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

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Presentation on theme: "P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics: Effect on Design of Clinical Trials P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics:"— Presentation transcript:

1 P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics: Effect on Design of Clinical Trials P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics: Effect on Design of Clinical Trials FDA / CDER Pediatric Advisory Committee Bethesda, MD 11 June ‘02 FDA / CDER Pediatric Advisory Committee Bethesda, MD 11 June ‘02 E RIC H ASSALL MD Division of Gastroenterology BC Children’s Hospital / University of British Columbia University of British Columbia Vancouver, BC, CANADA E RIC H ASSALL MD Division of Gastroenterology BC Children’s Hospital / University of British Columbia University of British Columbia Vancouver, BC, CANADA

2 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

3 D IFFICULTIES IN D OING P EDIATRIC S TUDIES Ethics: Placebo controls, etc Age-related differences in disease manifestations Fears of parents / investigators Feasibilities: What’s practicable? Time- and labor-intensiveness Need for flexibility: Optional tests Inexperience of centers: Uniformity of approach D IFFICULTIES IN D OING P EDIATRIC S TUDIES Ethics: Placebo controls, etc Age-related differences in disease manifestations Fears of parents / investigators Feasibilities: What’s practicable? Time- and labor-intensiveness Need for flexibility: Optional tests Inexperience of centers: Uniformity of approach

4 Gastroesophageal reflux [GER] vs Gastroesophageal reflux disease [GERD] Gastroesophageal reflux [GER] vs Gastroesophageal reflux disease [GERD] DEFINITIONSDEFINITIONS

5 C OMPLICATIONS OF GE R EFLUX Esophagitis Esophagitis Peptic stricture Peptic stricture Barrett’s esophagus Barrett’s esophagus Failure to thrive Failure to thrive Pulmonary / Pulmonary / ENT disease ENT disease Sandifer’s syndrome / Sandifer’s syndrome / torticollis Esophagitis Esophagitis Peptic stricture Peptic stricture Barrett’s esophagus Barrett’s esophagus Failure to thrive Failure to thrive Pulmonary / Pulmonary / ENT disease ENT disease Sandifer’s syndrome / Sandifer’s syndrome / torticollis

6 MANAGEMENT GOALS R ELIEVE SYMPTOMS R ELIEVE SYMPTOMS P REVENT COMPLICATIONS P REVENT COMPLICATIONS H EAL ESOPHAGITIS H EAL ESOPHAGITIS M AINTAIN REMISSION M AINTAIN REMISSION T REAT COMPLICATIONS T REAT COMPLICATIONS R ELIEVE SYMPTOMS R ELIEVE SYMPTOMS P REVENT COMPLICATIONS P REVENT COMPLICATIONS H EAL ESOPHAGITIS H EAL ESOPHAGITIS M AINTAIN REMISSION M AINTAIN REMISSION T REAT COMPLICATIONS T REAT COMPLICATIONS Gastroesophageal Reflux Disease [GERD]

7 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

8 P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151: P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151: * Based on IGER, Orenstein SR, et al. Clin Pediatr 1993;32: [20min] X-sectional, community practice-based X-sectional, community practice-based 948 healthy children <13mo 948 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 vomiting Main outcome measure: Reported frequency of vomiting X-sectional, community practice-based X-sectional, community practice-based 948 healthy children <13mo 948 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 vomiting Main outcome measure: Reported frequency of vomiting RESULTS RESULTS Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 5% at 10-12mo Vomiting at least 1/ day: 5% at 10-12mo Peak frequency: 4mo Peak frequency: 4mo Decrease from 61% to 21%: between 6-7mo Decrease 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 RESULTS RESULTS Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 5% at 10-12mo Vomiting at least 1/ day: 5% at 10-12mo Peak frequency: 4mo Peak frequency: 4mo Decrease from 61% to 21%: between 6-7mo Decrease 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

9 GE Reflux: Children v Adults Natural History GE Reflux: Children v Adults Natural History Very often physiological, esp < 6mo Very often physiological, esp < 6mo 90% resolve <12-18mo 90% resolve <12-18mo Vomiting > 2yr age never physiological Vomiting > 2yr age never physiological GERD usually a chronic relapsing disease GERD usually a chronic relapsing disease Very often physiological, esp < 6mo Very often physiological, esp < 6mo 90% resolve <12-18mo 90% resolve <12-18mo Vomiting > 2yr age never physiological Vomiting > 2yr age never physiological GERD usually a chronic relapsing disease GERD usually a chronic relapsing disease < 2yr age > 2yr age -adulthood CarreNelsonCarreNelson

10 GE Reflux: Children v Adults Presentation Presentation 2 - 4yr age Similar symptoms / signs Similar symptoms / signs to younger children to younger children Heartburn very unusual* Heartburn very unusual* Similar to adults Similar to adults Similar symptoms / signs Similar symptoms / signs to younger children to younger children Heartburn very unusual* Heartburn very unusual* Similar to adults Similar to adults > yr age * Nelson SP. Arch Ped & Adolesc Med, Feb 00

11 GE Reflux: Children v Adults Presentation Presentation NATURE OF VOMITING Effortless vs vs Forceful / ‘Projectile’ DISPOSITION OF CHILD ‘Fat happy spitters’ / thriving vs vs Unhappy, irritable child / poor wt gain NATURE OF VOMITING Effortless vs vs Forceful / ‘Projectile’ DISPOSITION OF CHILD ‘Fat happy spitters’ / thriving vs vs Unhappy, irritable child / poor wt gain

12 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

13 GE Reflux: Children & Adults Management GE Reflux: Children & Adults Management Explanation, reassurance Explanation, reassurance Diet, lifestyle Diet, lifestyle Position Position Antacids Antacids Anticholinergics [e.g., X bethanecol X ] Anticholinergics [e.g., X bethanecol X ] Prokinetics [ X metoclopramide X, X cisapride X ] Prokinetics [ X metoclopramide X, X cisapride X ] H 2 -Receptor Antagonists H 2 -Receptor Antagonists Prayer/Meditation/Vega therapy/‘Can-deeda’ Rx Prayer/Meditation/Vega therapy/‘Can-deeda’ Rx Explanation, reassurance Explanation, reassurance Diet, lifestyle Diet, lifestyle Position Position Antacids Antacids Anticholinergics [e.g., X bethanecol X ] Anticholinergics [e.g., X bethanecol X ] Prokinetics [ X metoclopramide X, X cisapride X ] Prokinetics [ X metoclopramide X, X cisapride X ] H 2 -Receptor Antagonists H 2 -Receptor Antagonists Prayer/Meditation/Vega therapy/‘Can-deeda’ Rx Prayer/Meditation/Vega therapy/‘Can-deeda’ Rx

14 Antireflux Surgery Antireflux Surgery Proton Pump Inhibitors Proton Pump Inhibitors [Endoscopic Rx] [Endoscopic Rx] Antireflux Surgery Antireflux Surgery Proton Pump Inhibitors Proton Pump Inhibitors [Endoscopic Rx] [Endoscopic Rx] GE Reflux: Children & Adults Management of Severe GERD GE Reflux: Children & Adults Management of Severe GERD

15 A NTIREFLUX S URGERY IN C HILDREN EXCLUDING ‘MINOR’ PROCEDURES [Inguinal herniorrhaphy, central line placement] ANTIREFLUX SURGERY IS THE COMMONEST OPERATION PERFORMED BY PEDIATRIC SURGEONS EXCLUDING ‘MINOR’ PROCEDURES [Inguinal herniorrhaphy, central line placement] ANTIREFLUX SURGERY IS THE COMMONEST OPERATION PERFORMED BY PEDIATRIC SURGEONS

16 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion, P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion, P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

17 Conditions Predisposing to Severe GE Reflux in Children Conditions Predisposing to Severe GE Reflux in Children Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR] Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR]

18 Conditions Predisposing to Severe GE Reflux in Children Conditions Predisposing to Severe GE Reflux in Children Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR] Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR]

19 Conditions Predisposing to Severe GE Reflux in Children Conditions Predisposing to Severe GE Reflux in Children Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR] Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR]

20 Conditions Predisposing to Severe GE Reflux in Children Conditions Predisposing to Severe GE Reflux in Children Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR] Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR]

21 Conditions Predisposing to Severe GE Reflux in Children Conditions Predisposing to Severe GE Reflux in Children Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR] Neurologic impairment [NI] Neurologic impairment [NI] Repaired esophageal atresia Repaired esophageal atresia Chronic lung disease [eg CF, BPD] Chronic lung disease [eg CF, BPD] Hiatal hernia Hiatal hernia Transient lower esophageal Transient lower esophageal sphincter relaxation [TLESR] sphincter relaxation [TLESR]

22 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

23 A CID S ECRETION Healthy term infants Healthy term infants Relative hypochlorhydria for 0-5hrs age, nl by 6-8hrs Relative hypochlorhydria for 0-5hrs age, nl by 6-8hrs [normal BAO 25+/-10  mol/kg/hr  in adults] [normal BAO 25+/-10  mol/kg/hr  in adults] Hypergastrinemia, despite nl acid secretion Hypergastrinemia, despite nl acid secretion Euler, Gastro 1977 Euler, Gastro 1977 Enteral feedings necessary for nl oxyntic mucosal secretion Enteral feedings necessary for nl oxyntic mucosal secretion - purely TPN-fed relatively hypochlorhydric - purely TPN-fed relatively hypochlorhydric Hyman, Gastro 1983 Hyman, Gastro 1983 Meal-stim secretion occurs, but weaker than older infants [>6mo] Meal-stim secretion occurs, but weaker than older infants [>6mo] Hyman, J Peds 1984 Healthy pre-term infants Healthy pre-term infants BAO by 7days 12  mol/kg/hr, incr over 4wks to 30 [nl] BAO by 7days 12  mol/kg/hr, incr over 4wks to 30 [nl] A few infants are achlorhydric [pentagastrin-fast] in first wk A few infants are achlorhydric [pentagastrin-fast] in first wk Hyman, J Peds 1985 Hyman, J Peds 1985 Healthy term infants Healthy term infants Relative hypochlorhydria for 0-5hrs age, nl by 6-8hrs Relative hypochlorhydria for 0-5hrs age, nl by 6-8hrs [normal BAO 25+/-10  mol/kg/hr  in adults] [normal BAO 25+/-10  mol/kg/hr  in adults] Hypergastrinemia, despite nl acid secretion Hypergastrinemia, despite nl acid secretion Euler, Gastro 1977 Euler, Gastro 1977 Enteral feedings necessary for nl oxyntic mucosal secretion Enteral feedings necessary for nl oxyntic mucosal secretion - purely TPN-fed relatively hypochlorhydric - purely TPN-fed relatively hypochlorhydric Hyman, Gastro 1983 Hyman, Gastro 1983 Meal-stim secretion occurs, but weaker than older infants [>6mo] Meal-stim secretion occurs, but weaker than older infants [>6mo] Hyman, J Peds 1984 Healthy pre-term infants Healthy pre-term infants BAO by 7days 12  mol/kg/hr, incr over 4wks to 30 [nl] BAO by 7days 12  mol/kg/hr, incr over 4wks to 30 [nl] A few infants are achlorhydric [pentagastrin-fast] in first wk A few infants are achlorhydric [pentagastrin-fast] in first wk Hyman, J Peds 1985 Hyman, J Peds 1985

24 A CID S ECRETION SUMMARY Pre-term and term infants make acid Pre-term and term infants make acid Acid secretion increases quickly to adult ranges Acid secretion increases quickly to adult ranges [  mol/kg/hr] [  mol/kg/hr] Pentagastrin-responsive by 1-4wks Pentagastrin-responsive by 1-4wks Increase in secretion depends on postnatal age Increase in secretion depends on postnatal age not gestational age not gestational age Require enteral feeds for nl acid output Require enteral feeds for nl acid output A CID S ECRETION SUMMARY Pre-term and term infants make acid Pre-term and term infants make acid Acid secretion increases quickly to adult ranges Acid secretion increases quickly to adult ranges [  mol/kg/hr] [  mol/kg/hr] Pentagastrin-responsive by 1-4wks Pentagastrin-responsive by 1-4wks Increase in secretion depends on postnatal age Increase in secretion depends on postnatal age not gestational age not gestational age Require enteral feeds for nl acid output Require enteral feeds for nl acid output

25 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

26 P HARMACOKINETICS FOR OMEPRAZOLE FOR OMEPRAZOLE Ontogeny [CY2C19, 3A]: metabolic capacity Ontogeny [CY2C19, 3A]: metabolic capacity [AUC, AUC normalized, t-half, C max, C max nl-ized] [AUC, AUC normalized, t-half, C max, C max nl-ized] - highest 1-6yrs, - highest 1-6yrs, - gradual decline with increasing age - gradual decline with increasing age NL adult values by ~12yrs NL 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 OMEPRAZOLE FOR OMEPRAZOLE Ontogeny [CY2C19, 3A]: metabolic capacity Ontogeny [CY2C19, 3A]: metabolic capacity [AUC, AUC normalized, t-half, C max, C max nl-ized] [AUC, AUC normalized, t-half, C max, C max nl-ized] - highest 1-6yrs, - highest 1-6yrs, - gradual decline with increasing age - gradual decline with increasing age NL adult values by ~12yrs NL 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?

27 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

28 E NDPOINTS, P RESENTING S YMPTOMS / S IGNS For purposes of study…. For purposes of study…. S YMPTOM /S IGN S HOULD B E : S YMPTOM /S IGN S HOULD B E : Definitely causally related to GERD Definitely causally related to GERD Most relevant to patient improvement Most relevant to patient improvement Common in the age group under study Common in the age group under study Measurable / ‘hard’ / objective Measurable / ‘hard’ / objective ‘Safely accessible’ in the given age group ‘Safely accessible’ in the given age group For purposes of study…. For purposes of study…. S YMPTOM /S IGN S HOULD B E : S YMPTOM /S IGN S HOULD B E : Definitely causally related to GERD Definitely causally related to GERD Most relevant to patient improvement Most relevant to patient improvement Common in the age group under study Common in the age group under study Measurable / ‘hard’ / objective Measurable / ‘hard’ / objective ‘Safely accessible’ in the given age group ‘Safely accessible’ in the given age group

29 ‘F EASIBILITY’ = Patient accrual, Retention, Success of Study ‘F EASIBILITY’ = Patient accrual, Retention, Success of Study

30 E NDPOINTS, P RESENTING S YMPTOMS / S IGNS Vomiting: frequency Vomiting: frequency Heartburn Heartburn Esophagitis Esophagitis ? Degree of acid reflux ? Degree of acid reflux - intraesophageal pH - intraesophageal pH ? Epigastric pain/ ? Epigastric pain/ irritability irritability ? Failure to thrive ? Failure to thrive Vomiting: frequency Vomiting: frequency Heartburn Heartburn Esophagitis Esophagitis ? Degree of acid reflux ? Degree of acid reflux - intraesophageal pH - intraesophageal pH ? Epigastric pain/ ? Epigastric pain/ irritability irritability ? Failure to thrive ? Failure to thrive ? ‘Feeding problems’ ? Respiratory ? ENT x Dysphagia / odynophagia x Apnea x Degree of acid suppression - intragastric pH - intragastric pH ? ‘Feeding problems’ ? Respiratory ? ENT x Dysphagia / odynophagia x Apnea x Degree of acid suppression - intragastric pH - intragastric pH S UBJECT T HESE TO ‘T HE T ESTS ’:

31 O UTLINE : F OCUS ON A GE -R ELATED D IFFERENCES B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY B ACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments P ATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion P HARMACOKINETICS E NDPOINTS: P RESENTING S YMPTOMS / S IGNS F EASIBILITY R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

32 Availability of other, equal or better treatments Availability of other, equal or better treatments [Can’t offer placebo] [Can’t offer placebo] Question worth asking Question worth asking Protocol simple Protocol simple Tests reliable Tests reliable Tests not ‘overly invasive’ given the child’s illness Tests not ‘overly invasive’ given the child’s illness Willingness of parents to enrol Willingness of parents to enrol Willingness of docs to discuss enrolment with parents Willingness of docs to discuss enrolment with parents Pediatric centers qualified to carry out protocol Pediatric 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 asking Question worth asking Protocol simple Protocol simple Tests reliable Tests reliable Tests not ‘overly invasive’ given the child’s illness Tests not ‘overly invasive’ given the child’s illness Willingness of parents to enrol Willingness of parents to enrol Willingness of docs to discuss enrolment with parents Willingness of docs to discuss enrolment with parents Pediatric centers qualified to carry out protocol Pediatric centers qualified to carry out protocol R EQUIREMENTS FOR P ERFORMANCE OF S UCCESSFUL S TUDY

33 Q UESTIONS Age Group: 1-2yr ….. Up to 17yr? Age Group: 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 groups? Are there indications for PPI use in all age 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? Q UESTIONS Age Group: 1-2yr ….. Up to 17yr? Age Group: 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 groups? Are there indications for PPI use in all age 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?

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35 GE Reflux: Children v Adults Presentation Presentation Vomiting Vomiting - commonest - commonest - very often physiological, esp <12mo - very often physiological, esp <12mo Failure to thrive Failure to thrive Irritability Irritability Food refusal / ‘feeding problems’ Food refusal / ‘feeding problems’ Chronic pulmonary symptoms Chronic pulmonary symptoms Anemia 2 o blood loss Anemia 2 o blood loss Hematemesis Hematemesis Vomiting Vomiting - commonest - commonest - very often physiological, esp <12mo - very often physiological, esp <12mo Failure to thrive Failure to thrive Irritability Irritability Food refusal / ‘feeding problems’ Food refusal / ‘feeding problems’ Chronic pulmonary symptoms Chronic pulmonary symptoms Anemia 2 o blood loss Anemia 2 o blood loss Hematemesis Hematemesis < 2yr age

36 I NDICATIONS FOR I NVESTIGATION Suspicion of Complication I NDICATIONS FOR I NVESTIGATION Suspicion of Complication Irritability with feeds Irritability with feeds Recurrent pneumonias / chronic cough Recurrent pneumonias / chronic cough Generally unhappy baby Generally unhappy baby Failing to thrive Failing to thrive Torti collis [?Sandifer’s syndrome] Torti collis [?Sandifer’s syndrome] Persistent vomiting at 18-24mo Persistent vomiting at 18-24mo Irritability with feeds Irritability with feeds Recurrent pneumonias / chronic cough Recurrent pneumonias / chronic cough Generally unhappy baby Generally unhappy baby Failing to thrive Failing to thrive Torti collis [?Sandifer’s syndrome] Torti collis [?Sandifer’s syndrome] Persistent vomiting at 18-24mo Persistent vomiting at 18-24mo GE Reflux in Children Approach < 2yrs age GE Reflux in Children Approach < 2yrs age

37 I NDICATIONS FOR I NVESTIGATION GE Reflux in Children Approach > 2yrs age GE Reflux in Children Approach > 2yrs age Persistence of vomiting since < 2yrs Persistence of vomiting since < 2yrs New onset recurrent vomiting New onset recurrent vomiting Suspicion of a complication Suspicion of a complication - undiagnosed anemia - undiagnosed anemia - dysphagia / odynophagia - dysphagia / odynophagia - recurrent pneumonias, cough - recurrent pneumonias, cough - nonseasonal asthma - nonseasonal asthma Persistence of vomiting since < 2yrs Persistence of vomiting since < 2yrs New onset recurrent vomiting New onset recurrent vomiting Suspicion of a complication Suspicion of a complication - undiagnosed anemia - undiagnosed anemia - dysphagia / odynophagia - dysphagia / odynophagia - recurrent pneumonias, cough - recurrent pneumonias, cough - nonseasonal asthma - nonseasonal asthma

38 GE Reflux in Children What tests to do / What they mean GE Reflux in Children What tests to do / What they mean CBC CBC U RINALYSIS & C ULTURE U RINALYSIS & C ULTURE U PPER GI C ONTRAST S TUDY U PPER GI C ONTRAST S TUDY - not a test for reflux - not a test for reflux - stricture / achalasia / mass - stricture / achalasia / mass - road map - road map U PPER GI E NDOSCOPY, B IOPSIES U PPER GI E NDOSCOPY, B IOPSIES 24 HR I NTRAESOPHAGEAL pH 24 HR I NTRAESOPHAGEAL pH E SOPHAGEAL M ANOMETRY E SOPHAGEAL M ANOMETRY G ASTRIC E MPTYING S TUDY G ASTRIC E MPTYING S TUDY CBC CBC U RINALYSIS & C ULTURE U RINALYSIS & C ULTURE U PPER GI C ONTRAST S TUDY U PPER GI C ONTRAST S TUDY - not a test for reflux - not a test for reflux - stricture / achalasia / mass - stricture / achalasia / mass - road map - road map U PPER GI E NDOSCOPY, B IOPSIES U PPER GI E NDOSCOPY, B IOPSIES 24 HR I NTRAESOPHAGEAL pH 24 HR I NTRAESOPHAGEAL pH E SOPHAGEAL M ANOMETRY E SOPHAGEAL M ANOMETRY G ASTRIC E MPTYING S TUDY G ASTRIC E MPTYING S TUDY

39 P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. One-year follow-up of symptoms of GE reflux during infancy PEDIATRICS Dec 1998; e-publication P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. One-year follow-up of symptoms of GE reflux during infancy PEDIATRICS 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] RESULTS RESULTS None of 63 cases was vomiting >1/day vs 1 of controls None 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 groups No 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] RESULTS RESULTS None of 63 cases was vomiting >1/day vs 1 of controls None 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 groups No difference in ENT complaints / wheezing between groups

40 T REATMENT OF GE R EFLUX Medical vs Surgical ? ISSUES ISSUES Indications Indications Efficacy Efficacy Safety Safety Durability [longevity] Durability [longevity] Compliance Compliance Relative cost Relative cost Indications Indications Efficacy Efficacy Safety Safety Durability [longevity] Durability [longevity] Compliance Compliance Relative cost Relative cost

41 GE Reflux Disease: Differences Between Children vs Adults Children: 1-2yr Children: 1-2yr Natural history Natural history Presentation Presentation Approach Approach Management Management GE Reflux Disease: Differences Between Children vs Adults Children: 1-2yr Children: 1-2yr Natural history Natural history Presentation Presentation Approach Approach Management Management

42 GE Reflux: Children Approach GE Reflux: Children Approach I NDICATIONS FOR I NVESTIGATION R ECURRENT F ORCEFUL V OMITING R ECURRENT F ORCEFUL V OMITING C OMPLICATION AT ANY A GE C OMPLICATION AT ANY A GE I NDICATIONS FOR I NVESTIGATION R ECURRENT F ORCEFUL V OMITING R ECURRENT F ORCEFUL V OMITING C OMPLICATION AT ANY A GE C OMPLICATION AT ANY A GE

43 E TIOLOGIES OF E SOPHAGITIS IN C HILDREN GE refluxGE reflux InfectionsInfections - candida albicans - herpes simplex - cytomegalovirus InfectionsInfections Crohn’s diseaseCrohn’s disease Idiopathic eosinophilic esophagitis (IEE)Idiopathic eosinophilic esophagitis (IEE) Pill-inducedPill-induced Caustic ingestionCaustic ingestion GE refluxGE reflux InfectionsInfections - candida albicans - herpes simplex - cytomegalovirus InfectionsInfections Crohn’s diseaseCrohn’s disease Idiopathic eosinophilic esophagitis (IEE)Idiopathic eosinophilic esophagitis (IEE) Pill-inducedPill-induced Caustic ingestionCaustic ingestion Post-sclerotherapy/ bandingPost-sclerotherapy/ banding Radiation/chemotherapy- inducedRadiation/chemotherapy- induced Collagen vascular diseaseCollagen vascular disease Graft-versus-host diseaseGraft-versus-host disease Bullous skin diseasesBullous skin diseases IdiopathicIdiopathic Post-sclerotherapy/ bandingPost-sclerotherapy/ banding Radiation/chemotherapy- inducedRadiation/chemotherapy- induced Collagen vascular diseaseCollagen vascular disease Graft-versus-host diseaseGraft-versus-host disease Bullous skin diseasesBullous skin diseases IdiopathicIdiopathic

44 P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151: P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151: X-sectional, community practice-based, Chicago area X-sectional, community practice-based, Chicago area 948 parents of healthy children <13mo 948 parents of healthy children <13mo Main outcome measure: Reported frequency of vomiting Main outcome measure: Reported frequency of vomiting RESULTS RESULTS Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 5% at 10-12mo Vomiting at least 1/ day: 5% at 10-12mo Peak frequency: 4mo Peak frequency: 4mo Decrease from 61% to 21%: between 6-7mo Decrease 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 area X-sectional, community practice-based, Chicago area 948 parents of healthy children <13mo 948 parents of healthy children <13mo Main outcome measure: Reported frequency of vomiting Main outcome measure: Reported frequency of vomiting RESULTS RESULTS Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 50% at 0-3mo Vomiting at least 1/ day: 5% at 10-12mo Vomiting at least 1/ day: 5% at 10-12mo Peak frequency: 4mo Peak frequency: 4mo Decrease from 61% to 21%: between 6-7mo Decrease 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%

45 GE Reflux: Children & Adults Management of Severe GERD GE Reflux: Children & Adults Management of Severe GERD Surgery [ARS] Surgery [ARS] Proton Pump Inhibitors Proton Pump Inhibitors [Endoscopic Rx] [Endoscopic Rx] Surgery [ARS] Surgery [ARS] Proton Pump Inhibitors Proton Pump Inhibitors [Endoscopic Rx] [Endoscopic Rx]

46 GE Reflux: Children & Adults Management of Severe GERD GE Reflux: Children & Adults Management of Severe GERD Proton Pump Inhibitors Proton Pump Inhibitors [omeprazole, lansoprazole] [omeprazole, lansoprazole] Surgery [ARS] Surgery [ARS] Endoscopic Rx Endoscopic Rx Proton Pump Inhibitors Proton Pump Inhibitors [omeprazole, lansoprazole] [omeprazole, lansoprazole] Surgery [ARS] Surgery [ARS] Endoscopic Rx Endoscopic Rx

47 O MEPRAZOLE: E FFICACY AND S AFETY PROSPECTIVE DOSE-FINDING FOR HEALING

48 P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during childhood. Arch Pediatr Adolesc Med 2000;154:150-4 P REVALENCE, N ATURAL H ISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during childhood. Arch Pediatr Adolesc Med 2000;154:150-4 X-sectional, community practice-based, Chicago area, 3-17yrs X-sectional, community practice-based, Chicago area, 3-17yrs 566 parents 3-9yrs, 584 parents of 10-17yrs, yrs 566 parents 3-9yrs, 584 parents of 10-17yrs, yrs Infant GER Questionnaire [IGER-SF], shortened, revised [5min] * Infant GER Questionnaire [IGER-SF], shortened, revised [5min] * Main outcome measure: Reported frequency of vomiting Main outcome measure: Reported frequency of vomiting

49 ETIOLOGIES OF VOMITING OTHER THAN REFLUX ETIOLOGIES OF VOMITING OTHER THAN REFLUX OTHER ACID PEPTIC DISORDERS FOOD ALLERGY EXTRA-INTESTINAL DISORDERS [UTI, INFECTIONS, METABOLIC] ETIOLOGIES OF VOMITING OTHER THAN REFLUX ETIOLOGIES OF VOMITING OTHER THAN REFLUX OTHER ACID PEPTIC DISORDERS FOOD ALLERGY EXTRA-INTESTINAL DISORDERS [UTI, INFECTIONS, METABOLIC]

50 A NTIREFLUX S URGERY BC C HILDREN’S H OSPITAL V ANCOUVER A NTIREFLUX S URGERY BC C HILDREN’S H OSPITAL V ANCOUVER : ~ 50 new operations/year : ~ 10 new operations/year : ~ 50 new operations/year : ~ 10 new operations/year G.B LAIR MD D ept S urgery BCCH G.B LAIR MD D ept S urgery BCCH


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