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International Journal of Nursing Studies

journal homepage: www.elsevier.com/locate/ijns

Effect of non-nutritive sucking and sucrose alone and in combination for
repeated procedural pain in preterm infants: A randomized controlled trial

Haixia Gaoa,⁎, Mei Lib, Honglian Gaoc, Guihua Xua, Fang Lib, Jing Zhoub, Yunsu Zoub,
Honghua Jiangb

a School of Nursing, Nanjing University of Chinese Medicine, Nanjing, China
b Children’s Hospital of Nanjing Medical University, China
c Binzhou Medical University Hospital, Binzhou, China

A R

I C L E I N F O

Keywords:
Preterm infants
Pain
Analgesia
Sucrose
Non-nutritive sucking

A B S T R A C T

Background: Sucrose combined with non-nutritive sucking provided better pain relief than sucrose or non-nu-
tritive sucking alone in a single painful procedure. However, whether the combination of non-nutritive sucking
with sucrose could obtain a significant difference in analgesic effect of the repeated procedural pain than any
single intervention has not been established.
Objective: To compare the effect of non-nutritive sucking and sucrose alone and in combination of repeated
procedural pain in preterm infants.
Design: Randomized controlled trial.
Setting: A level III neonatal intensive care unit of a university hospital in China.
Method: Preterm infants born before 37 weeks of gestation were randomly assigned to four groups: routine care
group (routine comfort through gentle touch when infants cried; n = 21), non-nutritive sucking group (n = 22),
sucrose group (0.2 ml/kg of 20%; n = 21), sucrose (0.2 ml/kg of 20%) plus non-nutritive sucking group
(n = 22). Each preterm infant received three nonconsecutive routine heel sticks. Each heel stick included three
phases: baseline (the last 1 min of the

min without stimuli), blood collection, recovery (1 min after blood
collection). Three phases of 3 heel stick procedures were videotaped. Premature infant pain profile (PIPP) score,
heart rate, oxygen saturation and percentage of crying time were assessed by five independent evaluators who
were blinded to the purpose of the study at different phases across three heel sticks. Data were analyzed by
analysis of variance, with repeated measures at different evaluation phases of heel stick.
Results: 86 preterm infants completed the protocol. During the blood collection and recovery phases, combi-
nation group, had lower PIPP score (4.4 ± 1.5; 3.0 ± 0.8), lower heart rate (138.6 ± 7.9; 137.4 ± 4.7),
higher oxygen saturation (95.2 ± 1.6; 96.0 ± 1.2), and smaller percentage of crying time (11.5 ± 8.6;
4.6 ± 3.4), compared with the group has given non-nutritive sucking (9.3 ± 1.3, 6.8 ± 1.4; 154.2 ± 9.0,
148.0 ± 9.3; 92.9 ± 2.4, 94.1 ± 1.0; 44.2 ± 9.6,

.2 ± 10.5; respectively) or sucrose (10.1 ± 2.0,
7.4 ± 1.6; 151.6 ± 9.6, 147.9 ± 6.9; 93.5 ± 1.7, 94.5 ± 1.2; 53.8 ± 16.7, 35.2 ± 13.9; respectively) or
routine care (13.3 ± 1.6, 10.6 ± 1.9; 156.8 ± 7.2, 151.7 ± 7.9; 92.9 ± 2.1, 93.8 ± 1.6; 80.6 ± 7.6,
68.2 ± 9.9; respectively). Both non-nutritive sucking and sucrose were more effective in reducing preterm
infants’ PIPP score and percentage of crying time than routine care. There was no difference in PIPP score, heart
rate, oxygen saturation and percentage of crying time between the non-nutritive sucking and sucrose groups.
Conclusion: The combination of non-nutritive sucking with sucrose provided better pain relief during repeated
painful procedures than when non-nutritive sucking or sucrose was used alone. The effect of non-nutritive
sucking was similar to that of sucrose on repeated procedural pain.

What is already known about the topic?

• In an neonatal intensive care unit, preterm infants are exposed to
various painful stimuli to guarantee their survival. Repeated painful

stimuli in neonates may have short- and long-term consequences on
preterm infants physically and developmentally.

• Repeated exposure of preterm infants to opioid may have a detri-
mental effect on child neurodevelopmental outcomes.

https://doi.org/10.1016/j.ijnurstu.2018.04.006
Received 8 August 2017; Received in revised form 4 April 2018; Accepted 5 April 2018

⁎ Corresponding author at: School of Nursing, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia District, Nanjing, Jiangsu Province 210023, China.
E-mail address: bpn456@163.com (H. Gao).

International Journal of Nursing Studies 83 (2018) 25–

http://www.sciencedirect.com/science/journal/00207489

https://www.elsevier.com/locate/ijns

https://doi.org/10.1016/j.ijnurstu.2018.04.006

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• The use of sucrose alone or combined with non-nutritive sucking has
been the most frequently studied non-pharmacological intervention
method for single procedural pain. However, there have been no
studies comparing the effect of sucrose and non-nutritive sucking
alone and in combination with repeated procedural pain for preterm
infants.

What this paper adds

• The combination of sucrose and non-nutritive sucking shows better
efficacy for repeated procedural pain than their single use in pre-
term infants.

• The effect of non-nutritive sucking was similar to that of sucrose on
repeated procedural pain.

• When both sucrose and non-nutritive sucking can be provided in a
unit, the combination of them can be recommended as an analgesic
alternative for repeated pain exposure in preterm infants.

1. Introduction

Preterm birth is a significant global health problem. Survival rates
for preterm infants have increased markedly in recent decades due to
significant advances in neonatal intensive care. However, preterm in-
fants are exposed to various painful stimuli to guarantee their survival
during their stay in the neonatal intensive care unit (Chen et al., 2012;
Cruz et al., 2016; Jeong et al., 2014). Greater exposure to neonatal
pain-related stress has been found to be associated with poorer long-
term neurodevelopmental outcomes (Brummelte et al., 2012; Doesburg
et al., 2013; Lax et al., 2013; Skranes et al., 2012; Smith et al., 2011;
Vinall et al., 2013; Nuseir et al., 2015). Therefore, pharmacological or
non-pharmacological pain management must be required for preterm
infants in current neonatal practice.

Opioid analgesia is now widely used in preterm neonates. It is no-
teworthy that several recent studies have demonstrated repeated ex-
posure of preterm infants to opioid may have a detrimental effect on
child neurodevelopmental outcomes (Nuseir et al., 2015). For example,
the result from Nunes et al. study showed that repeated morphine ex-
posure during early life could have intermediate and long-term adverse
effects on the nociceptive responses, which included thermal hyper-
algesia and mechanical allodynia (Nunes et al., 2017). Kocek et al.
observed decreasing cognitive scores at 20 months corrected age in
extremely low birth weight infants who had cumulative opioid ex-
posure while in the neonatal intensive care unit (Kocek et al., 2016).
Furthermore, Ranger et al. reported that higher cumulative doses of
neonatal morphine were related with higher internalizing behaviours at
school age (Ranger et al., 2014). Thus, the adverse effects of opioid
analgesic are not negligible. It is very important to better understand
the potential risks and benefits of repeated opioid exposure in preterm
infants.

In contrast to pharmacological pain management, non-pharmaco-
logical pain management may have lower risk and greater ease of use
for preterm infants. Sucrose and non-nutritive sucking are the most
frequently studied non-pharmacological methods for reducing a single
procedural pain in preterm infants, and have been recommended by
national and international guidelines to alleviate procedural pain.
Furthermore, recent systematic reviews have addressed sucrose and
non-nutritive sucking as effective interventions to provide analgesia
and comfort for infants during painful procedures (Pillai Riddell et al.,
2015; Stevens et al., 2016). However, the evidence regarding the effi-
cacy and safety of repeated sucrose alone or combined with other non-
pharmacological interventions across repeated procedural pain for
neonates was limited (Gao et al., 2016). What’s more, there have been
no studies examining whether the combined intervention of sucrose and
non-nutritive sucking could obtain a significant difference in analgesic
effect on repeated procedural pain compared to any single intervention
for preterm infants, although several studies have reported that sucrose

combined with non-nutritive sucking provided better pain relief than
sucrose or non-nutritive sucking alone in a single painful procedure (Liu
et al., 2017; Naughton, 2013; Thakkar et al., 2016). It is a remarkable
fact that preterm newborns could learn and react to painful experiences
in the neonatal intensive care unit (Goubet et al., 2001), and the re-
peated exposure to painful experiences may reduce the pain threshold
and provoke hyperalgesia (Gibbins et al., 2008; Grunau, 2002). Thus, it
is vital to determine if the effects of the combination of sucrose and
non-nutritive sucking are better than their single-use on repeated pro-
cedural pain for preterm infants. In addition, animal studies have
shown that continuous consumption of sucrose can induce some be-
havioral and physiological responses similar to those elicited by drugs
of abuse like cocaine or amphetamine (Avena et al., 2008). Therefore,
the safety of repeated administration of sucrose or non-nutritive
sucking or their combination during painful procedures for preterm
infants needs to be examined.

Hence, the purpose of this study was to compare the efficacy and
safety of sucrose, non-nutritive sucking, and in combination with re-
peated procedural pain in preterm infants. We hypothesized that: (1)
Combined intervention of sucrose and non-nutritive sucking could be
more effective than any single intervention across repeated procedural
pain; (2) It is safe for preterm infants to use non-nutritive sucking or
sucrose alone or their combination repeatedly across repeated painful
procedures.

2. Methods

2.1. Design

This randomized controlled trial evaluated and compared the ef-
fectiveness of sucrose and non-nutritive sucking alone and in combi-
nation with repeated procedural pain across three nonconsecutive
routine heel sticks in preterm infants. Preterm infants were randomly
allocated before the heel stick by a research nurse using a random
computer-generated table to one of the four groups: routine care group,
non-nutritive sucking group, oral sucrose group, combined oral sucrose
and non-nutritive sucking group.

2.2. Setting and sample

Preterm infants were recruited by convenience sampling from a
level III neonatal intensive care unit (NICU) of a university hospital in
China from August 2015 to February 2016. Infants were included if
they met the following inclusion criteria: (1) Singleton born before 37
weeks of gestation, (2) Cared for in an incubator, (3) Anticipated re-
ceiving at least three routine heel sticks for capillary blood sampling
within two weeks after birth, (4) Hospitalized for the first time, (5)
Non-nutritive sucking rate at a minimum of 30 times/min (Blass and
Watt, 1999), and (6) Not scheduled to receive sedatives, muscle re-
laxants, or analgesic drugs 24 h before a study session. Infants were
excluded by these criteria: (1) Apgar Score of less than five at five
minutes, (2) Required mechanical ventilation, (3) Suffered from a
neurologic disorder, (4) Had congenital anomalies, (5) Undergone
surgery, (6) Born to substance-abusing mother, (7) Had hyperglycemia,
and (8) Nothing by mouth status for any reason.

To identify unforeseen problems and calculate the sample size, we
conducted a pilot study. Our pilot study showed the average Preterm
Infant Pain Profile (PIPP) score in 10 preterm infants during heel sticks
were 11.7 (SD = ± 5.5) in routine care group, 10.8 (SD = ± 4.2) in
non-nutritive sucking group, 9.0 (SD = ± 3.6) in oral sucrose group,
7.3 (SD = ± 2.0) in combined oral sucrose and non-nutritive sucking
group. To detect a significant difference in PIPP score among the four
groups, considering a power of 0.90, alpha of 0.05, and a 10% attrition
rate, a sample size of 22 was required in each group.

H. Gao et al. International Journal of Nursing Studies 83 (2018) 25–33

2.3. Conditions in the four groups

All preterm infants, wearing only a diaper, were placed prone or in a
side-lying position in the incubator and remained undisturbed for
30 min before the heel stick procedure. The assigned treatment condi-
tion was administered by one researcher (the first author).

2.3.1. The condition in the routine care group
The preterm infant received only routine comfort through gentle

touch when he cried after the heel stick procedure. The effectiveness of
gentle touch as analgesia has been established in controlled clinical
trials (Bahman Bijari et al., 2012; Herrington and Chiodo, 2014). Thus,
for ethical reasons, preterm infants in the routine care group were given
gentle touch to alleviate procedural pain if they were crying.

2.3.2. The condition in the non-nutritive sucking group
The preterm infant was given a standard silicone newborn pacifier

to stimulate sucking in 2 min before, and throughout the recovery phase
of the heel stick.

2.3.3. The condition in the sucrose group
Sucrose 20% (0.2 ml/kg) was administrated to the preterm infant’s

mouth by 1 ml syringe without the needle in 2 min before the heel stick
procedure (Cignacco et al., 2012).

2.3.4. The condition in the combined oral sucrose and non-nutritive sucking
group

Sucrose 20% (0.2 ml/kg) was administrated to the preterm infant’s
mouth by 1 ml syringe without the needle in 2 min before the heel stick
procedure (Cignacco et al., 2012), and then a standard silicone new-
born pacifier was given to stimulate sucking until the recovery phase of
the heel stick.

2.4. Measures

Outcome variables included preterm infants’ procedural pain, phy-
siological response, behavioral response, and incidence of any adverse
events.

2.4.1. Measurement of procedural pain
The preterm infants’ procedural pain was measured by the

Premature Infant Pain Profile (PIPP) scale. The PIPP scale is a validated
seven-indicator scale for the assessment of procedural pain in pre-
mature and term infants (Stevens et al., 1996). It measures pain ac-
cording to two contextual indicators (gestational age and behavioral
state), two physiological indicators (heart rate and oxygen saturation),
and three behavioral indicators (brow bulge, eye squeeze, and nasola-
bial furrow). Each indicator is numerically scaled and scored on a 4-
point scale (0, 1, 2, 3), the total scores obtained for the seven indicators
range from 0 to 21. Higher total scores indicate greater pain response.
PIPP score < 6 means no pain, PIPP score ≥6 indicates pain, PIPP scores ≥12 signals moderate to severe pain. Validity and reliability of the PIPP instrument in infants at various gestational ages has previously been determined. For translation of PIPP scale from English into Chi- nese, the standard forward-backward procedure was applied. Transla- tion of the PIPP scale (English to Chinese) was independently per- formed by two professional translators, and then the temporary version was provided. The temporary version of the PIPP scale was backward translated into English by a native English translator who was blinded to the original instrument and not previously involved in the study. The back-translator and the expert committee evaluated the back-translated version, then the final version of the PIPP scale was provided.

Physiological indicators were continuously monitored by a pulse
oximeter set on the preterm infant’s foot and videotaped by one digital
camera (Canon sx30is). Behavioral indicators and behavioral state in-
dicator were continuously videotaped by another digital camera (Canon

sx30is) which was in close up focus on preterm infants’ face and al-
lowed for high-quality facial images. The two digital cameras (Canon
sx30is) were used synchronously by the research assistant. The beha-
vioral state indicator was evaluated using Prechtl’s categories of quiet
sleep or quiet awake or active sleep or active awake (Prechtl, 1974;
Prechtl and Beintema, 1977). Gestational age was determined ac-
cording to the electronic medical record. PIPP score was measured by
two trained evaluators (the second and third author) who were una-
ware of the purpose of the study during the blood collection phase and
recovery phase of each heel stick procedure. In order to ensure accep-
table inter-rater agreement, the two evaluators respectively assessed
PIPP score for each preterm infant at the blood collection phase of the
first heel stick, the inter-rater reliability among evaluators was 97%.
Intra-rater reliability was checked every three months, remaining more
than 90%.

2.4.2. Measurement of physiological response
The preterm infant’s physiological response to procedural pain was

assessed by the change in heart rate and oxygen saturation throughout
repeated heel sticks. Oxygen saturation and heart rate were con-
tinuously monitored by a pulse oximeter set on the preterm infant’s
foot, were manually recorded every 30 s by a nurse student, and then
were used to calculate the mean heart rate and oxygen saturation across
the baseline, blood collection and recovery phases of each heel stick
procedure.

2.4.3. Measurement of behavioral response
The preterm infant’s behavioral response to procedural pain was

measured by the percentage of crying time respectively in the blood
collection phase and recovery phase. Crying was defined as audible
vocalization that lasted five seconds or more (Ludington-Hoe et al.,
2005). Preterm infants’ voices were videotaped by a digital audio re-
corder (MODEL F97), and then two assessors calculated the percentage
of crying time through playing the tapes. To examine the inter-rater
agreement, the two assessors, respectively calculated the percentage of
crying time at the blood collection phase of the first heel stick, and the
inter-rater reliability between the assessors was 98%. Intra-rater relia-
bility was checked every three months, remaining more than 90%.

2.4.4. Measurement of incidence of adverse events
The safety of different interventions (non-nutritive sucking, sucrose,

and combined use of them) was assessed by the incidence of adverse
events during the study period. The adverse events included: (1)
Choking, coughing, vomiting, abdominal distension, oral infection,
necrotizing enterocolitis; (2) Sustained tachycardia (heart rate > 200
beats/min), bradycardia (heart rate < 80 beats/min), tachypnea (re- spiratory rate > 80 beats/min), dyspnea (respiratory rate < 20 beats/ min), or oxygen desaturation < 80% for > 15 s; (3) Hyperglycemia.
The adverse events were monitored and recorded by two trained re-
search nurses who were blind to the purpose of the study. A safety
committee was established prior to study commencement. If severe
adverse event such as choking or need for immediate medical inter-
vention (e.g., intubation or resuscitation) following the administration
of non-nutritive sucking, sucrose, or their combination occurred, the
trial would be stopped by the safety committee.

2.5. Procedures

The study protocol (Fig. 1) and consent forms were approved by the
institutional review board of the participating centre (approval number:
201507001-1). One research assistant screened admission log every
other day in the neonatal intensive care unit, and finalized potential
eligible infants, and informed the preterm infant’s parent of the purpose
of the study, and obtained parental oral consent. Participating preterm
infants were randomly assigned to the routine care group, non-nutritive
sucking group, oral sucrose group, or combined intervention group. The

H. Gao et al. International Journal of Nursing Studies 83 (2018) 25–33

research assistant collected preterm infant’s characteristics, set pulse
oximeter on the preterm infant’s foot at about 5 min before the heel-
stick procedure. One researcher administered the intervention ac-
cording to the assigned condition, and then the experienced laboratory
employee performed heel stick in a standardized manner. One research
nurse videotaped preterm infant’s physiological indicators in 15 s be-
fore and 30 s after the heel stick, and in 15 s before and 30 s after the
end of the heel stick, and videotaped preterm infant’s facial actions in
30 s after the heel stick and 30 s after the end of the heel stick. The other
research nurse videotaped preterm infants’ voices occurring in the heel
stick procedure by a digital audio recorder. Because the timing of blood
sampling was determined by clinical needs, there were no fixed time
points for data collection. Most heel-stick events took place in the
morning and the intervals of them ranged from 3 to 48 h.

Each heel stick included three phases: (1) Baseline: 1 min of baseline
was collected at the end of the 30 min without stimuli. (2) Blood col-
lection: includes locating the site, disinfecting, sticking, squeezing,
applying adhesive bandage to the site for hemostasis, which lasted
about 60 s according to our previous observation. (3) Recovery: one
min after blood collection. The mean heart rate and oxygen saturation
during three phases of each heel stick, which displays in a pulse oxi-
meter, were collected by a nurse student (see Section 2.4.2). Preterm
infants’ PIPP score and percentage of crying time across the whole heel
stick were evaluated by four assessors (see Sections 2.4.1; 2.4.3). All
personnel was trained separately by the first author.

Study fidelity was established by the first author having separate
weekly meetings with the investigators, research assistant, nursing
student, and laboratory employees.

2.6. Data analysis

SPSS version 21.0 software package was used to conduct all the
descriptive and comparative statistical analysis. Data were presented as
means and standard deviations for continuous variables and frequencies
for categorical variables. Preterm infant’s characteristics such as birth
weight were evaluated for significant differences between the four
groups by one-way ANOVA test or Kruskal–Wallis analysis when the
assumption of normality test could not be found. For preterm infant’s
characteristics such as sex and the incidence of adverse events, Chi-
square test was used to determine whether there was significant dif-
ference between groups. For comparisons among the different phases,

measurement parameters (PIPP score, heart rate, oxygen saturation,
and the percentage of crying time) through the repeated heel sticks
were averaged separately. Repeated measurement analysis of variance
was performed to analyze both between- and within-groups difference
in three phases, followed by the Bonferroni post-hoc test. For all com-
parisons, a p- value of less than 0.05 was considered statistically sig-
nificant.

3. Results

There were 137 preterm infants were screened during the data
collection period. 103 were eligible for the criteria and were ap-
proached, and 91 agreed to participate. The reasons for refusals in-
cluded parents: did not want their infants to be videotaped due to their
small size (n = 7), refused anything extra done to their infants (n = 3),
were not interested (n = 2). Five infants dropped out of the study be-
cause they were discharged from the unit prior to the required heel
stick (Fig. 2). Preterm infant’s characteristics did not vary significantly
between infants whose parents declined to participate or dropped out of
the study (n = 17) and those who completed the study protocol
(n = 86).

3.1. Preterm infant characteristics

The characteristics of preterm infants completed the study protocol
are shown in Table 1. The sample included 86 preterm infants with a
mean gestational age of 31.7 ± 0.9 weeks. The majority was male
(60%) and born by cesarean delivery (71%). The preterm infants’ mean
birth weight was 17

.0 ± 267.9 g, mean Apgar score at 5 min was
8.8 ± 0.7, and they had 15.7 ± 2.4 previous invasive procedures. No
significant differences were noted among the four groups with regard to
the preterm infants’ characteristics.

3.2. Comparison of pain measurement parameters during the three repeated
heel sticks between groups

3.2.1. Between-group differences in pain measurement parameters during
the repeated three heel sticks

We compared the effectiveness of routine care, non-nutritive
sucking, sucrose and their combination in reducing procedural pain
during repeated heel sticks. The results of repeated measurement

Fig. 1. The study protocol.

H. Gao et al. International Journal of Nursing Studies 83 (2018) 25–33

analysis of variance between groups revealed significant interactions of
all the pain measurement parameters except PIPP score between
treatment conditions and evaluation phases (PIPP score: F = 1.995,
p = 0.121; heart rate: F = 11.509, p < 0.0001; oxygen saturation: F = 2.886, p = 0.016; percentage of crying time: F = 72.517, p < 0.0001). Moreover, there was a significant main effect of the treatment groups for all the pain measurement parameters (PIPP score: F = 168.360, p < 0.0001; heart rate: F = 16.983, p < 0.0001; oxygen saturation: F = 10.165, p < 0.0001; percentage of crying time: F = 275.310, p < 0.0001). Post hoc analyses were performed to compare the treatment conditions with each other (Table 2). In the baseline phase, there was no significant difference in heart rate, oxygen saturation and percentage of crying time respectively between groups with each other. Thus, all pain parameters during the blood collection phase and the recovery phase were comparable between groups. During the blood collection phase and recovery phase, regarding PIPP score, the combination group was significantly lower than the other three groups, both the sucrose group and non-nutritive group were lower
than the routine care group. Regarding heart rate and oxygen satura-
tion, the combination group had achieved a significant improvement
compared with the other three groups, while there were no significant
difference among the routine care group, sucrose group and non-nu-
tritive sucking group. Regarding the percentage of crying, the combi-
nation group was significantly smallest, the routine care group was
significantly biggest, the non-nutritive sucking group was significantly

similar to the sucrose group.

3.2.2. Within-group differences in pain measurement parameters during the
repeated three heel sticks

PIPP score, heart rate, oxygen saturation and percentage of crying
time showed similar patterns in the four treatment groups, which
changing significantly followed by the blood collection phase and re-
covering afterwards (Table 3). In the blood collection phase, the mean
PIPP scores at heel stick 1, 2, and 3 for the four treatment groups were
as follows: 13.2 ± 2.1, 13.1 ± 1.7, 13.4 ± 2.6 respectively in the
control group, 9.9 ± 2.4, 8.5 ± 2.7, 9.5 ± 2.6 respectively in the
non-nutritive sucking group, 11.1 ± 2.1, 10.1 ± 3.9, 8.9 ± 4.0 re-
spectively in the sucrose group, 4.2 ± 2.1, 4.8 ± 2.9, 4.4 ± 2.0 re-
spectively in the combination group. In the recovery phase, the mean
PIPP score at heel stick 1, 2, and 3 for the four treatment groups were as
follows: 10.5 ± 2.5, 10.7 ± 1.9, 10.5 ± 2.5 respectively in the con-
trol group, 7.6 ± 2.2, 6.0 ± 2.6, 6.9 ± 2.6 respectively in the non-
nutritive sucking group, 7.9 ± 1.8, 7.3 ± 3.3, 7.1 ± 2.7 respectively
in the sucrose group, 3.1 ± 2.0, 3.1 ± 1.7, 2.8 ± 1.0 respectively in
the combination group. The dada above showed that preterm infants in
the combination group didn’t feel pain at each heel stick, infants in the
sucrose and non-nutritive sucking group felt mild pain, while infants in
the control group felt moderate to severe pain.

Within-group comparison showed that significant differences in
heart rate and oxygen saturation between the baseline phase and

Assessed for eligibility (n=137)

Excluded (n =46)
Mee ng exclusion criteria (n =34)
Refused to par cipate (n = 12)

n =91
Randomly allocated

Allocated to rou ne care
group (n=23)

In all three nonconsecu ve
heel s cks, infants received
allocated incubator
condi on
Heel s ck 1 (n=23)
Heel s ck 2 (n=23)
Heel s ck 3 (n=21) :
2 infants discharged prior to
the third heel s ck

Allocated to nonnutri ve
sucking group (n=23)

In all three nonconsecu ve
heel s cks, infants received
allocated nonnutri ve
sucking
Heel s ck 1 (n=23)
Heel s ck 2 (n=23)
Heel s ck 3 (n=22) :
1 infant discharged prior to
the third heel s ck

Allocated to sucrose group
(n=23)

In all three nonconsecu ve
heel s cks, infants received
allocated oral sucrose
Heel s ck 1 (n=23)
Heel s ck 2 (n=23)
Heel s ck 3 (n=21):
2 infants discharged prior
to third heel s ck

Allocated to combina on
group

(n=22)

In all three nonconsecu ve
heel s cks, infants received
allocated combined
treatment
Heel s ck 1 (n=22)
Heel s ck 2 (n=22)
Heel s ck 3 (n=22)

Analyzed
Repeated three heel s cks

(n=21)

Analyzed
Repeated three heel s cks
(n=22)
Analyzed
Repeated three heel s cks
(n=21)
Analyzed
Repeated three heel s cks
(n=22)

Fig. 2. Flow diagram of the recruitment and randomization process.

H. Gao et al. International Journal of Nursing Studies 83 (2018) 25–33

recovery phase approached for all groups except the combination
group. For the routine care group, sucrose group, non-nutritive sucking
group, heart rate remained significantly quicker in recovery phase than
in baseline phase, oxygen saturation remained significantly lower in
recovery phase than in baseline phase. However, both heart rate and
oxygen saturation in the combination group remained steady across all
phases. In addition, compared to the other three group infants, com-
bination group infants’ mean percentage of crying time in the recovery
phase was near to the baseline phase percentage, although significant
differences occurred in all groups between the baseline phase and the
recovery phase.

3.3. Comparison of incidence of adverse events in the study period between
groups

The incidence of adverse events in the study period was as follows:
three preterm infants vomited (1 in the combination group, 1 in the
routine care group, 1 in the non-nutritive sucking group); two preterm
infants had abdominal distension (1 in the combination group, 1 in the
routine care group). The Chi-square test exhibited that there were no
statistically significant differences between groups in the incidence of
adverse events (vomit: χ2 = 1.006, p = 0.800; abdominal distension:
χ2 = 2.050, p = 0.562).

Table 1
Comparisons of characteristics of preterm infants between groups.

Variable Routine care group Nonnutritive sucking group Sucrose group Combination group P value

Gestational age, week
30–32a 21 16 17 18
33–34a 0 6 4 4 0.102

Gender
Malea 13 15 10 14
Femalea 8 7 11 8 0.550

Method of delivery
Vaginal deliverya 5 9 6 5
Cesarean deliverya 16 13 15 17 0.530

Birth weight, gb 1682.7 ± 200.2 1767.3 ± 302.7 1780.8 ± 304.6 1697.1 ± 254.7 0.547
Gestational age at birth, weekb 31.3 ± 0.6 31.9 ± 1.1 31.7 ± 0.9 32.0 ± 0.8 0.068
5 min Apgar scoreb 8.7 ± 0.6 8.8 ± 0.6 8.9 ± 0.7 8.8 ± 0.8 0.846

Postnatal days
Heel stick 1b 3.2 ± 0.6 3.5 ± 0.6 3.4 ± 0.6 3.2 ± 0.7 0.262
Heel stick 2b 5.4 ± 0.6 5.4 ± 0.7 5.3 ± 0.6 5.6 ± 0.7 0.580
Heel stick 3b 9.5 ± 1.0 8.2 ± 2.0 8.5 ± 1.4 9.0 ± 2.9 0.179

Previous invasive proceduresb 15.7 ± 2.2 14.9 ± 2.9 16.1 ± 2.0 16.0 ± 2.3 0.359

Duration of blood collection phase, seconds
Heel stick 1b 61.9 ± 12.5 61.5 ± 9.3 59.8 ± 9.7 57.7 ± 9.9 0.544
Heel stick 2b 65.5 ± 9.6 62.7 ± 12.8 66.9 ± 18.2 61.6 ± 13.7 0.573
Heel stick 3b 64.1 ± 9.2 58.7 ± 11.1 63.2 ± 9.0 59.1 ± 13.2 0.240

Behavioral state score at baseline phase
Heel stick 1b 0.9 ± 0.7 0.8 ± 0.7 0.8 ± 0.7 0.9 ± 0.9 0.893
Heel stick 2b 1.1 ± 0.7 0.7 ± 0.6 0.8 ± 0.7 0.9 ± 0.6 0.216
Heel stick 3b 0.4 ± 0.5 0.4 ± 0.5 0.4 ± 0.5 0.3 ± 0.5 0.938

a n.
b Mean (standard deviation).

Table 2
Between-group comparison of pain measurement parameters during the repeated three heel sticks.

RC group −NS group RC group −S group RC group −C group NS group-S group NS group- C group S group- C group

PIPP score
Blood collectiona P < 0.0001 P < 0.0001 P < 0.0001 0.694 P < 0.0001 P < 0.0001 Recoverya P < 0.0001 P < 0.0001 P < 0.0001 1.000 P < 0.0001 P < 0.0001

Heat rate (beats/min)
Baselinea 0.203 1.000 1.000 0.283 1.000 1.000
Blood collectiona 1.000 0.305 P < 0.0001 1.000 P < 0.0001 P < 0.0001 Recoverya 0.621 0.610 P < 0.0001 1.000 P < 0.0001 P < 0.0001

Oxygen saturation (%)
Baselinea 1.000 1.000 1.000 1.000 1.000 1.000
Blood collectiona 1.000 1.000 0.002 1.000 0.002 0.035
Recoverya 1.000 0.602 P < 0.0001 1.000 P < 0.0001 0.001

Percentage of crying time (%)
Baselinea – – – – – –
Blood collectiona P < 0.0001 P < 0.0001 P < 0.0001 0.035 P < 0.0001 P < 0.0001 Recoverya P < 0.0001 P < 0.0001 P < 0.0001 1.000 P < 0.0001 P < 0.0001

Note: Data are listed as mean ± SD. PIPP: premature infant pain profile; RC: Routine care; NS: Nonnutritive sucking; S: Sucrose; C: Combination of nonnutritive
sucking and sucrose.

a Bonferroni correction for multiples comparisons.

H. Gao et al. International Journal of Nursing Studies 83 (2018) 25–33
30

4. Discussion

Studies have demonstrated that preterm infants could mount both
physiological and behavioral responses to painful stimuli. Repeated
painful stimuli in neonates may have short- and long-term con-
sequences on preterm infants physically and developmentally.
Therefore, it is imperative to provide relief for preterm infants during
repeated painful procedures. Sucrose and non-nutritive sucking have
been established for managing a single procedural pain. However, to
our knowledge, this is the first study to examine the analgesic effect of
non-nutritive sucking across repeated painful procedure, and to de-
termine if the combined intervention of sucrose and non-nutritive
sucking could obtain a significant difference in analgesic effect on re-
peated procedural pain compared to any single intervention for preterm
infants.

Our study represents that both sucrose and non-nutritive sucking
could reduce preterm infants’ PIPP score and percentage of crying time,
but neither of them could decrease preterm infants’ physiological re-
sponse during the repeated heel sticks, which is consistent with the
previous studies (Table 2). Gaspardo et al. study found that preterm
neonates in the sucrose group had significantly fewer facial actions and
crying than the control group, but no statistical difference in the per-
centage of neonates with a heart rate of > 160 beats/min between
groups during repeated procedural pain (Gaspardo et al., 2008).
Cignacco et al. study, using the Bernese Pain Scale for Neonates to
measure preterm infants’ pain response caused by five heel sticks, re-
ported that sucrose was significantly more effective in relieving re-
peated procedural pain than facilitated tucking (Cignacco et al., 2012).
Boyer et al. study reported routine sucrose alone had no effect on the
change in cortisol level and variability of heart rate which resulted from
repeated procedural pain for preterm infants (Boyer et al., 2004).
However, these previous studies differed from our study in the fol-
lowing respects: (1) The method of evaluating procedural pain: we
assessed preterm infants’ pain not only using Preterm Infant Pain

Profile, but also using physiological and behavioral response, whereas
other studies only used a pain scale, or physiological and behavioral
response to measure preterm infants’ pain. (2) The methodological as-
pect of study design: enough sample size used in our study, while small
sample size in Gaspardo et al. study and moderate attrition rates in
Boyer et al. study. These results suggest that clinicians in Neonatal
Intensive Care Unit can provide non-nutritive sucking and sucrose to
reduce preterm infants’ repeated procedural pain.

It is worthwhile to note that we could not find any study that
compared the analgesic effects of non-nutritive sucking in preterm in-
fants to the analgesic effects of sucrose during repeated painful proce-
dure. Our findings indicated that the analgesic effects of non-nutritive
sucking in preterm infants was similar to that of sucrose during re-
peated painful procedure. These study results provide an alternative to
sucrose to relieve preterm infants’ repeated procedural pain.

However, we consider that either sucrose or non-nutritive sucking is
not perfect analgesics, because both of them couldn’t reduce preterm
infants’ physiological response following by repeated procedural pain.
This present study demonstrated that the PIPP score, percentage of
crying time, and magnitude of physiological response following by re-
peated painful procedures were lowest in the combination of sucrose
and non-nutritive sucking group, which indicated that sucrose plus non-
nutritive sucking produced the most efficacious means of pain reduc-
tion for repeated painful procedures. To date, only one study has
evaluated the effect of sucrose combined with non-nutritive sucking on
repeated procedural pain for preterm infants, which reported PIPP
score was significantly lower in the sucrose with pacifier intervention
group compared with the standard care group (Stevens et al., 2005). Yet
in Stevens et al. study, the Premature Infant Pain Profile (PIPP) scores
were not available on all preterm infants at all fixed data collection
points due to some of the infants did not receive routine painful pro-
cedure at each time point, which may affect the reliability of the con-
clusion. The specific contribution of our study was that we analyzed
exclusively sucrose in comparison to nonnutritive sucking, their

Table 3
Within-group comparison of pain measurement parameters during the repeated three heel sticks.

Baselinea Blood collectiona Recoverya P (one-way RM ANOVA)

PIPP score
Routine care group – 13.3 ± 1.6 10.6 ± 1.9 P < 0.0001 Nonnutritive sucking group – 9.3 ± 1.3 6.8 ± 1.4 P < 0.0001 Sucrose group – 10.1 ± 2.0 7.4 ± 1.6 P < 0.0001 Combination group – 4.4 ± 1.5 3.0 ± 0.8 P < 0.0001

Heat rate (beats/min)
Routine care group 133.1 ± 5.8b,c 156.8 ± 7.2 151.7 ± 7.9 P < 0.0001 Nonnutritive sucking group 137.0 ± 5.8b,d 154.2 ± 9.0 148.0 ± 9.3 P < 0.0001 Sucrose group 133.4 ± 5.6b,e 151.6 ± 9.6 147.9 ± 6.9 P < 0.0001 Combination group 134.7 ± 6.1b,f 138.6 ± 7.9 137.4 ± 4.7 0.080

Oxygen saturation (%)
Routine care group 95.7 ± 1.5b,c 92.9 ± 2.1 93.8 ± 1.6 P < 0.0001 Nonnutritive sucking group 95.8 ± 0.9b,d 92.9 ± 2.4 94.1 ± 1.0 P < 0.0001 Sucrose group 96.1 ± 1.5b,e 93.5 ± 1.7 94.5 ± 1.2 P < 0.0001 Combination group 96.1 ± 1.2b,f 95.2 ± 1.6 96.0 ± 1.2 0.024

Percentage of crying time (%)
Routine care group 0b,c 80.6 ± 7.6 68.2 ± 9.9 P < 0.0001 Nonnutritive sucking group 0b,d 44.2 ± 9.6 31.2 ± 10.5 P < 0.0001 Sucrose group 0b,e 53.8 ± 16.7 35.2 ± 13.9 P < 0.0001 Combination group 0b,g 11.5 ± 8.6 4.6 ± 3.4 P < 0.0001

Note: Data are listed as mean ± SD. PIPP: premature infant pain profile.
a Mean (standard deviation).
b Bonferroni correction for multiples comparisons.
c Significant difference when compared with recovery–Routine Care group (P < 0.05). d Significant difference when compared with recovery–Nonnutritive sucking group (P < 0.05). e Significant difference when compared with recovery–Sucrose group (P < 0.05). f No significant difference when compared with recovery–Combination group (P > 0.05).
g Significant difference when compared with recovery–Combination group (P < 0.05).

H. Gao et al. International Journal of Nursing Studies 83 (2018) 25–33
31

combination and routine care, whereas Stevens et al. used combined
sucrose plus pacifier in the same group in comparison with pacifier plus
water and standard care.

Furthermore, our results found that preterm infants’ mean heart rate
and oxygen saturation in the recovery phase had been back to baseline
phase, and the percentage of crying time in the recovery phase had
been near to baseline phase in the combination group (Table 3). The
ability to recover quickly is a sign of ability to maintain homeostasis, a
major task that the very preterm neonate must accomplish in order to
grow and develop (Moore and Anderson, 2007). In summary, the
combination of sucrose and non-nutritive sucking could have a better
analgesic effect on repeated procedural pain than both methods sepa-
rately. The plausible reason could be the multimodal stimulation that
the preterm infant experiences when sucrose and non-nutritive sucking
were administered together. These findings can guide nurses and other
clinicians to combine sucrose and non-nutritive sucking to minimize
preterm infants’ repeated procedural pain.

Establishing the safety of sucrose, non-nutritive sucking and their
combination for repeated procedural pain might be the first priority.
Our study demonstrated no significant difference in the incidence of
adverse events between different groups. Thus, it indicates sucrose,
non-nutritive sucking or their combination had no short-term side ef-
fects on the health status of the preterm infants. Other authors have
reported the similar results (Banga et al., 2016; Gaspardo et al., 2008;
Stevens et al., 2005; Taddio et al., 2008).

The strengths of the present study included: (1) It was a randomized
controlled trial with sufficient sample size. (2) Multiple outcome vari-
ables (PIPP score, behavioral and physiological response) were used to
evaluate the effect of sucrose, non-nutritive sucking, and in combina-
tion on repeated procedural pain, which not only provided a detailed
analysis over the entire sampling period, but also examined their ef-
fectiveness on the overall changes in the summary scores. (3)
Videotaping, evaluating, offering treatment conditions were performed
by different persons respectively, which enhanced the internal validity
of the study results.

Despite its strengths, the study had some limitations: (1) Preterm
infants enrolled in the study were stable and aged more than 30 weeks.
Thus, its results can not be generalized to the unstable and extremely
preterm infants. (2) The study only focused on the analgesic effects of
sucrose, non-nutritive sucking and their combination on repeated heel
sticks, yet whether they could have the same analgesic effects on other
repeated procedural pain as on repeated heel sticks had not been de-
termined by the study. (3) The study examined the short-term safety of
repeated sucrose, non-nutritive sucking and their combination for
preterm infants, while the long-term impact of repeatedly offering a
pacifier or sucrose or in combination during repeated procedural pain
on preterm infants’ readiness for breastfeeding, weight gain and even
neurobehavioral development had not been discussed. (4) The
Premature Infant Pain Profile especially its grimacing indicator evalu-
ating procedure was impossible to be completely blind, because non-
nutritive sucking had to be continued until 1 min after the painful
procedure. (5) The control condition for our study was routine care,
which might have led to unnecessary pain for preterm infants assigned
to this condition, although this limitation was minimized by offering
preterm infants in this condition gentle touch.

The implications for future research and practice may be as follows:
Firstly, future studies should include the preterm infants with gesta-
tional age less than 30 weeks and being medically unstable, and then
examine and compare the efficacy and safety of sucrose, non-nutritive
sucking, and their combination for repeated procedural pain in them.
Secondly, researchers can further evaluate the effects of sucrose, non-
nutritive sucking, and their combination on different types of repeated
procedural pain except heel stick pain in preterm infants. Thirdly,
further randomized controlled trials are needed to examine the long-
term impact of repeatedly offering a pacifier or sucrose or their com-
bination in repeated procedural pain on preterm infants during their

stay in neonatal intensive care unit.

5. Conclusion

Both sucrose and non-nutritive sucking have a good analgesic effect
for preterm infants on repeated procedural pain, but a combination of
the two interventions shows better efficacy. Our results provide evi-
dence supporting clinicians’ incorporation of the combined use of su-
crose and non-nutritive sucking into clinical practice while preterm
infants undergo repeated painful procedures. Thus, when both sucrose
and non-nutritive sucking can be provided in a unit, the combination of
them could be recommended as an analgesic alternative for repeated
pain exposure in preterm infants.

Acknowledgments

We acknowledge the financial contribution of National Natural
Science Foundation of China (81703246), the Preponderant Discipline
Project of Universities in Jiangsu Province, Nursing Science Open Fund
of Nanjing University of Chinese Medicine (YSHL2016-018), Top-notch
Academic Programs Project of Jiangsu Higher Education Institutions
(PPZY2015C258) and Project of nursing science in Nanjing University
of Chinese Medicine (NZYHLXPPJG2017-54).

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Effect of non-nutritive sucking and sucrose alone and in combination for repeated procedural pain in preterm infants: A randomized controlled trial

What is already known about the topic?
What this paper adds
Introduction
Methods
Design
Setting and sample
Conditions in the four groups
The condition in the routine care group
The condition in the non-nutritive sucking group
The condition in the sucrose group
The condition in the combined oral sucrose and non-nutritive sucking group
Measures
Measurement of procedural pain
Measurement of physiological response
Measurement of behavioral response
Measurement of incidence of adverse events
Procedures
Data analysis
Results
Preterm infant characteristics
Comparison of pain measurement parameters during the three repeated heel sticks between groups
Between-group differences in pain measurement parameters during the repeated three heel sticks
Within-group differences in pain measurement parameters during the repeated three heel sticks
Comparison of incidence of adverse events in the study period between groups
Discussion
Conclusion
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