Gastroesophageal Reflux (GER) in Preterm Neonates:

An Evidence Based Therapeutic Approach & Case Presentation

Tauhid Ahmed Bhuiyan, PharmDPharmacy Practice Resident (R2)

King Faisal Specialist Hospital & Research Center (KFSH&RC)

An Application Based Activity

King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. (UAN# 0833-0000-15-036-L01-P, 0833-0000-15-036-L01-T)

Objectives• To discuss the general overview of

gastroesophageal reflux (GER) in preterm neonates

• To identify possible diagnostic measures for diagnosing GER

• To provide an evidenced based therapeutic approach for management of GER

• To evaluate a topic related patient case I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

Important Terminologies • Gestational age (or

“menstrual age”)▫ First day of the last normal

menstruation to day of delivery

• Chronological age (or “postnatal” age)▫ time elapsed after birth

• Prematurity:▫ Gestational age <37 weeks

• Birth weight:▫ Normal: 2500 g +▫ Low: <2500 g▫ Very low: <1500 g

AAP. Age Terminology. Pediatrics 2004; 114:1362–64

Definition • “Gastroesophageal reflux (GER) is the passage of

gastric contents into the esophagus with or without regurgitation and vomiting”

• “Gastroesophageal reflux disease (GERD), when reflux of gastric acid contents causes troublesome symptoms and/or complications”

Vandenplas Y et al. J Pediatr Gastroenterol Nutr 2009; 49:498–547

Gastroesophageal Reflux (GER)

• Common phenomenon in all newborn infants, especially in premature babies

• Normal physiological process associated with transient relaxation of the lower esophageal sphincter (LES)

• Associated factors in premature babies▫ Posture ▫ Immature esophageal motility ▫ Abundant milk intake

• “Regurgitation” and “spitting up” are the two most visible symptoms

Lightdale JR et al. Pediatrics 2013; 131(5):e1684-95

Regurgitation • “Passage of refluxed gastric contents into the

pharynx or mouth and sometimes expelled out of the mouth”

• Regurgitation is generally assigned as effortless and non-projectile

• Occurs daily in about 50%of the infants < 3 months of age

• Resolves spontaneously in most healthy infants by 12 to 14 months of age

Vandenplas Y et al. J Pediatr Gastroenterol Nutr 2009; 49:498–547

Epidemiology• Occurs in all healthy infants ≥30 times daily that lasts <3 mins

(“happy spitters”)

• Common: healthy preterm > term

• Dhillon AS et al., one year multicenter observation study (77 NICU in England and Wales) using standard questionnaire ▫ The incidence of symptomatic GER in those babies born before 34 weeks of

gestation ~22%▫ Common treatment strategies:

Body positioning (98%) Placement on a slope (96%) H2-receptor antagonists (100%) Feed thickeners (98%) Antacids (96%) Prokinetic agents (79%) Proton-pump inhibitors (65%) Dopamine-receptor antagonists (53%)

Incidence of GERD• Babies with history of regurgitation, the peak

prevalence of GERD, ▫ ~50% at 4 months of age▫ 5% to 10% of infants at 12 months

• Prospective birth cohort study (n=693) in children who were followed for 2 years from birth and then contacted 8 to 11 years later▫ Children with history of frequent regurgitation (defined as

>90 days of "spilling out" during the first two years of life) were relatively 2.3 times higher likelihood of reporting GERD symptoms during follow-up years (95% CI 1.3-4.0)

Dhillon AS et al. Acta Paediatr 2004;93(1):88-93Martin AJ et al. Pediatrics. 2002;109(6):1061

Pathogenesis of GER in Premature Babies

“Multifactorial”

• Relaxation of lower esophageal sphincter (LES)▫ Linked to 92-94% of the overall GER episodes

• Gastric emptying ( ↑time ≈ ↓gestational age)

• Esophageal motility

• Respiratory disorders (e.g. BPD)

• Gastric tube (e.g. naso/oro gastric tube)▫ Cause ↑ LES relaxation and/or ↓ gastric emptying

BPD: bronchopulmonary dysplasia

Complications• Frequent feeding problems

• Failure to thrive

• Esophagitis

• Lung aspiration wheezing or pneumonia▫ Can increase the length of hospitalization

• Apnea & chronic lung disease; still controversial

Corvaglia L et al. Gastroenterology Research and Practice 2013

Diagnosis

Diagnostic Evaluations • Constant challenge

• Symptoms are nonspecific and diagnostic tests are limited due to ▫ Sensitivity and Specificity▫ Condition of the babies

History & Physical Examination▫ Nonspecific signs: regurgitation of milk, vomiting, irritability,

unexplained crying, arching, grimace, desaturation, sleep disturbances, feeding refusal, or respiratory symptoms

▫ Differential diagnoses: bilious vomiting, gastrointestinal bleeding, diarrhea, constipation, fever, lethargy, abdominal tenderness and distension, and hepatosplenomegaly

Martin R. et al. Gastroesophageal reflux in premature infants. Uptodate. Accessed on: May 13, 2015

Available Tests• Esophageal pH probe (most widely

used in preterm)▫ Detect reflux of gastric contents (pH <4)▫ Trans-nasal passage of microelectrode to

measure pH▫ Limitation: detection of acid refluxes only

• Multiple intraluminal impedance (MII)▫ Higher sensitivity compared to pH probe ▫ Detect both acidic and non-acidic fluid, solids, and air

• Combination of latter two▫ Best diagnostic choice, detects acid, weakly acid, and nonacid reflux episodes▫ Recognized by both NASPGHAN & ESPGHAN

NASPGHAN: North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition ESPGHAN: European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Martin R. et al. Gastroesophageal reflux in premature infants.

Uptodate. Accessed on: May 13, 2015

Management

Step-wise Approach:

1st line: Non-pharmacological

2nd line: Pharmacological

Guidelines2009

2013

Goals of Therapy•Short term:

▫Minimize signs and symptoms ▫Prevent adverse drug reactions▫Improve health related outcomes (e.g. weight

gain)

•Long term: ▫Prevention of development of GERD

Non-pharmacological Therapy • First-line treatment in symptomatic babies who

are experiencing frequent vomiting and effortless regurgitations without significant clinical complications

• Available options:

Corvaglia L et al. Gastroenterology Research and Practice 2013

Body positioning

Feeding strategies

Feed thickening

Hydrolyzed formulas

Body Posture• Widely used: prone or left-side positions

• Ewer et al. [1999] studied prospectively using 24h lower esophageal pH monitoring in 18 preterm (<37 weeks of gestation) who received full feeds (150 ml/kg/day) ▫ Infants were nursed for 8 hours in three positions

(prone, left, right lateral)▫ Results:

Ewer AK. et al. Arch Dis Child Fetal Neonatal Ed 1999;81:F201–F205

Body Posture Cont. • Omari TI et al. [2004] combined esophageal

manometry and MII to investigate the efficacy of left vs. right lateral position on GER in 10 healthy preterm (35-37 wks)▫ Compared to right lateral position, left lateral position

had significantly less GER (P < .01) Higher proportion of liquid GER (P < .05) Faster GE (P < .005)

Omari TI. et al. J Pediatr 2004;145:194-200

Feeding Strategies • Feeding frequency:

▫ Omari et al. [2002] observed a positive correlation between the frequency of feedings (every 2,3,or 4 hrs) and the occurrence of nonacid GER episodes with concomitant decrease in acidic GER episodes in mildly symptomatic infants

▫ Study recommendation: frequent, small volume feeds may improve GER

• Bolus vs. continuous tube feedings▫ Assessed by Jadcherla et al. [2012]: found a significant

negative correlation (P < .03) between feeding duration and total GER events, number of nonacidic GERs

▫ Useful strategy: reduction in feeding flow rate (mL/min)

Corvaglia L et al. Gastroenterology Research and Practice 2013

Available Pharmacological Options

1. Alginate-based formulations

2. Histamine-2 receptor blockers

3. Proton pump inhibitors

4. Prokinetic agents

Alginate-Based Formulations

• Reported to be the most commonly prescribed anti-reflux medication in preterm infants with symptomatic for GER

• Mechanism of action:▫ Forms low density but viscous foamy gel in the presence of gastric

acid ▫ Floats on the surface of gastric content during GER episodes

• Available forms:▫ Sodium alginate + sodium bicarbonate (Gaviscon®)

• Adverse drug reactions:▫ “Aluminum toxicity”, abdominal distension, hypernatremia,

constipation (products contain aluminum), thickening of the stool and anal fissure Corvaglia L et al. Gastroenterology Research and Practice

2013

Clinical Evidence• Limited data

• Covaglia et al. [2011] evaluated the efficacy sodium alginate (Gaviscon®) using a 24 h pH-MII in 22 symptomatic preterm newborn

▫ Sodium alginate was given 4X at alternate meals [drug-given (DG) vs. drug-free (DF) meals] and was found to have significant effect in decreasing the number of GER detected either by: pH monitoring (DG vs. DF: median 17.00 vs. 29.00, P = 0.002) MII (DG vs. DF: 4.0 vs. 6.00, P = 0.050) Acid esophageal exposure (DG vs. DF: 4.0% vs. 7.6%, P = 0.030)

Corvaglia L et al. Gastroenterology Research and Practice 2013

H2RA• FDA approved in ages ≥ 1 month

• Mechanism of action: ▫ Decrease acid secretion by inhibiting the histamine-2 receptor

on the gastric parietal cells

• Available forms:▫ Ranitidine, famotidine, cimetidine, nizatidine

• Adverse drug reactions:▫ New evidence:

Linked to infection (in VLBW) and development of necrotizing enterocolitis (NEC)

▫ Increased risk of liver disease and gynecomastia (cimetidine) Corvaglia L et al. Gastroenterology Research and Practice

2013

Clinical Evidence

• Efficacy of use in preterm, “an issue of debate”

• Kuusela AL et al. [1998] studied the optimal doses of ranitidine for both preterm and term infants▫ 16 preterm (gestational age under

37 weeks) and term infants treated with three different bolus doses of ranitidine (0.5 mg, 1.0 mg, and 1.5 mg per kg)

▫ Results:Corvaglia L et al. Gastroenterology Research and Practice

2013

Premature & term neonates <2 weeks:Oral: 2 mg/kg/day divided every 12 hoursIV: 1.5 mg/kg/day loading followed by maintenance dose every 12 hours

H2RA & NEC• Guillet et al. [2006] performed a retrospective case-

control study on VLBW infants to investigate the association between the incidence of NEC and the use of H2-blockers, as ranitidine, famotidine, and cimetidine▫ Found overall incidence of NEC of 7.1%, especially with longer

duration (18.9 ± 15.5 days)

• Recent study [2012] confirmed by Terrin et al. ▫ NEC was more frequent in infants treated with ranitidine (rate

9.8%) compared to those who did not (rate 1.6%)

• Latest evidence [2013] by Bilali et al.▫ NEC in preterm infants treated with ranitidine when compared

to the control group (17.2% vs. 4.3%)

Corvaglia L et al. Gastroenterology Research and Practice 2013

PPI• Not approved for children <1 year and clinically

ineffective to relieve GER symptoms

• Mechanism of action:▫ Blocks gastric proton pump that catalyzes the final phase of the

acid secretory process of parietal cells

• Available forms:▫ Omeprazole, esomeprazole, rabeprazole, lansoprazole,

pantoprazole

• Adverse drug reactions:▫ Headache, diarrhea, constipation, and nausea (2% to 7%)▫ Growing evidence of NEC & hypochlorhydria

Corvaglia L et al. Gastroenterology Research and Practice 2013

Clinical Evidence• Data on the safety and efficacy of PPIs in the preterm

population are few and somewhat controversial

• Omari et al. [2007] conducted 2-week randomized, double blinded, placebo-controlled trial for effectiveness of omeprazole [dose: 0.7 mg/kg/day] on preterm infants (n= 10) with GERD ▫ Omeprazole therapy significantly reduced gastric acidity (%time

pH <4, 54% vs 14%, P < 0.0005)▫ Esophageal acid exposure (%time pH <4, 19% vs 5%, P < 0.01) ▫ Number of acid GER episodes (119 vs 60 episodes, P < 0.05)▫ Limited by lack of sample size

Corvaglia L et al. Gastroenterology Research and Practice 2013

Clinical Evidence• Moore DJ et al. [2003] conducted a double-blinded,

randomized, placebo-controlled trial to assess the efficacy of omeprazole with GER and/or esophagitis in 30 irritable infants (3-12 months)▫ Using visual analogue scale, irritability were measure at baseline and

the end of each 2-week treatment period▫ Results:

Reflux index fell significantly during omeprazole treatment vs. placebo (-8.9% ± 5.6%, -1.9% ± 2.0%, P < .001)

VA score (assessed by parents) for the level of irritability while taking omeprazole or placebo did not differ significantly (n = 30, 5.0 ± 3.1 versus 5.9 ± 2.1, P = .214)

• No difference in GER reduction between lansoprazole (54%) vs. placebo (54%) (Orenstein SR et al. [2009])▫ Rate of respiratory infection was higher in lansoprazole group (10

vs 2; P= .032)Corvaglia L et al. Gastroenterology Research and Practice

2013

Prokinetic Agents• Improve gastric emptying, to reduce emesis, and

to enhance LES tone

• Agents▫ Cisapride ▫ Domperidone▫ Erythromycin▫ Metoclopramide

Corvaglia L et al. Gastroenterology Research and Practice 2013

Cisapride (Propulsid®) • Largely investigated

• Mechanism of action:▫ Enhance the release of acetylcholine from the mesenteric plexus

decreasing GER▫ Antagonist of the rapid component of the delayed rectifier current of

potassium in cardiac cells (antiarrhythmic effect)

• Ariagno et al. [2001] demonstrated▫ A significant reduction in reflux indexes and in the number of GER

episodes lasting ≥5 minutes ▫ Ineffective on the total number of refluxes/24 hours and on the

duration of the longest episode

• Dose dependent QTc prolongation and cardiac arrhythmias—no longer used for GER

Corvaglia L et al. Gastroenterology Research and Practice 2013

Domperidone (Motilium®) • Mechanism of action:

▫ Blocks dopamine receptors in chemoreceptor trigger zone of the CNS Enhance the response to acetylcholine of tissue in upper GI tract

causing enhanced motility and accelerated gastric emptying without stimulating gastric, biliary, or pancreatic secretions

• Few evidence in infants and children but none for preterm infants

• Safety alerts:▫ Increased risk of serious adverse cardiac effects including

dose dependent QTc prolongation, arrhythmias and sudden cardiac death

Corvaglia L et al. Gastroenterology Research and Practice 2013

Erythromycin • Mechanism of actions:

▫ Strong non-peptide motilin receptor agonist that contributes to enhance gastric emptying and intra-digestive migratory motor complex

• Although use of erythromycin large randomized controlled trial demonstrated significant improvement on parenteral-nutrition associated cholestasis in preterm infants, however, no significant improvement were found in resolution of GER

• Adverse drug reactions:▫ Reported cases of increased risk of infantile hypertrophic

pyloric stenosis (especially use during the first 2 weeks of life) ▫ Reported cases of cardiac arrhythmias

Corvaglia L et al. Gastroenterology Research and Practice 2013

Metoclopramide (Reglan®) • Mechanism of action:

▫ Similar to domperidone

• A Cochrane review published in 2004 affirmed the effectiveness of metoclopramide in reducing both clinical symptoms and reflux indexes in infants with GERD, but limited by ▫ Conflicting results of the studies▫ Lack of a valid demonstration of the metoclopramide‘s efficacy

or toxicity

• Adverse drug reactions:▫ Irritability (most frequent), followed by dystonic reactions,

drowsiness, oculogyric crisis, emesis, and, eventually, apnea

Corvaglia L et al. Gastroenterology Research and Practice 2013

By now, you are probably here??

Take Home Message • Although GER is very common condition among preterm infants

with unclear treatment management,

▫ Therapy should be tailored based on clinical presentation and complications

▫ Nonpharmacological management should be considered as first line “happy spitters”

▫ To avoid any harmful overtreatment, pharmacological therapy should strictly be limited to selected infants suffering from GER complications or failure of conservative measures

▫ When choosing pharmacological options: Consider risk vs. benefit ratio based on current evidence

Pharmacist Role • Provide evidence based guidance for selection of

appropriate pharmacotherapeutic agents

• Identify inappropriate doses, drug-drug interactions, or dose adjustments (if necessary)

• Monitor adverse drug reactions

• Provide bedside teaching to other health care providers (when necessary)

• Provide discharge counselling to the parents and/or caregivers

Patient Case• SS, B.Boy twin II, preterm (32 weeks) delivered on 18th of April from an

unbooked mother as a case of emergency C/S

• Mother: 19 yo Saudi, female married to her 1st cousin, no known chronic illness, G1P2 + 0

• At birth: ▫ Apgar score: 6 in 1 min, 8 in 5 min▫ Vital: Temp: Afebrile | HR 120 bpm | BP: 45/25 mmHg | RR: 40 brths/min | O2 Sat:

92% RA▫ Physical exam: unremarkable, head circ: 29 cm, abd girth: 20.5 cm (non distended)▫ Case of very low birth weight (VLBW): 1.13 kg

• NKA

• After birth, developed mild respiratory distress

• Shifted to NICU with high flow nasal cannula (7 L/min)

NICU, Day 0• Reason for admission: prematurity, R/O of sepsis, mild RDS, VLBW

• Physical Exams:• Skin: normal • CNS: active baby• Chest: clear, on 1 L/min NC, FiO2: 21%• CVS: S1 + S2+ 0; not on any inotropes• Vitals: Temp: 36.5 | HR 125 bpm | BP: 52/25 mmHg | RR: 65 brths/min on | O2 Sat: 92%

RA• GI: soft + lax; NPO, TPN (10% dextrose) + Lipids (2.5 gm/kg)

• TFI: 70 mL/kg/day

• Medications: • Ampicillin 55 mg IV q12h; Gentamicin 5 mg IV q36h, Caffeine Citrate 22 mg IV load

followed by 6 mg IV daily, Hepatitis B immunoglobulin 100 IU IV once

• Assessment: Stable patient with no active issues

• Plan: Start feeding after placing OGT; US (head) next week

NICU, Day 1• CNS: active, moving all four limbs

• CVS: HD stable; BP: 60/29 mmHg; HR: 130’s

• Resp: On 0.5 L/min NC; on/off tachypnea; O2 sat: 98%

• GI: started feeding according to the protocol; UOP: 3.9 ml/kg/hr

• Lab:

• Medication: same

• Assessment: stable

• Plan: ▫ Keep O2 sat >92% with supplemental oxygen▫ CXR, CBC daily, CRP, blood culture, blood glucose q8h▫ Continue same management & increase TFI to 110 mL/kg/day

Na: 145

K: 4.8 Cl: 110 CO2: 19.2

BUN: 3.2 Cr: 82

WBC: 5

Hgb: 16.7

Hct: 46.7

Plt: 179 Glu: 3.1 Ca: 2.33

PO41.62

Alb: 31 ALP: 198

AST: 5 Tot. Bill: 84.3

NICU, Day 2• CNS: very active; Temp: afebrile

• CVS: HD stable; BP: 55/32 mmHg; HR: 130’s

• Resp: still on NC; RR: 65-32; O2 sat: 95%

• GI: feeding per protocol; UOP: 3.8 ml/kg/hr; Abd girth: ↑ 1.5 cm and no passage of stool

• Lab: unremarkable; ROP: negative; Blood culture: no growth

• Medication: same

• Assessment: stable, mild RDS

• Plan: ▫ D/C antibiotic; oxygen▫ Glycerin suppository once as needed ▫ Preparation for transfer to HDU

NICU, Day 3-5• CNS: no complaints; head circ: same

• CVS: stable; BP: 60’s/30’s mmHg; HR: 130’s

• Resp: At RA with occasional tachypnea; RR: 32-60 brth/min; O2 sat: >95%

• GI:▫ On full feed (5-10 mL q2-3h); TPN + lipid (same), Wt: 1.02 kg (↓ by 10

gm)▫ Abd girth: ↑ 1.0 cm; not passing stool▫ Vomited once (small amount)

• UOP: ~3 mL/kg/hr

• Medication: Caffeine Citrate 6 mg PO once daily

• Plan: ▫ TFI ↑sed to 140 mL/kg/day; kept on prone position; d/c TPN

NICU, Week 2 (24/04—29/04)• CNS: unremarkable CVS: stable; BP: 60’s-70’s/20’s-30’s mmHg; HR: 130-

190 bpm• Resp: on RA; RR: 32-45 brth/min; O2 sat: 100%

• GI:▫ Abd: soft + lax; passed stool; girth: same ▫ Feed ↑ to 13 mL q2-3h▫ Patient kept on elevated, right lateral prone position (26/04)▫ Frequent regurgitation and vomiting (milk); multiple times a day; feed

refusal ▫ Started feed thickening on 26/04

• Lab: Wt gain: static (1.116 kg)

• Medication: Caffeine Citrate 6 mg PO once daily; Ranitidine 0.56 mg IV q12h (27/04)

• Plan: ▫ Continue same management; head US to R/O IVH; shift to HDU

Na: 139 K: 5.8 Cl: 97

CO2: 19.9

BUN: 2.2

Cr: 58

Vomiting Frequency

26/4 27/4 28/4 29/4

2X 3X 2X --

Continuation of Care • HDU: Stable over the weekend; active; not crying

• CNS + CVS: unremarkable; BP: 50-60’s/20-30’s; HR: 130-140 bpm

• Resp: on RA; RR: 35-40; O2 sat: >98%

• GI: Wt: 1.190 kg (↑ 70 gm) ▫ Abd: soft + lax; passing stool▫ No reports of regurgitation or vomiting

• TFI: 150 mL/kg/day

• UOP: 6.4 mL/kg/hr

• Lab: unremarkable; US: negative for IVH

• Medication: Caffeine Citrate 6 mg PO once daily; Ranitidine 0.8 mg PO q12h

• Plan: ▫ Start Ranitidine 2 mg PO q8h X 2-3 days if no vomiting, weight gain, improvement of

feeding

Thank you

Self Assessment Questionnaire????