ~12yrsNL adult values by ~12yrs

• Much higher doses [per kg basis] reqd in older Much higher doses [per kg basis] reqd in older

Andersson, Am J Gastro 2000 Andersson, Am J Gastro 2000 Hassall, J Pediatr 2000 Hassall, J Pediatr 2000

• PK similar to benzodiazepines…..extrapolate to <1yr?PK similar to benzodiazepines…..extrapolate to <1yr?

FOR OMEPRAZOLEFOR OMEPRAZOLE

• Ontogeny [Ontogeny [CY2C19CY2C19, 3A]: metabolic capacity, 3A]: metabolic capacity [AUC, AUC normalized, t-half, C[AUC, AUC normalized, t-half, Cmax, max, CCmax max nl-ized]nl-ized]

- highest 1-6yrs, - highest 1-6yrs, - gradual decline with increasing age- gradual decline with increasing age

• NL adult values by ~12yrsNL adult values by ~12yrs

• Much higher doses [per kg basis] reqd in older Much higher doses [per kg basis] reqd in older

Andersson, Am J Gastro 2000 Andersson, Am J Gastro 2000 Hassall, J Pediatr 2000 Hassall, J Pediatr 2000

• PK similar to benzodiazepines…..extrapolate to <1yr?PK similar to benzodiazepines…..extrapolate to <1yr?




Rx, Rx,










Rx, Rx,








EENDPOINTS, NDPOINTS, PPRESENTING RESENTING SSYMPTOMS / YMPTOMS / SSIGNSIGNSEENDPOINTS, NDPOINTS, PPRESENTING RESENTING SSYMPTOMS / YMPTOMS / SSIGNSIGNS

For purposes of study….For purposes of study….

SSYMPTOMYMPTOM/S/SIGNIGN S SHOULDHOULD B BEE::

• Definitely causally related to GERDDefinitely causally related to GERD

• Most relevant to patient Most relevant to patient improvementimprovement

• Common in the age group under Common in the age group under studystudy

• Measurable / ‘hard’ / objectiveMeasurable / ‘hard’ / objective

• ‘ ‘Safely accessible’ in the given age Safely accessible’ in the given age groupgroup

For purposes of study….For purposes of study….

SSYMPTOMYMPTOM/S/SIGNIGN S SHOULDHOULD B BEE::

• Definitely causally related to GERDDefinitely causally related to GERD

• Most relevant to patient Most relevant to patient improvementimprovement

• Common in the age group under Common in the age group under studystudy

• Measurable / ‘hard’ / objectiveMeasurable / ‘hard’ / objective

• ‘ ‘Safely accessible’ in the given age Safely accessible’ in the given age groupgroup

‘‘FFEASIBILITY’EASIBILITY’

= Patient accrual, Retention, Success of Study= Patient accrual, Retention, Success of Study

‘‘FFEASIBILITY’EASIBILITY’

= Patient accrual, Retention, Success of Study= Patient accrual, Retention, Success of Study

EENDPOINTS, NDPOINTS, PPRESENTING RESENTING SSYMPTOMS / YMPTOMS / SSIGNSIGNSEENDPOINTS, NDPOINTS, PPRESENTING RESENTING SSYMPTOMS / YMPTOMS / SSIGNSIGNS

Vomiting: frequencyVomiting: frequency HeartburnHeartburn Esophagitis Esophagitis ?? Degree of acid refluxDegree of acid reflux - intraesophageal pH- intraesophageal pH ? ? Epigastric pain/Epigastric pain/ irritabilityirritability

?? Failure to thriveFailure to thrive

Vomiting: frequencyVomiting: frequency HeartburnHeartburn Esophagitis Esophagitis ?? Degree of acid refluxDegree of acid reflux - intraesophageal pH- intraesophageal pH ? ? Epigastric pain/Epigastric pain/ irritabilityirritability

?? Failure to thriveFailure to thrive

?? ‘Feeding problems’ ‘Feeding problems’

?? Respiratory Respiratory

?? ENTENT

xx Dysphagia / odynophagiaDysphagia / odynophagia

xx ApneaApnea

xx Degree of acid suppressionDegree of acid suppression - intragastric pH- intragastric pH

?? ‘Feeding problems’ ‘Feeding problems’

?? Respiratory Respiratory

?? ENTENT

xx Dysphagia / odynophagiaDysphagia / odynophagia

xx ApneaApnea

xx Degree of acid suppressionDegree of acid suppression - intragastric pH- intragastric pH

SSUBJECTUBJECT T THESEHESE TOTO ‘T ‘THEHE T TESTSESTS’:’:SSUBJECTUBJECT T THESEHESE TOTO ‘T ‘THEHE T TESTSESTS’:’:




Rx, Rx,










Rx, Rx,








• Availability of other, equal or better treatments Availability of other, equal or better treatments [Can’t offer placebo][Can’t offer placebo]

• Question worth askingQuestion worth asking

• Protocol simpleProtocol simple

• Tests reliableTests reliable

• Tests not ‘overly invasive’ given the child’s Tests not ‘overly invasive’ given the child’s illnessillness

• Willingness of parents to enrolWillingness of parents to enrol

• Willingness of docs to discuss enrolment with Willingness of docs to discuss enrolment with parentsparents

• Pediatric centers qualified to carry out protocolPediatric centers qualified to carry out protocol

• Availability of other, equal or better treatments Availability of other, equal or better treatments [Can’t offer placebo][Can’t offer placebo]

• Question worth askingQuestion worth asking

• Protocol simpleProtocol simple

• Tests reliableTests reliable

• Tests not ‘overly invasive’ given the child’s Tests not ‘overly invasive’ given the child’s illnessillness

• Willingness of parents to enrolWillingness of parents to enrol

• Willingness of docs to discuss enrolment with Willingness of docs to discuss enrolment with parentsparents

• Pediatric centers qualified to carry out protocolPediatric centers qualified to carry out protocol


QQUESTIONS UESTIONS

• Age Group: <1yr vs >1-2yr ….. Up to 17yr?Age Group: <1yr vs >1-2yr ….. Up to 17yr? Is this a sufficiently sensitive age breakdown?Is this a sufficiently sensitive age breakdown?

Do we need others? What should they be?Do we need others? What should they be?

• Are there indications for PPI use in all age Are there indications for PPI use in all age

groups?groups?

• Efficacy: Can we study it in all age groups?Efficacy: Can we study it in all age groups?

If not, can we impute efficacy from other studies?If not, can we impute efficacy from other studies?

• What are the appropriate study endpoints What are the appropriate study endpoints

in each age group?in each age group?• What are the dosages in each age group?What are the dosages in each age group?

QQUESTIONS UESTIONS

• Age Group: <1yr vs >1-2yr ….. Up to 17yr?Age Group: <1yr vs >1-2yr ….. Up to 17yr? Is this a sufficiently sensitive age breakdown?Is this a sufficiently sensitive age breakdown?

Do we need others? What should they be?Do we need others? What should they be?

• Are there indications for PPI use in all age Are there indications for PPI use in all age

groups?groups?

• Efficacy: Can we study it in all age groups?Efficacy: Can we study it in all age groups?

If not, can we impute efficacy from other studies?If not, can we impute efficacy from other studies?

• What are the appropriate study endpoints What are the appropriate study endpoints

in each age group?in each age group?• What are the dosages in each age group?What are the dosages in each age group?



• VomitingVomiting - commonest- commonest - very often physiological, esp - very often physiological, esp <12mo<12mo

• Failure to thriveFailure to thrive

• IrritabilityIrritability

• Food refusal / ‘feeding problems’Food refusal / ‘feeding problems’

• Chronic pulmonary symptomsChronic pulmonary symptoms

• Anemia 2Anemia 2oo blood loss blood loss

• HematemesisHematemesis

• VomitingVomiting - commonest- commonest - very often physiological, esp - very often physiological, esp <12mo<12mo

• Failure to thriveFailure to thrive

• IrritabilityIrritability

• Food refusal / ‘feeding problems’Food refusal / ‘feeding problems’

• Chronic pulmonary symptomsChronic pulmonary symptoms

• Anemia 2Anemia 2oo blood loss blood loss

• HematemesisHematemesis

< 2yr age< 2yr age< 2yr age< 2yr age

IINDICATIONS FORNDICATIONS FOR I INVESTIGATIONNVESTIGATION

Suspicion of ComplicationSuspicion of Complication


Suspicion of ComplicationSuspicion of Complication

• Irritability with feedsIrritability with feeds

• Recurrent pneumonias / chronic coughRecurrent pneumonias / chronic cough

• Generally unhappy babyGenerally unhappy baby

• Failing to thriveFailing to thrive

• Torti collis [?Sandifer’s syndrome]Torti collis [?Sandifer’s syndrome]

• Persistent vomiting at 18-24moPersistent vomiting at 18-24mo

• Irritability with feedsIrritability with feeds

• Recurrent pneumonias / chronic coughRecurrent pneumonias / chronic cough

• Generally unhappy babyGenerally unhappy baby

• Failing to thriveFailing to thrive

• Torti collis [?Sandifer’s syndrome]Torti collis [?Sandifer’s syndrome]

• Persistent vomiting at 18-24moPersistent vomiting at 18-24mo

GE Reflux in GE Reflux in

ChildrenChildren

Approach < 2yrs Approach < 2yrs

ageage

GE Reflux in GE Reflux in

ChildrenChildren

Approach < 2yrs Approach < 2yrs

ageage

IINDICATIONS FORNDICATIONS FOR I INVESTIGATIONNVESTIGATIONIINDICATIONS FORNDICATIONS FOR I INVESTIGATIONNVESTIGATION

GE Reflux in GE Reflux in ChildrenChildren

Approach > 2yrs Approach > 2yrs ageage

GE Reflux in GE Reflux in ChildrenChildren

Approach > 2yrs Approach > 2yrs ageage

• Persistence of vomiting since Persistence of vomiting since < 2yrs< 2yrs

• New onset recurrent vomitingNew onset recurrent vomiting

• Suspicion of a complicationSuspicion of a complication - undiagnosed anemia- undiagnosed anemia - dysphagia / odynophagiadysphagia / odynophagia - recurrent pneumonias, coughrecurrent pneumonias, cough - nonseasonal asthma- nonseasonal asthma

• Persistence of vomiting since Persistence of vomiting since < 2yrs< 2yrs

• New onset recurrent vomitingNew onset recurrent vomiting

• Suspicion of a complicationSuspicion of a complication - undiagnosed anemia- undiagnosed anemia - dysphagia / odynophagiadysphagia / odynophagia - recurrent pneumonias, coughrecurrent pneumonias, cough - nonseasonal asthma- nonseasonal asthma


What tests to do / What they meanWhat tests to do / What they meanGE Reflux in ChildrenGE Reflux in Children

What tests to do / What they meanWhat tests to do / What they mean

• CBCCBC

• UURINALYSIS & RINALYSIS & CCULTUREULTURE

• UUPPERPPER GI C GI CONTRASTONTRAST S STUDYTUDY

-- not a test for reflux not a test for reflux -- stricture / achalasia / mass stricture / achalasia / mass -- road maproad map

• UUPPERPPER GI E GI ENDOSCOPYNDOSCOPY, B, BIOPSIESIOPSIES

• 2424HRHR I INTRAESOPHAGEALNTRAESOPHAGEAL pH pH

• EESOPHAGEALSOPHAGEAL M MANOMETRYANOMETRY

• GGASTRICASTRIC E EMPTYINGMPTYING S STUDYTUDY

• CBCCBC

• UURINALYSIS & RINALYSIS & CCULTUREULTURE

• UUPPERPPER GI C GI CONTRASTONTRAST S STUDYTUDY

-- not a test for reflux not a test for reflux -- stricture / achalasia / mass stricture / achalasia / mass -- road maproad map

• UUPPERPPER GI E GI ENDOSCOPYNDOSCOPY, B, BIOPSIESIOPSIES

• 2424HRHR I INTRAESOPHAGEALNTRAESOPHAGEAL pH pH

• EESOPHAGEALSOPHAGEAL M MANOMETRYANOMETRY

• GGASTRICASTRIC E EMPTYINGMPTYING S STUDYTUDY

PPREVALENCE, REVALENCE, NNATURAL ATURAL HHISTORYISTORYNelson SP, et al. One-year follow-up of symptoms of GE reflux during Nelson SP, et al. One-year follow-up of symptoms of GE reflux during

infancyinfancy

PEDIATRICS Dec 1998; e-publicationPEDIATRICS Dec 1998; e-publication

PPREVALENCE, REVALENCE, NNATURAL ATURAL HHISTORYISTORYNelson SP, et al. One-year follow-up of symptoms of GE reflux during Nelson SP, et al. One-year follow-up of symptoms of GE reflux during

infancyinfancy

PEDIATRICS Dec 1998; e-publicationPEDIATRICS Dec 1998; e-publication

• Follow-up survey of parents of 63 children with vomiting Follow-up survey of parents of 63 children with vomiting identified at 6-12 mo, vs 92 controls identified at 6-12 mo, vs 92 controls

• IGER-SF & Children’s Eating Behavior Inventory [CEBI]IGER-SF & Children’s Eating Behavior Inventory [CEBI]

RESULTSRESULTS

• None of 63 cases was vomiting >1/day vs 1 of controlsNone of 63 cases was vomiting >1/day vs 1 of controls

• Parents of cases reported more Parents of cases reported more - feeding refusals [odds ration 4.2] times- feeding refusals [odds ration 4.2] times - longer eating times [>1hr]- longer eating times [>1hr] - their own anxiety re feeding- their own anxiety re feeding

• No difference in ENT complaints / wheezing between groupsNo difference in ENT complaints / wheezing between groups

• Follow-up survey of parents of 63 children with vomiting Follow-up survey of parents of 63 children with vomiting identified at 6-12 mo, vs 92 controls identified at 6-12 mo, vs 92 controls

• IGER-SF & Children’s Eating Behavior Inventory [CEBI]IGER-SF & Children’s Eating Behavior Inventory [CEBI]

RESULTSRESULTS

• None of 63 cases was vomiting >1/day vs 1 of controlsNone of 63 cases was vomiting >1/day vs 1 of controls

• Parents of cases reported more Parents of cases reported more - feeding refusals [odds ration 4.2] times- feeding refusals [odds ration 4.2] times - longer eating times [>1hr]- longer eating times [>1hr] - their own anxiety re feeding- their own anxiety re feeding

• No difference in ENT complaints / wheezing between groupsNo difference in ENT complaints / wheezing between groups

TTREATMENT OFREATMENT OF GE R GE REFLUXEFLUXTTREATMENT OFREATMENT OF GE R GE REFLUXEFLUX

Medical Medical vsvs

Surgical ?Surgical ?

ISSUESISSUES

Medical Medical vsvs

Surgical ?Surgical ?

ISSUESISSUES• Indications Indications • EfficacyEfficacy• SafetySafety• Durability Durability

[longevity][longevity]• ComplianceCompliance• Relative costRelative cost

• Indications Indications • EfficacyEfficacy• SafetySafety• Durability Durability

[longevity][longevity]• ComplianceCompliance• Relative costRelative cost

GE Reflux Disease: Differences Between GE Reflux Disease: Differences Between

Children vs AdultsChildren vs Adults

Children: <1yr vs >1-2yrChildren: <1yr vs >1-2yr

• Natural historyNatural history

• PresentationPresentation

• ApproachApproach

• ManagementManagement

GE Reflux Disease: Differences Between GE Reflux Disease: Differences Between

Children vs AdultsChildren vs Adults

Children: <1yr vs >1-2yrChildren: <1yr vs >1-2yr

• Natural historyNatural history

• PresentationPresentation

• ApproachApproach

• ManagementManagement

GE Reflux: ChildrenGE Reflux: ChildrenAApppproachroach

GE Reflux: ChildrenGE Reflux: ChildrenAApppproachroach


• RRECURRENTECURRENT F FORCEFULORCEFUL

VVOMITINGOMITING

• CCOMPLICATION ATOMPLICATION AT ANY ANY AAGEGE


• RRECURRENTECURRENT F FORCEFULORCEFUL

VVOMITINGOMITING

• CCOMPLICATION ATOMPLICATION AT ANY ANY AAGEGE

EETIOLOGIES OF TIOLOGIES OF EESOPHAGITIS SOPHAGITIS IN IN CCHILDRENHILDREN

EETIOLOGIES OF TIOLOGIES OF EESOPHAGITIS SOPHAGITIS IN IN CCHILDRENHILDREN

• GE refluxGE reflux• Infections Infections

- candida albicans- candida albicans- herpes simplex- herpes simplex- cytomegalovirus- cytomegalovirus

• Infections Infections • Crohn’s diseaseCrohn’s disease• Idiopathic eosinophilic Idiopathic eosinophilic

esophagitis (IEE)esophagitis (IEE)• Pill-inducedPill-induced• Caustic ingestionCaustic ingestion

• GE refluxGE reflux• Infections Infections

- candida albicans- candida albicans- herpes simplex- herpes simplex- cytomegalovirus- cytomegalovirus

• Infections Infections • Crohn’s diseaseCrohn’s disease• Idiopathic eosinophilic Idiopathic eosinophilic

esophagitis (IEE)esophagitis (IEE)• Pill-inducedPill-induced• Caustic ingestionCaustic ingestion

• Post-sclerotherapy/ Post-sclerotherapy/ bandingbanding

• Radiation/Radiation/chemotherapy-inducedchemotherapy-induced

• Collagen vascularCollagen vasculardiseasedisease

• Graft-versus-hostGraft-versus-hostdiseasedisease

• Bullous skin diseasesBullous skin diseases

• IdiopathicIdiopathic

• Post-sclerotherapy/ Post-sclerotherapy/ bandingbanding

• Radiation/Radiation/chemotherapy-inducedchemotherapy-induced

• Collagen vascularCollagen vasculardiseasedisease

• Graft-versus-hostGraft-versus-hostdiseasedisease

• Bullous skin diseasesBullous skin diseases

• IdiopathicIdiopathic


Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy.

Arch Pediatr Adolesc Med 1997;151:569-72Arch Pediatr Adolesc Med 1997;151:569-72


Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy.


• X-sectional, community practice-based, Chicago areaX-sectional, community practice-based, Chicago area• 948 parents of healthy children <13mo948 parents of healthy children <13mo• Main outcome measure: Reported frequency of vomitingMain outcome measure: Reported frequency of vomiting

RESULTSRESULTS

• Vomiting at least 1/ day: 50% at 0-3moVomiting at least 1/ day: 50% at 0-3mo• Vomiting at least 1/ day: 5% at 10-12moVomiting at least 1/ day: 5% at 10-12mo• Peak frequency: 4moPeak frequency: 4mo• Decrease from 61% to 21%: between 6-7moDecrease from 61% to 21%: between 6-7mo• Peak frequency of vomiting reported as ‘problem’:Peak frequency of vomiting reported as ‘problem’: - 23% at 6mo to 14% at 7mo- 23% at 6mo to 14% at 7mo• Perception of ‘problem’: Perception of ‘problem’: - freq, volume; crying, fussiness, discomfort, back arching- freq, volume; crying, fussiness, discomfort, back arching• Rx: Rx: - formula change 8%, thickened 2%, stop breast 1%, med 0.2%- formula change 8%, thickened 2%, stop breast 1%, med 0.2%

• X-sectional, community practice-based, Chicago areaX-sectional, community practice-based, Chicago area• 948 parents of healthy children <13mo948 parents of healthy children <13mo• Main outcome measure: Reported frequency of vomitingMain outcome measure: Reported frequency of vomiting

RESULTSRESULTS

• Vomiting at least 1/ day: 50% at 0-3moVomiting at least 1/ day: 50% at 0-3mo• Vomiting at least 1/ day: 5% at 10-12moVomiting at least 1/ day: 5% at 10-12mo• Peak frequency: 4moPeak frequency: 4mo• Decrease from 61% to 21%: between 6-7moDecrease from 61% to 21%: between 6-7mo• Peak frequency of vomiting reported as ‘problem’:Peak frequency of vomiting reported as ‘problem’: - 23% at 6mo to 14% at 7mo- 23% at 6mo to 14% at 7mo• Perception of ‘problem’: Perception of ‘problem’: - freq, volume; crying, fussiness, discomfort, back arching- freq, volume; crying, fussiness, discomfort, back arching• Rx: Rx: - formula change 8%, thickened 2%, stop breast 1%, med 0.2%- formula change 8%, thickened 2%, stop breast 1%, med 0.2%

GE Reflux: Children & AdultsGE Reflux: Children & AdultsManagement of Management of SevereSevere

GERDGERD


GERDGERD

• Surgery [ARS]Surgery [ARS]









GERDGERD


GERDGERD

• Proton Pump Proton Pump Inhibitors Inhibitors [omeprazole, [omeprazole, lansoprazole]lansoprazole]


• Endoscopic RxEndoscopic Rx

• Proton Pump Proton Pump Inhibitors Inhibitors [omeprazole, [omeprazole, lansoprazole]lansoprazole]


• Endoscopic RxEndoscopic Rx

OOMEPRAZOLE: MEPRAZOLE: EEFFICACY AND FFICACY AND SSAFETY AFETY

OOMEPRAZOLE: MEPRAZOLE: EEFFICACY AND FFICACY AND SSAFETY AFETY

PROSPECTIVE DOSE-FINDING FOR HEALINGPROSPECTIVE DOSE-FINDING FOR HEALINGPROSPECTIVE DOSE-FINDING FOR HEALINGPROSPECTIVE DOSE-FINDING FOR HEALING


Nelson SP, et al. Prevalence of symptoms of GE reflux during Nelson SP, et al. Prevalence of symptoms of GE reflux during childhood. childhood.



Nelson SP, et al. Prevalence of symptoms of GE reflux during Nelson SP, et al. Prevalence of symptoms of GE reflux during childhood. childhood.

Arch Pediatr Adolesc Med 2000;154:150-4Arch Pediatr Adolesc Med 2000;154:150-4• X-sectional, community practice-based, Chicago area, 3-X-sectional, community practice-based, Chicago area, 3-17yrs17yrs

• 566 parents 3-9yrs, 584 parents of 10-17yrs, 615 10-566 parents 3-9yrs, 584 parents of 10-17yrs, 615 10-17yrs17yrs

• Infant GER Questionnaire [IGER-SF], shortened, revised Infant GER Questionnaire [IGER-SF], shortened, revised [5min] [5min] **

• Main outcome measure: Reported frequency of vomitingMain outcome measure: Reported frequency of vomiting

ETIOLOGIES OF VOMITING OTHER THAN REFLUXETIOLOGIES OF VOMITING OTHER THAN REFLUX

OTHER ACID PEPTIC DISORDERSOTHER ACID PEPTIC DISORDERS

FOOD ALLERGY FOOD ALLERGY

EXTRA-INTESTINAL DISORDERS EXTRA-INTESTINAL DISORDERS [UTI, INFECTIONS, METABOLIC][UTI, INFECTIONS, METABOLIC]

ETIOLOGIES OF VOMITING OTHER THAN REFLUXETIOLOGIES OF VOMITING OTHER THAN REFLUX

OTHER ACID PEPTIC DISORDERSOTHER ACID PEPTIC DISORDERS

FOOD ALLERGY FOOD ALLERGY

EXTRA-INTESTINAL DISORDERS EXTRA-INTESTINAL DISORDERS [UTI, INFECTIONS, METABOLIC][UTI, INFECTIONS, METABOLIC]

AANTIREFLUXNTIREFLUX S SURGERYURGERY

BC CBC CHILDREN’SHILDREN’S H HOSPITALOSPITAL

VVANCOUVERANCOUVER

AANTIREFLUXNTIREFLUX S SURGERYURGERY

BC CBC CHILDREN’SHILDREN’S H HOSPITALOSPITAL

VVANCOUVERANCOUVER

1980 - 1990: ~ 50 new operations/year1980 - 1990: ~ 50 new operations/year




G.BG.BLAIRLAIR MDMDDDeptept

SSurgeryurgeryBCCHBCCH

G.BG.BLAIRLAIR MDMDDDeptept

SSurgeryurgeryBCCHBCCH

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