Cochrane Database of Systematic Reviews (Reviews) || Sucrose for analgesia in newborn infants...

Sucrose for analgesia in newborn infants undergoing painful

procedures (Review)

Stevens B, Yamada J, Ohlsson A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2009, Issue 4

http://www.thecochranelibrary.com

Sucrose for analgesia in newborn infants undergoing painful procedures (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iSucrose for analgesia in newborn infants undergoing painful procedures (Review)


[Intervention Review]

Sucrose for analgesia in newborn infants undergoing painfulprocedures

Bonnie Stevens2, Janet Yamada1, Arne Ohlsson3

1Nursing, The Hospital for Sick Children, Toronto, Canada. 2Associate Chief of Nursing Research, The Hospital for Sick Children,

Toronto, Canada. 3Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University

of Toronto, Warkworh, Canada

Contact address: Janet Yamada, Nursing, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8,

Canada. [email protected]. (Editorial group: Cochrane Neonatal Group.)

Cochrane Database of Systematic Reviews, Issue 4, 2009 (Status in this issue: Unchanged)


DOI: 10.1002/14651858.CD001069.pub2

This version first published online: 19 July 2004 in Issue 3, 2004.

Last assessed as up-to-date: 19 April 2004. (Help document - Dates and Statuses explained)

This record should be cited as: Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful

procedures. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD001069. DOI: 10.1002/14651858.CD001069.pub2.

A B S T R A C T

Background

Management of pain for neonates is less than optimal. The administration of sucrose with and without non-nutritive sucking (pacifiers)

has been the most frequently studied non-pharmacological intervention for relief of procedural pain in neonates.

Objectives

To determine the efficacy, effect of dose, and safety of sucrose for relieving procedural pain as assessed by validated individual pain

indicators and composite pain scores.

Search strategy

Standard methods as per the Neonatal Collaborative Review Group. A MEDLINE search was carried out for relevant randomized

controlled trials (RCTs) published from January 1966 - March 2004, EMBASE from 1980 - 2004 and search of the Cochrane

Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004). Key words and (MeSH) terms included

infant/newborn, pain, analgesia and sucrose. Language restrictions were not imposed. Bibliographies, personal files, the most recent

relevant neonatal and pain journals and recent major pediatric pain conference proceedings were searched manually. Unpublished

studies, or studies reported only as abstracts, were not included. Additional information from published studies was obtained.

Selection criteria

RCTs in which term and/or preterm neonates (postnatal age maximum of 28 days after reaching 40 weeks corrected gestational age)

received sucrose via oral syringe, NG-tube, dropper or pacifier for procedural pain from heel lance or venepuncture. In the control

group, water, pacifier or positioning/containing were used. Studies in which the painful stimulus was circumcision were excluded.

Data collection and analysis

Trial quality was assessed according to the methods of the Neonatal Collaborative Review Group. Quality measures included blinding

of randomization, blinding of intervention, completeness of follow up and blinding of outcome measurement. Data were abstracted

and independently checked for accuracy by the three investigators.

Statistical Analysis

1Sucrose for analgesia in newborn infants undergoing painful procedures (Review)


mailto:[email protected]

http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdf

The statistical package (RevMan 4.2) of the Cochrane Collaboration was used. For meta-analysis, a weighted mean difference (WMD)

with 95% confidence intervals (CI) using the fixed effects model was reported for continuous outcome measures.

Main results

Forty-four studies were identified for possible inclusion in this review. Seven studies reported only as abstracts, and sixteen additional

studies were excluded, leaving 21 studies (1,616 infants) included in this review. Sucrose in a wide variety of dosages was generally found

to decrease physiologic (heart rate) and behavioural (the mean percent time crying, total cry duration, duration of first cry, and facial

action) pain indicators and composite pain scores in neonates undergoing heel stick or venepuncture. When pain scores (Premature

Infant Pain Profiles) were pooled across 3 studies (Gibbins 2001; Johnston 1999a; Stevens 1999), they were significantly reduced in

infants who were given sucrose (dose range 0.012 g to 0.12 g) compared to the control group, [WMD -1.64 (95% CI -2.47,- 0.81);

p = 0.0001] at 30 seconds and [WMD -2.05, (95% CI -3.08, -1.02); p = 0.00010] at 60 seconds after heel lance. When results for

change in heart rate were pooled for two studies (Haouari 1995, Isik 2000), there were no significant differences between changes in

heart rate for infants given sucrose (dose range 0.5 g to 0.6 g) compared to the control group, [WMD 0.90 (95% CI -5.81, 7.61); p =

0.8] at one minute and [WMD -6.20 (95% CI -15.27, 2.88); p = 0.18] at three minutes after heel lance.

Authors’ conclusions

Sucrose is safe and effective for reducing procedural pain from single painful events (heel lance, venepuncture). There was inconsistency

in the dose of sucrose that was effective (dose range of 0.012 g to 0.12 g), and therefore an optimal dose to be used in preterm and/or

term infants could not be identified.

The use of repeated administrations of sucrose in neonates needs to be investigated as does the use of sucrose in combination with

other behavioural (e.g., facilitated tucking, kangaroo care) and pharmacologic (e.g., morphine, fentanyl) interventions. Use of sucrose

in neonates who are of very low birth weight, unstable and/or ventilated also needs to be addressed.

P L A I N L A N G U A G E S U M M A R Y

Sucrose for analgesia in newborn infants undergoing painful procedures

Sucrose provides pain relief for newborn babies having painful procedures such as needles or heel lances. Newborn babies undergoing

painful procedures need help to have their pain reduced. This is done routinely for major procedures but may not be done for tests

(such as taking blood) or needles. Drugs can be used to reduce pain but there are several other methods including sucking a pacifier

with or without sucrose (sugar). The review of trials found that giving sucrose to babies decreases their crying time and other pain

indicators such as facial action. More research is needed into the effect of repeated doses of sucrose, especially for very low birthweight

or ventilated babies.

B A C K G R O U N D

Management of pain for neonates in the neonatal intensive care

unit (NICU) is less than optimal (Anand 2001; AAP 2000). Al-

though strategies to manage pain from surgery, medical illness,

and major procedures exist, means to prevent or reduce pain from

investigational procedures including heel lance and venepuncture

are lacking (Anand 1995; Fernandes 1994; Johnston 1997b). The

challenge of providing simple, safe and effective pain-relieving in-

terventions for these infants is an ongoing dilemma.

A wide variety of pharmacologic and nonpharmacologic interven-

tions are available for management of pain in infants. Pharmaco-

logic interventions are infrequently employed for procedural pain

due to concerns about adverse effects and a lack of conviction

that pain is important to the infant’s present or future well being.

Nonpharmacologic interventions are more feasible alternatives as

concerns about the risk of adverse effects are minimal.

The administration of sucrose with and without non-nutritive

sucking (pacifiers) has been the most frequently studied nonphar-

macologic intervention for relief of procedural pain in neonates.

Sucrose has been examined for its calming effects in crying new-

borns (Barr 1993; Barr 1994; Haynes 1995; Smith 1992) and its

pain-relieving effects for invasive procedures in term and preterm

neonates (Stevens 1997a). The effects of sucrose and non-nutri-

tive sucking are thought to be mediated by both the endogenous

opioid and non-opioid systems (Gunnar 1988) but the underlying



mechanisms may differ. These mechanisms may be additive or syn-

ergistic but most likely depend on normal functioning of central

mechanisms. In a systematic review/meta-analysis of the efficacy of

sucrose for procedural pain management, Stevens (Stevens 1997a)

found that proportion of time crying was decreased with 0.24 -

0.48 g (2ml of a 12-24% sucrose solution) administered orally 2

minutes prior to a painful procedure (heel lance or venepuncture).

This systematic review is a substantive update of the original 1998

review and the update completed in 2001(Stevens 1998,Stevens

2001).

O B J E C T I V E S

To determine the efficacy, effect of dose, method of administra-

tion and safety of sucrose for relieving procedural pain as assessed

by physiologic [heart rate, respiratory rate, transcutaneous pO2

(tcpO2), tcpCO2] and/or behavioural (cry duration, proportion

time crying, facial actions) pain indictors and/or composite pain

scores.

M E T H O D S

Criteria for considering studies for this review

Types of studies

RCTs. Language restrictions were not imposed. Studies published

in abstract form were not included as we have identified discrepan-

cies in numbers enrolled between abstracts and final publications

(Walia 1999). Unpublished studies were not included. Additional

information was sought from authors of published studies.

Types of participants

The study population was term and/or preterm neonates, post-

natal age maximum of 28 days after reaching 40 weeks corrected

gestational age.

Types of interventions

The interventions included administration of sucrose via oral sy-

ringe, NG-tube, dropper or pacifier, for treatment of procedural

pain from heel lance or venepuncture. In the control group, water

(sterile, tap, distilled, spring), pacifier or positioning/containing

were used. Studies in which the painful stimulus was circumcision

were excluded.

Types of outcome measures

The outcomes were individual behavioural (cry duration, propor-

tion of time crying, facial actions) and/or physiological (heart rate,

respiratory rate, tcpO2, tcpCO2) pain indicators and/or compos-

ite pain scores (including a combination of behavioural, physio-

logical and contextual indicators).

Search methods for identification of studies

Standard methods as per the Neonatal Collaborative Review

Group. A MEDLINE search was carried out for relevant random-

ized controlled trials (RCTs) published from January 1966 - March

2004, EMBASE from 1980-2004 and search of the Cochrane

Central Register of Controlled Trials (CENTRAL, The Cochrane

Library, Issue 1, 2004). Key words and (MeSH) terms included

infant/newborn, pain, analgesia and sucrose. Bibliographies, the

most recent relevant neonatal and pain journals and recent ma-

jor pediatric pain conference proceedings were searched manu-

ally. Personal files were searched. Unpublished studies were not

included. Identified abstracts are listed under excluded studies.

Language restrictions were not imposed.

Data collection and analysis

As per the previous Cochrane review update, we did not include

abstracts. Studies published in abstract form were not included

as we have identified discrepancies in numbers enrolled between

abstracts and final publications (Walia 1999). The types of par-

ticipants were more clearly defined to include postnatal age maxi-

mum of 28 days after reaching 40 weeks corrected gestational age.

IM injections (e.g., immunizations) were removed as a painful

procedure, as most studies evaluating IM injections would include

infants who were older than our inclusion criteria. As pacifiers

and positioning of infants during painful procedures have become

more widely evaluated in control groups, we included these mea-

sures.

Standard methods of the Neonatal Collaborative Review Group

were used to assess the methodological quality of the included

trials. The questions asked regarding quality were

1) Blinding of randomization?

2) Blinding of intervention?

3) Complete follow-up?

4) Blinding of outcome measurement?

There were three possible answers to these questions; Can’t tell,

yes and no.

The methodological quality of each study was assessed indepen-

dently by three review authors, who were not blinded to trial au-

thors or institutions.

Methods to collect data from the included trials: three authors

abstracted data separately; these were compared and differences

were resolved. Additional data were provided by investigators in

two studies (Johnston 1999a; Stevens 1999).

Statistical Analysis



The statistical package (RevMan 4.2) provided by the Cochrane

Collaboration was used. For meta-analysis, a weighted mean dif-

ference (WMD) with 95% confidence intervals (CI) using the

fixed effects model was reported for continuous outcome mea-

sures.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Forty-four studies were identified as possibly eligible for inclusion

in this review, including six studies which were identified in this

current update. Seven studies reported only as abstracts were ex-

cluded (Abad 1993; Gibbins 2000; Gormally 1996; Isik 2000b;

Johnston 2000; Stevens 1997b; Stevens 2000). Sixteen additional

studies were excluded (See Table - Characteristics of Excluded

Studies). In three RCTs the authors did not provide information

on how many infants were randomized to treatment vs control

groups (Allen 1996; Barr 1993; Blass 1991); one study was de-

signed as a controlled trial without randomization and the number

of infants in each group was not stated (Blass 1991); in one RCT

no painful procedure was used (Graillon 1997); in three studies,

the painful procedure was circumcision (Herschel 1998; Mohan

1998; Stang 1997); three studies used non-sucrose interventions (

Ahuja 2000; Bucher 2000; Skogsdal 1997); in two studies, infants

were older than the inclusion criteria (Lewindon 1998; Harrison

2003); in one study results from the first exposure to sucrose or

placebo could not be isolated (Mellah 1999); in one study we could

not separate data for the sample (Abad 2001); one study was a

duplicate of a previously published study (Bilgen 2001). Twenty-

one studies (1,616 infants) were included in this systematic re-

view, including four studies which were added in this update (

Acharya 2004; Greenberg 2002; Guala 2001; Storm 2002). A sub-

sample of Stevens 1999 was reported by Johnston 1999. Details

of each study are given in the Table, Characteristics of Included

Studies (Abad 1996; Acharya 2004; Blass 1999; Bucher 1995;

Carbajal 1999;Gibbins 2001; Gormally 2001; Greenberg 2002;

Guala 2001; Haouari 1995; Isik 2000a; Johnston 1997b; Johnston

1999a; Ors 1999; Overgaard 1999; Ramenghi 1996a; Ramenghi

1996b; Ramenghi 1999; Rushforth 1993; Stevens 1999; Storm

2002).

Of the twenty-one studies eligible for inclusion in this review, 11

studies evaluated term infants, nine studies evaluated preterm in-

fants and one study included both preterm and term infants. The

majority of infants received a heel lance as the painful procedure

(n = 18 studies). In three studies, infants received a venepuncture.

Of the 15 studies that evaluated cry behaviour, nine studies (in-

cluding 588 infants) reported information on the outcome of time

crying over three minutes but could not be combined as data were

not provided for all studies. Fourteen studies assessed the effect of

sucrose on changes in heart rate and two studies evaluated vagal

tone. Four studies evaluated oxygen saturation changes (two of

these studies also measured respiratory rate changes) and one study

evaluated tcp02 and tcpC02. One study assessed the intensity of

sucking in infants who received sucrose compared to those who

received water. One study measured facial grimacing in infants to

evaluate pain. Seven studies used multidimensional behavioural

pain measures while four studies used multidimensional compos-

ite pain measures. For the three studies that evaluated pain as a

composite score using the Premature Infant Pain Profile (PIPP) at

30 seconds and 60 seconds after heel lance, means and standard

deviations were provided in one of the studies (Gibbins 2001) and

was obtained from the authors for the two remaining studies (

Johnston 1999a; Stevens 1999). Two studies reported the percent

changes in heart rate at one and three minutes after heel lance.

Means and standard errors of the mean were reported for both

studies (Haouari 1995; Isik 2000a). Standard errors were con-

verted to standard deviations. Only six of the 21 studies evalu-

ated/reported adverse effects.

Risk of bias in included studies

Although all the studies included in this systematic review were

RCTs, there was inadequate information regarding assurance of

blinding of randomization. Thirteen of the included studies (Blass

1999; Carbajal 1999; Gibbins 2001; Gormally 2001; Greenberg

2002; Guala 2001; Isik 2000a; Johnston 1997b; Ors 1999;

Ramenghi 1996b; Ramenghi 1999; Stevens 1997a; Storm 2002)

were not double-blind. In these studies, additional interventions

(e.g., use of pacifiers) were utilized that precluded blinding. In

general the sample sizes of the studies were small.

Regarding whether the method of randomization was concealed, 8

studies (38%) adequately reported allocation concealment (scored

as “A” under included studies table) and 13 studies (62%) did not

clearly report this (scored as “B” under included studies table).

Few studies provided a definition of pain or how it was concep-

tualized in relation to the outcomes. There were also differences

in study methods. The majority of studies utilized heel lance as

the pain stimulus. However, little detail about this procedure was

provided. Therefore, it is impossible to know if the painful stimuli

were comparable in intensity, duration or frequency. The length of

infant observation following the heel lance was not reported fre-

quently. This may have implications for the incidence of adverse

effects.

The delivery method of sucrose differed between studies (syringe,

NG-tube, dropper or pacifier). Outcomes were reported inconsis-

tently; as means with SD or SE, medians with ranges, and often

in graph form without providing actual numbers.



Effects of interventions

Because inconsistencies in outcome measures and differences in

the statistical reporting of results existed across most studies, pre-

venting comprehensive meta-analytic techniques, the results were

reported by outcome for each accepted study separately. A descrip-

tion of the outcomes is presented in the Additional Tables 01-09 (

Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table

8; Table 9).

Table 1. Trials assessing cry behaviour outcomes

Study Participants Procedure Interventions Outcomes Metrics used Results

Abad 1996 28 preterm (29

- 36 weeks ges-

tational age) in-

fants, postnatal

age 1-26 days

Venepuncture 2ml of 12% su-

crose via syringe

(n = 8)

2ml of 24% su-

crose via syringe

(n = 8)

2ml of spring wa-

ter via syringe (n

= 12) 2 minutes

prior to

venepuncture

Time crying for

3 minutes after

venepuncture

Median, IQR Cry duration

for 3 minutes af-

ter venepuncture

was significantly

reduced in 2ml

of 24% (0.48 g)

sucrose group, p

<0.05 (19.1 sec),

but not in 2ml

of 12% (.24g) su-

crose group (63.1

sec) compared to

water (72.9 sec).

Significant group

effect noted, F (2,

25) = 4.26; p =

0.0256

Acharya 2004 39 preterm

neonates (mean

30.5wk’s

gestational age),

mean postnatal

age 27.2 days

Venepuncture 2ml

of 25%(0.5g) su-

crose ad-

ministered by sy-

ringe into front

of infant’s mouth

over 2 minutes, 4

minutes prior to

venepuncture

Duration of first

cry (beginning to

end of first cry);

total duration of

crying (onset of

first cry to cessa-

tion of all crying)

Mean SD Mean duration of

first cry lower in

infants

who received su-

crose 18.6 (24.4)

seconds com-

pared to infants

who received wa-

ter 52.3 (56) sec-

onds (estimated

treatment effect

= 33.7, p<.001).

Mean total du-

ration of crying

was significantly

lower in infants

who received su-



Table 1. Trials assessing cry behaviour outcomes (Continued)

crose 31.9(41.9)

seconds com-

pared to infants

who received wa-

ter 72.5(66.7)

seconds (esti-

mated treatment

effect =40.6, p

<.001).

Blass 1999 40 term new-

born infants, 34

- 55 hours old

Heel Lance 2ml of 12% su-

crose over 2 min-

utes via syringe

(n=10)

2ml of water via

syringe over 2

minutes (n=10)

Pacifier dipped

every 30 seconds

in 12% su-

crose solution for

2 minutes (n=10)

Pacifier dipped in

water every

30 seconds for 2

minutes (n = 10)

prior to heel lance

% time crying 3

minutes after heel

lance

Not reported 2ml

of 12% (0.24g)

sucrose alone di-

minished cry du-

ration from heel

lance compared

to water ( 8%

vs. 50%, p =

0.003) and wa-

ter with pacifier

( 8% vs. 35%,

p = 0.002). Su-

crose with paci-

fier (pacifier with

12%

sucrose) more ef-

fective in reduc-

ing cry duration

compared to wa-

ter with pacifier

(5% vs. 35%, p

= 0.001) or water

alone (50%, p =

0.002)

Bucher 1995 16 preterm in-

fants (27

- 34 weeks gesta-

tional age), post-

natal age approx-

imately 42 days


crose via syringe

into the mouth

2 minutes before

heel lance.

2ml of distilled

water via syringe

into the mouth

2 minutes before

heel lance (n =

% time crying

Recovery

time until crying

stopped

Not reported Cry duration (%

of total

duration of inter-

vention) signifi-

cantly reduced in

2ml of 50% (1.0

g) sucrose group

(71.5%) com-

pared to control




16, cross-over de-

sign)

group (93.5%), p

= 0.002

Gormally 2001 94 term new-

borns, mean ges-

tational age 39.4

weeks on 2nd or

3rd day of life

Heel Lance No

holding and ster-

ile water given by

pipette (n=21)

No holding and

0.250 ml of 24%

sucrose

solution given by

pipette (n=22)

Holding and ster-

ile water given by

pipette (n=20)

Holding

and 0.250 ml of

24% sucrose so-

lution by pipette

(n=22)

All solutions

given 3 times at

30 second inter-

vals

% time crying 1,

2, 3 minutes after

heel lance

Not reported Crying decreased

over time

[F(2,80) = 10.0,

p<0.001] but no

significant inter-

action noted for

time with

holding, taste, or

holding and taste.

Effect of taste on

crying was signif-

icant [F(1,81) =

4.1, p<0.05] in

favour of

0.250ml of 24%

(0.18g) sucrose.

Effect of holding

not statis-

tically significant

[F(1,81) = 3.0, p

= 0.09)]. No sta-

tistically signifi-

cant interaction

between taste and

holding to reduce

crying [F(1,81) =

0.80, p = 0.37].

Ef-

fect of combined

interventions was

additive

Greenberg 2002 84 term new-

borns, approx.

17-19 hours old.

Heel Lance Sugar coated

pacifier (n=21)

water moistened

pacifier (n=21)

2ml of 12% su-

crose (n =21)

routine care

(n=21)

Duration

of cry from pro-

cedure phase to

3 minutes post-

procedure

Not reported Significant

decrease in dura-

tion of cry for

the sugar-coated

paci-

fier group com-

pared to the con-

trol group (p =

.001) and the wa-




ter-pacifier group

(p =.001).

Haouari 1995 60 term (37-42

weeks gestation)

infants. 1-6 days

of age

Heel Lance 2ml of 12.5% su-

crose 2 minutes

prior to heel lance

(n = 15)

2 ml of 25% su-

crose 2 minutes

prior to heel lance

(n = 15).

2 ml of 50 % su-

crose 2 minutes

prior to heel lance

(n = 15).

2ml of sterile wa-

ter 2 min-

utes prior to heel

lance (n = 15).

All solutions were

given by syringe

on the tongue

over less than one

minute

Total time crying

over 3 minutes.

Time of first cry

after lance

Median, IQR After

heel lance, signif-

icant decreases in

total crying time

and duration of

first cry in 2ml of

50% (1.0 g) su-

crose group com-

pared with water

(p = 0.02). Signif-

icant reduction in

median time cry-

ing at end of first

minute (p <0.02)

in

2ml of 50%(1.0

g) sucrose group

(35 sec; range 14

- 60) compared

with water (60

sec; range 50 -

60). In second

minute, duration

of cry was sig-

nificantly less in

2ml of 50%(1.0

g) sucrose group

(0 sec; range 0 -

25) and in 2ml

of 25%(0.5 g) su-

crose group (18

sec; range 0 - 55)

compared to wa-

ter (60 sec; range

40 - 60), p =

0.003, p = 0.02

respectively

Isik 2000 113 healthy term

newborns gesta-

tional ages be-

tween 37 and 42

weeks, median


crose (n=28)

2ml of 10% glu-

cose (n=29)

Mean cry time

during 3 minutes

after lance

Reported means,

SD

Infants

who received 2ml

of 30% (0.6g) su-

crose (mean cry-

ing time of




post natal age=

2days (range 2-5

days)

2ml of 30% glu-

cose (n=28)

2ml of distilled

water (n=28)

syringed into the

anterior third of

the tongue for 1

minute

2 minutes prior

to heel lance

61 seconds) cried

significantly less

than those who

re-

ceived 30% glu-

cose (mean cry-

ing

time of 95 sec-

onds), 10% glu-

cose (mean cry-

ing time of 103

seconds) or ster-

ile water (mean

crying time of

105 seconds), p =

0.02

Ors 1999 102

healthy term in-

fants, gestational

age 37-42 weeks,

median postna-

tal age 1.6 days

(range1-15 days)


crose (n=35)

2ml of human

milk (n=33)

2ml of sterile wa-

ter (n=34)

syringed to ante-

rior part

of tongue for one

minute

Heel prick done 2

minutes after in-

tervention

Median cry time

during 3 minutes

after lance

Median, IQR Signif-

icant decrease in

crying times for

2ml of 25% (0.5

g) sucrose group

(median 36, in-

terquartile range

18-43) compared

to human milk

(median 62, in-

terquartile range

29-107) and ster-

ile water [(me-

dian

52, interquartile

range 32-158), p

= 0.0009]. Re-

covery time for

crying was signif-

icantly reduced in

2ml of 25% (0.5g

)sucrose group

(median 72, in-

terquartile range

48-116)

compared to hu-

man milk

(median 112, in-




terquartile range

72-180) and ster-

ile water [(me-

dian

124, interquartile

range 82-180), p

= 0.004]

Overgaard 1999 100 new-

born term in-

fants [mean age 6

days (range 4-9)]


crose solution via

syringe into the

mouth over 30

seconds 2 min-

utes prior to heel

lance

2ml of sterile wa-

ter via syringe

into the mouth

over 30 seconds 2

minutes prior to

heel lance

Me-

dian crying time

during heel lance,

fraction of crying

during sampling,

crying time dur-

ing first minute

after end of sam-

pling, total crying

time

Median, 5th and

95th percentiles

Median duration

of

first cry in group

receiving 2ml of

50%(1g) sucrose

was significantly

lower (18 seconds

(2-75) compared

to placebo group

[(22 seconds (11-

143), p = 0.03].

Median crying

time during heel

lance in the su-

crose group was

lower (26 seconds

(2-183) com-

pared to placebo

group [(40 sec-

onds (12 - 157), p

= 0.07]. Median

fraction of cry-

ing during sam-

pling in 2ml of

50% (1g) sucrose

group was signif-

icantly

lower (43% (4-

100) compared

to placebo group

[(83% (20 - 100),

p

= 0.004]. Median

crying time dur-

ing first minute

after end of sam-

pling in 2ml of




50% (1g) sucrose

group was signif-

icantly

lower (3 seconds

(0-58) compared

to placebo group

[(16 seconds

(0-59), p=0.004].

Me-

dian total time

crying in 2ml of

50% (1g) sucrose

group was signif-

icantly lower (30

seconds (2-217)

compared

to placebo group

[(71 seconds (13-

176), p = 0.007]

Ramenghi

1996a

15 preterm(32-

34 weeks gesta-

tion) infants

greater than 24

hours of age

Heel Lance 1 ml of 25%

sucrose via sy-

ringe into mouth

2 minutes prior

to heel lance

1 ml of sterile

water via syringe

into mouth via

syringe 2 minutes

before heel lance.

(n=15, cross-over

design)

Duration of first

cry and

% time crying

5 minutes after

lance

Median, IQR Sig-

nificant decrease

in total percent-

age of time crying

over 5 minutes

(median 6%, in-

terquartile range

3.3 - 15.3) in

the 1ml of 25%

(0.25 g) sucrose

group compared

with water group

[(median 16.6%,

range 5 - 27.3),

p = 0.018]. Du-

ration of first cry

was significantly

decreased in the

1ml of

25% (0.25g) su-

crose group (me-

dian 12 sec, in-

terquartile range

8 - 22 sec) com-

pared to control




group [(median

quartile 23 sec,

range 15 - 45), p

= 0.004]

Ramenghi

1996b

60 term (37 -

42 weeks gesta-

tional age) 2 - 5

days old infants


sucrose via sy-

ringe into mouth

2 minutes prior

to heel lance (n =

15).

2ml of 50% su-

crose via syringe

into

mouth 2 minutes

prior to heel lance

(n =15).

2ml of commer-

cial sweet tasting

solution (Calpol)

via syringe into

mouth 2 minutes

prior to heel lance

(n = 15).

2ml of sterile wa-

ter via sy-

ringe into mouth

2 minutes prior

to heel lance (n =

15).

Duration of first

cry after lance

% time crying

over 3 minutes af-

ter heel lance

Median, IQR Signif-

icant decrease in

duration of first

cry and percent

crying during 3

minutes after heel

lance in the 2ml

of 25% (0.5 g)

sucrose, 2ml of

50% (1.0 g) su-

crose and Calpol

groups (p = 0.02)

(data in graph

form only)

Ramenghi 1999 30 preterm in-

fants (GA 32-36

weeks, postnatal

age < 24 hours)

Heel Lance 25 % sucrose so-

lution (volume

not reported) was

given via syringe

into the mouth

or via NG tube

2 minutes prior

to first heel lance

(n = 15), and

via the alternate

route for the sec-

ond heel lance

within 48 hours

% cry over 5 min-

utes after sam-

pling

Median, IQR Median percent-

age cry in intrao-

ral

water group was

22% (interquar-

tile range 10.6 -

40) and 27% (in-

terquartile range

11.6 - 47) for

infants in NG-

tube water group.

Median percent-

age cry in in-

traoral 25% su-




Sterile water via

syringe into

the mouth or via

NG-tube 2 min-

utes prior to first

heel lance and for

the second heel

lance the alter-

nate route within

48 hours

(cross over de-

sign, n= 30)

crose group was

6% (interquartile

range 0.6-15)

and 18.3% (in-

terquartile range

11.6-

41.6) for NG-

tube 25% sucrose

group. Signifi-

cant reduction in

crying time (p =

0.006) noted in

the 25% sucrose

group compared

with water group

when infants re-

ceived 25% su-

crose intraorally,

not via NG-tube

route. For infants

in 25% sucrose

group, significant

reduction in cry-

ing time noted

(p = 0.008) when

solu-

tion given intrao-

rally compared to

NG-tube route

Rushforth 1993 52 term infants

(37 - 42 weeks

gestational age)

2-7 days of age.

Heel Lance 2ml of 7.5% su-

crose

administered by

a dropper into

the mouth over

a one minute pe-

riod prior to heel

lance (n = 26).

2ml of sterile wa-

ter administered

by dropper into

the mouth over

a one minute pe-

riod prior to heel

lance (n = 26

% cry over 3 min-

utes after sam-

pling

Median only No significant

differences in me-

dian percentage

time crying be-

tween group re-

ceiving 2ml

of 7.5% (0.15g)

sucrose (74.3%)

com-

pared to group re-

ceiving wa-

ter (73.2%). No

significant differ-

ences be-

tween groups in




duration of cry

after 1 minute (p

= 0.65), 2 min-

utes (p = 0.52)

and 3 minutes (p

= 0.72). No dif-

ference in time to

cessation of cry-

ing (p = 0.16)

Storm 2002 48 preterm, me-

dian gestational

age of 32 wk,

median postna-

tal age of 14 days


crose, n = 12

1ml of 25% su-

crose, n =12

milk via nasogas-

tric tube, n= 12

milk via nasogas-

tric tube, + 25%

sucrose, n = 12

All infants were

given water prior

to a second heel

lance

Differences

in crying time for

pre heel lance to

heel lance proce-

dure

Not reported Significantly less

crying in Infants

receving 1ml of

25% sucrose (p

< .05) and food

(milk) + 1ml of

25% sucrose (p

<.05).

Table 2. Trials assessing heart rate/vagal tone outcomes



- 36 weeks ges-

tational age) in-

fants, postnatal

age 1-26 days


crose via syringe

(n = 8)

2ml of 24% su-

crose via syringe

(n = 8)

2ml of spring wa-

ter via syringe (n

= 12) 2 minutes

prior to

venepuncture

Heart rate:

pre solution,

post solution

5 minutes after

venepuncture

Reported means

and SEM

Significant group

effect, F (2, 25) =

6.37, p = 0.006

Overall time ef-

fect, F (2, 50) =

14.15, p < 0.001

No significant in-

teraction be-

tween treatment

group and time.

Post hoc Tukey

test showed that

group receiving 2

ml of 12% su-

crose (0.24g) had

lower HR com-



Table 2. Trials assessing heart rate/vagal tone outcomes (Continued)

pared to the 2ml

of 24% sucrose

group (0.48g) or

water group

Arachya 2004 39 preterm

neonates (mean

30.5wk’s

gestational age),

mean postnatal

age 27.2 days

Venepuncture 2ml

of 25%(0.5g) su-

crose ad-

ministered by sy-

ringe into front

of infant’s mouth

over 2 minutes, 4

minutes prior to

venepuncture

Mean change in

heart rate from

pre-

procedure, proce-

dure and post-

procedure phase

of venepuncture

Mean, SD Mean change in

heart

rate from pre pro-

cedure to proce-

dure was lower in

the infants receiv-

ing sucrose com-

pared to water

(estimated treat-

ment effect = 7.5,

p =.003). Mean

change in heart

rate from pre-

procedure to post

proce-

dure was lower in

the infants who

received sucrose

compared to wa-

ter (estimated

treatment effect =

4.16, p =.036).

Blass 1999 40 term new-

born infants, 34

- 55 hours old

Heel lance 2ml of 12% su-

crose over 2 min-

utes via syringe

(n=10)

2ml of water via

syringe over 2

minutes (n=10)

Pacifier dipped

every 30 seconds

in 12% su-

crose solution for

2 minutes (n=10)

Pacifier dipped in

water every

30 seconds for 2

minutes (n = 10)

prior to heel lance

Change in mean

HR

Not reported Mean heart rate

increased signifi-

cantly from treat-

ment

to heel lance in

infants receiving

water

alone (mean in-

crease of 17 beats

per minute, p =

0.002) and wa-

ter with pacifier

(mean increase of

20

beats per minute,

p = 0.005). Mean

increase in heart

rates




also increased for

the 2ml of 12%

(.24g)

sucrose and paci-

fier group (mean

difference of 7.4

beats per minute,

p = 0.05) but

not for infants

receiving 2ml of

12%(0.24g) su-

crose

alone (mean dif-

ference of 5.9

beats per minute,

p = 0.142)


fants (27

- 34 weeks gesta-

tional age), post-

natal age approx-

imately 42 days


crose via syringe

into the mouth

2 minutes before

heel lance.

2ml of distilled

water via syringe

into the mouth

2 minutes before

heel lance (n =

16, cross-over de-

sign)

Increase in HR

Recovery time for

HR

Median, IQR Median increase

in heart rate

[beats per minute

(bpm)] after heel

lance were signif-

icantly re-

duced in the 2ml

of 50%(1.0 g)

of sucrose group

(35 bpm) com-

pared to water

(51 bpm), p =

0.005


borns, mean ges-

tational age 39.4

weeks on 2nd or

3rd day of life

Heel lance No

holding and ster-

ile water given by

pipette (n=21)

No holding and

0.250 ml of 24%

sucrose

solution (0.06g)

given by pipette

(n=22)

Holding and ster-

ile water given by

pipette (n=20)

Mean HR prein-

tervention, 1, 2, 3

minutes after heel

lance, Mean vagal

tone index prein-

tervention, 1, 2, 3

minutes after heel

lance

Not reported for

both HR and va-

gal tone

Although

no significant dif-

ferences in mean

heart rate due to

holding or su-

crose as main ef-

fects, there was

significant inter-

action between

holding and taste

[F(1,61)

= 8.89, p<0.004],

indicating syner-

gistic effect that

was also depen-




Holding

and 0.250 ml of

24% sucrose so-

lution (0.06 g) by

pipette (n=22)

All solutions

given 3 times at

30 second inter-

vals

dent on preinter-

vention heart rate

[F(1,61) = 9.23,

p<0.004]. No sig-

nificant main ef-

fects noted for va-

gal tone; as with

heart rate, effect

of vagal tone was

dependent on

preinterven-

tion vagal tone

for both holding

and taste inter-

ventions [F(1,60)

= 4.82, p<0.03].

Preinterven-

tion levels inter-

acted to decrease

heart rate and va-

gal tone in infants

who had higher

rates before inter-

ventions


borns, approx.

17-19 hours old.

Heel lance Sugar coated

pacifier (n=21)

water moistened

pacifier (n=21)

2ml of 12% su-

crose (n =21)

routine care

(n=21)

Vagal tone and

Vagal tone index

Not reported Lower vagal tone

during heel lance

in the

sugar coated paci-

fier group com-

pared to the con-

trol

group (p = .008)

and oral sucrose

group (p=.018).

Lower vagal tone

index in the sugar

coated pacifier

group compared

to control group

at heel lance (p

= .019), and 6-

10 minutes after

(p = .007) and

11-15 minutes (p




= .049) after heel

lance.

Guala 2001 140 term (38-41

wk’s gestational

age)

Heel lance Nothing (n=20)

Water (n = 20)

5% Glucose (n =

20) 33% Glucose

(n = 20 50% Glu-

cose (n = 20) 33%

Sucrose (n = 20)

50% Sucrose (n =

20)

Heart rate be-

fore, during and 3

minutes after heel

lance

Mean, SD No

significant differ-

ences were found

between groups

for differences in

heart rate at each

of the 3 phases

of the heel lance

(p value reported

for 3 minutes af-

ter heel lance, p

= .087; the dif-

ference between 3

minutes after heel

lance and during

heel lance, p =

.068).

Haouari 1995 60 term (37-42

weeks gestation)

infants. 1-6 days

of age

Heel lance 2ml of 12.5% su-

crose 2 minutes

prior to heel lance

(n = 15)

2 ml of 25% su-

crose 2 minutes

prior to heel lance

(n = 15).

2 ml of 50 % su-

crose 2 minutes

prior to heel lance

(n = 15).

2ml of sterile wa-

ter 2 min-

utes prior to heel

lance (n = 15).

All solutions were

given by syringe

on the tongue

over less than one

minute

Percent change in

HR at 1, 3, 5

minutes after heel

lance

Reported Means

and SEM

Significant de-

crease in percent

change in heart

rate 3 minutes af-

ter heel lancing

(p = 0.02) in the

2ml of 50% (1.0

g) sucrose group

(mean 0.1%, SE

3.3) compared to

water group

(mean 17.5%, SE

6.0)




Isik 2000 113 healthy term

newborns gesta-

tional ages be-

tween 37 and 42

weeks, median

post natal age=

2days (range 2-5

days)


crose (n=28)

2ml of 10% glu-

cose (n=29)

2ml of 30% glu-

cose (n=28)

2ml of distilled

water (n=28)

syringed into the

anterior third of

the tongue for 1

minute

2 minutes prior

to heel lance

Mean maximum

heart rate 3 min-

utes from heel

lance

Mean

recovery time for

heart rate

% change

in heart rate at 1,

2, 3 minutes after

heel lance

Reported Means

and SEM

No

significant differ-

ence between

groups with re-

spect to maxi-

mum heart rate

after heel

lance, (p = 0.71),

or mean recovery

time,(p = 0.09).

No significant

difference found

in percent change

in heart rate at 1

or 3 minutes af-

ter heel lance, (p

= 0.14, p = 0.53),

respectively. At 2

minutes after heel

lance, percent

change in heart

rate favoured

group re-

ceiving sucrose (p

= 0.05) compared

to other groups

Johnston 1997a 85 preterm in-

fants (25

- 34 weeks gesta-

tional age) 2 - 10

days of age

Heel lance 0.05 ml of 24%

sucrose via

syringe into the

mouth just prior

to heel lance (n =

27)

0.05 ml of 24%

su-

crose via syringe

into the mouth

just prior to heel

lance and simu-

lated rocking 15

minutes prior to

heel lance (n =

14)

0.05 ml of sterile

water via syringe

HR at baseline

and 3 x 30 second

blocks

Not reported Al-

though heart rate

increased across

all phases of pro-

cedure [F(3,59) =

2.94, p <0.04],

there was no sig-

nificant

differences noted

between groups

[F(3,59)=0.682,

p = 0.566]




into the mouth

just prior to heel

lance and simu-

lated rocking 15

minutes prior to

heel lance (n =

24)

0.05 ml of sterile

water via syringe

into the mouth

just prior to heel

lance

Ors 1999 102

healthy term in-

fants, gestational

age 37-42 weeks,

median postna-

tal age

1.6 days(range1-

15 days)


crose (n=35)

2ml of human

milk (n=33)

2ml of sterile wa-

ter (n=34)

syringed to ante-

rior part

of tongue for one

minute

Heel prick done 2

minutes after in-

tervention

Percent

change HR 1,2,3

minutes after heel

lance

Median, IQR Percent change in

heart rate after

heel lance was sig-

nificantly lower

in the group re-

ceiving 2ml of

25%(.5g) sucrose

compared

to groups receiv-

ing human milk

and sterile water

at 1, 2 and 3 min-

utes (p = 0.008, p

= 0.01, p = 0.002,

respectively)


born term in-

fants [mean age 6

days (range 4-9)]


crose solution via

syringe into the

mouth over 30

seconds 2 min-

utes prior to heel

lance

2ml of sterile wa-

ter via syringe

into the mouth

over 30 seconds 2

minutes prior to

heel lance

Change HR 0,1

minutes

Median, 5th and

95th percentiles

No signif-

icant differences

between groups,

p = 0.05




Ramenghi

1996a

15 preterm (32-

34 weeks gesta-

tion) infants

greater than 24

hours of age

Heel lance 1 ml of 25%

sucrose via sy-

ringe into mouth

2 minutes prior

to heel lance

1 ml of sterile

water via syringe

into mouth via

syringe 2 minutes

before heel lance.

(n=15, cross over

design)

Heart rate (at -2,

0, 1,3,5 minutes

from heel lance)

Median, IQR No signif-

icant differences

between groups,

p-value not re-

ported

Ramenghi

1996b

60 term (37 -

42 weeks gesta-

tional age) 2 - 5

days old infants

Heel lance 2 ml of 25%

sucrose via sy-

ringe into mouth

2 minutes prior

to heel lance (n =

15).

2ml of 50% su-

crose via syringe

into

mouth 2 minutes

prior to heel lance

(n =15).

2ml of commer-

cial sweet tasting

solution (Calpol)

via syringe into

mouth 2 minutes

prior to heel lance

(n = 15).

2ml of sterile wa-

ter via sy-

ringe into mouth

2 minutes prior

to heel lance (n =

15).

Percent change in

heart rate over 5

minutes (at -2,

0, 1,3,5 minutes

from heel lance)

Not reported Significant

increase in heart

rate for 3 minutes

after heel lance in

water group com-

pared with 2ml of

50% (1.0 g) su-

crose group and

Calpol group, p =

0.009


dian gestational

age of 32 wk,

median postna-

tal age of 14 days


crose, n = 12

1ml of 25% su-

crose, n =12

Changes in heart

rate from pre-

heel lance to heel

lance procedure

Not reported No

significant differ-

ences between

groups in changes

in heart rate from




milk via nasogas-

tric tube, n= 12

milk via nasogas-

tric tube, + 25%

sucrose, n = 12

All infants were

given water prior

to a second heel

lance

pre-heel lance to

heel lance proce-

dure (no p value

reported)

Table 3. Trials assessing oxygen saturation/respiratory status outcomes



- 36 weeks ges-

tational age) in-

fants, postnatal

age 1-26 days


crose via syringe

(n = 8)

2ml of 24% su-

crose via syringe

(n = 8)

2ml of spring wa-

ter via syringe (n

= 12) 2 minutes

prior to

venepuncture

Mean 02satura-

tion and respira-

tory rate pre so-

lution, post solu-

tion, 5 minutes

after

venepuncture

Reported means,

SD

No significant

differences noted

between

groups over time

for oxygen satu-

ration and respi-

ratory rates (no p-

values reported )


neonates (mean

30.5wk’s

gestational age),

mean postnatal

age 27.2 days

Venepuncture 2ml

of 25%(0.5g) su-

crose ad-

ministered by sy-

ringe into front

of infant’s mouth

over 2 minutes, 4

minutes prior to

venepuncture

Mean Sa02 (%)

at pre-procedure,

procedure and

post-procedure

Mean, SD No

significant differ-

ences between

groups with re-

spect to changes

in oxygen satu-

ration from pre-

procedure to pro-

cedure phase, p

=.17


fants (27

- 34 weeks gesta-

tional age), post-

natal age approx-

imately 42 days


crose via syringe

into the mouth

2 minutes before

heel lance.

tcpO2 (max in-

crease -kPa);

tcpO2 (max de-

crease -

kPa); tcpO2 (dif-

ference

Median, IQR No signif-

icant differences

between groups

with respect

to measures for

tcP02( p = 0.05)



Table 3. Trials assessing oxygen saturation/respiratory status outcomes (Continued)

2ml of distilled

water via syringe

into the mouth

2 minutes before

heel lance (n =

16, cross-over de-

sign)

between baseline

and 10 minutes

after end of in-

tervention -kPa);

tcpCO2 (max de-

crease -kPa);

tcpCO2 (differ-

ence between

baseline and 10

min after the end

of intervention),

recovery time for

respirations.

and tcPC02(p =

0.21)


fants (25

- 34 weeks gesta-

tional age) 2 - 10

days of age

Heel Lance 0.05 ml of 24%

sucrose via

syringe into the

mouth just prior

to heel lance (n =

27)

0.05 ml of 24%

su-

crose via syringe

into the mouth

just prior to heel

lance and simu-

lated rocking 15

minutes prior to

heel lance (n =

14)

0.05 ml of sterile

water via syringe

into the mouth

just prior to heel

lance and simu-

lated rocking 15

minutes prior to

heel lance (n =

24)

0.05 ml of sterile

water via syringe

into the mouth

just prior to heel

lance

02 saturation Not reported 02 sat-

uration dropped

from analysis



Table 3. Trials assessing oxygen saturation/respiratory status outcomes (Continued)


born term in-

fants [mean age 6

days (range 4-9)]


crose solution via

syringe into the

mouth over 30

seconds 2 min-

utes prior to heel

lance

2ml of sterile wa-

ter via syringe

into the mouth

over 30 seconds 2

minutes prior to

heel lance

02 saturation at

0, 1 minutes

Median, 5th and

95th percentiles

No signif-

icant differences

between groups

with respect to

changes in oxy-

gen saturation, p

= 0.8

Table 4. Trials assessing the quality of sucking outcomes


Ramenghi

1996a

15 (32-34 weeks

gestation)

infants greater

than 24 hours of

age

Heel Lance 1 ml of 25% su-

crose via sy-

ringe into mouth

2 minutes prior to

heel lance

1 ml of sterile wa-

ter via syringe into

mouth via syringe

2 minutes before

heel lance.

(n=15, cross-over

design)

Quality/intensity

of sucking

Not reported The clinical interpre-

tation of the quality

of sucking was signifi-

cantly more intense in

the 1ml of 25%(0.25

g) sucrose group than

in the water group

(p=0.04).

Table 5. Trials assessing grimace outcomes


Blass 1999 40 term newborn

infants, 34 - 55

hours old

Heel Lance 2ml of 12% sucrose

over two minutes

via syringe (n=10)

2ml of water via sy-

ringe over 2 min-

utes (n=10)

% time grimacing Not reported 2ml of 12%(0.24g) su-

crose reduced grimacing

compared to water, p =

0.0003 12%(0.24g) su-

crose with pacifier re-

duced grimacing com-

pared to water, p = 0.002



Table 5. Trials assessing grimace outcomes (Continued)

Pacifier dipped ev-

ery 30 seconds in

12% sucrose solu-

tion for two min-

utes (n=10)

Pacifier dipped in

water every 30 sec-

onds for two min-

utes (n = 10) prior

to heel lance

and water with pacifier, p

= 0.04

Table 6. Trials assessing multidimentional behavioural pain measure outcomes



neonates (mean

30.5wk’s

gestational age),

mean postnatal

age 27.2 days

Venepuncture 2ml

of 25%(0.5g) su-

crose ad-

ministered by sy-

ringe into front

of infant’s mouth

over 2 minutes, 4

minutes prior to

venepuncture

NFCS changes

across 3 phases of

venepuncture

Mean, SD Changes in mean

NFCS scores were

significantly lower in

the sucrose group

compared to water

group from pre-pro-

cedure to procedure

phase (estimated

treatment effect =

1.08), p =.013 and

between the pre-pro-

cedure and post-pro-

cedure phase (esti-

mated treatment ef-

fect = 2.39), p <

.001.

Carbajal 1999 150 term new-

born infants, 3-4

days old

Venepuncture No treatment (n

= 25)

2 ml of sterile

water via syringe

over 30 seconds

(n = 25)

2 ml of 30% glu-

cose via syringe (n

= 25)

2 ml of 30% su-

crose (n = 25)

Douleur

Aigue du Nou-

veau-ne (DAN)

scale

Median, IQR Median pain scores

with interquar-

tile ranges during

venepuncture were:

No treatment 7

(5-10); sterile water

group 7 (6-10); 30%

glucose group 5 (3-

7); 2ml of 30% su-

crose (0.6g) group 5

(2-8); pacifier alone

group 2 (1-4); 2ml

of 30% (0.6g) su-



Table 6. Trials assessing multidimentional behavioural pain measure outcomes (Continued)

Pacifier

alone (n = 25) 2

minutes prior to

venepuncture

2 ml of 30% su-

crose via syringe

followed by suck-

ing a pacifier (n =

25

crose with pacifier

group 1 (1-2). All

groups had signif-

icantly lower pain

scores compared to

ster-

ile water group: 30%

glucose (p = 0.005),

2ml of 30% (0.6g)

sucrose (p = 0.01),

pacifier (p <0.0001),

2ml of 30% (0.6g)

sucrose with pacifer

(p <0.0001). Pacifier

alone group had sig-

nificantly lower pain

scores than infants

receiving 30% glu-

cose (p = 0.0001) or

2ml of 30% (0.6g)

sucrose (p = 0.001).

Trend towards lower

pain scores for in-

fants receiving 2ml

of 30% (0.16g) su-

crose with pacifier

compared to pacifier

alone (p <0.06)


borns, mean ges-

tational age 39.4

weeks on 2nd or

3rd day of life

Heel Lance No

holding and ster-

ile water given by

pipette (n=21)

No holding and

0.250 ml of 24%

sucrose

solution given by

pipette (n=22)

Holding and ster-

ile water given by

pipette (n=20)

Holding

and 0.250 ml of

Pain concatena-

tion scores for fa-

cial activity

preintervention,

1, 2, 3 minutes af-

ter heel lance

Not reported Pain concatenation

scores measuring fa-

cial expressions of

pain decreased over

time [F(1,65)

= 28.5, p<0.001].

Only the effect

of holding reduced

pain scores [F(1,65)

= 5.6, p<0.02].No

difference as

to whether infant re-

ceived sucrose (taste

main effect F[1,65]

0.17,p=0.68




24% sucrose so-

lution by pipette

(n=22)

All solutions

given 3 times at

30 second inter-

vals


fants (25

- 34 weeks gesta-

tional age) 2 - 10

days of age

Heel Lance 0.05 ml of 24%

sucrose via

syringe into the

mouth just prior

to heel lance (n =

27)

0.05 ml of 24%

su-

crose via syringe

into the mouth

just prior to heel

lance and simu-

lated rocking 15

minutes prior to

heel lance (n =

14)

0.05 ml of sterile

water via syringe

into the mouth

just prior to heel

lance and simu-

lated rocking 15

minutes prior to

heel lance (n =

24)

0.05 ml of sterile

water via syringe

into the mouth

just prior to heel

lance

Behavioural

facial

actions(Neonatal

Facial

Coding System-

NFCS) at base-

line and 3 x30

second blocks

Not reported De-

crease in percent fa-

cial action in 0.05ml

of 24% (0.012g) su-

crose alone

group and combined

0.05ml

of 24%(0.012g) su-

crose and rocking

group compared to

water group, F (6,

150) = 2.765, p <

0.02

Ramenghi

1996a

15 (32-34 weeks

gestation)

infants greater

than 24 hours of

age


sucrose via sy-

ringe into mouth

2 minutes prior

to heel lance

Behavioral scores

(four facial ex-

pressions and the

presence of cry) -

Not reported Mean pain

scores were signifi-

cantly lower in the

groups receiving 1ml

of




1 ml of sterile

water via syringe

into mouth via

syringe 2 minutes

before heel lance.

(n=15, cross-over

design)

2,-1,0,1,2,3,5

minutes

25% sucrose(0.25g

)of sucrose at both 1

minute and 3 min-

utes after heel lance

( p = 0.01, p = 0.03,

respectively)

Ramenghi

1996b

60 term (37 -

42 weeks gesta-

tional age) 2 - 5

days old infants


sucrose via sy-

ringe into mouth

2 minutes prior

to heel lance (n =

15).

2ml of 50% su-

crose via syringe

into

mouth 2 minutes

prior to heel lance

(n =15).

2ml of commer-

cial sweet tasting

solution (Calpol)

via syringe into

mouth 2 minutes

prior to heel lance

(n = 15).

2ml of sterile wa-

ter via sy-

ringe into mouth

2 minutes prior

to heel lance (n =

15).

Behavioral scores

(four facial ex-

pressions and the

presence of cry) -

2,-1,0,1,2,3,5

minutes

Median, IQR Pain score (0 - 5) was

significantly higher

in water group (score

= 2, range 1-5) than

in other three groups

[(2ml of 50%(1 g

)sucrose group score

= 0, range 0 - 3;

2ml of 25%(0.5 g)

sucrose group score

= 0, range 0 - 2;

Calpol group score =

0, range 0 -1), p =

0.05

Ramenghi 1999 30 preterm in-

fants (GA 32-36

weeks, postnatal

age < 24 hours)

Heel Lance 25 % sucrose so-

lution (volume

not reported) was

given via syringe

into the mouth

or via NG tube

2 minutes prior

to first heel lance

(n = 15), and

via the alternate

Behavioral scores

(four facial ex-

pressions and the

presence of cry)

at 1, 3, and 5

minutes after the

lance for a total

behavioral score

Median, IQR Behavioral scores for

the intraoral water

group was 9 (in-

terquartile range 6-

12) and 10 (in-


14)

for N-G tube water

group. Behavioural

scores for intraoral




route for the sec-

ond heel lance

within 48 hours

Sterile water via

syringe into

the mouth or via

NG-tube 2 min-

utes prior to first

heel lance and for

the second heel

lance the alter-

nate route within

48 hours

(cross over de-

sign, n= 30)

25% sucrose group

was 5 (interquartile

range 3-6) and 9 (in-


10) for NG-tube su-

crose group. Signifi-

cant reduction in be-

havioral scores noted

in 25% sucrose

group (p = 0.002)

compared with wa-

ter group when in-

fants received 25%

sucrose in-

traorally but not via

N-G route. For in-

fants in 25% sucrose

group, there was sig-

nificant reduction in

behavioral score, p

= 0.001 when solu-

tion was given in-

traorally compared

to via NG-tube

Table 7. Trials assessing multidimentional composite pain measure outcomes


Gibbins 2001 190 preterm and

term

infants , mean

gestational age of

33.7 weeks, un-

der 7 days post

natal age

Heel Lance 0.5ml of 24% su-

crose via syringe

to

the anterior sur-

face of the tongue

followed by paci-

fier (n=64)

0.5ml 24% su-

crose without

pacifier (n=62)

0.5ml sterile wa-

ter with pacifier

(n=64)

Premature

Infant Pain Profile

(PIPP) scores at

30 and 60 seconds

after heel lance

Reported Means,

SD

Statistically signif-

icant difference in

mean PIPP scores

at both 30 seconds

(F

= 8.23, p<0.001)

and 60 seconds (F

= 8.49, p<0.001)

after heel lance in

favour of 0.5ml

of 24%(0.12g) su-

crose

group and 0.5ml

of 24%(0.12g) su-

crose with paci-



Table 7. Trials assessing multidimentional composite pain measure outcomes (Continued)

2 minutes prior to

heel lance

fier group. Post-

hoc Tukey tests

showed infants

who received su-

crose and pacifier

had significantly

lower PIPP scores

after heel lance at

30 seconds (mean

8.16, SD 3.24)

compared to in-

fants receiving su-

crose alone (mean

9.77, SD 3.04, p

= 0.007) and wa-

ter with pacifier

(mean 10.19, SD

2.67,

p<0.001). At 60

seconds after heel

lance, PIPP scores

were significantly

lower for 0.5ml

of 24%(0.12g) su-

crose with paci-

fier group (mean

8.78, SD 4.03)

compared to the

0.5ml of

24%(0.12g)sucrose

alone group

(mean 11.20, SD

3.25, p = 0.005)

and water with

pacifier group

(mean 11.20, SD

3.47, p = 0.007).

No significant dif-

ferences in PIPP

scores found be-

tween 0.5ml

0f 24%(0.12g) su-

crose alone group

or

water with pacifier

group at both fol-

low-up times




Johnston 1999a 48 preterm

neonates

mean gestational

age of 31

weeks (range 25-

34 weeks) within

10 days of birth

Heel Lance 0.05ml of 24%

sucrose as a single

dose, followed by

2 doses of sterile

water (n=15)

3 doses of 0.05ml

of 24% sucrose

(n=17)

3 doses of 0.05ml

of sterile water

(n=16)

given by syringe to

anterior surface of

the tongue at:

2 minutes prior to

heel lance

just prior to lanc-

ing

2 minutes after

lancing

Premature Infant

Pain Pro-

file( PIPP) scores

in five 30 second

blocks

Reported Means,

SD

Statistically signif-

i-

cant difference be-

tween groups (F =

9.143, p<0.0001)

for mean

PIPP scores. Post-

hoc analysis found

significantly lower

PIPP scores with

repeated

doses of 0.05ml of

24%(0.012g)

sucrose compared

to placebo groups

across all blocks

of time, p<0.05.

PIPP

scores for repeated

doses of 0.05ml of

24%(0.012g) su-

crose were signifi-

cantly lower com-

pared to single

doses of 0.05ml of

24%(0.012g)sucrose

(8.25 vs. 6.25)

only at last block

of time, p<0.05.

PIPP

scores for single

doses of 0.05ml of

24%(0.012g)

sucrose compared

to placebo showed

trend towards sta-

tistical signifi-

cance in favour of

0.05ml of

24%(0.012g)sucrose

(F = 3.465, p =

0.07)





born term in-

fants [mean age 6

days (range 4-9)]


crose solution via

syringe into the

mouth over 30

seconds 2 minutes

prior to heel lance

2ml of sterile wa-

ter via syringe into

the mouth over 30

seconds 2 minutes

prior to heel lance

NIPS

scores 1 minute

after heel lance

and 1 minute after

blood sampling

Median, 5th and

95th percentiles

Median NIPS

scores 1 minute

after heel lance

were lower in 2ml

of 50% (1.0 g) su-

crose group com-

pared to placebo

group [(3(0-

7), 6(0-7), respec-

tively), p = 0.04].

Me-

dian NIPS scores

1 minute after end

of blood sampling

were lower in 2ml

of 50% (1.0g) su-

crose group (0 (0-

7) compared to

placebo group[(2

(0-7), p = 0.05]

Stevens 1999 122 neonates, 27

- 31 weeks ges-

tational age, less

than 28 days of

age

Heel Lance Prone positioning

30 minutes prior

to heel lance

Pacifier dipped in

sterile water and

placed into the

mouth 2 minutes

prior to heel lance

Pacifier dipped in

24% sucrose and

placed into the

mouth 2 minutes

prior to heel lance

Control:Containment

in SnuggleUp de-

vice (n = 122)

NB: All infants

were contained in

SnuggleUp device

Premature Infant

Pain Profile(PIPP)

scores at 30 and

60 seconds

Reported Means,

SD

Main

effect of treatment

for mean PIPP

scores, [F (16.20),

p < 0.0001]. Post

hoc analysis re-

vealed significant

reduction in PIPP

scores 30 seconds

after heel lance

in sucrose group

(pacifier dipped in

24 % sucrose - es-

timated at 0.02g),

(mean 7.87, SD

3.35), compared

to control group

[(mean 9.80, SD

3.55), F (24.09),

p< 0.0001]. Sta-

tistically sig-

nificant reduction

in PIPP scores in

pacifier and wa-

ter group (mean




8.44, SD 3.55)

compared to con-

trol group [(mean

9.80, SD 3.55),

F (9.00), p =

0.003]. Trend to-

wards lower PIPP

scores with su-

crose and paci-

fier group com-

pared to water and

pacifier group [(F

(3.62), p<0.05)]

Table 8. Cortisol Levels

Study Participants Procedures Intervention Outcomes Metrics used Results


borns, approx.

17-19 hours old.

Heel Lance Sugar coated paci-

fier (n=21)

water moistened

pacifier (n=21)

2ml of 12% su-

crose (n =21)

routine care

(n=21)

Salivary cortisol

levels

Not reported No significant differ-

ences were found in

salivary cortisol levels

across groups (no p

value reported).

Table 9. Skin Conductance



dian gestational

age of 32 wk, me-

dian postnatal age

of 14 days


crose, n = 12

1ml of 25% su-

crose, n =12

milk via nasogas-

tric tube, n= 12

milk via nasogas-

tric tube, + 25%

sucrose, n = 12

Difference in skin

conductance from

pre heel lance to

heel lance proce-

dure

Not reported No statistically signifi-

cant smaller increase in

skin conductance vari-

ables compared to their

water control session (p

value not reported).



Table 9. Skin Conductance (Continued)

All infants were

given water prior to

a second heel lance

Behavioural Outcomes

1. Cry Behaviour

Of the 15 studies that evaluated cry behaviour in term and preterm

neonates, all but two studies (Greenberg 2002; Rushforth 1993)

found significant reductions in crying in the sucrose groups.

In these 15 studies, eight studies evaluated time crying during

three minutes after a painful procedure (Abad 1993; Blass 1999;

Gormally 2001; Greenberg 2002; Haouari 1995; Isik 2000; Ors

1999; Ramenghi 1996b). Doses of as little as 0.25 ml of 24% su-

crose (Gormally 2001) to as high as 2ml of 50% sucrose (Ramenghi

1996b) reduced cry behaviour three minutes after venepuncture

or heel lance. In the study by Abad (1996), cry duration was sig-

nificantly reduced in the group receiving 2ml of 24% (0.48g) su-

crose at three minutes after venepuncture compared to water (p <

0.05) but not in the group receiving 2ml of 12% (0.24g). Haouri

(1995) assessed total crying time over three minutes using 2ml

of 12.5% (0.25g) sucrose, 2ml of 25% (0.5g) sucrose and 2ml of

50% (1.0g) sucrose. Results showed a reduction in total crying

time and the time of first cry (p < 0.02), median time crying at

the end of the first and second minutes in the group receiving

2ml of 50% (1.0g) sucrose compared to the control group (p <

0.02 and p = 0.003, respectively). In the second minute, duration

of cry was also lower in the group receiving 2ml of 25% (0.5g)

sucrose compared to the control group (p = 0.02). The study by

Overgaard (1999) evaluated various measures of cry behaviour and

reported significant reductions in cry behaviour for the group re-

ceiving 2ml of 50% (1.0g) sucrose compared to the control group.

Cry behaviour was also reduced over five minutes after heel lance

in infants who received sucrose compared to the control groups

(Ramenghi 1996a, Ramenghi 1999). Duration of first cry was

also lower in the groups receiving sucrose compared to the control

groups (Ramenghi 1996a, Ramenghi 1999).

2. Quality of Sucking

The one study, by Ramenghi 1996b, that assessed the quality of

sucking in preterm infants found that the quality of sucking was

significantly more intense in infants who received 1ml of 25%

(0.25g) sucrose compared to those who were in the control group

(p = 0.04).

3. Grimace

The one study by Blass 1999, that evaluated percent time grimac-

ing in term infants undergoing heel lance found reduced grimac-

ing in infants who received 2ml of 12% (0.24g) sucrose alone com-

pared with water (p = 0.0003) and sucrose with pacifier compared

to water alone (p = 0.002) and water with pacifier (p = 0.04).

Physiologic Outcomes

1. Heart Rate/Vagal Tone

Of the 15 studies measuring heart rate/vagal tone, sucrose had a

significant effect in reducing heart rate in eight studies (Abad 1993,

Acharya 2004, Blass 1999, Bucher 1995, Gormally 2001, Hauoari

1995, Ors 1999, Ramenghi 1996b). When results for change in

heart rate were pooled for two of these studies (Haouari 1995,

Isik 2000a), there was statistically significant heterogeneity found

between studies at one minute after heel lance and no heterogeneity

between studies at three minutes after heel lance. There were no

significant differences in per cent change in heart rate for infants

given sucrose (dose range 0.5 g to 0.6 g) compared to the control

group, [WMD 0.90% (95% CI -5.81, 7.61); p = 0.8] at one

minute and [WMD -6.20% (95% CI -15.27, 2.88); p = 0.18] at

three minutes after heel lance. The one study that assessed vagal

tone (Gormally 2001) reported no significant main effects.

2. Oxygen Saturation/Respiratory Status

None of the five studies that assessed the effects of sucrose on

oxygen saturation and respiratory rates reported significant differ-

ences between groups.

Multidimensional Behavioural Pain Measures

Of the seven studies that used multidimensional behavioural pain

measures, six studies (Acharya 2004, Carbajal 1999, Johnston

1997a, Ramenghi 1996a, Ramenghi 1996b, Ramenghi 1999)

found significant results in favour of sucrose. In the study by Car-

bajal (1999), pain was measured using the Douleur Aigue du Nou-

veau-ne (DAN) scale, which assesses facial expression, limb move-

ments and vocal expression. Although this study reported signifi-

cantly lower pain scores in all intervention groups compared to the

control group, there were also lower pain scores for the infants who

were given a pacifier alone compared to the groups who received

glucose or 30% sucrose (p = 0.0001). Johnston (1997a) measured

pain using the Neonatal Facial Coding System which includes

10 facial actions and found that the groups receiving 0.05ml of

24% (0.012g) sucrose and combined sucrose with rocking had

decreased facial actions compared to the control group (p < 0.02).

The three studies by Ramenghi (1996a, 1996b, 1999) measured

pain using their own pain scale that included four facial expres-



sions and the presence of cry. Sucrose doses used ranged from 1ml

of 25% (0.25g) sucrose to 2ml of 50%(1.0g) sucrose. Pain scores

were significantly lower in the groups that received sucrose com-

pared to the control groups.

Multidimensional Composite Pain Measures

Three studies used the Premature Infant Pain Profile (PIPP) to

evaluate pain (Gibbins 2001, Johnston 1999a, Stevens 1999). The

PIPP is a validated pain measure that includes behavioural (three

facial actions), physiologic (heart rate and oxygen saturation) and

contextual indicators(gestational age and behavioural state). When

PIPP scores were pooled across three studies (Gibbins 2001, John-

ston 1999a, Stevens 1999), there was no statistically significant

heterogeneity found. PIPP scores were significantly reduced in in-

fants who were given sucrose (dose range 0.012 g to 0.12 g) com-

pared to the control group, [WMD -1.64 (95% CI -2.47, - 0.81);

p = 0.0001] at 30 seconds and [WMD -2.05, (95% CI -3.08, -

1.02); p = 0.00010] at 60 seconds after heel lance. In the study by

Overgaard (1999), the Neonatal Infant Pain Scale (NIPS), com-

posed of behavioural and physiologic indicators, was used to assess

pain in infants receiving 2ml of 50% (1.0g) sucrose compared to

water. NIPS scores were significantly lower in the group receiving

sucrose compared to the control group.

Adverse Effects

Of the six studies that evaluated adverse effects (Acharya 2004,

Carbajal 1999, Gibbins 2001, Guala 2001, Ramenghi 1996a,

Stevens 1999), one study by Gibbins 2001 reported side effects in

infants. In this study, minor adverse effects were found in six in-

fants. None of the adverse events occurred in the sucrose with paci-

fier group. One neonate who received water with pacifier choked

when administered the water and stabilized within 10 seconds.

Three infants randomized to the sucrose group and two infants

randomized to the water with pacifier groups desaturated when

the study intervention was administered. Each neonate recovered

spontaneously with no medical interventions required.

D I S C U S S I O N

In the reviewed studies, sucrose was generally found to decrease

pain from heel lance and venepuncture in neonates hospitalized

in the NICU. This conclusion is based on decreases in individ-

ual physiologic (heart rate) and behavioural pain indicators (the

mean percent time crying, total cry duration, duration of first cry,

and facial action) and composite (PIPP, Stevens 1996) pain scores.

There was inconsistency in the dose of sucrose that was effective,

although a dose range of 0.012g to 0.12g was identified. In the

studies by Johnston (Johnston 1997a) and Stevens (Stevens 1999),

very small volumes of 24% sucrose (estimated at 0.01g - 0.02 g)

significantly reduced pain as compared to the control interven-

tions in preterm infants in the NICU. However, in the meta-anal-

ysis by Stevens (Stevens 1997a), which was primarily comprised

of healthy term neonates, 0.18g of sucrose was ineffective in re-

ducing proportion of time crying and did not differ from the con-

trol solution (water). Doses of 0.24g or greater were most effective

.There was some additional, although not statistically significant

benefit from administering 0.48g - 0.50g sucrose (as evidenced

in the decrease in proportion of cry between 0.24g and 0.48g or

0.50g) but there did not appear to be any benefit in administering

doses of sucrose greater than 0.50g. The results of this systematic

review found a significant reduction in PIPP scores using sucrose

doses 0.012g to 0.12g (0.05ml to 0.5ml of 24% sucrose solution)

at both 30 seconds and 60 seconds after heel lance. The con-

trol groups either had a positioning and containing intervention

(Stevens 1999), water (Johnston 1999a), or water and pacifier (

Gibbins 2001). It is important to note that (a) for ethical reasons,

there were no “no treatment” interventions used in these three

studies, so the control groups were really comparison groups and

(b) a validated measure of pain was used as compared to the previ-

ous review where one behavioural indicator (cry) was commonly

used as a proxy for pain. Of the three studies reporting PIPP scores,

the study by Gibbins (Gibbins 2001) administered 0.12g (0.5ml

of 24% sucrose) of sucrose to both preterm and term neonates and

reported only minor adverse effects that resolved spontaneously.

Sucrose administration was also associated with decreases in heart

rate, facial actions and motor activity during the immediate post

stimulus period. When results for percent change in heart rate at

one minute and three minutes after heel lance were pooled for two

studies, there was no significant difference between groups. For

the studies that evaluated oxygen saturation and respiratory rates,

there were no significant effects of the interventions found in each

of the studies.

Different concentrations of sucrose administered at varying time

intervals have indicated that the greatest analgesic effect is realized

when sucrose is administered approximately two minutes before

the painful stimulus. This interval is thought to coincide with

endogenous opioid release. Adverse effects were evaluated in four

studies. In the study that most carefully observed for adverse events

(Gibbins 2001), only 6 infants (3%) experienced minor side ef-

fects (e.g., oxygen desaturation, choking) which did not require

any intervention. It is not clear whether investigators in the other

three studies carefully monitored for adverse effects or for how

long. Reporting on the incidence of any adverse effects of single

or repeated administration of sucrose of various concentrations

needs to be undertaken in both term and preterm infants. One

group of investigators, 25 years ago, reported that frequent (8-

12 times per day) small volumes (0.5-1 ml) of 20% sucrose con-

centration (mixed with calcium lactate given 20 minutes prior to

gavage feeding) could be a contributor to necrotizing enterocolitis

(NEC) in very low birth weight infants (Willis 1977). This find-

ing was hypothesized to be the result of the hyperosmolality of

the undiluted calcium lactate solution that led to local trauma to



the upper gut wall, initiating the pathological process resulting in

NEC. Since the methodologic rigor of this study was somewhat

questionable, specific attention to the efficacy and the safety of

sucrose administration in very-low-birth-weight preterm infants

needs to be considered.

Generally, babies were healthy and stable and very few were less

than 27 weeks gestational age at birth. Although the preterm in-

fant’s pain response is generally consistent with that of the term

infant, it is often more subtle, less sustained and affected by the

infant’s behavioural state and severity of illness. There was no sig-

nificant difference in this systematic review between the cry out-

comes in term and preterm infants; however, the incidence of cry-

ing following painful stimuli has been reported to be 50% less in

preterm infants as compared to term infants in other research (

Stevens 1994), therefore not making it a reliable indicator of pain

in this population. We have limited knowledge of what dose of

sucrose or administration method provides the least risk for less

healthy preterm infants and very low birth weight infants (Gibbins

2001).

The strength of the studies reviewed was in the design. Most were

carefully planned prospective randomized controlled clinical trials

with a control group and one or more treatment interventions. Ten

studies were not double-blinded as additional interventions (e.g.,

use of pacifiers) were utilized that precluded blinding. Several stud-

ies could not be included as the methods of allocation and/or the

number of infants in each condition (intervention group) were not

clearly stated. Methods of blinding of randomization frequently

were not reported. Attempts to obtain missing information were

generally met with limited success.

There were both conceptual and methodological limitations in the

studies that were identified in the systematic review. Few studies

provided a definition of pain or how it was conceptualized in rela-

tion to the outcomes. If the reported outcomes reflect the investi-

gators’ conceptualization of pain, then we can assume that most in-

vestigators considered proportion, percentage or duration of time

crying to be the most valid indicator of pain in neonates. Few in-

vestigators used composite pain assessments or multidimensional

approaches to pain measurement that reflect a more comprehen-

sive conceptualization of pain. Although research on infant cry

has delineated certain cry characteristics such as pitch, intensity,

melody and harmonics as being good indicators of pain, these were

not assessed in the sucrose studies reviewed. Cry duration may give

some indication of distress. However, alone, it does not necessar-

ily confirm or deny that the infant is in pain. For unstable and

ventilated infants who do not cry following painful procedures,

cry may be an inappropriate outcome. Recent research suggests

that a multivariate approach or composite pain score including

physiologic, behavioural and contextual indices would be a more

valid measure of pain (Stevens 1997c).

There were also differences in study methods. The majority of

studies utilized heel lance as the pain stimulus. However, little de-

tail about this procedure was provided. Therefore, it is impossible

to know if the painful stimuli (or painful procedures) were compa-

rable in intensity, duration or frequency. Preparation for the heel

lance through heel warming, and soothing interventions through-

out the procedure such as containment or positioning, could pro-

vide comfort to the infant and act as co-interventions. The length

of infant observation following the heel lance was not reported

frequently. This lack of methodologic standardization may have

implications for the incidence of adverse effects.

The delivery method of sucrose varied between studies. Sucrose

was delivered to the infant by syringe, dropper or pacifier. The

pacifier promotes non-nutritive sucking and calming that may also

contribute to reducing pain-elicited distress (Campos 1994). Blass

(1994) suggests that sucking exerts a profound behavioural effect

and induces feelings of calm. Other researchers have found that

non-nutritive sucking reduces heart rate and metabolic rate, causes

infants to bring their hands to their mouths and elevates the pain

threshold. However, contact has not been shown to affect cortisol

response, heart rate, vagal tone and oxygen saturation (DiPietro

1994; Gunnar 1992). The calming effects have not been sustained

following cessation of the contact. This is in contrast to sucrose

administration where the effects persist beyond the cessation of

contact for several minutes. Blass and Hoffmeyer (Blass 1991) ex-

amined the combined effectiveness of sucrose and pacifiers for re-

lieving procedural pain in neonates and reported that physiologic

and behavioural changes resulted from both sucrose and non-nu-

tritive interventions. More research addressing the analgesic and

calming effects of sucrose and their interaction needs to be under-

taken to increase understanding of the underlying mechanisms of

sucrose and pain relief in the infant.

There were no major changes made to the methods used for this

systematic review. Some minor refinements to the inclusion crite-

ria for the first update of the review were made (e.g., intramuscu-

lar injections were not included as a painful procedure; abstracts

were not included). Otherwise, standard review procedures were

followed for the present review, as for the previous review.

In summary, the four new included studies in this review con-

firm the previous results that support the efficacy and safety of

sucrose for reducing pain from single heel lance and venepuncture

for neonates. However, one study (Carbajal 1999) supported the

efficacy of a pacifier over sucrose. Additional research is required

to better determine the efficacy and safety of sucrose for repeated

administration used alone and in combination with other phar-

macologic and nonpharmacologic interventions.

A U T H O R S ’ C O N C L U S I O N SImplications for practice

This review indicates that sucrose reduces procedural pain from



heel lance and venepuncture in neonates, with minimal to no side

effects. Very small doses of 24% sucrose (0.01 - 0.02g) have been

reported to be efficacious in reducing pain in very low birth weight

infants while larger doses (0.24 - 0.50g) reduce the proportion of

time crying in term infants following a painful procedure. A dose

range for reducing pain associated with procedures in neonates was

identified as 0.012 - 0.12g (0.05ml to 0.5ml of 24% solution) of

sucrose. Based on these findings, we would recommend the routine

use of sucrose 0.012 - 0.12g to be administered approximately

2 minutes prior to single heel lances and venepunctures for pain

relief in neonates. However, given that composite pain scores were

only reduced on average by approximately 20%, we would also

recommend that other methods of pain relief be considered for use

in combination with sucrose administration to more significantly

reduce or eliminate pain in this population.

Implications for research

Investigators embarking on further research should utilize existing

evidence to answer questions on efficacy and safety when used with

painful procedures other than heel lance (e.g. intravenous starts,

lumbar punctures, percutaneous line insertions). Considerations

for future research are to describe the painful procedure and in-

tervention in detail, to use appropriate sample size to show a sta-

tistically significant reduction in pain, to use a multidimensional

conceptualization of pain, to select outcome measures that are re-

liable and valid pain indicators and to account for the variation

in the infant’s response and context in which the pain is experi-

enced. The use of repeated administrations of sucrose in neonates

needs to be investigated in terms of clinical, developmental and

economic outcomes. Also, there is a need to evaluate the use of

sucrose in combination with other behavioural (e.g., facilitated

tucking, kangaroo care) and pharmacologic (e.g. morphine, fen-

tanyl) interventions for more invasive procedures (e.g. circumci-

sion). Use of sucrose in neonates that are very low birth weight,

unstable and/or ventilated also needs to be addressed. Replication

of existing studies of high methodological quality and using iden-

tical validated outcomes would allow for combination of results

in meta-analyses.

A C K N O W L E D G E M E N T S

We would like to acknowledge the assistance of:

Ms. Moira Lynch for conducting an extensive updated search of

MEDLINE, EMBASE and the Cochrane Database in April of

2001 and Tamsin Adams-Webber for her assistance with our cur-

rent 2004 update.

Dr. Celeste Johnston, Dr. Aage Knudsen and Dr. Sharyn Gibbins

for providing unpublished data.

Dr. Sharyn Gibbins for her assistance with quality assessment and

data extraction of the studies for the review update.

R E F E R E N C E S

References to studies included in this review

Abad 1996 {published data only}

Abad F, Diaz NM, Domenech E, Robayna M, Rico J. Oral sweet

solution reduces pain-related behavior in preterm infants. Acta Pae-

diatr 1996;85:854–8.

Acharya 2004 {published data only}

Acharya AB, Annamali S, Taub NA, Field D. Oral sucrose analgesia

for preterm infant venepuncture. Arch Dis Child Fetal Neonatal Ed

2004;89:F17–F18.

Blass 1999 {published data only}

Blass EM, Watt LB. Suckling- and sucrose-induced analgesia in hu-

man newborns. Pain 1999;83:611–23.

Bucher 1995 {published data only}

Bucher H-U, Moser T, von Siebenthal K, Keel M, Wolf M, Duc G.

Sucrose reduces pain reaction to heel lancing in preterm infants: A

placebo-controlled, randomized and masked study. Pediatr Res 1995;

38:332–5.

Carbajal 1999 {published data only}

Carbajal R, Chauvet X, Couderc SD, Olivier-Martin M. Randomised

trial of analgesic effects of sucrose, glucose, and pacifiers in term

neonates. BMJ 1999;319:1393–7.

Gibbins 2001 {published data only}∗ Gibbins S. Efficacy and safety of sucrose for procedural pain relief

in preterm and term neonates[dissertation]. Toronto: University of

Toronto, 2001.

Gibbins S, Stevens B, Hodnett E, Pinelli J, Ohlsson A. Efficacy

and safety of sucrose for procedural pain relief in preterm and term

neonates. Nurs Res 2002;51:375–82.

Gormally 2001 {published data only}

Gormally S, Barr RG, Wertheim L, Alkawaf R, Calinoiu N, Young

SN. Contact and nutrient caregiving effects on newborn infant pain

responses. Dev Med Child Neurol 2001;43:28–38.

Greenberg 2002 {published data only}

Greenberg CS. A sugar-coated pacifier reduces procedural pain in

newborns. Pediatr Nurs 2002;28:271–7.

Guala 2001 {published data only}

Guala A, Pastore G, Liverant MF, Giroletti G, Gulino F, Meriggi

AI, Licardi G, Garipoli V. Glucose or sucrose as an analgesic for

newborns: A randomized controlled blind trial. Minerva Pediatr

2001;53:271–4.

Haouari 1995 {published data only}

Haouari N, Wood C, Griffiths G, Levene M. The analgesic effect

of sucrose in full term infants: a randomised controlled trial. BMJ



1995;310:1498–500.

Isik 2000a {published data only}

Isik U, Ozek E, Bilgen H, Cebeci D. Comparison of oral glucose

and sucrose solutions on pain response in neonates. J Pain 2000;1:

275–8.

Johnston 1997a {published data only}

Johnston C, Stremler R, Stevens B, Horton L, Stremler R. Effec-

tiveness of oral sucrose and simulated rocking on pain response in

preterm neonates. Pain 1997;72:193–9.

Johnston 1999a {published data only}

Johnston CC, Stremler R, Horton L, Friedman A. Effect of repeated

doses of sucrose during heel stick procedure in preterm neonates.

Biol Neonat 1999;75:160–6.

Ors 1999 {published data only}

Ors R, Ozek E, Baysoy G, Cebeci D, Bilgen H, Turkuner M, Basaran

M. Comparison of sucrose and human milk on pain response in

newborns. Eur J Pediatr 1999;158:63–6.

Overgaard 1999 {published data only}

Overgaard C, Knudesen A. Pain-relieving effect of sucrose in new-

borns during heel prick. Biol Neonate 1999;75:279–84.

Ramenghi 1996a {published data only}

Ramenghi LA, Wood CM, Griffith GC, Levene MI. Reduction of

pain response in premature infants using intraoral sucrose. Arch Dis

Child 1996;74:F126–8.

Ramenghi 1996b {published data only}

Ramenghi L, Griffith G, Wood C, Levene M. Effect of non-sucrose

sweet tasting solution on neonatal heel prick responses. Arch Dis

Child 1996;74:F129–31.

Ramenghi 1999 {published data only}

Ramenghi LA, Evans DJ, Levene MI. “Sucrose analgesia”: absorptive

mechanism or taste perception?. Arch Dis Child Fetal Neonatal Ed

1999;80:F146–F147.

Rushforth 1993 {published data only}

Rushforth JA, Levene MI. Effect of sucrose on crying in response to

heel stab. Arch Dis Child 1993;69:388–9.

Stevens 1999 {published data only}

Johnston CC, Sherrard A, Stevens B, Franck L, Stremler R, Jack

A. Do cry features reflect pain intensity in preterm neonates?. Biol

Neonat 1999;76:120–4.∗ Stevens B, Johnston C, Franck P, et al.The efficacy of developmen-

tally sensitive interventions and sucrose for relieving pain in very low

birth weight infants. Nurs Res 1999;48:35–43.

Storm 2002 {published data only}

Storm H, Fremming A. Food intake and oral sucrose in preterms

prior to heel prick. Acta Paediatr 2002;91:555–60.

References to studies excluded from this review


Abad F, Diaz NM, Domenech E, et al.Attentuation of pain related

behavior in neonates given oral sweet solutions. 7th World Congress

on Pain. Paris, 1993.


Abad F, Diaz-Gomez NM, Domenech E, Gonzalez D, Robayna M,

Feria M. Oral sucrose compares favourably with lidocaine-prilocaine

cream for pain relief during venepuncture in neonates. Acta Paediatr

2001;90:160–5.

Ahuja 2000 {published data only}

Ahuja VK, Daga SR, Gosavi DV, Date AM. Non-sucrose sweetener

for pain relief in sick newborns. Indian J Pediatr 2000;67:487–9.

Allen 1996 {published data only}

Allen K, White D, Walburn J. Sucrose as an analgesic agent for infants

during immunization injections. Arch Pediatr Adolesc Med 1996;

150:270–4.

Barr 1993 {published data only}

Barr RG, Oberlander T, Quek V, Brian J, Cassidy K-L, Beauparlant

J, Young S. Dose-response analgesic effect of intraoral sucrose in

newborns [abstract]. Prog Soc Res Child Develop. 1993.

Bilgen 2001 {published data only}

Bilgen H, Ozek E, Cebeci D, Ors R. Comparison of sucrose, ex-

pressed breast milk, and breast-feeding on the neonatal response to

heel prick. J Pain 2001;2:301–5.


Blass EM, Hoffmeyer LB. Sucrose as an analgesic for newborn infants.

Pediatrics 1991;87:215–8.


Blass EM, Shah A. Pain-reducing properties of sucrose in human

newborns. Chem Senses 1995;20:29–35.

Bucher 2000 {published data only}

Bucher HU, Baumgartner R, Bucher N, Seiler M, Fauchere JC. Arti-

ficial sweetner reduces nociceptive reaction in newborn infants. Early

Hum Dev 2000;59:56–60.

Gibbins 2000 {published data only}

Gibbins S, Stevens B, Ohlsson A, Hodnett E, Pinelli J. Safety and

efficacy of sucrose for procedural pain in neonates. The 5th Interna-

tional Symposium on Paediatric Pain. London, 2000:P98.

Gormally 1996 {published data only}

Gormally SM, Barr RG, Young SN, Alhawaf R, Wersheim L. Com-

bined sucrose and carrying reduces newborn pain response more than

sucrose or carrying alone. Arch Pediatr Adolesc Med 1996;150:47.

Graillon 1997 {published data only}

Graillon A, Barr RG, Young SN, Wright JH, Hendricks LA. Differ-

ential response to intraoral sucrose, quinine and corn oil in crying

human newborns. Physiol Behav 1997;62:317–25.

Harrison 2003 {published data only}

Harrison D, Johnston L, Loughan P. Oral sucrose for procedural pain

in sick hospitalized infants: A randomized-controlled trial. J Paediatr

Child Health 2003;39:591–7.

Herschel 1998 {published data only}

Herschel M, Khoshnood B, Ellman C, Maydew N, Mittendorf R.

Neonatal circumcision. Randomized trial of sucrose pacifier for pain

control. Arch Pediatr Adolesc Med 1998;152:279–84.

Isik 2000b {published data only}

Isik U, Ozek E, Bilgen H, Ors R, Cebeci D, Basaran M. Comparison

of oral dextrose and sucrose solutions on pain response in neonates.

Pediatr Res 2000;47:403A.

Johnston 2000 {published data only}

Johnston C, Filion F, Majnemer A, et al.The efficacy of sucrose anal-

gesia for procedural pain in preterm infants < 32 weeks in the first

week of life. Pediatr Res 2000;47:405A.



Lewindon 1998 {published data only}

Lewindon PJ, Harkness L, Lewindon N. Randomized controlled trial

of sucrose by mouth for the relief of infant crying after immunization.

Arch Dis Child 1998;78:453–5.

Mellah 1999 {published data only}

Mellah D, Gourrier E, Merbouche S, Mouchino G, Crumiere C,

Leraillez J. Analgesia with intraoral administration of saccharose dur-

ing heel prick: a randomised, placebo controlled study in 37 new-

born infants [Analgesie au saccharose lors des prelevements capillaires

au talon. Etude randomisee chez 37 nouveau–nes de plus de 33 se-

maines d’amenorrhee]. Arch Pediatr 1999;6:610–6.

Mohan 1998 {published data only}

Mohan CG, Risucci DA, Casimir M, Gulrajani-LaCorte M. Com-

parison of analgesics in ameliorating the pain of circumcision. J Peri-

natol 1998;18:13–9.

Skogsdal 1997 {published data only}

Skogsdal Y, Eriksson M, Schollin J. Analgesia in newborns given oral

glucose. Acta Paediatrica 1997;86:217–20.

Stang 1997 {published data only}

Stang HJ, Snellman LW, Condon LM, Conroy MM, Liebo R,

Brodersen L, Gunnar MR. Beyond dorsal penile nerve block: a more

humane circumcision. Pediatrics 1997;100:E3.

Stevens 1997b {published data only}

Stevens B, Johnston C, Franck P, et al.Nonpharmacologic interven-

tions for decreasing procedural pain in preterm neonates. Fourth

International Symposium on Pediatric Pain. Helsinki, 1997:154.

Stevens 2000 {published data only}

Stevens B, Petryshen P, Johnston C, Franck L, Jack A. The influ-

ence of consistent pain management on neonatal outcomes: prelimi-

nary findings. The 5th International Symposium on Paediatric Pain.

London, UK, 2000:P96.

Additional references

AAP 2000

American Academy of Pediatrics (the Committee on Fetus and New-

born, Committee on Drugs, Section on Anesthesiology, Section on

Surgery). Canadian Paediatric Society (the Fetus and Newborn Com-

mittee). Prevention and management of pain and stress in the new-

born infant. Pediatrics 2000;105:454–61.

Anand 1995

Anand KJS. Managing pain in newborns. How far have we really

come?. MD News Atlanta 1995;Oct/Nov:8–12.

Anand 2001

Anand KJS, Abu-Saad HH, Aynsley-Green A, Bancalari E, Benini

E, Champion GD, Craig KA, Dangel TS, Fournier-Charriere E,

Franck LS, Eckstein Grunau R, Hertel SA, Jacqz-Aigrain E, Jorch G,

Kopelman BI, Koren G, Larsson B, Marlow N, McIntosh N, Ohlsson

A, Porter F, Richter R, Stevens B, Taddio A. Consensus statement

for the prevention and management of pain in the newborn. Arch

Pediatr Adolesc Med 2001;153:173–80.

Barr 1994

Barr RG, Quek V, Cousineau D, Oberlander T, Brian J, Young S.

Effects of intraoral sucrose on crying, mouthing and hand-mouth

contact in newborn and six-week old infants. Dev Med Child Neurol

1994;36:608–18.

Campos 1994

Campos RG. Rocking and pacifier; two comforting interventions for

heel stick pain. Res Nurs Health 1994;17:321–31.

DiPietro 1994

DiPietro JA, Cusson RM, O’Brian CM, et al.Behavoural and phys-

iological effects of nonnutritive sucking during gavage feeding in

preterm infants. Pediatr Res 1994;36:207–14.

Fernandes 1994

Fernandes CV, Rees EP. Pain management in Canadian level 3 neona-

tal intensive care units. Can Med Assoc J 1994;150:469–70.

Gunnar 1988

Gunnar MR, Connors J, Isensee J, Wall L. Adrenocortical activity

and behavioral distress in human newborns. Dev Psychobiol 1988;

21:297–310.

Gunnar 1992

Gunnar MR. Reactivity of the hypothalamic-pituitary-adrenocorti-

cal system to stressors in normal infants and children. Pediatrics

1992;90:491–7.

Haynes 1995

Haynes MJ, Smith BA, Herrick S, et al.Behavioural differences be-

tween term and postmature infants in sucrose calming test [abstract].

Prog Soc Res Child Develop 1995.

Johnston 1997b

Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A cross-sec-

tional survey of pain and pharmacological analgesia in Canadian

neonatal intensive care units. Clin J Pain 1997;13:308–12.

Ohlsson 2000

Ohlsson A. Prevention and management of pain and stress in the

newborn infant. Paediatr Child Health 2000;5:31–47.

Smith 1992

Smith BA, Stevens K, Torgerson WS, et al.Diminished reactivity of

postmature human infants to sucrose compared with term infants.

Dev Psychol 1992;29:811–20.

Stevens 1994

Stevens B, Johnston C, Horton L. Factors that influence the behav-

ioral responses of premature infants. Pain 1994;59:101–9.

Stevens 1996

Stevens B, Johnston C, Petryshen P, Taddio A. Premature infants pain

profile: developmental and initial validation. Clin J Pain 1996;12:

13–22.

Stevens 1997a

Stevens B, Taddio A, Ohlsson A, Einarson T. The efficacy of sucrose

for relieving procedural pain in neonates - a systematic review and

meta-analysis. Acta Paediatr 1997;86:837–42.

Stevens 1997c

Stevens B. Composite measures of pain in children. In: Finley GA,

McGrath PJ editor(s). Measurement of pain in infants and children.

Progress in Pain Research and Management. Vol. 10, Seattle: IASP

Press, 1997:161–77.

Walia 1999

Walia R, Ohlsson A. Clinical trials in neonatal medicine. 7th Annual

Cochrane Colloquium, Abstracts, October 1999. Rome, 1999.



Willis 1977

Willis D, Chabot J, Radde I, Chance G. Unsuspected hyperosmolal-

ity of oral solutions contributing to necrotizing enterocolitis in very-

low-birth-weight infants. Pediatrics 1977;60:535–8.

References to other published versions of this review

Stevens 1998

Stevens B, Ohlsson A. Sucrose for analgesia in newborn infants un-

dergoing painful procedures. Cochrane Database of Systematic Reviews

1998, Issue 1. [DOI: 10.1002/14651858.CD001069]

Stevens 2001

Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn

infants undergoing painful procedures. Cochrane Database of System-

atic Reviews 2001, Issue 1. [DOI: 10.1002/14651858.CD001069]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Abad 1996

Methods Double blind, randomized controlled trial

I Blinding of randomization - can’t tell

II Blinding of intervention - yes

III Complete follow-up - yes

IV Blinding of outcome measurement - yes

Participants 28 (29 - 36 weeks gestational age) infants, postnatal age 1-26 days

Interventions 2ml of 12% sucrose via syringe (n = 8) 2 minutes prior to venepuncture (n = 8).

2ml of 24% sucrose via syringe (n = 8) 2 min prior to venepuncture (n = 8).

2ml of spring water via syringe (n = 12) 2 min prior to venepuncture (n = 12).

Outcomes Oxygen saturation, respiratory rate, heart rate (just before and just after administering the solution and 5

min after venepuncture), time spent in audible crying for three min following venepuncture.

Notes One-way and two-way ANOVA used to evaluate outcomes

Data were reported as means and standard deviations for the three physiologic outcomes and as medians and

interquartile ranges for cry duration. Data were collected at three time points; just before the administration

of the solution, just after the solution and 5 minutes after venepuncture.

Adverse effects - were not evaluated

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Acharya 2004

Methods Double blind, randomized controlled cross-over trial

I Blinding of randomization - yes


III Complete follow-up - no


Participants 39 preterm neonates (mean 30.5 wks gestational age), mean post natal age 27.2 days

Interventions 2ml of 25% (0.5g) sucrose (n=39)

2ml of water

(n=39)



Acharya 2004 (Continued)

via syringe over 2 minutes into infant’s mouth

Outcomes Rise in heart rate, 02 saturation, duration of first cry, total duration of crying, NFCS at the 3 phases of

the venepuncture

Notes Data were reported using means, standard deviations over the 3 phases of the venepuncture. Adverse

effects - were evaluated.

Risk of bias


Allocation concealment? Yes A - Adequate

Blass 1999

Methods Randomized controlled trial

I Blinding of randomization -can’t tell

II Blinding of intervention - yes, for some comparisons


IV Blinding of outcome measurement - yes, blinded for some interventions

Participants 40 term newborn infants,

34 - 55 hours old

Interventions 2ml of 12% sucrose over two minutes via syringe (n=10)

2ml of water via syringe over 2 minutes (n=10)

Pacifier dipped every 30 seconds in 12% sucrose solution for two minutes (n=10)

Pacifier dipped in water every 30 seconds for two minutes (n = 10) prior to heel lance

Outcomes Percentage of time spent crying 3 minutes after heel lance. Percentage of time spent grimacing, change in

mean HR

Notes Data were reported in graph forms only.

Results of ANOVA reported as p-values only (We have contacted the authors to obtain additional infor-

mation)

Adverse effects:

were not evaluated

Risk of bias





Bucher 1995

Methods Randomized, double blind, placebo controlled cross over trial.





Participants 16 preterm infants (27 - 34 weeks gestational age), postnatal age approximately 42 days

Interventions 2ml of 50% sucrose via syringe into the mouth 2 minutes before heel lance.

2ml of distilled water via syringe into the mouth 2 minutes before heel lance.

(n = 16, cross over design).

Outcomes Increase in HR (bpm); Recovery time for HR (sec); recovery time for respirations (sec); crying (percent

of total intervention); recovery time until crying stopped (sec); tcpO2 (max increase -kPa); tcpO2 (max

decrease -kPa); tcpO2 (difference between baseline and 10 minutes after end of intervention -kPa); tcpCO2

(max decrease -kPa); tcpCO2 (difference between baseline and 10 min after the end of intervention).

Notes Results were presented in graph forms without mean values and standard deviations and/or in tables with

medians with interquartile ranges. Wilcoxon signed rank test

Adverse effects - were not evaluated

Risk of bias



Carbajal 1999



II Blinding of intervention - no


IV Blinding of outcome measurement - no

Participants 150 term newborn infants, 3-4 days old

Interventions No treatment (n = 25)

2 ml of sterile water via syringe over 30 seconds (n = 25)

2 ml of 30% glucose via syringe (n = 25)

2 ml of 30% sucrose (n = 25)

Pacifier alone (n = 25) 2 minutes prior to venepuncture

2 ml of 30% sucrose via syringe followed by sucking a pacifier (n = 25)

Outcomes Douleur Aigue du Nouveau-ne (DAN) scale



Carbajal 1999 (Continued)

Notes Mann-Whitney U test used to evaluate pain scores

Adverse effects:

were evaluated

Risk of bias



Gibbins 2001






Participants 190 preterm and term infants, mean gestational age of 33.7 weeks, under 7 days post natal age

Interventions 0.5ml of 24% sucrose via syringe to the anterior surface of the tongue followed by pacifier (n=64)

0.5ml 24% sucrose without pacifier (n=62)

0.5ml sterile water with pacifier (n=64)

2 minutes prior to heel lance

Outcomes Premature Infant Pain Profile (PIPP) at 30 and 60 seconds after heel lance

Notes One-way ANOVA to evaluate mean pain scores.

Results were reported as means and standard deviations

Adverse effects:

were evaluated

Risk of bias





Gormally 2001

Methods Randomized controlled trial, factorial design


II Blinding of intervention - coders were blind to infant assignment but not to holding condition



Participants 94 normally developing newborns, mean gestational age 39.4 weeks on 2nd or 3rd day of life

Nine infants did not complete the study due to early discharge, nurse or testing room unavailability to

obtain heel stick, infant removed from study prior to start date, technical difficulties.

Interventions No holding and sterile water given by pipette (n=21)

No holding and 0.25 ml of 24% sucrose

solution (0.06g) given by pipette (n=22)

Holding and sterile water given by pipette (n=20)

Holding and 0.25 ml of 24% sucrose solution (0.06 g) by pipette (n=22)

All solutions given 3 times at 30 second intervals

Outcomes Percentage of time crying

Pain concatenation scores for facial activity

Mean heart rate

Mean vagal tone index

Measurements at preintervention, 1, 2, and 3 minutes after heel lance

Notes Factorial ANOVA to assess effects on behavioural and physiological

measures

No means or standard deviations reported

Adverse effects:

were not evaluated

Risk of bias



Greenberg 2002






Participants 84 term newborns, approx. 17-19 hours old.



Greenberg 2002 (Continued)

Interventions Sugar coated pacifier held in infant’s mouth pre procedure to 3 minutes post procedure (n=21)

Water moistened pacifier (n=21)

2ml of 12% sucrose via syringe into side of infant’s mouth (n =21)

routine care (n=21)

Outcomes Salivary cortisol levels

Duration of cry

Vagal tone

Notes Analysis using

MANOVA to evaluate outcomes by groups.

Results were presented in graph forms without mean values and standard deviations

Adverse effects: were not evaluated.

Risk of bias



Guala 2001






Participants 140 term (38-41 wks gestational age)

Interventions Nothing (n=20)

Water (n = 20)

5% Glucose (n = 20)

33% Glucose (n = 20

50% Glucose (n = 20)

33% Sucrose (n = 20)

50% Sucrose (n = 20)

via syringe into infant’s mouth over 30 seconds

Outcomes Heart rate before, during and 3 minutes after heel lance

Notes ANOVA to evaluate heart rate across groups at each phase of the heel lance. Means and SD provided

Adverse effects: were evaluated.



Guala 2001 (Continued)

Risk of bias



Haouari 1995

Methods Randomized, double blind placebo controlled trial





Participants 60 term (37-42 weeks gestation) infants. 1-6 days of age.

Interventions 2ml of 12.5% sucrose 2 minutes prior to heel lance (n = 15)

2 ml of 25% sucrose 2 minutes prior to heel lance (n = 15).

2 ml of 50 % sucrose 2 minutes prior to heel lance (n = 15).

2ml of sterile water 2 minutes prior to heel lance (n = 15).

All solutions were given by syringe on the tongue over less than one minute.

Outcomes Total time (seconds) crying over three minutes following heel lance

Time of first cry (seconds) following heel lance

Per cent change in heart rate after heel lance (at 1 min, 3 min and 5 min)

Notes Analysis of non-parametric data was by the Mann-Whitney U test or a trend test. Total time crying in

the first three minutes after heel lance was reported as medians and interquartile ranges. Changes in heart

rate were expressed in means and standard deviations as a percentage of resting heart rate.

Adverse effects -

were not evaluated

Risk of bias





Isik 2000a



II Blinding of intervention - can’t tell



Participants 113 healthy newborns gestational ages between 37 and 42 weeks, median post natal age= 2days (range 2-

5 days)

Interventions 2ml of 30% sucrose (n=28)

2ml of 10% glucose (n=29)

2ml of 30% glucose (n=28)

2ml of distilled water (n=28)

syringed into the anterior third of the tongue for 1 minute


Outcomes Mean cry time during 3 minutes after heel lance

Mean maximum heart rate 3 minutes from heel lance

Mean recovery time for heart rate

Percent change in heart rate at 1, 2, 3 minutes after heel lance

Notes One way ANOVA was used to evaluate mean cry time, recovery time and % change in heart rate

Results reported as means and standard errors of the mean

Adverse effects -

were not evaluated

Risk of bias



Johnston 1997a



II Blinding of intervention - not for two interventions (rocking, and sucrose + rocking)



Participants 85 preterm infants (25 - 34 weeks gestational age) 2 - 10 days of age.

Interventions 0.05 ml of 24% sucrose via syringe into the mouth just prior to heel lance (n = 27)

0.05 ml of 24% sucrose via syringe into the mouth just prior to heel lance and simulated rocking 15

minutes prior to heel lance (n = 14)



Johnston 1997a (Continued)

0.05 ml of sterile water via syringe into the mouth just prior to heel lance and simulated rocking 15

minutes prior to heel lance (n = 24)

0.05 ml of sterile water via syringe into the mouth just prior to heel lance

Outcomes Heart rate, oxygen saturation, behavioural facial actions, behavioural state

(NFCS) baseline and at three 30 second blocks

Notes Data were analyzed using MANOVA (facial action). For heart rate repeated measures ANOVA was used

with mean values but no standard deviations presented in graph form. For state repeated measures ANOVA

was performed and no univariate means and standard deviations were presented.

02 saturation was dropped from analysis

Adverse effects -

were not evaluated

Risk of bias



Johnston 1999a






Participants 48 preterm neonates mean gestational age of 31 weeks (range 25-34 weeks) within 10 days of birth

Interventions 0.05ml of 24% sucrose as a single dose, followed by 2 doses of sterile water (n=15)

3 doses of 0.05ml of 24% sucrose (n=17)

3 doses of 0.05ml of sterile water (n=16)

given by syringe to anterior surface of the tongue at:


just prior to lancing

2 minutes after lancing

Outcomes Premature Infant Pain Profile

(PIPP)

measured over five 30 second blocks of time



Johnston 1999a (Continued)

Notes Repeated measures ANOVA was used to evaluate the effect of single versus repeated doses of sucrose.

Means and standard deviations for pain scores were obtained from the author

Adverse effects -

were not evaluated

Risk of bias



Ors 1999



II Blinding of intervention -no



Participants 102 healthy term infants, gestational age 37-42 weeks, median postnatal age 1.6 days (range1-15 days)

Interventions 2ml of 25% sucrose (n=35)

2ml of human milk (n=33)

2ml of sterile water (n=34)

syringed to anterior part of tongue for one minute

Heel prick done 2 minutes after intervention

Outcomes Median crying time 3 minutes after heel lance

Percent change in heart rate 1, 2, 3 minutes after heel lance

Notes Kruskal-Wallis 1-way ANOVA used to assess differences between groups

Medians and interquartile ranges reported for outcomes

Adverse effects -

were not evaluated

Risk of bias





Overgaard 1999

Methods Double-blind randomized controlled trial





Participants 100 newborn term infants [mean age 6 days (range 4-9)]

Interventions 2ml of 50% sucrose solution via syringe into the mouth over 30 seconds 2 minutes prior to heel lance

2ml of sterile water via syringe into the mouth over 30 seconds 2 minutes prior to heel lance

Outcomes NIPS

Crying time (duration of first cry, crying time during heel lance, fraction of crying during sampling, crying

time during first minute after end of sampling, total crying time)

NIPS one minute after heel lance and one minute after blood sampling

Change in heart rate at 0,1 minutes

Change in 02 saturation at 0,1 minutes

Notes Results were reported as medians and 5 and 95 percentiles

Statistical testing used Mann Whitney-U and Fisher’s exact test

Adverse effects:

were not evaluated

Risk of bias



Ramenghi 1996a

Methods Randomized, double blind, placebo controlled crossover study





Participants 15 (32-34 weeks gestation) infants greater than 24 hours of age

Interventions 1 ml of 25% sucrose via syringe into mouth 2 minutes prior to heel lance

1 ml of sterile water via syringe into mouth via syringe 2 minutes before heel lance.

(n=15, cross over design)



Ramenghi 1996a (Continued)

Outcomes Duration of first cry (sec) following heel lance, percentage of time crying 5 minutes after heel lance, heart

rate (at -2, 0, 1, 3, 5 min from heel lance), Behavioral scores (four facial expressions and the presence of

cry (at -2, 0, 1, 3, 5 min from heel lance)

Notes Medians and ranges were reported for duration of first cry, percent cry over 5 minutes and heart rate. For

composite behavioural outcome scores data were presented in graph form only with no indication if data

represent medians or means. Wilcoxon matched pairs signed rank test used to evaluate outcomes

Adverse effects -

were evaluated

Risk of bias



Ramenghi 1996b

Methods Randomized, single blind, placebo controlled trial


II Blinding of intervention - blind to all interventions except one (3/4). Calpol intervention not possible

to blind due to pink colour of solution.



Participants 60 (37 - 42 weeks gestational age) 2 - 5 days old infants

Interventions 2 ml of 25% sucrose via syringe into mouth 2 minutes prior to heel lance (n = 15).

2ml of 50% sucrose via syringe into mouth 2 minutes prior to heel lance (n =15).

2ml of commercial sweet tasting solution (Calpol) via syringe into mouth 2 minutes prior to heel lance

(n = 15).

2ml of sterile water via syringe into mouth 2 minutes prior to heel lance (n = 15).

Outcomes Duration of first cry (sec) following heel lance, percent time crying over 3 minutes following heel lance,

percent change in heart rate over 5 min (-2, 0, 1, 3, 5 min from heel lance), Behavioral scores (four facial

expressions and the presence of cry (-2, 0, 1, 3, 5 min after heel lance)

Notes Results were presented as medians and interquartile ranges for the pain score. For cry duration and percent

crying over three minutes the data were presented as medians and inter quartile ranges. Percent change in

heart rate was reported in graph form without indicating if data represent means or medians with standard

deviations or errors. Mann-Whitney U test used to evaluate outcomes

Adverse effects -

were not evaluated



Ramenghi 1996b (Continued)

Risk of bias



Ramenghi 1999

Methods Randomized double blind placebo controlled cross over trial


II Blinding of intervention - can’t tell.


IV Blinding of outcome measurement - can’t tell

Participants 30 preterm infants (GA 32-36 weeks, postnatal age < 24 hours)

Interventions 25 % sucrose solution (volume not reported) was given via syringe into the mouth or via NG tube 2

minutes prior to first heel lance (n = 15), and via the alternate route for the second heel lance within 48

hours

Sterile water via syringe into the mouth or via NG-tube 2 minutes prior to first heel lance and for the

second heel lance the alternate route within 48 hours

(cross over design, n= 30)

Outcomes Percentage cry over 5 minutes after sampling;

Behavioral scores (four facial expressions and the presence of cry) at 1, 3, and 5 minutes after the lance

for a total behavioral score

Notes Mann Whitney-U and Wilcoxon matched pairs signed ranked test used to evaluate outcomes

Results reported as median and interquartile and total range

Adverse effects:

were not evaluated

Risk of bias





Rushforth 1993

Methods Randomized, double blind, placebo controlled study





Participants 52 infants (37 - 42 weeks gestational age) 2-7 days of age.

Interventions 2ml of 7.5% sucrose administered by a dropper into the mouth over a one minute period prior to heel

lance (n = 26).

2ml of sterile water administered by dropper into the mouth over a one minute period prior to heel lance

(n = 26).

Outcomes Percentage time crying during sampling and 3 minutes following the completion of the heel lance recorded

on a standard audio tape recorder and analysed blindly at a later date.

Notes Results are presented as medians only with no ranges.

Mann Whitney-U test to evaluate duration of cry

Adverse effects -

were not evaluated

Risk of bias



Stevens 1999

Methods Randomized, cross-over

controlled trial





Participants 122 neonates, 27 - 31 weeks gestational age, less than 28 days of age

Johnston, 1999b

Subsample of 25 preterm neonates, 27-31 weeks gestational age, less than 28 days of age (refer to Stevens,

1999)

Interventions Prone positioning 30 minutes prior to heel lance. Pacifier dipped in sterile water and placed into the

mouth 2 minutes prior to heel lance

Pacifier dipped in 24% sucrose and placed into the mouth 2 minutes prior to heel lance

No treatment. (n = 122, crossover design)



Stevens 1999 (Continued)

Outcomes Premature Infant Pain Profile

(PIPP)

Notes Repeated measures ANOVA and ANCOVA used to evaluate efficacy of treatment interventions

Means and standard deviations provided for pain scores

Adverse effects -

were evaluated

Risk of bias



Storm 2002

Methods Randomized, controlled trial


II Blinding of intervention - can’t tell


IV Blinding of outcome measurement - can’t tell

Participants 48 preterm, median gestational age 32 wk, median postnatal age 14 days

Interventions 2ml of 15% sucrose, n = 12

1ml of 25% sucrose, n =12

milk via nasogastric tube, n= 12

milk via nasogastric tube, + 25% sucrose, n = 12

All infants were given water prior to a second heel lance

Oral solutions were administered via syringe into infant’s mouth 2 minutes prior to heel lance.

Milk was given during the last hour prior to heel lance.

Outcomes Changes from before heel lance to during heel lance for:

Crying time

Changes in behavioural state

Skin conductance

Heart rate

Notes Paired non-parametric tests (Wilcoxon test) used to compare the infant’s intervention and control session.

No median or IQR reported for each outcome.

Adverse effects: were not evaluated.

Risk of bias




Storm 2002 (Continued)




Characteristics of excluded studies [ordered by study ID]

Abad 1993 Abstract

Abad 2001 Although this is a randomized controlled trial, four newborns were included twice (i.e. there were 55 events

recorded for 51 participants), therefore, it was not possible to separate data for 51 newborns.

Ahuja 2000 This is a non-randomized study. A single cohort was studied. The intervention was a non-sucrose sweetener

Allen 1996 Although this is a randomized double blind controlled trial it is not possible to determine the number of infants

in the treatment and control groups.

Barr 1993 Although a randomized controlled trial, the authors do not provide information on the number of infants in each

group. Results are presented in graph form without indicating whether means or medians were used. No standard

deviations are presented.

Bilgen 2001 This manuscript was published previously in the European Journal of Pediatrics (“Comparison of sucrose and

human milk on pain response in newborns” by Ors et al, Eur J Pediatr, 158:63-66, 1999) and therefore, this article

has been retracted by the Journal of Pain.

The editor of the Journal of Pain states that “Anyone citing this article must cite from the European Journal of

Pediatrics and not from the Journal of Pain”.

Blass 1991 Although this is a randomized controlled trial the number of neonates in each group is not stated.

Blass 1995 This is a controlled trial without randomization. The number of patients in each group is not stated

Bucher 2000 This study used an artificial sweetner, glycine or breast milk as the intervention

Gibbins 2000 Abstract

Gormally 1996 Abstract

Graillon 1997 A randomized controlled crossover study. 60 crying infants were randomized to receive 250 ul of 24% sucrose

solution, 0.25% quinine hydrochloride solution, or corn oil as well as water in a mixed parallel crossover design.

Relative to water, sucrose persistently reduced crying, and transiently increased mouthing and hand-mouth contact.

No painful stimulus was applied to the neonates.

Harrison 2003 The infants in this study did not meet the inclusion criteria. Thirty (23%) of the 128 randomized infants were

older than the neonatal period of 28 postnatal days.

Herschel 1998 The painful procedure in this study was circumcision

Isik 2000b Abstract

Johnston 2000 Abstract



(Continued)

Lewindon 1998 The infants in this study were older than the inclusion criteria for this review (mean age 17.1 weeks).

Mellah 1999 Randomized double blind cross-over study. Data analyzed by paired t-test. Results from the first exposure to sucrose

or placebo could not be isolated.

Mohan 1998 The painful procedure in this study was circumcision

Skogsdal 1997 This study used glucose and breast milk as the interventions

Stang 1997 The painful procedure in this study was circumcision

Stevens 1997b Abstract

Stevens 2000 Abstract



D A T A A N D A N A L Y S E S

Comparison 1. Sucrose (sucrose or sucrose+NNS) vs. Control (NNS+water, water or positioning and containing

intervention)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Premature Infant Pain Profile

(PIPP) at 30 seconds after heel

lance

3 220 Mean Difference (IV, Fixed, 95% CI) -1.64 [-2.47, -0.81]

2 Premature Infant Pain Profile

(PIPP) at 60 seconds after heel

lance

3 195 Mean Difference (IV, Fixed, 95% CI) -2.05 [-3.08, -1.02]

Comparison 2. Sucrose 25 - 30 % vs. Control (Sterile water)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 % change in heart rate 1 minute

after heel lance

2 86 Mean Difference (IV, Fixed, 95% CI) 0.90 [-5.81, 7.61]

2 % change in heart rate 3 minutes

after heel lance

2 86 Mean Difference (IV, Fixed, 95% CI) -6.20 [-15.27, 2.88]

W H A T ’ S N E W

Last assessed as up-to-date: 19 April 2004.

3 February 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 2, 1998

Review first published: Issue 2, 1998



20 April 2004 New search has been performed This review updates the existing review “Sucrose in neonates

undergoing painful procedures” initially published in The

Cochrane Library, Issue 2, 1998 and updated in 2001.

In an updated search to 2004, six new studies were iden-

tified, of which four were eligible for inclusion. Results of

these studies continue to support the efficacy and safety

of sucrose for procedural pain relief in term and preterm

neonates. Sucrose in a wide variety of dosages was generally

found to decrease physiologic (heart rate) and behavioural

(the mean percent time crying, total cry duration, duration

of first cry, and facial action) pain indicators and composite

pain scores in neonates undergoing heel stick or venepunc-

ture. A dose range to reduce pain associated with procedures

in neonates was identified as 0.012 - 0.12g (0.05 to 0.5ml

of 24% sucrose solution) given approximately two minutes

prior to the painful procedure.

20 April 2004 New citation required and conclusions have changed Substantive amendment

C O N T R I B U T I O N S O F A U T H O R S

Bonnie Stevens

Literature search and identification of trials for inclusion

Evaluation of methodologic quality of included trials

Abstraction and meta-analysis of data

Verifying and entering data into RevMan

Writing of text of review

Janet Yamada



Abstraction and meta-analysis of data



Arne Ohlsson



Abstraction of data





D E C L A R A T I O N S O F I N T E R E S T

None

S O U R C E S O F S U P P O R T

Internal sources

• Faculty of Nursing, University of Toronto, Canada.

• Mount Sinai Hospital, Toronto, Canada.

• The Hospital for Sick Children, Toronto, Canada.

External sources

• No sources of support supplied

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Analgesics [administration & dosage]; ∗Punctures; ∗Sucrose [administration & dosage; adverse effects]; Infant, Newborn; Pain [phys-

iopathology; ∗prevention & control]; Pain Measurement; Randomized Controlled Trials as Topic

MeSH check words

Humans



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