Gastroesophageal Reflux in Children

Definitions

Passage of gastric contents into esophagus is called GER

Definitions
GER Passage of gastric contents into esophagus Regurgitation Passage of refluxed gastric / Spitting-up content into oral Pharynx & mouth Drooling Vomiting Expulsion of refluxed gastric contents from mouth GERD Gastric contents reflux into the Esophagus/oropharynx & produce symptoms/complications Voluntary, habitual regurgitation of recently ingested Rumination food that is subsequently spitted up or re-swallowed

Definitions

Pathogenic Factors in GER

Mechanisms of GER: TLESR: transient lower esophageal sphincter relaxation Delayed gastric emptying Impaired esophageal clearance Impaired airway protection

Pathogenic Factors in GER

TLESR:
Primary mechanism for reflux to occur TLESRs occur independent of swallowing, reducing LES pressure to 02 mm Hg (above gastric), and last >10 sec; 0 they appear by 26 wk of gestation A vagovagal reflex, composed of afferent reflex, mechanoreceptors in the proximal stomach, a brainstem pattern generator, and efferents in the LES, regulates TLESRs Gastric distention (postprandially, or due to abnormal gastric emptying or air swallowing) is the main stimulus for TLESRs

Pathogenic Factors in GER

TLESR:
Whether GERD is caused by a higher frequency of TLESRs or by a greater incidence of reflux during TLESRs is debated; each is likely in different individuals. Straining during a TLESR makes reflux more likely, as do positions that place the gastroesophageal junction below the air-fluid interface in the stomach airOther factors influencing gastric pressure-volume pressuredynamics, such as increased movement, straining, straining, obesity, largeobesity, large-volume or hyperosmolar meals, and meals, increased respiratory effort (coughing, wheezing) can have the same effect

Prevalence
GER is a physiological phenomenon, occurring in every
individual. Most episodes of reflux are limited to the distal esophagus, and are brief and asymptomatic. asymptomatic.

Sometimes GER is a normal esophageal function,

serving a protective role, e.g. during meals, or in the immediate postprandial period; if the stomach is overdistended, GER serves to decompress it.

Regurgitation may be physiological in healthy, thriving,

happy infants. Primary GER results from a primary disorder of function of the upper GI tract

In secondary GER, reflux results from dysmotility GER,

occurring in systemic disorders such as neurological impairment or systemic sclerosis

Prevalence
It may also result from mechanical factors at play in
chronic lung disease or upper airway obstruction, as in chronic tonsillitis. Other causes include systemic or local infections (urinary tract infection, gastroenteritis), food allergy, metabolic disorders, intracranial hypertension and medications such as chemotherapy. In some cases, secondary reflux results from stimulation of the vomiting center by afferent impulses from circulating bacterial toxins, or stimulation from sites such as the eye, olfactory epithelium, labyrinths, pharynx, gastrointestinal and urinary tracts, and testes. These stimuli usually cause vomiting.
Textbook of Pediatric Gastroenterology and Nutrition, Stefano Guandalini, 1st Ed, 2004

Prevalence
A small degree of reflux is common in all infants, infants, and it is only infants who have moderate to severe chronic reflux that tend to come to the pediatrician's attention One of the most common causes of GER is overfeeding, so a careful history is important A history of coughing, gagging, and arching of the back with extensor posturing during feeding may result from direct aspiration, whereas the aspiration, presence of these symptoms soon after feeding may suggest GER In severe reflux, the infant may have poor weight gain

Definitions

Prevalence of Regurgitation: Infants

Recurrent vomiting occurs in 50% of infants in the first three months of life, in 67% of four month old infants, & in 5% of 10 to 12 month old infants. Vomiting resolves spontaneously in nearly all by 24 months!

Prevalence of Regurgitation: Infants

Determination of the exact prevalence of GER &
GERD at any age is virtually impossible because most reflux episodes are asymptomatic, show the absence asymptomatic, of specific symptoms, undergo self-treatment and lack selfmedical referral.

Prevalence of GERD in children is not well defined,

but community based studies suggest that symptoms may be present in 1.8 to 22% of children aged 3 to 18 years. 1

A prevalence of 10% was found among Indian children

in the age group of 1month to 2 years.2
1. J Pediatr 2005; 146 : S3 S12 2.Trop Gastroenterol 2001;22:99-102 2001;22:99-

Etiology
 Genetic predisposition  Environmental factors  Food habit  Eating fast  Obesity  Stress  Exposure to tobacco smoke  Neurologically impaired children, Repaired esophageal atresia, BPD, cystic fibrosis, ?H. pylori

Etiology

Factors affecting GER

Spectrum of Manifestations

Sign & Symptoms

Infants resistance Recurrent vomiting Failure to thrive Fussiness/irritability Apnea/choking episodes Opisthotonic posturing
Feeding

Older Children & Adolescents

Abdominal Heartburn Recurrent

pain

vomiting Dysphagia Chronic cough/wheezing cough/wheezing Hoarseness Postnasal drip

Manifestations

Manifestations

Complications
Esophagitis Peptic stricture Barretts esophagus Failure to thrive Pulmonary / ENT disease Sandifers syndrome / torticollis

GERD & Asthma

GERD

Asthma
5050-60% of childhood asthmatic patients experience GERD
Pedatr Drugs.2005;7:177-186 Drugs.2005;7:177-

Does GERD Trigger Asthma?

 Aspiration of refluxed
gastric contents (micro- or (micromacromacro-aspiration)

 Vagally-mediated reflex Vagallybronchospasm

 GERD & rhinosinusitis

cause chronic, intermittent cough. Both can be comorbidities of asthma
Am J Med 2001; 111: 37S

When to Suspect GERD Related Asthma

 Progressive and resistant asthma  Symptoms of GERD present  Exacerbations during sleep and after
meals

 Symptoms worsen after bronchodilator

administration
AGA Consensus Development Conference, 2002

Asthma & GERD

Asthma & GERD

Diagnosis
GERD is diagnosed on basis of history & clinical features
No fool proof test for diagnosis An empiric trial of PPI therapy is a widely used
diagnostic test for GERD in adults and this approach is expanding to pediatric practice now1

oBarium meal series oEndoscopy and biopsy oIntraesophageal pH monitoring

1.Am J Med 2004; 117: 23S 29S

Differential Dx of GER
Emesis shortly after feeds GER If the emesis is projectile & the child is 1 to 3 months old pyloric stenosis Poor weight gain & emesis pyloric stenosis or metabolic disorder Drug Tx: Macrolide antibiotics emesis and diarrhea, chemotherapeutic agents & toxic ingestions emesis Child with VP shunt, vomiting shunt obstruction & o icp Emesis with seizure or headache or both intracranial process Diarrhea, emesis, & fever gastroenteritis. Fever, abdominal pain, & emesis appendicitis Bilious emesis & abdominal pain I.O.

Differential Dx of GER
Most cases of emesis are caused by GER, acute gastroenteritis, or systemic disorders such as tonsillitis, otitis media, or urinary tract infection The differential diagnosis for GER in the adolescent may include pneumonia, costochondritis, pericarditis, pulmonary embolism, arrhythmias, ischemia due to an anomalous coronary artery, pancreatitis, cholecystitis, peptic ulcer disease, and anxiety In the older child, GER is often manifested as epigastric abdominal or chest pain. Define the pain's location and severity and whether it radiates and is constant or intermittent. Burning epigastric or chest pain is probably reflux in the adolescent, especially if it occurs after meals when the patient lies down.

GERD vs Dyspepsia
 Distinguish from Dyspepsia
o Ulcer-like symptoms-burning, epigastric Ulcersymptomspain o Dysmotility like symptoms-nausea, symptomsbloating, early satiety, anorexia

 Distinct clinical entity  In addition to antisecretory meds and

an EGD need to consider an evaluation for Helicobacter pylori

GER: Natural History

< 2 yr age

Very often physiological, esp < 6 mo 90% resolve <12-18mo <12Carre Nelson

> 2yr age adulthood Vomiting > 2 yr age never physiological GERD usually a chronic, relapsing disease with waxing & waning Completely resolving in no more than half

GER: Approach in < 2 yrs age

INDICATIONS FOR INVESTIGATION
Suspicion of Complication

Irritability with feeds Recurrent pneumonias / chronic cough Generally unhappy baby Failing to thrive Torticollis [?Sandifers syndrome] Persistent vomiting at 18-24mo 18-

GER: Approach in > 2 yrs age

INDICATIONS FOR INVESTIGATION Persistence of vomiting since < 2yrs New onset recurrent vomiting Suspicion of a complication o undiagnosed anemia o dysphagia / odynophagia o recurrent pneumonias, cough o nonseasonal asthma

Investigations
CBC: Normal Electrolytes: hypochloremic, hypokalemic
metabolic alkalosis with severe reflux CXR: for aspiration pneumonia & changes due to recurrent aspiration UPPER GI CONTRAST STUDY - not a test for reflux - stricture / achalasia / mass - road map UPPER GI ENDOSCOPY, BIOPSIES 24HR INTRAESOPHAGEAL pH GASTRIC EMPTYING STUDY

Contrast Studies for GER

Gastrografin (Diatrizoate Meglumine & Diatrizoate Sodium
Solution) is a palatable lemon-flavored water-soluble lemonwateriodinated radiopaque contrast medium Following oral administration only about 3% is absorbed from the stomach and intestines In children up to 10 years of age, 15-30 mL is generally 15sufficient. This dose can be diluted with twice its volume of water. For babies and young children it is recommended that the contrast medium be diluted with 3 times its volume of water Not to be administered to patients who are hypersensitive to iodine (C.I. in hyperthyroid)

Contrast Studies for GER

Aspiration of Gastrografin into the trachea and airways may result in serious pulmonary complications including, pulmonary edema, pneumonitis or death Bronchial entry of edema, any orally administered contrast medium causes a copious osmotic effusion. Therefore, avoid use of Gastrografin in patients with tracheo-esophageal fistula and minimize risks tracheofor pulmonary aspiration in all patients. Anaphylactic reactions, including fatalities, have been reported with the use of Gastrografin. Patients at increased risk include those with a history of a previous reaction to a contrast medium, patients with a known sensitivity to iodine, and patients with a known clinical hypersensitivity (bronchial asthma, hay fever, and food allergies)

Contrast Studies for GER

An upper GI BARIUM STUDY, although no longer the diagnostic study of choice, may be useful. The sensitivity in diagnosing the occurrence of reflux and the presence of esophagitis is low, but esophageal motility and anatomic abnormalities (e.g., hiatal hernia, achalsia, stricture, malrotation, GOO) may be identified. Helps to plan surgical intervention, if required (cf. Milk intervention, Scan) Less palatable, hence difficult to use in young children palatable, Both an upper GI barium study and GE scintigraphy may be helpful in the diagnosis of GER but are not sensitive. The primary diagnostic tool for GER today is the pH probe study. Impedance/pH monitoring is currently under investigation as a potentially superior diagnostic modality.

Contrast Studies for GER

Contrast Studies for GER

Milk Scan: Gastric emptying scintigraphy
milk, Involves ingestion of a radiolabeled (Tc99m) meal/ milk, with serial images recorded up to 60 minutes after ingestion. This study may be used to diagnose and quantitate reflux but is primarily used to assess gastric emptying and to identify delayed GE.
Late images showing isotope in the lungs indicate pulmonary aspiration. No sedation / prolonged observation / high sensitivity / low radiation exposure Procedure: burped and placed supine, anterior and posterior imaging of abdomen / thorax / mouth

pH Monitoring
The 24-hour pH probe monitor is the gold standard for Dx 24A catheter at the LES measures episodes of reflux over a 2424-hour period: requires hospitalization An esophageal intraluminal pH < 4.0 for at least 15 seconds defines an episode of reflux Recorded values include total time with pH below 4.0, upright time with pH less than 4.0, supine time with pH less minutes, than 4.0, number of reflux episodes longer than 5 minutes, and duration of the longest reflux episode. Disadvantages: inability to diagnose nonacid reflux and to Disadvantages: distinguish primary and secondary (allergy to milk protein or other food) causes of reflux, the inability to determine the presence or severity of esophagitis, and poor tolerance of the probe in some children

Impedance Monitoring
Esophageal impedance/pH monitoring is a novel technique that can be used to detect both acid and nonacid reflux. reflux. This test uses a probe similar to that used in standard pH monitoring to measure the change in electrical resistance that occurs across its sensors with the passage of intraluminal material Advantages of this test include the ability to identify the content, direction, and localization of any reflux. This test reflux. may yield better diagnostic sensitivity than pH probe in patients treated with antacids Disadvantages include a lack of standardized pediatric normal ranges and increased cost relative to standard pH probe Investigational tool

Endoscopy
Endoscopy is used to visualize and obtain a biopsy sample from the esophageal mucosa and to diagnose esophagitis, stricture, & Barrett esophagus. esophagus. Although there is no validated grading system for children, erosion or ulceration is indicative of esophagitis Biopsy should be performed in most cases, even if the mucosa appears relatively normal, because there is a normal, significant tendency for histologic grade to exceed visual endoscopic findings Endoscopic ultrasonography has been described as an adjunct to endoscopy to evaluate the integrity of Nissen fundoplication in children and adults

Treatment Goals of GERD

Goals

Eliminate symptoms

Manage or prevent complications

Prevent relapse

Heal esophageal mucosa

Treatment Goals of GERD

Pediatric GERD

Adult GERD

Treatment of childhood GERD results in better disease outcome in adults!

Management

Explanation, reassurance Diet, lifestyle Position Antacids Anticholinergics [e.g., XbethanecolX] bethanecolX Prokinetics [XmetoclopramideX, XcisaprideX] [XmetoclopramideX cisaprideX H2H2-Receptor Antagonists PPI AntirefluxAntireflux-Surgery

Lifestyle Changes in Infant with GER

Small frequent feeds Thickening of milk feeds (1 TBS of rice cereal
per oz of formula)

Avoid overfeeding Holding upright and burping: prone head-up headposition for at least 20 minutes after a feeding

Avoid tight clothing and passive smoking A short trial of a hypoallergenic diet can be
used to exclude milk or soy protein allergy before pharmacotherapy

Post-feed Positioning

RightRight-side lying position after feeding: Neonates

Whaley & Wongs Essentials of Pediatric Nursing, 5th Ed, Mosby, 1997

Lifestyle Changes in Older Children with GER

No food or drink for 2 hours before bed-time bedElevate head of bed (6) if nocturnal symptoms Avoid foods (caffeine, chocolates, spicy or fatty
foods, citrus foods, tomato, carbonated beverages)

Weight loss if overweight Avoidance of smoking and alcohol The efficacy of positioning for older children is
unclear, but some evidence suggests a benefit to left side position & head elevation during sleep

GER Bed

Elevation

Pharmacologic Therapy of GERD

Directed at ameliorating the acidity of the gastric contents or at promoting their aboral movement Acid Reducers o Antacids o H2 receptor antagonists-ranitidine,famotidine antagonistso Proton pump inhibitors (PPIs) omeprazole, lansoprazole Prokinetics o Cisapride o Metoclopramide o Domperidone
Acid suppression is the mainstay of GERD management in both children and adults1 1.Aliment Pharmacol Ther 2004; 19 (suppl 1) 22-27

Prokinetics
e.g. metoclopramide (dopamine-2 and 5HT-3 (dopamine5HTantagonist), bethanechol (cholinergic agonist), and erythromycin (motilin receptor agonist) & cisapride Act on through their effects on LES pressure, esophageal peristalsis or clearance and/or gastric emptying, No effect on TLESR No clear scientific evidence on efficacy Not US FDA approved for GERD in children Cisapride-cardiac side effect: Banned CisaprideMetaclopramide- extra pyramidal side effects Metaclopramide(>20%)

Antacids (Alginate-) (AlginateRapid but transient relief of symptoms by acid neutralization No role on source of acid secretion Needs to be given more than 6 doses per day Can not be used for a prolonged period because of side effects of diarrhea (magnesium) and constipation (aluminum) and rare reports of more serious side effects of chronic use Aluminium containing antacids may cause aluminium toxicity Occasional formation of large bezoar-like bezoarmasses of agglutinated intragastric material

H2RAs
Acid-suppressant therapy is recommended in Acidsevere esophagitis, but this does not rectify primary disordered motility, a major pathophysiological mechanism Definite benefit in treatment of mild-to-moderate mild-toreflux esophagitis. H2RAs have been esophagitis. recommended as first-line therapy because of firsttheir excellent overall safety profile, but they are being superseded by PPI in this role, as increased experience with pediatric use and safety Less potent compared to PPI Associated with tachyphylaxis
Drugs: cimetidine, famotidine, nizatidine, & ranitidine

PPI
Provide the most potent antireflux effect by blocking the H+,K+-ATPase (proton pump) H+,K+channels of the final common pathway in gastric acid secretion In typical doses, diminish the daily production of acid (basal and stimulated) by 8095% 80 PPIs are superior to H2RAs in the treatment of severe and erosive esophagitis All proton pump inhibitors have equivalent efficacy at comparable doses An acidic pH is required for drug activation, & since food stimulates acid production, these drugs ideally should be given about 30 minutes before meals

PPI
Younger patients generally have increased metabolic capacity, resulting in the need for higher dosages of PPI per Kg in children compared to adults Generally cause remarkably few adverse effects. effects. The most common are nausea, abdominal pain, constipation, flatulence, & diarrhea. Subacute myopathy, arthralgias, headaches, and rashes also have been reported
Can interact with warfarin (esomeprazole, lansoprazole, omeprazole, & rabeprazole), diazepam (esomeprazole & omeprazole), & cyclosporine (omeprazole and rabeprazole). Omeprazole inhibits CYP2C19 (thereby decreasing the clearance of disulfiram, phenytoin, and other drugs) and induces the expression of CYP1A2 (thereby increasing the clearance of imipramine, several antipsychotic drugs, tacrine, and theophylline)

PPI
Prolonged use of PPIs can result in vitamin B12 deficiency as a consequence of impaired release of vitamin B12 from food in a non-acid nonenvironment Potential consequences of prolonged acid suppression, include the risk of proliferation of gastric flora and the risk of developing enterochromaffinenterochromaffin-like cell hyperplasia, hypergastrinemia) (hypergastrinemia) gastric malignancy

PPI Trial
Expect response in 2-4 weeks (whether using H2RA or PPI) If no response Change from H2RA to PPI If no response Maximize dose of PPI Therapy indicated for a minimum of 8-12 weeks If PPI response inadequate despite maximal dosage, confirm diagnosis : EGD, 24 hour pH monitor Failure to control symptoms with high-dose PPI highnon-acidtreatment raises the likelihood of non-acidrelated causes for the symptoms

PPI Doses
Medication
H2RAs
Famotidine Ranitidine 1 mg/kg/day 5-10 mg/kg/day Twice daily Twice daily or thrice daily

Dose

Frequency

PPIs
Lansoprazole 0.4-2.8 mg/kg/day 0.4e30 Kg: 15 mg/d > 30 Kg: 30 mg/d 0.2-3.5 mg/kg/day 0.2< 10 Kg: 10 mg/d u 10 Kg: 20 mg/d 2020-40 mg/day, 0.5 -1 mg/kg/d < 20 kg: 10 mg 20 kg: 20 mg Once daily > 1 yr

Omeprazole

Once daily

> 2 yr

Pantoprazole Esomeprazole

> 5 yr > 1 yr

PPI: Highlights of Clinical Studies

At the end of 12 weeks of the treatment period, 70-75% of children 70had resolution or improvement in their overall symptoms. During the first 2 weeks of treatment, there was significant reduction in the average severity of GERD. Percentage of days antacid used is reduced from 50% at pretreatment period to 0 in last week. By end of the therapy there is healing of lesions of erosive esophagitis in 95-100% of cases. 95At the end of 12 weeks of the treatment period, 79% of children had resolution or improvement in cough and 63% in wheeze. 92% of children were highly compliant. Healthy children preferred the taste of strawberry flavoured lansoprazole ODT to the peppermint flavoured ranitidine syrup.

J Pediatr Gastroenterol Nutr 2002; 35: 308-317,J Pediatr Gastroenterol Nutr 2005; 40: 319 - 327

Protocol for Management

Am Fam Physician. 2001

Protocol for Management

Initiate Tx with H2RA or PPI H2RA taken BID PPI taken QD No Good response Good response Yes Frequent relapses No On demand Tx Symptoms persist Maintenance therapy with lowest effective dose Yes Good response No Consider EGD if risk factors present (> 45, white, male and > 5 yrs of sx) Confirm diagnosis EGD, ph monitor Increase to max dose QD or BID Yes Yes No

Surgery: Nissen Fundoplication

Effective therapy for intractable GERD in children, particularly those with refractory esophagitis or strictures and those at risk for significant morbidity from chronic pulmonary disease It may be combined with a gastrostomy for feeding or venting Long-term studies suggest that Longfundoplications frequently become incompetent in children, as in adults; this fact currently combines with the potency of PPI therapy that is now available to shift practice toward longlongterm pharmacotherapy in many cases.

Surgery: Nissen Fundoplication

Even those patients who do not fully respond to medical management should be treated for 8 weeks before surgical therapy is considered, unless the patient is experiencing life-threatening symptoms! life-

PPI: Lansoprazole

Lansoprazole: Other indications

Peptic ulcer (duodenal ulcer, gastric ulcer) Drug induced gastritis (anti TB, antimalarial, antibiotics) ICU patients to avoid stress induced ulcer H. pylori gastritis GERD in children with cerebral palsy Resistant asthma Contraindications: in patients with known hypersensitivity to any component of the formulation of Lansoprazole

PPI: Warnings & Precautions

Renal impairment: No dosage adjustment appears impairment: necessary for patients with renal impairment Hepatic impairment: In adults, dosage of PPI should be impairment: reduced by 50% . PPI disposition in children has never been studied Pregnancy: This drug should be used during Pregnancy: pregnancy only if clearly needed Lactation: Breast-feeding should be discontinued if the Breastuse of lansoprazole is considered essential

PPI: Side Effects Lansoprazole

 Generally well tolerated  15% of children experience side effects,
which are mild to moderate in nature  GI events (nausea, vomiting, diarrhea, constipation) and headache are common side effects  No clinically significant changes in hematological and biochemical parameters
Drugs 2005; 65:2129-35 65:2129-

Lansoprazole: Junior Lanzol

 Contains 15/30 mg of Lansoprazole  Available in orally disintegrating tablet
form (ODT), Strawberry flavored  Junior Lanzol should not be chewed  Tablet should be placed on the tongue and allowed to disintegrate with or without water  Can also be administered with a spoon: Place the tablet in a teaspoon or two 15 mg tablets in a tablespoon of water & wait till tablet/tablets get disintegrated

Key Points
GER can be physiological or
pathological (GERD)

Physiologic resolves by the

age of 24 months in most cases

Medical management remains

the mainstay of treatment

GER should be looked for in

cases of resistant asthma