Most common symptom in infants GER a physiological phenomenon May be seen in 80 percent of healthy infants normal infants SIGNIFICANT INCREASE IN USAGE PPIS FOR TREATMENT OF EXCESSIVE CRYING RAPID INCREASE IN PRESCRIPTIONS FOR H2 BLOCKERS AND PPIS ID: 534234
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Colic affects30 percent of infants.
Most common symptom in infantsSlide2
GER a physiological phenomenon
May be seen in 80 percent of healthy infants normal infantsSlide3
SIGNIFICANT INCREASE IN USAGE PPIS FOR TREATMENT OF EXCESSIVE CRYINGSlide4
RAPID INCREASE IN PRESCRIPTIONS FOR H2 BLOCKERS AND PPISSlide5
PHYSIOLOGY OF GE REFLUX
REVIEW HISTORY OF GASTROESOPHAGEAL REFLUX
HOW WE HAVE SOME TO TREAT A PHYSIOLOGICAL PHENOMENON WITH MULTIPLE DRUGS
CRYING INFANT: COLIC AND GERD IS THERE A CORELATION
TREATMENT OF CRYING INFANT WITH PPISSlide6
HISTORY OF GASTROESOPHAGEAL REFLUXSlide7Slide8
SEVEN STAGES OF MANKINDSlide9Slide10Slide11
HISTORY OF GASTROESOPHAGEAL REFLUX: TIMELINE
PUBMED SEARCHBEFORE 1950
01950-1960 101960-1970 121 ESOPHAGITIS IN PTS WITH TEF1970-1980 324 INTEREST IN PHYSIOLOGY
1980-90 863 EDOSCOPY AND Ph probe1990-2000 1354 PHARMACOLOGY 2000-2010 1899 PHARMACOLOGY
Slide12
1950-1960 RADIOLOGY DOMINATED STUDIES
CLASSIFIED REFLUX AS GRADE 1- GRADE4Slide13
BAS
UPPER ENDOSOCPY DEVELOPED TO STUDY THE DISEASES OF ESOPHAGUS AND STOMACH IN 1957Slide14
BASIL HIRSCHOWITZ
(1925-2013)
INVENTED THE FIRST FIBEROPTIC ENDOSOCPE
1957Slide15
Ph
probe
1960 TUTTLE:GLASS PROBE
1964 MILLER : 12 HR PROBE(HANDS IN SALINE)1974 JOHNSON AND DEMASTER, MODERN PH PROBE Slide16
ES
ESOPHAGEAL MOTILITY STUDIES Slide17
PHARMACOLOGIC INDUSTRY EXPLODED 1980S ONWARDSlide18
H2
H2 RECEPTOR POSTULATED IN 1964
CIMETIDINE (H2 ANTAGONIST) 1976
RANITIDINE LAUNCHED IN 1981
BY 1988 WAS THE BIGGEST SELLING PRESCRIPTION DRUGSlide19
PROPRO
PROTON PUMP SECRETORY MEMBRANE OF PARIETAL CELL 1970S
FINAL STEP IN ACID SECRETION
MAXIMUM DECREASE IN ACID PRODUCTIONSlide20
OMEPRAZOLE LAUNCHED IN 1988 IN EUROPE,
IN 1990 USASlide21Slide22
Gastroesophageal
reflux and crying infant
JOURNEY FROM GER TO GERD
NO CITATIONS FOR GERD BEFORE 1984PHARMACOLOGY INDUSTRYSlide23
Cisapride
: what can we learn from the rise and fall of a prokinetic
?Quigley EM.Cisapride
, the prototype serotogenic agent Impressed by its in vitro properties and encouraged by clinical trial data,
cisapride became the drug of choice serious cardiac events began to be reported in association with
cisapride therapy, dark clouds rapidly gathered and soon enveloped the drug, leading to its widespread withdrawal from markets.
What lessons can we learn from the story of cisapride? Slide24
Physiology of GERSlide25
PHYSIOLOGY OF GER
LES controls the traffic at GE junction
Anatomically LES is well formed in infantsSPONTANEOUS TRANSIENT RELAXATION OF LES leads to GERSlide26
GASTROESOPHAGEAL REFLUX IN INFANTS
INVOLUNTARY RETROGRADE PASSAGE OF GASTRIC CONTENTSWITH OR WITHOUT REFURGITATION OR VOMITING
FREQUENTLY EXPERIENCED PHYSIOLOGIC CONDITIONSEVERAL TIMES A DAYMOSTLY POST PRANDIALAND CAUSES NO SYMPTOMSSlide27
GASTROESOPHAGEAL REFLUX DISEASE
FAILURE TO THRIVE : A HEALTHY INFANT WITH NO UNDERLYING PROBLEM WILL NEVER HAVE FAILURE TO THRIVE FROM SIMPLE REFLUX
IF THE WEIGHT GAIN IS POOR: LOOK FORCALORIC INTAKE: MOST COMMON CAUSE OF POOR WT GAINGI TRACT ANOMALIES: DUODENAL WEBMILK PROTEIN ALLERGY: TRIAL OF ELEMENTAL FORMULA
APNEA: ASSOCIATION OF APNEA AND GERD IS QUESTIONABLEHEMATEMESIS: SWALLOWED BLOOD, HIATAL HERNIASlide28
SO WE CONCLUDE GER IS PHYSIOLOGICALSlide29
GER and GERD
We have known about GER for centuriesWhen how did it turn to GERDWhy did we start treating these infants with drugs
drugs and drugsHas anatomy or function of LES evolved in the last 40 yrs
Is it the effect of enviromnment around us that leads to GERSlide30
GER AND GERD
Labeling an otherwise healthy infant as having a "disease"
GERDIncreased parents
' interest in medicating their infant Increased incistence to use drugs observed
. Slide31
Rise of prescriptions
Mostly due to advertisingSpecifically to use of the term “ACID REFLUX”
Before Mid 90s this term was hardly ever usedMedical terms were GER and GERD1990s rules regarding Direct to consumer advertising were relaxedBroadcast advertising was the order of the day
ACID REFLUX TERM was promoted for treatmentIn 2005 PPI sales grossed 13 billionSlide32
POWER OF ADVERTISINGSlide33
Rise of prescriptions
Due to DTC advertising a definite shift was notedInstead of patients complaining of heartburns
Presenting complaints became self diagnosisOr diagnosis of their child ACID REFLUXMY BABY HAS ACID REFLUXDOCTOR YOU ARE NOT GOING TO PRESCRIBE MEDICINESlide34
Ga
G
GERD in Children and adolescentsSlide35Slide36
GASTROESOPHAGEAL REFLUX DISEASE CHILDREN
EXPLOSION OF PPIS
MULTIPLE STUDIES PERFORMED BETWEEN 2-17 YRS OF AGEPPIS WERE SHOWN TO TREAT REFRACTORY EROSIVE ESOPHAGITISREFRACTORY TO H2 RECEPTOR ANTAGONISTREFRACTORY TO ANTI REFLUX SURGERYSlide37
GERD in children
80 percent of children requiring long term treatment for GERDHave underlying disorderSlide38
GERD in Children
In children without these disorders‘GERD is not severe and not chronicMay be related to an acute GE
Mild dysmotility following GENot requiring chronic usage of PPIsSlide39
GER in Infants
PPIs have now been prescribed for infants alsoUS health database >
7 fold increase in PPI (1999-2004)PPIs dispensed in liquid form----16 fold increase
in the last 6 yrsSlide40
GER in infants and PPIS
Health database study50 % infants started taking PPI before 4 monthsSlide41
GER and PPIs in New Zealand
Between 2006 and 2010Omeprazole prescriptions increased from 4650 to 8273 in infants under 1
yrMaximum increase occurred under 3 months of age( 111%)Slide42
Two common phenomenonSlide43
Gastroesophageal reflux
40-70 infants spit up daily
Feeding volume per kg basis are large(comparison to older children)Poor gastric compliance in infancyEsophagus is relatively shortLarge volume spills out thru mouth
Transient relaxation of LESSELF RESOLVINGSlide44
UNEXPLAINED CRYING AND IRRITABLE INFANTS
EXCESSIVE INCONSOLABLE CRYINGRULE OF THREE
3 HRS A DAY3 DASY A WEEKLASTS FOR THREE MONTHSCAUSE AND EFFECT NOT CLEARSlide45
CRYING AND REFLUX
TEMPORAL RELATION OF CRYING AND REFLUX HAVE BEEN OBSERVEDBUT THIS MAY BE DUE TO DISTENSION OF
STOMACHESOPHAGUSCRYING ITSELF MAY LEAD TO RELUXSlide46
UNEXPLAINED CRYING AND GER
THESE SYMPTOMS ARE NOW BEING CALLED GERD
REFLUX CONTENTS : MOSTLY BUFFERED (FREQUENT FEEDS)SELDOM IS OF ACID PHHENCE CRYING IS NOT DUE TO ACID EXPOSURE OF THE ESOPHAGUSSlide47
.
J
Pediatr
. 2009 Apr;154(4):514-520. j.jpeds.2008.09.054.Multicenter
, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease.
Orenstein SR, Hassall E, Furmaga-Jablonska W
, Atkinson S, Raanan M.
Author information: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. sro.pitt.edu@verizonSlide48
Objectives
To assess the safety and efficacy of lansprazole in treating infants with symptoms attributed to
Gastroesophageal reflux disease(GERD) that have persisted despite a >or = 1-week course of non pharmacologic managementrSlide49
Study design
Multicenter, double blind, parallel-group study randomized infantsPersisting symptoms due to GERD
Symptoms were tracked through daily diariesWeekly visitsEfficacy defined as >50% reduction in measures of feeding related cryingGlobal assessment
AEs recorded in both groupsSlide50
RESULTS
162 infants met criteria44/81 were responders in each group identical for
lansprazole –placeboNo significant difference seen in any secondary measures62 percent lansprazole
treated infants experienced 1 or more adverse events vs 46 percent placebo controlledSerious adverse events occurred in12 infants10 infants in the lansprazole
group and 2 infants in placebo groupSlide51
CONCLUSION
NO DIFFERENCE IN EFFICACY BETWEEN LANSPRAZOLE AND PLACEBOFOR SYMPTOMS ATTRIBUTED TO GERD IN INFANTS( 1-12 MONTHS)
AEs PARTICULARLY LOWER RESPIRATORY TRACT INFS OCCURRED MORE FREQUENTLY IN WITH LANSPRAZOLESlide52
Moore Dj
et alJ Pediatr 2003: 143:219-23
Double blind placebo controlled trial of omeprazole in infants with gastroesophageal reflux.Smaller placebo-controlled, cross-over study with a different PPI showed similar results (NO EFFECT)Slide53
Davidson G,MBBS,MD et al
Efficacy and Safety of once daily Esomerprazole: GERD I Neonatal patients
Randomized, Double Blind, placebo-controlled multicenter study
Neonates premature to 1 month(corrected age) n=52Sign and symptoms of GERDEsomeprazole 0.5 mg/kg or placebo once daily for 14 days
Changes from baseline in total number of gerd symptomsChanges from baseline to GERD related signs (cardiorespiratory monitoring)Simultaneous pH,
impedence, CVS, 8 hr video monitoring monitoringSlide54
Davidson
et alMulticenter study
No significant difference between the two groups in the percentage change from baseline
Total number of GERD related signs and symptoms( -14.7% vs -14.1%)Mean change from baseline in Total number of reflux episodes: no differencePercentage of time pH was < 4 (-10.7 vs2.2)Acid reflux episode >5 minutes (5.5 vs1.0)
significant decrease in esomerprazole grpNumber of patients with AE similar in both
groupsSlide55
Conclusions
Signs and symptoms traditionally attributed to acidic reflux in neonates were not significantly altered by esomeprazole treatment. It was well tolerated
reduced esophageal acid exposure and the number of acidic reflux eventsSlide56
Efficacy of proton-pump inhibitors in children with
gastroesophageal reflux disease: a systematic review.van der Pol RJ,
Smits MJ, van Wijk MP, Omari TI
, Tabbers MM, Benninga MA
. \Pediatrics. 2011 May;127(5):925-35.
doi: 10.1542/peds.2010-2719. Epub 2011 Apr 4Department of Pediatric Gastroenterology and Nutrition, Emma Children's Academic
Medical Center,AmsterdamSlide57
Objectives
systematic review to determine effectiveness and safety of PPIs in children with GERD.Slide58
PPIS in infants: systematic review
For infants, PPIs were more effective in 1 study (compared with hydrolyzed formula
), not effective in 2 studies, and equally effective in 2 studies (compared with placebo) for the reduction of GERD symptomsSlide59
Hudson B
etal N Z Med J. 2012 Dec 14;125(1367):119-26
infants have periods of unsettledness, or irritability, Spilling (or posseting) due to reflux of gastric contents n
ormal patterns of infancy that resolve with the passage of time
increasingly been ascribed to pathology and treated There is
clear evidence, however, that acid suppression has no role in the management of these behaviours. In addition, recent data illustrate increased risk of
adverse effects of these drugs in infantsSlide60
GER AND APNEA
Apnea of prematurity
and GER are both common and widely perceived to be causally related..
Available physiologic data suggest that when there is a temporal relationship
apnea may be more likely to predispose to GER via esophageal sphincter relaxation than vice versa.
Pharmacotherapy including acid suppression therapy may have adverse effectsSlide61
ACID SUPPRESSION AND SIDE EFFECTS
COMMON ASSUMPTION ACID SUPPRESSION IS BENIGNWELL TOLERATED WITH FEW IMMEDIATE SIDE EFFECTSSlide62
PPIS AND H2 BLOCKERS
SIDE EFFECTSCommunity acquired pneumonia(children)
NEC preterm infants( treated with H2 blockers)Candidemia in neonatal intensive care units (H2RA)Pneumonia (infants PPI)Bacterial overgrowth (adults PPI)
Clostridium associated disease (adults PPI)Hip fractures (adults PPI)Slide63
INFANTILE COLIC
Behavioral syndrome of infancyLong crying boutsHard to soothe behavior
Arching of backTurning away from bottle and breastWe attribute it to abd. Pain and
gerdBut may be inability to change state, to calm oneself( Barr RG)Slide64
INFANTILE COLIC
HOWEVER IN SOME INFANTS: IDENTIFIABLE CAUSESOME OF THESE CAUSES MAY BE GASTROINTESTINAL
SENSITIVITY TO INGESTED ANTIGENSMILK PROTEINANTIGENS THAT CROSS BREAST MILKGAS DUE TO MALDIGESTION
INFANTILE DYSCHEZIASlide65
Lactobacillus vs simethicone
Ninety breast fed colicky infantsRandomly assigned to receive
Either probiotic L reuteri(10*(8) live bacteria per dayOr simethicone 60 mg /day
For 28 daysMonitored by daily crying times and a detailed questionareSlide66Slide67
Lactobacillus reuteri
Vs simethicone
83 of 90 infants completed the studySimilar in gestational age, birth weight, gender and crying timeDaily mean crying timeGroup start 7
th day 28th day Probiotic 197 159 51
Simethicone 197 177 145On day 28 39 patients were responders in probiotic gp
compared to 3 patietns(7%) in simethicone