REVIEW

Y. Vandenplas · D. Belli · P. Benhamou · S. CadranelJ. P. Cezard · S. Cucchiara · C. Dupont · C. FaureF. Gottrand · E. Hassall · H. Heymans · C. M. F. KneepkensB. Sandhu

A critical appraisal of current management practicesfor infant regurgitation – recommendations of a working party

Received: 26 July 1996 / Accepted: 22 November 1996

Abstract Regurgitation is a common manifestation ininfants below the age of 1 year and a frequent reason ofcounselling of general practitioners and paediatricians.Current management starts with postural and dietarymeasures, followed by antacids and prokinetics. Recentissues such as an increased risk of sudden infant death inthe prone sleeping position and persistent occult gastro-oesophageal reflux in a subset of infants receiving milkthickeners or thickened ‘‘anti-regurgitation formula’’challenge the established approach. Therefore, the clin-ical practices for management of infant regurgitationhave been critically evaluated with respect to their effi-cacy, safety and practical implications.The updated recommendations reached by the workingparty on the management of infant regurgitation contain

five phases: (1A) parental reassurance; (1B) milk-thick-ening agents; (2) prokinetics; (3) positional therapy as anadjuvant therapy; (4A) H2-blockers; (4B) proton pumpinhibitors; (5) surgery.

Key words Regurgitation · Vomiting · Gastro-oesophageal reflux · Infant · Treatment

Abbreviations GOR(D) gastro-oesophageal reflux(disease) · LOS lower oesophageal sphincter · TLOSRtransient lower oesophageal sphincter relaxation · SIDSudden infant death · CNS central nervous system

Introduction

Regurgitation is the sudden effortless return of smallvolumes of gastric contents into the pharynx and mouth.It is a manifestation of gastro-oesophageal reflux (GOR)which per definition occurs whenever gastric content re-fluxes into the oesophagus. Regurgitation does not nec-essarily present with GOR disease (GORD), but it is afrequent cause of discomfort to the infant, a matter ofconcern to the parents and a common reason for con-sulting primary care physicians and paediatricians.Counselling of the parents about its frequently inoffensivenature is recommended and may solve the problem, al-though parents often request more effective control of thesymptoms and greater improvement of the discomfort.

In 1993, the European Society of Paediatric Gastro-enterology and Nutrition published guidelines for thetreatment of GORD in infants [132]. These recommen-dations were published prior to, or simultaneously with‘anti-prone-sleeping position’ campaigns conducted andsupported by governments and medical societies.Moreover, some of the recommendations of 1993 can bechallenged upon critical analysis of the efficacy data,such as the effect of milk thickeners on pH-metric orscintigraphic parameters [4, 92, 99, 127, 128, 133].

This paper reviews the recommended therapeuticapproaches to regurgitation in infants, with special at-

Eur J Pediatr (1997) 156: 343 – 357 Springer-Verlag 1997

Y. Vandenplas (&)Academisch Ziekenhuis Kinderen, Vrije Universiteit Brussel,Laarbeeklaan 101, B-1090 Brussels, Belgium

D. BelliH _opital Cantonal, Geneve, Switzerland

P-H. Benhamou · C. DupontH _opital Saint Vincent de Paul, Paris, France

S. CadranelH _opital Universitaire d’ Enfants Reine Fabiola, Brussels, Belgium

J. P. Cezard · C. FaureH _opital Robert Debre, Paris, France

S. CucchiaraNaples, Italy

F. GottrandH _opital C. Huriez, CHU Lille, France

E. HassallChildren’s Hospital, University of British Columbia, Vancouver,Canada

H. S. A. HeymansAcademisch Medisch Centrum, Amsterdem, The Netherlands

C. M. F. KneepkensVrije Universiteit, Amsterdem, The Netherlands

B. K. Sandhu,Institute of Child Health, Bristol, Great Britain

tention to practical implications, benefits and risk.Complicated GORD is only indirectly covered, beingimplicated in persistent regurgitation, refractory to ini-tial treatment. Guidelines for management of regurgi-tation in infants below 1 year of age are updatedaccording to the recent consensus of the working party.

Symptoms, epidemiology and diagnosis

Symptoms

Regurgitation is the almost spontaneous return of gas-tric contents into the pharynx and the mouth [125]. Itcan be best differentiated from emesis by the absence ofpreceding nausea, retching, or autonomic symptoms,and lack of abdominal and thoracic muscle contraction.Vomiting is synonymous with emesis; the refluxed ma-terial is emitted from the mouth with force. However, itsometimes may be difficult to distinguish regurgitationfrom vomiting and both symptoms may occur in thesame patient.

More subtle symptoms associated with GORD ininfants include excessive crying and irritability (possiblyrelated to oesophageal pain), which are sometimes er-roneously attributed to ‘colic’ or ‘gas’. A close correla-tion between this behaviour and GOR has beenconfirmed by pH monitoring and split-screen video [48].In addition to regurgitation, drooling and burping, alsoepisodes of discomfort with crying or frowning, yawn-ing, stridor, stretching and mouthing, are found closelyand temporarily associated with reflux events. Respira-tory symptoms, such as recurrent cough, wheezing,stridor and apnoea may occur with and without regur-gitation or vomiting, and are more frequently present inthe preterm or older child.

Some children present with symptoms of more severeGORD, such as oesophagitis, failure to thrive or weightloss – the latter symptoms being consequences of insuf-ficient food intake due to oesophageal pain and/or ex-cessive loss of calories due to the vomited volume [125].

Fitting the above symptoms into the broad spectrumof GORD, three types can be distinguished (Fig. 1)[132]: (1) infants with regurgitation; (2) infants withGORD: with persistent regurgitation, vomiting, failureto thrive and/or oesophagitis (eventually haematemesis);sometimes with persistent crying (pain), sleeping prob-lems or concomitant extra-intestinal symptoms; (3)children with chronic respiratory symptoms, apnoeicspells or apparent life-threatening events, but withoutregurgitation and vomiting.

Epidemiology and prognosis

The prevalence of regurgitation varies between 18%(general infant population) [10] and 40% (of childrenconsulting a physician’s practice) [24]. The latter prev-alence corresponds to the finding that, although withregional differences, 40%–50% of the milk formulae soldin Belgium are thickened ‘‘anti-regurgitation’’ formulae(Institute National Statistics, Belgium). However, theprevalence of excessive GOR according to pH-metriccriteria, is lower (8%) [106].

Little has been published about the natural history ofregurgitation and GORD in infants and its impact onmorbidity or mortality if untreated. Generally, regurgi-tation is considered a ‘benign’ condition, spontaneouslyresolving 12–18 months after birth. However, limitedstudies have shown better prognosis if treatment startsearly with positional measures, thickening of feeds and/or prokinetics [16–18, 24, 66, 111]. The data indicate thatearly recognition and attention to the problem aremandatory.

Diagnosis

The approach to diagnosis of uncomplicated GORD inregurgitating infants has been well described els-where [132]. Stepwise empirical treatment is recom-

Fig. 1 The approach to di-agnosis of GORD in infantsaccording to the ESPGANrecommendations of 1993[1].

344

mended and a therapeutic trial of a prokinetic is rec-ommended prior to invasive investigation (Fig. 1).Symptoms which should prompt the primary care phy-sician to refer immediately include overt emesis (possiblysecondary to another problem), suspected oesophagitis,haematemesis, failure to thrive, or persistent extra-in-testinal symptoms (crying, coughing, wheezing, sleepingproblems). pH monitoring is the investigation of choiceto diagnose GOR in non-regurgitating or non-vomitingchildren, while endoscopy is recommended for oesop-hagitis.

Pathophysiology

Little is known about the mechanisms of regurgitation.Current knowledge mainly relates to the pathophysiol-ogy of GORD [51, 58]. Factors relevant to GORD ininfants include: the length of the lower oesophagealsphincter (LOS), an immature LOS, transient LOS re-laxations, (TLOSRs) decreased gravitational and peri-staltic clearance of the refluxed material from the distaloesophagus and delayed gastric emptying.

Although it can be argued that standard values onLOS length and function are lacking in infants below 1year, there are indications that children with GOR mayhave a shorter LOS than those without GOR [86] (theintra-abdominal segment of the oesophagus almost be-ing absent during early life) and that LOS pressure andoesophageal clearing peristalsis may be reduced or dis-ordered [9, 29, 57]. Gastric emptying may or may not bedelayed [19, 44]. Inappropriate TLOSRs, independent ofswallowing, have been identified as a major pathologicalmechanism in infants with increased GOR or oesop-hagitis [31, 138]. Increased abdominal or intragastricpressure [31] associated with delayed gastric empty-ing [26] or gastric distension [59] or attenuated swallowsfailing to induce peristalsis [84] may be involved incausing the inappropriate relaxations. But also duringappropriate relaxations, reflux can be observed [31].

Clearance of the refluxed material from the oesoph-agus by gravitational and peristaltic forces is an im-portant mechanism limiting GOR in infants. Forinstance, the effect of the prone 30° anti-Trendelenburgposition reducing GOR [83, 90, 91, 126], is probablypartly related to the effect of gravity. Reduced swal-lowing rates during sleep [114] and dysfunction of oe-sophageal peristalsis [9, 29, 57] have been found ininfants with GORD. Increased intragastric pressure mayplay a role because infant GOR is worse in seated thanin prone position [91, 99].

Gradual functional maturation of the LOS [8, 9] mayexplain the benign course of infant GOR. It is also in-teresting that the oesophageal motor defects seen in in-fants with oesophagitis (not secondary to other disease)resolve following healing of the oesophagitis [29].However, relapse is almost the rule in children withGORD after repaired oesophageal atresia or GORD-associated with connective tissue disorders and neuro-

logical disease [37]. In these children, oesophageal motorabnormalities persist after healing of the oesophagi-tis [36] and resemble that in adults [46, 60, 112, 113, 115,120].

Treatment by parental reassurance

Parental reassurance is essential. Careful questioning(and observation) of how the mother prepares the for-mula, feeds and handles the baby after feeding, may helpin solving the complaints. Reassuring the parents thatnothing is wrong with their baby may preclude the needfor any further measures.

The impact of the infant’s reflux symptoms on theparents’ anxiety is difficult to qualify or quantify. Iden-tical manifestations of GOR elicit different reactions, thedegree of anxiety being influenced by former experi-ences. Therefore, it is important for the physician tolisten to the parents and to explain the physiologicalnature of regurgitation and its spontaneous resolution inthe majority of infants.

From the above results the following recommenda-tion: whatever the subsequent management, parentalreassurance remains important: a good therapeutic set-ting may act as a ‘positive placebo’ (Treatment Phase1A).

Dietary advice

Small, frequent feedings. This dietary measure is basedon the observation that pH-metric GOR decreases whenthe feeding volume (of a single 5% dextrose feeding) isdecreased [129]. However, to maintain sufficient caloricintake, feeding smaller volumes demands more frequentfeeding, with more postprandial periods. In practice, themeasure is difficult to apply, as frequent feedings maycompromise work and daily activities of the parents; thereduced feeding volumes may also cause distress to thebaby, when hungry and not wanting to stop drinking.

Low-fat, high-carbohydrate formula. These formulaeare based on the idea that long-chain fatty acids delaygastric emptying and their reduction may result in lessreflux due to improved gastric emptying. Controlledstudies [117, 122, 129] do not support their efficacy inimproving pH-metric GOR variables (Table 1). Suchformulae should in any case fulfil the nutritional needsof the infant.

Milk-thickening agents, include bean gum prepara-tions prepared from St John’s bread, a galactomannan(Nutriton, Carobel, Nestargel, Gumilk; Nestargel alsocontains 3.5% calcium lactate); sodium carboxymethyl-cellulose (Gelilact) and a combination of pectin andcellulose (Gelopectose); cereal and rice products.

Milk thickeners have been reported to reduce regur-gitation in infants [4, 92, 99, 127, 128, 133] and to im-prove sleep (possibly due to an improved satiety relatedto the higher caloric intake in the case of rice-thickened

345

Tab

le1

Effe

ctof

spec

ialf

orm

ula

and

milk

-thi

cken

ing

prod

ucts

onG

OR

,gas

tric

empt

ying

(GE

)an

dcl

inic

alpa

ram

eter

sin

infa

nts

wit

hG

OR

dise

ase

(‘=

’:un

chan

ged,

‘<’:

wor

se,‘

>’:

bett

er)

(Oop

en,

SB

sing

lebl

ind,

XO

cros

sove

r,N

Dno

data

,N

Sno

tsi

gnifi

cant

)

Ref

eren

ceN

oA

gea

Des

ignb

Fee

dth

icke

ner/

spec

ial

form

ulab

GO

Ran

dG

Epa

ram

eter

sC

linic

alas

sess

men

tsc

Com

men

ts

Spec

ial

form

ula

[117

]19

3.7

mon

ths

(0.7

–13.

2m

onth

s)O

,XO

Dex

tros

ein

wat

er5%

–10%

Stan

dard

ente

ral

gluc

ose

poly

mer

solu

tion

2h

pHm

onit

orin

g(p

ostp

rand

ially

):•

10%

dext

rose

<5%

dext

rose

=st

anda

rdso

luti

on

ND

Infa

nts

plac

edin

hori

zont

alpr

one

posi

tion

[122

]28

<1

year

O,X

OC

asei

n-fo

rmul

a(C

PF

)So

y(S

F)

Whe

y-hy

drol

ysat

e(W

HF

)

Scin

tigr

aphy

(1h

post

pran

dial

ly):

•G

OR

:C

PF

=SF

=W

HF

•G

E:

CP

F=

SF,

CP

F>

WH

F

ND

[129

]11

Pre

term

infa

nts

DB

,XO

Hig

hfa

t/lo

wca

rboh

ydra

tefo

rmul

a(

=H

F/L

C)

Low

fat/

high

carb

ohyd

rate

form

ula

=(L

F/H

C)

24h

pHm

onit

orin

g:•

LF

/HC

<H

F/L

C(p

ostp

rand

ial)

ND (a

sym

ptom

atic

GO

R)

Fee

dth

icke

ners

[4]

523.

6m

onth

s(4

days

–14

mon

ths)

O,X

OR

ice

cere

al(a

dded

toap

ple

juic

e)2

hpH

mon

itio

ring

(pos

tpra

ndia

lly):

•F

T=

noF

Tin

pron

e,su

pine

and

unre

stri

cted

posi

tion

•F

T<

noF

Tin

30°

pron

epo

siti

on

ND

Seve

ral

posi

tion

sin

vest

igat

ed

[92]

20(4

–34

wee

ks)

O,X

OR

ice

cere

al(a

dded

tous

ual

form

ula)

Scin

tigr

aphy

(1.5

hpo

stpr

andi

ally

):•

GO

R:

FT

=no

FT

•G

E(3

0m

in):

FT

>no

FT

•R

egur

gita

tion

:F

T>

noF

T•

Tim

esp

ent

cryi

ng:

FT

>no

FT

•T

ime

spen

taw

ake:

FT

>no

FT

Pos

itio

nno

tm

enti

oned

[93]

257.

5w

eeks

(2–2

6w

eeks

)SB

,XO

Ric

ece

real

(add

edto

usua

lfo

rmul

a)N

D•

Cou

ghin

g(a

fter

feed

ing)

:F

T<

noF

T

Pos

itio

nno

tm

enti

oned

[99]

34(1

wee

ks–1

2mon

ths)

O,X

OR

ice

cere

al(a

dded

toin

fant

form

ula)

2h

pHm

onit

orin

g(b

efor

ean

daf

ter

FT

):•

FT

>no

FT

(n=

21)

and

FT

<no

FT

(n=

10)

ND

Pos

itio

nno

tcl

earl

ym

enti

oned

(pos

sibl

ych

ange

din

aco

ntro

lled

fash

ion)

[127

,12

8]30

(6–8

wee

ks)

(4–1

2w

eeks

)O

,XO

Car

obbe

angu

m1

g/11

5m

l24

hpH

mon

itor

ing:

•F

T=

noF

Tor

FT

<no

FT

•no

rmal

izat

ion:

n=

6(2

0%)

•R

egur

gita

tion

:F

T>

B(n

=25

;83

%)In

fant

ske

ptin

30°

pron

epo

siti

on

[133

]40

(1–4

8w

eeks

)O

,PA

Com

mer

cial

form

ula

+be

angu

mvs

)be

angu

m

24h

pHm

onit

orin

g:•

FT

=no

FT

•(F

T>

Bfo

rre

flux

inde

x)

Reg

urgi

tati

on:

FT

>no

FT

(N.S

.)P

aren

talr

eass

uran

ce,i

nfan

tske

ptin

30°

pron

epo

siti

onin

both

grou

ps

a Mea

nsof

age

ingr

oups

(ran

gebe

twee

nbr

acke

ts),

bT

hick

ened

mea

l(F

T)

vers

usun

thic

kene

dm

eal

(noF

T)

orve

rsus

base

line

(B)

orco

mpa

riso

nof

spec

ial

form

ula

346

formula) [92]. However, their effects on the oesophagealacid exposure are inconsistent, as shown by pH moni-toring [4, 99, 127, 128, 133] and scintigraphy [92] (Table1). The number of reflux episodes may increase or de-crease [99], the oesophageal acid exposure increase de-pending on the baby’s position [4]. The duration of thelong-lasting reflux episodes has been reported to signif-icantly increase [127, 128] or remain unchanged [133].These findings are in line with the recent observations ininfants that increased food volume and osmolality in-crease the rate of TLORs and drifts in LOS pressure toalmost undetectable levels [35]. Increased coughing hasalso been demonstrated in infants receiving milk thick-eners [93].

Milk thickeners are usually well tolerated, althoughabdominal pain, colic and diarrhoea may ensue fromfermentation of bean gum derivatives in the colon. Se-rious complications are rare and limited to anecdotalcases of acute intestinal obstruction in newborns [85].The use of Gelopectose is not advised in infants withcystic fibrosis and Hirschsprung disease.

Although often wrongly considered ‘inexpensive’,they are not. In practice, milk thickeners or ‘‘anti-re-gurgitation formula’’ cannot be given to breast-fed in-fants. Nevertheless, in view of their safety and efficacy indecreasing regurgitation, milk thickeners remain avaluable first-line measure in relieving regurgitation inmany infants. In contrast, their efficacy as single therapyis questionable in complicated GORD, since their im-pact on GOR parameters is unpredictable.

From the above follows another recommendation:small, frequent feedings with low-fat high carbohydrateformulae are not recommended because of their benefithas not been proven and they are difficult ro realise. It isrecommended to thicken the formula since it decreasesthe amount and severity of regurgitation, although itdoes not have a beneficial effect on GOR (TreatmentPhase 1B).

Prokinetic agents

Prokinetic agents, i.e. metoclopramide, domperidone,and cisapride, act on regurgitation via their effects onLOS pressure, oesophageal peristalsis or clearance and/or gastric emptying [135]. Metoclopramide and dom-peridone also have anti-emetic properties due to theirdopamine receptor blocking action, while cisapride is aprokinetic, mainly acting via indirect release of ace-tylcholine from the myenteric plexus [135].

Metoclopramide

Data supporting the efficacy of this prokinetic(Primperan, Reglan) in relieving infant regurgitation arecontradictory and positive results are limited to someobservations with i.v. doses (Table 2) [2, 14, 42, 49, 61,62, 76, 79, 97, 121]. Application in infants is limited

because of severe adverse events, including Centralnervous system (CNS) effects and interactions with theendocrine system. The adverse effects regarding the CNSare mainly related to its dopamine receptor blockingproperties in the substantia nigra, and include extrapy-ramidal effects (dystonic reactions, irritability) anddrowsiness. Isolated cases of metoclopramide-inducedmethaemoglobinaemia have been reported [71, 140].

Domperidone

The studies supporting efficacy of domperidone (Motil-ium, Nauzelin) in improving regurgitation and GOR ininfants are limited (Table 3) [5, 20, 25, 42, 45, 53, 63,127]. Most studies have been performed in older child-ren, or investigate the effects of domperidone co-ad-ministered with other anti-reflux agents [20, 63, 127].Although pH-metric results [5, 20, 45, 53] appearsomewhat better than those with oral metoclopramide[49, 76], domperidone controls GOR more consistentlywhen used in combination with antacids or Gaviscon.Domperidone is better tolerated than metoclopr-amide [22] since dystonic reactions (tremors) and anxietyare infrequent. Plasma prolactine levels may increase [43]due to pituitary gland stimulation.

Cisapride

Cisapride (Prepulsid, Propulsin, Alimix, Acenalin) (Ta-ble 4), a benzamide derivative, is a non-dopamine-re-ceptor blocking, non-cholinergic prokinetic drug with5HT4-antagonistic properties [102]. It promotes gastro-intestinal motility by facilitating the release of ace-tylcholine from the myenteric (Auerbach) plexus, with-out interfering with dopamine receptors [135]. Thisagent has been shown to improve regurgitation [15, 21,30, 33, 64, 131, 134], gastric emptying [19] and pH-metric GOR variables [12, 15, 21, 30, 33, 38, 39, 47, 64,80, 103–105, 107, 108, 130, 131] in infants. Studies usinga control group or placebo are limited [19, 21, 30, 33,108, 131, 134] (Table 4). Improvement of pH-metricGOR parameters has been demonstrated during differ-ent periods of the day (total period, night, awake, asleep,postcibal, fasted) [33, 38, 39, 107, 108, 130, 131, 134] andin different positions (sitting up/erect, prone, supine) [38,39, 103–105]. Cisapride increases the LOS pressure [33],although this effect was not seen in infants with oesop-hagitis having a normal LOS pressure [30]. It also in-creases amplitude and duration of oesophagealcontractions [30, 33] and improves gastric emptying [19].When compared to conservative measures alone (30°prone and milk thickening), its addition normalises thepH-metric parameters in more infants [33] and reducesthe long-lasting reflux episodes [33, 103–105, 131].However, cisapride might be less effective in neurologi-cally impaired children [12].

347

Tab

le2

Effe

cts

ofm

etoc

lopr

amid

e(M

CL

)on

GO

RD

inin

fant

s.

Ref

eren

ceN

oA

ge(r

ange

)D

esig

nT

reat

men

tD

MG

OR

and

GE

para

met

ers

Clin

ical

asse

ssm

ents

bC

omm

ents

[2]

20N

DD

B,

PA

MC

L0.

1m

g/kg

,bm

PL

A(b

m)

(6w

eeks

)

ND

ND

•Vom

itin

g:M

CL

=P

LA

[14]

136.

8m

onth

s(1

–24

mon

ths)

OM

CL

0.1

mg/

kg,

bm(i

v,1

day)

ND

Man

omet

ry(L

OSp

ress

ure)

,24

hpH

mon

itor

ing:

MC

L>

B

ND

IVad

min

istr

atio

n

[42]

476–

9m

onth

s3

wee

ks–8

year

s)D

B,P

AD

O0.

3m

g/kg

tid

MC

L0.

3m

g/kg

tid

PL

Ati

d(2

wee

ks)

FT

ND

•N

ause

a:D

O>

MC

L=

PL

•V

omit

ing:

DO

>M

CL

>P

LA

(wee

k2)

•G

loba

lre

spon

se:

DO

=M

CL

>P

L[4

9]10

65–7

1mon

ths

(4m

onth

s–17

year

s)

OM

CL

0.5

mg/

kg/d

ay(3

dose

s)G

AV

10–2

0m

lqi

dP

Lti

d(1

day)

SD24

hpH

mon

itor

ing:

MC

L=

GA

V=

PL

=B

ND

Old

erch

ildre

n

[61]

423.

2m

onth

s(0

.5–1

3mon

ths)

OM

CL

0.1–

0.2–

0.3

mg/

kgti

div

,1

day

5% dex

CF

24h

pHm

onit

orin

g:•

fed

5%de

x:M

CL

(0.3

)>

MC

L(0

.1–0

.2)

=B

•fe

dC

F:

MC

L=

B

ND

IVad

min

istr

atio

nSu

pine

inin

fant

seat

(30°

)A

cute

dyst

onic

reac

tion

(n=

1)

[62]

96

mon

ths

(4–1

2m

onth

s)O

MC

L1

mg/

kgiv

,1d

ay5% gl

uD

iluti

onte

chni

que

(GE

):M

CL

>B

ND

IVad

min

istr

atio

nIn

fant

sfa

iling

toim

prov

ew

ith

post

ural

(30°

pron

e)or

diet

ary

chan

ges.

[75]

325

mon

ths

(0.6

mon

ths–

3yea

rs)

OM

CL

5m

g/kg

/day

(4do

ses)

CO

(n=

9)(4

wee

ks)

SFN

DR

egur

gita

tion

:M

CL

>C

OSo

lidfo

odst

arte

dw

ith

trea

tmen

t;30

°pr

one

reco

mm

ende

dSi

deeff

ects

(n=

5;dr

owsi

ness

,ir

rita

bilit

y,oc

ulog

yric

cris

is)

[76]

28 (8)

9m

onth

sO (D

B,

PA

)M

CL

0.12

5m

g/kg

qid

(iv,

man

omet

ryan

dpH

mon

itor

ing)

(po,

6m

onth

sin

DB

tria

l)

FT

•M

anom

etry

(LO

SP):

MC

L>

B•

24h

pHm

onit

orin

g:M

CL

=B

Reg

urgi

tati

on(n

=8)

:M

CL

=P

LA

IVad

min

istr

atio

n(G

OR

,G

E)

Infa

nts

kept

45°

pron

edu

r-in

g slee

pE

xace

rbat

ion

ofsy

mpt

oms

and

mar

ked

irri

tabi

lity

wit

hM

CL

(n=

3)[9

7]24

(1–1

8mon

ths)

DB

,P

AM

CL

0.1–

0.2–

0.4

mg/

kgbm

PL

Abm

(iv,

sing

ledo

se)

CF

5h

pHm

onit

orin

g(1

hraf

ter

feed

ing)

:M

CL

=P

LA

ND

Sing

le,

ivad

min

istr

atio

nSu

pine

posi

tion

[121

]30

<1y

ear

(1–9

mon

ths)

DB

,P

AM

CL

0.1

mg/

kgqi

dP

LA

qid

(1w

eek)

CF

a•

Scin

tigr

aphy

(sup

ine,

1-h

afte

rm

eal)

:M

CL

=P

LA

•18–

24h

pHm

onit

orin

g:M

CL

>or

=P

LA

Reg

urgi

tati

on:

MC

L=

PL

AW

eigh

tga

in:

MC

L=

PL

A

Fee

dth

icke

ning

and

post

ural

trea

tmen

tke

ptco

nsta

ntG

OR

vari

able

sre

mai

ned

abno

rmal

inin

fant

s

aP

rior

ther

apeu

tic

mea

sure

sco

ntin

ued

(pos

itio

nal

and

/or

diet

ory)

bO

utco

me:

‘>’

=be

tter

than

,=

wor

seth

an,

‘=

’=

unch

ange

d,re

ferr

ing

toth

em

ain/

all

para

met

ers

eval

uate

din

pape

r;ex

cept

ions

for

sing

lepa

ram

eter

sar

em

enti

oned

sepa

rate

ly.

Sym

ptom

s:if

not

spec

ified

,cl

inic

alas

sess

men

tin

clud

ing

regu

rgit

atio

nan

d/or

vom

itin

g.(O

open

,DB

doub

lebl

ind,

PA

para

llel,

XO

cros

s-ov

erw

illw

ash

outp

erio

dC

ISci

sapr

ide,

PL

Apl

aceb

o,M

CL

met

oclo

pram

ide,

DO

dom

peri

done

,CIM

cim

etid

ine,

GA

VG

avis

con,

AA

anta

cid,

FT

feed

thic

kene

r,B

base

line

CO

cont

rols

;bm

befo

rem

eals

/eac

hfe

edin

g;af

maf

ter

mea

ls.D

Mdi

etar

ym

easu

res,

SD

stan

dard

diet

,dex

dext

rose

,glu

gluc

ose,

CF

cust

omar

yfo

rmul

a,S

Fso

lidfo

odst

arte

dif

not

yet

done

so,

PN

pare

nter

alnu

trit

ion)

348

Tab

le3

Effe

cts

ofdo

mpe

rido

ne(D

O)

onG

OR

Din

infa

nts

(for

abbr

evia

tion

s:se

eT

able

2).

Ref

eren

ceN

oA

geD

esig

nT

reat

men

tD

MG

OR

and

GE

para

met

ers

Clin

ical

asse

ssm

ents

Com

men

ts

[5]

172–

3.6

year

s(5

mon

ths–

11.5

year

s)

DB

,P

AD

O0.

6m

g/kg

qid

PL

Aqi

d(4

wee

ks)

CF

•8–

12h

pHm

onit

orin

g:D

O>

or=

PL

•Sc

inti

grap

hy(G

E):

DO

=P

L

Sym

ptom

s:D

O=

PL

Old

erch

ildre

nno

n-re

spon

sive

tono

n-ph

arm

acol

ogic

alth

er-

apy

[25]

324–

6ye

ars

(2m

onth

s–10

year

s)

DB

,P

AD

O0.

3–0.

6m

g/kg

tid

PL

Ati

d(2

–4w

eeks

)F

TN

DV

omit

ing:

DO

>P

LA

(wee

k4)

Reg

urgi

tati

on:

DO

>P

LG

loba

lre

spon

se:

DO

>P

L

Old

erch

ildre

n

[20]

804.

6m

onth

s(1

–18

mon

ths)

O,

PA

DO

0.3

mg/

kgbm

+P

LA

afm

DO

bm+

AA

1+

2h

afm

DO

bm+

GA

Vaf

mP

LA

bm+

afm

(8w

eeks

)

FT

24h

pHm

onit

orin

g:•

DO

+A

A>

DO

+G

AV

=D

O=

PL

A•

exce

ptlo

nges

tep

isod

e:D

O+

AA

=D

O+

GA

V=

DO

>P

LA

His

tolo

gica

loe

soph

agit

is:

DO

+A

A>

DO

+G

AV

=D

O=

PL

A

No

eros

ive

oeso

phag

itis

[42]

476–

9m

onth

s(3

wee

ks–8

year

s)D

B,

PA

DO

0.3

mg/

kgti

dM

CL

0.3

mg/

kgti

dP

LA

tid

(2w

eeks

)

FT

ND

Nau

sea:

DO

>M

CL

=P

LV

omit

ing:

DO

>M

CL

>P

LA

Glo

bal

resp

onse

:D

O=

MC

L>

PL

[45]

184.

9ye

ars

(1m

onth

s–12

year

s)O

DO

2m

g/kg

/day

(3m

onth

s)n.

d.24

hpH

mon

itor

ing:

DO

=B

•ex

cept

%ti

me

atni

ght:

DO

>B

Res

pira

tory

sym

ptom

s:D

O>

BM

ostl

yol

der

child

ren

wit

hG

OR

-ass

ocia

ted

resp

irat

ory

dise

ase

[53]

157.

9m

onth

s(3

–13m

onth

s)O

DO

0.3–

0.6

mg/

kgti

d(i

m,

sing

le,

man

omet

ry)

(po,

6w

eeks

)

FT

•M

anom

etry

(LO

SP,

ampl

itud

eco

ntra

ctio

ns):

DO

=B

•3

hpH

mon

itor

ing:

DO

=or

>B

•Sc

inti

grap

hy(G

E):

DO

=B

Spit

ting

,vo

mit

ing,

coug

hing

):D

O>

BW

eigh

tga

in:

DO

=B

‘Vom

itin

g’or

GO

R-a

sso-

ciat

edpr

oble

ms

[63]

2815

mon

ths

(1m

onth

s–10

year

s)O

DO

0.3

mg/

kgti

d+A

Aaf

mD

O0.

3m

g/kg

tid+

GA

Vaf

m

FT

24h

pHm

onit

orin

g:•

DO

+A

A>

B•

DO

+G

AV

2 B

Reg

urgi

tati

on:

DO

+A

A=

DO

+G

AV

Ove

rall:

DO

+A

A>

DO

+G

A

[127

]24

(4–1

2wee

ks)

OD

O0.

8–1

mg/

kg/d

aybm

+G

AV

3–5

ml

afm

(10–

14da

ys)

FT

24h

pHm

onit

orin

g:•

DO

+G

AV

>B

•no

rmal

izat

ion:

n=

17

Reg

urgi

tati

on:

DO

+G

AV

>B

349

Tab

le4

Effe

cts

ofci

sapr

ide

(CIS

)on

GO

RD

inin

fant

s(f

orle

gend

and

abbr

evia

tion

s:se

eT

able

2)

Ref

eren

ceN

oA

geD

esig

nT

reat

men

tD

MG

OR

and

GE

para

met

ers

Clin

ical

asse

ssm

ents

Com

men

ts

[12]

7†N

DO

CIS

0.2

mg/

kgti

d(3

wee

ks)

ND

24h

pHm

onit

orin

g:C

IS=

B•

exce

ptfo

rN

oof

epis

odes

:C

IS>

B

ND

†N

euro

logi

cally

im-

pair

edch

ildre

n(6

cere

-br

alpa

lsy,

1D

own

synd

rom

e)15

ND

OC

IS0.

2m

g/kg

tid

(3w

eeks

)N

D24

hpH

mon

itor

ing:

CIS

>B

ND

[15]

34(4

mon

ths–

2yea

rs)

OC

IS0.

2m

g/kg

tid

(3m

onth

s)N

D24

hpH

mon

itor

ing:

CIS

>B

Sym

ptom

s:C

IS>

BE

ndso

copy

/his

tolo

gy:

CIS

>B

[19]

208m

onth

s(3

–13m

onth

s)O

CIS

0.33

mg/

kgti

d(8

wee

ks)

•24

hpH

mon

itor

ing:

CIS

>B

•U

ltra

soun

d(G

E):

CIS

>B

ND

Com

pare

dto

CO

-gr

oup

wit

hout

GO

R:

B<

CO

;C

IS=

CO

[21]

30(3

mon

ths–

5yea

rs)

DB

,P

AC

IS0.

2m

g/kg

bmP

LA

(2–4

wee

ks)

ND

24h

pHm

onit

orin

g:C

IS>

PL

ASy

mpt

oms:

CIS

>P

LA

Res

pira

tory

sym

ptom

s:C

IS>

PL

A[3

0]17

24.5

mon

ths

(2.5

–47m

onth

s)D

B,

PA

CIS

0.33

mg/

kgti

dP

LA

(12

wee

ks)

ND

•M

anom

etry

(LO

SP):

CIS

=P

LA

=B

;(p

eris

tals

is):

CIS

>B

•5-

hpH

mon

itor

ing

(pos

tpra

ndia

llyaf

ter

appl

eju

ice)

:C

IS>

B;

PL

A=

B

Sym

ptom

s:C

IS>

PL

AH

isto

logy

:C

IS>

B;

PL

A=

BE

ndos

copy

:C

IS>

PL

A

Infa

nts

wit

hpe

ptic

oe-

soph

agit

is(n

orm

alba

-sa

lL

ES

pres

sure

)

[33]

1415

.7(2

–38m

onth

s)D

B,

PA

CIS

0.15

mg/

kgP

LA

(iv,

sing

le)

FT

•M

anom

etry

(LO

SP,

peri

stal

sis)

:C

IS>

PL

AN

DSi

ngle

,iv

adm

inis

tra-

tion

24O

,P

AC

IS0.

2m

g/kg

tid

CO (4

–6w

eeks

)

FT

24hr

Hm

onit

orin

g:C

IS>

CO

•no

rmal

izat

ion:

CIS

>C

OSy

mpt

oms:

CIS

>C

OB

oth

grou

psre

ceiv

ing

post

ural

and

diet

ary

trea

tmen

t[3

8]9

83da

ys(6

–150

days

)O

CIS

0.2

mg/

kgqi

d(3

mon

ths)

ND

24h

pHm

onit

orin

g:C

IS>

B(b

oth

upri

ght

and

seat

ed):

ND

Infa

nts

wit

hG

OR

and

apne

a[3

9]42

2.6

year

s(1

2da

ys–1

2yea

rs)

OC

IS0.

2m

g/kg

tid

(3m

onth

s)N

D24

hpH

mon

itor

ing:

CIS

>B

(bot

hup

righ

tan

dse

ated

):R

espi

rato

rysy

mpt

oms:

CIS

>B

Infa

nts

wit

hG

OR

-re-

late

dch

roni

cre

-sp

irat

ory

sym

ptom

s[4

7]22

7m

onth

s(2

–44

mon

ths)

DB

,P

AC

IS0.

2m

g/kg

,qid

+G

AV

CIM

5m

g/kg

qid

+G

AV

(6w

eeks

)

ND

24h

pHm

onit

orin

g:C

IS=

CIM

Wid

eva

riat

ion

inG

OR

-var

iabl

es;

62%

impr

oved

wit

hC

ISve

rsus

50%

wit

hC

IM[5

2]50

(2–1

8mon

ths)

O,

PA

CIS

0.2

mg/

kgqi

d()

FT

)G

AV

(1/2

sach

et/9

0m

lfe

ed)

+C

arob

el(=

FT

)(4

wee

ks)

+/)

FT

24h

pHm

onit

orin

g:C

IS()

FT

)=

GA

V+

FT

Sym

ptom

s:C

IS)

FT

=G

AV

+F

TD

esig

nm

isle

adin

g:C

ISw

itho

utF

T,

GA

Vw

ith

FT

[84]

2516

.2m

onth

s(1

mon

ths–

7yea

rs)

OC

IS0.

33m

g/kg

tid

(8w

eeks

)N

D24

hpH

mon

itor

ing:

CIS

>B

Sym

ptom

s:C

IS>

B

350

[80]

3826

mon

ths

(2w

eeks

–7ye

ars)

OC

IS0.

3m

g/kg

bm(6

mon

ths)

ND

Scin

tigr

aphy

:C

IS>

B•

24h

pHm

onit

orin

g:C

IS>

BR

espi

rato

rysy

mpt

oms:

CIS

>B

Infa

nts

wit

hG

OR

-re-

late

dre

spir

ator

ydi

seas

e[8

7]35

(1–3

6m

onth

s)D

B,

PA

CIS

0.2

mg/

kgbm

MC

L0.

2m

g/kg

bm(1

0w

eeks

)

ND

ND

Sym

ptom

s:C

IS>

MC

LO

vera

llre

spon

se:

CIS

>M

CL

(NS)

Adv

erse

even

ts:

n=

4w

ith

CIS

and

n=

9w

ith

MC

L(d

iarr

hoea

,ir

rita

bilit

y)[1

03]

406.

5m

onth

sO

CIS

1m

g/kg

/day

(in

3do

ses)

(1da

y)SD

28-h

pHm

onit

orin

g:C

IS>

B(e

rect

,su

pine

and

pron

e)N

DA

cute

stud

y

[104

]18

6.5

mon

ths

O,

XO

CIS

0.33

mg/

kgti

dM

CL

0.2

mg/

kgti

d(1

day)

SD28

-hpH

mon

itor

ing:

CIS

>M

CL

•lo

ng-l

asti

ngG

OR

,cl

eara

nce:

CIS

>M

CL

•%

tim

e,N

o.ep

isod

es:

CIS

=M

CL

>B

ND

Acu

test

udy

CIS

>M

CL

inal

lpo

siti

ons

(ere

ct,

supi

nean

dpr

one)

[105

]30

10m

onth

sO

CIS

1m

g/kg

/day

(in

3do

ses)

(3w

eeks

)

ND

28-h

pHm

onit

orin

g:C

IS>

B(e

rect

,su

pine

,pr

one)

Sym

ptom

s:C

IS>

B

[107

]14

29m

onth

s(4

mon

ths–

11ye

ars)

DB

.P

AC

IS0.

3+0.

15m

g/kg

/4hr

sP

LA

(1da

y)N

D16

-hpH

mon

itor

ing:

CIS

>P

LA

(exc

ept

No.

epis

odes

:C

IS=

PL

A)

ND

Old

erch

ildre

nw

ith

GO

R-r

elat

edch

roni

cre

spir

ator

ysy

mpt

oms

[108

]19

7ye

ars

(3m

onth

s–10

year

s)O

CIS

0.3

mg/

kgti

d(4

wee

ks)

ND

24h

pHm

onit

orin

g:C

IS>

B(e

xcep

tN

o.of

epis

odes

:C

IS=

BA

)N

DO

lder

child

ren

wit

hG

OR

-rel

ated

chro

nic

resp

irat

ory

sym

ptom

s[1

30]

22(4

–22w

eeks

)O

CIS

0.2

mg/

kgqi

d(1

3–16

days

)N

D24

hpH

mon

itor

ing:

CIS

>B

(asl

eep,

awak

e,po

stci

bal,

fast

ed):

•B

elch

ing,

coug

h,no

ctur

nal

whe

ezin

g,ir

rita

bilit

y:C

IS>

B•

Slee

pdy

sfun

ctio

n:C

IS>

B

Infa

nts

wit

hir

regu

lar

slee

ppa

tter

nSi

mul

tane

ous

posi

tion

altr

eatm

ent

(30°

pron

e)[1

31]

29(2

–4m

onth

s)D

B,

PA

CIS

0.2

mg/

kgqi

dP

LA

(13–

16da

ys)

FT

24h

pHm

onit

orin

g:C

IS>

B•

Lon

g-la

stin

gep

isod

es:

CIS

>P

LA

=B

A

Sym

ptom

s:C

IS>

PL

A(N

S)B

oth

grou

pspl

aced

onpo

siti

onal

and

diet

ary

trea

tmen

t[1

34]

69(5

–12m

onth

s)O

CIS

0.15

–0.3

mg

tid

(4w

eeks

)C

Fa

ND

Glo

bal

resp

onse

:C

IS>

B

23D

B,

PA

CIS

0.15

mg

tid

PL

A(2

–4w

eeks

)

CF

aN

DG

loba

lre

spon

se:

CIS

>P

LA

Sym

ptom

s:C

IS>

PL

A

45D

B,

PA

CIS

0.2–

0.3

mg

tid

PL

A(2

–4w

eeks

)

CF

aN

DG

loba

lre

spon

se:

CIS

>P

LA

Sym

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Cisapride also improves GOR-related manifestations,such as a disturbed and irregular sleep pattern [38, 130],coughing, wheezing, restlessness at night and belching ininfants with GOR-related respiratory dysfunction [130]or chronic bronchopulmonary disease [39, 80, 107, 108].As indicated by a few observations in infants [15, 30] andseveral studies in adults [6, 101], the drug can heal oe-sophagitis. When given in monotherapy, it is as effectiveas the combination of Gaviscon (an alginate-antacid)and a milk thickener (Carobel) [52]. It is at least as ef-fective as cimetidine in reducing oesophageal acid expo-sure time (both given in combination with Gaviscon) [47].

In general, cisapride is well tolerated. The mostcommon adverse events at therapeutic doses (0.2 mg/kg,3–4 times daily, maximum 0.8 mg/kg/day) are transientdiarrhoea and colic (in about 2%). Serious adverseevents in infants have not been reported in clinical trials.Package labelling indicates isolated reports of more se-rious adverse events:notably extrapyramidal reactions,seizures in epileptic patients, cholestasis in very prema-tures [50] (not confirmed by others [65]), and cardiacinteractions with ‘azole antifungals’ (ketokonazole, flu-conazole, itraconazole, miconazole), erythromycin,claritromycin and troleandomycin [142]. All these med-ications are metabolized by the cytochrome P-450 3A4isozyme.The cardiac effects appear to be associated withhigh plasma cisapride levels as recently illustrated by anadult case [11] and by two cases of cisapride poison-ing [141]. A study of therapeutic doses in newbornsshowed no adverse effects on cardiac function [23], al-though a long QT interval induced by cisapride in a 2-month-old infant has been reported [77]. Cisapride is notmore expensive than alginate-antacid preparations ormilk-thickening agents.

From this follows the next recommendation: cisa-pride is recommended when other measures are insuffi-cient or in regurgitating breast-fed infants, when therapyis indicated (Treatment Phase 2).

Postural treatment

Despite gravity, the upright seated position leads tosignificantly more and larger reflux episodes than thesimple prone [99, 126] and 30° elevated prone position[83, 90, 91], both when the infant is awake or asleep [83].This is likely due to increased abdominal or intragastricpressure. The seated position is also associated with lesssleeping time and more crying than the prone posi-tion [89]. This position is not to be recommended ininfants.

The supine (lying on back) and lateral positions (lyingon left or right side) usually result in intermediate pH-metric GOR values and do not appear to influenceGOR [7, 83, 126].

The prone elevated position, with the baby fixedprone (face down) in a cot at an angle of 30° (headelevated), has been proven to be more effective in re-ducing the incidence of GOR than in comparison with

the upright, supine or lateral position [83, 90, 91, 126].This position reduces abdominal wall tension, elevatesthe gastro-oesophageal junction [90] and increases theeffect of gravity. One study has shown that GOR vari-ables normalize in 25% of infants [127].

However, there is now ample evidence that the pronesleeping position is a risk factor in sudden infant death(SID), independent of overheating, smoking or way offeeding [98, 139]. Although a direct causal relationshipbetween the prone elevated position and SID has notbeen demonstrated [73], and only a small number ofchildren at risk for SID may suffer from GOR (and viceversa), it has become difficult to recommend positionaltreatment as a ‘first-line’ measure in the regurgitatinginfant for ethical, legal and psychological reasons. Par-ents may not accept the idea that exactly the positiontold inappropriate for their (healthy) baby, will be ap-propriate for their sick baby.

Conflicting opinions and data are published regard-ing the role of GOR in apparent life-threatening eventsand, obstructive and central apnoea, with or withoutbradycardia [3, 40, 67, 68, 75, 78, 94–96, 100, 124, 136].Most data, although there is no consensus, suggest thatGOR episodes need to be acid to be related to ob-structive apnoea. Central apnoea does not occur whenthe reflux contains a saline solution or tracheal fluid.Reflex bradycardia is reported during feeding and reflux.However, these associations are reported in a limitednumber of infants and are not considered as relevant iflarge groups of patients are studied. The absence ofscientific data regarding the association between apnoeaand GOR in preterm and term infants makes it haz-ardous to recommend a given approach in this partic-lular population. It is obvious that further studies in thisfield are needed.

From this results the following recommendation:positional treatment remains, in view of its efficacy, as avalid ‘adjuvant’ treatment in patients not responding toother therapeutic approaches or beyond the age of SIDrisk (Treatment Phase 3).

Antacids, H2-receptor antagonists and proton pumpinhibitors

Antacids, alginate-antacid preparations, H2-receptorantagonists and proton pump inhibitors attempt toneutralise or reduce the gastric acidity, rather thanacting on the primary causes of regurgitation in infants[1].

Experience with antacids (Gelusil, Maalox, Mylanta,Muthesa, etc) is limited in infants [132]. Their effects onregurgitation are not well documented. Intensive antacidtreatment with large quantities has been shown as ef-fective as cimetidine in reducing pH-metric parametersand in healing oesophagitis [28]. However, their efficacyin buffering gastric acidity in infants is strongly influ-enced by the time of administration [118] and requiresmultiple administrations. Side-effects include diarrhoea

352

with magnesium-rich preparations [28], and excessiveabsorption of aluminium in infants [123].

Alginate-antacids (Gaviscon and Algicon) form aviscous fluid with surface-active properties, floating as araft on the surface of the gastric contents, and henceform an artificial protective barrier against reflux. Theirefficacy as a monotherapy for regurgitation is not con-vincing [13, 137]. The reported effects of Gaviscon onpH-metric GOR variables are contradictory [13, 49],even in combination with prokinetics [20, 127]. They areless effective in healing oesophagitis than H2-receptorantagonists [88]. Gaviscon contains a considerableamount of sodium carbonate, so that its administrationmay increase the sodium content of the feeds to an un-desirable degree, especially in preterm infants (1 g ofGaviscon contains 46 mg of sodium and the suspensioncontains twice this amount) [72]. Algicon, having a bettertaste than Gaviscon, has a lower sodium load, but ahigher aluminium content. Occasional formation of largebezoar-like masses of agglutinated intragastric materialhas been reported in association with Gaviscon [56].

Dimethicone (Polysilon, Dimethicon, Polysilon gel) isused in some regions for regurgitation. Although oftenclassified as an antacid, it acts more as a feed thickener,as it contains more than 50% of bean gum and hashardly any acid neutralising properties. There are noreliable studies demonstrating its efficacy in the treat-ment of GOR in infants [132].

H2-receptor antagonists, such as cimetidine (Taga-met), ranitidine (Zantac) and famotidine (Pepcid), areeffective in healing reflux oesophagitis in infants [28, 32,88]. High-dose ranitidine appears to be comparable toomeprazole in this respect [34]. The experience withproton pump inhibitors (omeprazole, lansoprazole) islimited. Excellent results have been reported in refrac-tory GORD in older children at doses of 0.7 to 2.0 mg/

kg per day [1, 34, 54, 55, 69, 74], while pH-metric im-provement was not seen at the normal therapeutic dosein young infants [54, 55, 81] . The most frequent side-effects of H2-receptor antagonists and proton pump in-hibitors, are fatigue, dizziness, headache, dyspepsia,nausea, abdominal pain, flatulence, constipation anddiarrhoea. Their incidence is 1%–6%. Serious adverseeffects of omeprazole, such as impaired liver function,haemolytic anaemia, peripheral neuropathia, gynaeco-mastia, skin rash, subacute myopathy, and excessiveurinary sodium loss have been reported in isolated cases[27, 41, 81, 82] or are mentioned in the package insert.The safety of its long-term administration in children isstill a matter of debate. Hypergastrinaemia occurs innearly all patients treated with omeprazole [55] , causinghyperplasia and pseudohypertrophy of the parietal cellsas recently shown in 93% of adult patients on long-termomeprazole [70].

From this results the next recommendation: anti-acidagents such as antacids, alginate-antacids, H2-receptorblockers and proton pump inhibitors should be reservedfor cases of complicated reflux which persist after con-servative measures plus a prokinetic, or in case of (se-vere) oesophagitis, such as in neurologically impairedchildren, children with repaired oesophageal atresia andthose with severe chronic lung disease such as cystic fi-brosis (Treatment Phase 4).

Conclusions and recommendations

The number of placebo-controlled studies is ratherlimited, which probably reflects the reluctance of parentsto participate. Few followup studies are availabledocumenting the long-term outcome of treatment ofregurgitation and GORD. A practical dilemma presents

Table 5 Schematic therapeuticapproach for regurgitation ininfants

aThe use of these measures forregurgitation in infants is notsupported by clinical studies inthe published literature and,therefore, no longer re-commended.

Recommended by ESPGAN 1993 Recommended by Working Party 1995

Phase 1 Phase 11.A. Parental reassurance 1.A. Parental reassurance1.B. Position: prone reversed (head elevated)

Trendelenburg position (30°)1.C. Milk-thickening agents1.D. Dietary recommendations (increased

frequency/small volume)a

1.E. Alginic acid (± antacid)a

1.B. Milk-thickening agents

Phase 2 Phase 2Prokinetics: cisapride (If symptoms resistant Prokinetics: cisapride (If symptoms resistantto cisapride: domperidone, metoclopramide) to cisapride: domperidone, metoclopramide)

Phase 3 Phase 3: Adjuvant therapy in patients3.A. H2-blockers: cimetidine, ranitidine etc. resistant to phase 1 and 23.B. Proton pump inhibitors: omeprazole Position: prone reversed (head elevated)

Trendelenburg position (30°)

Phase 4 Phase 4Surgery 3.A. H2-blockers: cimetidine, ranitidine etc.

3.B. Proton pump inhibitors: omeprazole

Phase 5Surgery

353

in the initiation of treatment of regurgitation. Scarcereports suggest that early effective treatment of infantregurgitation [10] or GORD [16, 18, 66] improves theprognosis.

The guidelines for the treatment of regurgitation andGORD are listed in Table 5. Management should alwaysstart with adequate parental counselling and reassur-ance, explaining the physiological nature of regurgita-tion and spontaneous resolution in the vast majority ofinfants. Milk thickeners can be used only if infants arebottle-fed. They frequently result in a decrease of thenumber and severity of regurgitations. However, objec-tive evidence for an unequivocal effect on GOR orGORD is missing: (occult) GOR may persist in a subsetof infants, likely due a negative effect of high food vol-umes and osmolality of milk thickeners on gastro-oe-sophageal motility, gastric emptying and transientrelaxations. If pharmacological treatment is needed,prokinetics are indicated. Cisapride has the most con-sistent effect on GOR parameters and the best safetyprofile. Positional treatment in the prone-elevated (30°)position is recommended as an adjuvant therapeuticintervention. H2-receptor antagonists and proton pumpinhibitors are reserved for cases with oesophagitis orpersisting GORD. Surgery [1] is to be considered incases of persistent, complicated GORD.

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