# Presentation: 165982

## PATHOLOGIC GE REFLUX IN CHILDREN

- Age-Related Characteristics:
- Effect on Design of Clinical Trials

- FDA / CDER Pediatric Advisory Committee
- Bethesda, MD
- 11 June ‘02

- ERIC HASSALL MD
- Division of Gastroenterology
- BC Children’s Hospital /
-    University of British Columbia
- Vancouver, BC, CANADA

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- _Difficulties in ped studies,_ Definitions, Complications, Goals of Rx,
- Prevalence, Natural history, Available treatments
- PATHOPHYSIOLOGY
- Etiologies, Mechanisms, Acid secretion, Underlying diseases
- PHARMACOKINETICS
- ENDPOINTS: PRESENTING SYMPTOMS / SIGNS
- FEASIBILITY
- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

## DIFFICULTIES IN DOING PEDIATRIC STUDIES

- 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

## DEFINITIONS

**vs**
**Gastroesophageal reflux disease [GERD]**

**DEFINITIONS**

## COMPLICATIONS OF GE REFLUX

-   Esophagitis
-   Peptic stricture
-   Barrett’s esophagus
-   Failure to thrive
-   Pulmonary /
-       ENT disease
-   Sandifer’s syndrome /
-          torticollis

## MANAGEMENT GOALS

**  ****R****ELIEVE SYMPTOMS**
**  ****P****REVENT COMPLICATIONS**
**  ****H****EAL ESOPHAGITIS**
**  ****M****AINTAIN REMISSION**
**  ****T****REAT COMPLICATIONS**

**Gastroesophageal Reflux Disease [GERD]**

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- Difficulties in ped studies, Definitions, Complications, Goals of Rx,
- _Prevalence, Natural history,_ Available treatments
- PATHOPHYSIOLOGY
- Etiologies, Mechanisms, Acid secretion, Underlying diseases
- PHARMACOKINETICS
- ENDPOINTS: PRESENTING SYMPTOMS / SIGNS
- FEASIBILITY
- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

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

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

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

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

-                                RESULTS
-   Vomiting at least 1/ day: 50% at 0-3mo
-   Vomiting at least 1/ day:   5% at 10-12mo
-   Peak frequency: 4mo
-   Decrease from 61% to 21%:  between 6-7mo
-   Peak frequency of vomiting reported as ‘problem’:
-     - 23% at 6mo to 14% at 7mo

## GE Reflux: Children v Adults

_***Natural History***_

-   Very often physiological, esp < 6mo
-   90% resolve <12-18mo
-   Vomiting > 2yr age never physiological
-   GERD usually a chronic relapsing disease

- < 2yr age

- > 2yr age -adulthood

*Carre*
*Nelson*

## GE Reflux: Children v Adults

_***Presentation***_

**2 - 4yr age**

-  Similar symptoms / signs
-     to younger children
-  Heartburn very unusual*
-  Similar to adults

**> 8 - 10yr age**

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

## GE Reflux: Children v Adults

_***Presentation ***_

- NATURE OF VOMITING
- Effortless
-  vs
- Forceful / ‘Projectile’
- DISPOSITION OF CHILD
- ‘Fat happy spitters’ / thriving
-  vs
- Unhappy, irritable child / poor wt gain

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- Difficulties in ped studies, Definitions, Complications, Goals of Rx,
- Prevalence, Natural history, _Available treatments_
- PATHOPHYSIOLOGY
- Etiologies, Mechanisms, Acid secretion, Underlying diseases
- PHARMACOKINETICS
- ENDPOINTS: PRESENTING SYMPTOMS / SIGNS
- FEASIBILITY
- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

## GE Reflux: Children & Adults

_***Mana***_***g***_***ement ***_

-   Explanation, reassurance
-   Diet, lifestyle
-   Position
-   Antacids
-   Anticholinergics [e.g., **X**bethanecol**X**]
-   Prokinetics [**X**metoclopramide**X**, **X**cisapride**X**]
-   H2-Receptor Antagonists
-   Prayer/Meditation/Vega therapy/‘Can-deeda’ Rx

##  Antireflux Surgery

** ****Proton Pump Inhibitors**
** ****[Endoscopic Rx]**

- GE Reflux: Children & Adults
***Management of ***_***Severe***_*** GERD***

## ANTIREFLUX SURGERY IN CHILDREN

**EXCLUDING ‘MINOR’ PROCEDURES**
**[Inguinal herniorrhaphy, central line placement]**
**ANTIREFLUX SURGERY IS THE COMMONEST **
**OPERATION PERFORMED BY PEDIATRIC SURGEONS**

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- Difficulties in ped studies, Definitions, Complications, Goals of Rx,
- Prevalence, Natural history, Available treatments
- PATHOPHYSIOLOGY
- _Etiologies, Underlying diseases,  Mechanisms,_ Acid secretion,
- PHARMACOKINETICS
- ENDPOINTS: PRESENTING SYMPTOMS / SIGNS
- FEASIBILITY
- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

## Conditions Predisposing to Severe 

**GE Reflux in Children**

**  ****Neurologic impairment [NI]**
**  ****Repaired esophageal atresia**
**  ****Chronic lung disease [eg CF, BPD]**
**  ****Hiatal hernia**
**  ****Transient lower esophageal **
**     ****sphincter relaxation [TLESR]**

## Conditions Predisposing to Severe 

**GE Reflux in Children**

**  ****Neurologic impairment [NI]**
**  ****Repaired esophageal atresia**
**  ****Chronic lung disease [eg CF, BPD]**
**  ****Hiatal hernia**
**  ****Transient lower esophageal **
**     ****sphincter relaxation [TLESR]**

## Conditions Predisposing to Severe 

**GE Reflux in Children**

**  ****Neurologic impairment [NI]**
**  ****Repaired esophageal atresia**
**  ****Chronic lung disease [eg CF, BPD]**
**  ****Hiatal hernia**
**  ****Transient lower esophageal **
**     ****sphincter relaxation [TLESR]**

## Conditions Predisposing to Severe 

**GE Reflux in Children**

**  ****Neurologic impairment [NI]**
**  ****Repaired esophageal atresia**
**  ****Chronic lung disease [eg CF, BPD]**
**  ****Hiatal hernia**
**  ****Transient lower esophageal **
**     ****sphincter relaxation [TLESR]**

## Conditions Predisposing to Severe 

**GE Reflux in Children**

**  ****Neurologic impairment [NI]**
**  ****Repaired esophageal atresia**
**  ****Chronic lung disease [eg CF, BPD]**
**  ****Hiatal hernia**
**  ****Transient lower esophageal **
**     ****sphincter relaxation [TLESR]**

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- Difficulties in ped studies, Definitions, Complications, Goals of Rx,
- Prevalence, Natural history, Available treatments
- PATHOPHYSIOLOGY
- Etiologies, Underlying diseases,  Mechanisms, _Acid secretion _
- PHARMACOKINETICS
- ENDPOINTS: PRESENTING SYMPTOMS / SIGNS
- FEASIBILITY
- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

## ACID SECRETION

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

## ACID SECRETION

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

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- Difficulties in ped studies, Definitions, Complications, Goals of Rx,
- Prevalence, Natural history, Available treatments
- PATHOPHYSIOLOGY
- Etiologies, Underlying diseases,  Mechanisms, Acid secretion_ _
**P****HARMACOKINETICS**
- ENDPOINTS: PRESENTING SYMPTOMS / SIGNS
- FEASIBILITY
- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

## PHARMACOKINETICS

**                 ****FOR OMEPRAZOLE**
-  Ontogeny [_CY2C19_, 3A]:   metabolic capacity
-    [AUC, AUC normalized, t-half, Cmax, Cmax nl-ized]
-     - highest 1-6yrs,
-     - gradual decline with increasing age
-  NL adult values by ~12yrs
-   Much higher doses [per kg basis] reqd in older
*                                                   **Andersson, Am J Gastro 2000 *
*                                                             **Hassall, J Pediatr 2000 *
-  PK similar to benzodiazepines.....extrapolate to <1yr?

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- Difficulties in ped studies, Definitions, Complications, Goals of Rx,
- Prevalence, Natural history, Available treatments
- PATHOPHYSIOLOGY
- Etiologies, Underlying diseases,  Mechanisms, Acid secretion_ _
- PHARMACOKINETICS
**E****NDPOINTS:**** P****RESENTING**** S****YMPTOMS ****/ S****IGNS**
**F****EASIBILITY**
- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

## ENDPOINTS, PRESENTING SYMPTOMS / SIGNS

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

## ‘FEASIBILITY’

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

## ENDPOINTS, PRESENTING SYMPTOMS / SIGNS

** **Vomiting: frequency
**  **Heartburn
**  **Esophagitis
**?**** **Degree of acid reflux
-     - intraesophageal pH
** **
**? **Epigastric pain/
-         irritability
**?**** **Failure to thrive

**?****  **‘Feeding problems’
**?****  **Respiratory
**?****  **ENT
**x****  **Dysphagia / odynophagia
**x****  **Apnea
**x****  **Degree of acid suppression
-       - intragastric pH

**S****UBJECT**** T****HESE**** ****TO**** ‘T****HE**** T****ESTS****’:**

## OUTLINE: FOCUS ON AGE-RELATED DIFFERENCES

- BACKGROUND
- Difficulties in ped studies, Definitions, Complications, Goals of Rx,
- Prevalence, Natural history, Available treatments
- PATHOPHYSIOLOGY
- Etiologies, Underlying diseases,  Mechanisms, Acid secretion_ _
- PHARMACOKINETICS
- ENDPOINTS: PRESENTING SYMPTOMS / SIGNS
- FEASIBILITY
**R****EQUIREMENTS FOR ****P****ERFORMANCE OF ****S****UCCESSFUL ****S****TUDY**

## REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

-     [Can’t offer placebo]
-   Question worth asking
-   Protocol simple
-   Tests reliable
-   Tests not ‘overly invasive’ given the child’s illness
-   Willingness of parents to enrol
-   Willingness of docs to discuss enrolment with parents
-   Pediatric centers qualified to carry out protocol

- REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

## QUESTIONS  

** ****Age Group: <1yr vs >1-2yr ..... Up to 17yr?**
**   **Is this a sufficiently sensitive age breakdown?
-     Do we need others?  What should they be?
** ****Are there indications for PPI use in all age groups?**
** ****Efficacy: Can we study it in all age groups?**** **
**   **If not, can we impute efficacy from other studies?
** ****What are the appropriate study endpoints **
**   ****in each age group?**
** ****What are the dosages in each age group?**

## Slide 34

##  Anemia 2o blood loss 

_***Presentation***_

-  Vomiting
-     - commonest
-     - very often physiological, esp <12mo
-  Failure to thrive
-  Irritability
-  Food refusal / ‘feeding problems’
-  Chronic pulmonary symptoms
-  Anemia 2o blood loss
-  Hematemesis

**< 2yr age**

## GE Reflux in Children

**I****NDICATIONS FOR**** I****NVESTIGATION**
**Suspicion of Complication**

-   Irritability with feeds
-   Recurrent pneumonias / chronic cough
-   Generally unhappy baby
-   Failing to thrive
-   Torti collis [?Sandifer’s syndrome]
-   Persistent vomiting at 18-24mo

**GE Reflux in Children**
***Approach < 2yrs age***

## GE Reflux in Children

**I****NDICATIONS FOR**** I****NVESTIGATION**

**GE Reflux in Children**
***Approach > 2yrs age***

** ****Persistence of vomiting since < 2yrs**
** ****New onset recurrent vomiting**
** ****Suspicion of a complication**
-     - undiagnosed anemia
-     - dysphagia / odynophagia
-     - recurrent pneumonias, cough
-     - nonseasonal asthma

## What tests to do / What they mean

**What tests to do / What they mean**

** ****CBC**
** ****U****RINALYSIS & ****C****ULTURE**
** ****U****PPER**** GI C****ONTRAST**** S****TUDY**
-    - not a test for reflux
-    - stricture / achalasia / mass
-    - *road map***  **
** ****U****PPER**** GI E****NDOSCOPY****, B****IOPSIES**
** ****24****HR**** I****NTRAESOPHAGEAL**** pH**
** ****E****SOPHAGEAL**** M****ANOMETRY**
** ****G****ASTRIC**** E****MPTYING**** S****TUDY**

## PREVALENCE, NATURAL HISTORY

- 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
-    identified at 6-12 mo, vs 92 controls
-  IGER-SF & Children’s Eating Behavior Inventory [CEBI]
-                                     RESULTS
-   None of 63 cases was vomiting >1/day vs 1 of controls
-   Parents of cases reported more
-     - feeding refusals [odds ration 4.2] times
-     - longer eating times [>1hr]
-     - their own anxiety re feeding
-   No difference in ENT complaints / wheezing between groups

## TREATMENT OF GE REFLUX

**Medical ****vs**** Surgical ?**
**ISSUES**

**  ****Indications **
**  ****Efficacy**
**  ****Safety**
**  ****Durability [longevity]**
**  ****Compliance**
**  ****Relative cost**

##  Natural history

**Children vs Adults**
** ****Children: <1yr vs >1-2yr**
-  Natural history
-  Presentation
-  Approach
-  Management

## GE Reflux: Children

_***A***_***pp***_***roach***_

**I****NDICATIONS FOR**** I****NVESTIGATION**
** ****R****ECURRENT**** F****ORCEFUL**** V****OMITING**
** ****C****OMPLICATION AT**** ****ANY ****A****GE**

## ETIOLOGIES OF ESOPHAGITIS IN CHILDREN 

**GE reflux**
**Infections **
**	****- candida albicans**
**	****- herpes simplex**
**	****- cytomegalovirus**
**Infections **
**Crohn’s disease**
**Idiopathic eosinophilic esophagitis (IEE)**
**Pill-induced**
**Caustic ingestion**

**Post-sclerotherapy/ banding**
**Radiation/chemotherapy-induced**
**Collagen vascular****disease**
**Graft-versus-host****disease**
**Bullous skin diseases**
**Idiopathic**

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

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

-  X-sectional, community practice-based, Chicago area
-  948 parents of healthy children <13mo
-  Main outcome measure: Reported frequency of vomiting
-                                        RESULTS
-  Vomiting at least 1/ day: 50% at 0-3mo
-  Vomiting at least 1/ day:   5% at 10-12mo
-  Peak frequency: 4mo
-  Decrease from 61% to 21%:  between 6-7mo
-  Peak frequency of vomiting reported as ‘problem’:
-    - 23% at 6mo to 14% at 7mo
-  Perception of ‘problem’:
-    - freq, volume; crying, fussiness, discomfort, back arching
-  Rx:
-    - formula change 8%, thickened 2%, stop breast 1%, med 0.2%

##  Surgery [ARS]

- GE Reflux: Children & Adults
***Management of ***_***Severe***_*** GERD***

** ****Surgery [ARS]**
** ****Proton Pump Inhibitors**
** ****[Endoscopic Rx]**

## GE Reflux: Children & Adults

***Management of ***_***Severe***_*** GERD***

** ****Proton Pump Inhibitors **
** **   [omeprazole, lansoprazole]
**  ****Surgery [ARS]**
**  ****Endoscopic Rx**

## OMEPRAZOLE: EFFICACY AND SAFETY 

**O****MEPRAZOLE: ****E****FFICACY AND ****S****AFETY **

**PROSPECTIVE DOSE-FINDING FOR HEALING**

## PREVALENCE, NATURAL HISTORY

- 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
-  566 parents 3-9yrs,  584 parents of 10-17yrs, 615 10-17yrs
-  Infant GER Questionnaire [IGER-SF], shortened, revised [5min] *****
** **Main outcome measure: Reported frequency of vomiting

##  ETIOLOGIES OF VOMITING OTHER THAN REFLUX

**OTHER ACID PEPTIC DISORDERS**
**FOOD ALLERGY **
**EXTRA-INTESTINAL DISORDERS **
**[UTI, INFECTIONS, METABOLIC]**

## ANTIREFLUX SURGERY

**BC C****HILDREN’S**** H****OSPITAL**
**V****ANCOUVER**

**1980 - 1990: ~ 50 new operations/year**
**1990 - 2002: ~ 10 new operations/year**

***G.B******LAIR****** ******MD***
***D******ept****** S******urgery***
***BCCH***