1. family and parenting
2. babies and toddlers

The Journal of Pain, Vol -, No - (-), 2012: pp 1-10
Available online at www.jpain.org and www.sciencedirect.com
Effects of Skin-to-Skin Contact on Autonomic Pain Responses in
Preterm Infants
Xiaomei Cong,* Regina M. Cusson,* Stephen Walsh,* Naveed Hussain,*
Susan M. Ludington-Hoe,y and Di Zhang*
*School of Nursing, University of Connecticut, Storrs, Connecticut.
y
Bolton School of Nursing, Case Western Reserve University, Cleveland, Ohio.
Abstract: The purpose of this randomized crossover trial was to determine the effects on autonomic
responses in preterm infants of longer Kangaroo Care (30 minutes, KC30) and shorter KC (15 minutes,
KC15) before and throughout heel stick compared with incubator care (IC). Beat-to-beat heart rate
(HR) and spectral power analysis of heart rate variability, low frequency power (LF), high frequency
power (HF), and LF/HF ratio were measured in 26 infants. HR changes from Baseline to Heel Stick were
significantly less in KC30 and KC15 than in IC, and more infants had HR decrease in IC than in 2 KC
conditions. In IC, LF and HF significantly increased from Baseline to Heel Stick and dropped from
Heel Stick to Recovery; in 2 KC conditions, no changes across study phases were found. During
Heel Stick, LF and HF were significantly higher in IC than in KC30. In all 3 conditions, LF/HF ratio decreased from Baseline to Heel Stick and increased to Recovery; no differences were found between IC
and two KC conditions. Both longer and shorter KC before and throughout heel stick can stabilize HR
response in preterm infants, and longer KC significantly affected infants’ sympathetic and parasympathetic responses during heel stick compared with incubator care.
Perspective: This study showed that KC has a significant effect on reducing autonomic pain responses in preterm infants. The findings support that KC is a safe and effective pain intervention
in the neonatal intensive care unit.
ª 2012 by the American Pain Society
Key words: Pain, skin-to-skin contact, heart rate variability, heel stick, preterm infant.
I
n the high-tech neonatal intensive care unit (NICU),
preterm infants are subjected to an average of 10 to
16 painfully invasive procedures per day, with repeated heel sticks accounting for 55 to 86% of these procedures.11,15,30 Unrelieved pain caused by invasive
procedures is associated with detrimental physiologic
and behavioral outcomes in all major organ systems,
can be life-threatening, and has lasting implications
for impairment of biobehavioral outcomes in adulthood.1,22,24,39,46
Although
recent
advances
in
neurobiology and clinical studies have demonstrated
that preterm infants do experience and respond to
pain,6,17,46,53 40 to 90% of infants do not receive
Received May 20, 2011; Revised February 15, 2012; Accepted February 26,
2012.
Supported by the University of Connecticut Foundation.
The authors declare no financial and other conflicts of interest with respect to the research project and authorship.
Address reprint requests to Xiaomei Cong, PhD, RN, Assistant Professor,
University of Connecticut School of Nursing, 231 Glenbrook Road,
U-2026, Storrs, CT 06269-2026. E-mail: [email protected]
1526-5900/$36.00
ª 2012 by the American Pain Society
doi:10.1016/j.jpain.2012.02.008
preventive and/or effective treatment to reduce
procedural pain.11,30,34,55 Opioids have been found
ineffective against procedural pain in preterm infants
and are not recommended.4,10 Nonpharmacologic
interventions, especially those incorporating parental
involvement, are highly recommended but are known
to need further investigation.3 Unmanaged procedural
pain is a significant problem in most NICUs, and documenting effective interventions to reduce painful experiences in neonates is of utmost importance.9
Skin-to-skin contact, also called Kangaroo Care (KC), is
operationally defined as the upright prone positioning
of the diaper-clad infant skin-to-skin and chest-to-chest
with an adult. Several reports have shown that KC has
a powerful effect on reducing procedural pain in
preterm infants compared to standard incubator
care.12-14,16,19,25,26,28,36 In addition, a recent metaanalysis49 on nonpharmacological management of infant pain shows KC is effective in reducing pain reactivity
and improving pain-related regulation for preterm infants. Various durations/doses of KC intervention, the effect of KC on pain response when used for 10 to15
minutes,12,16,19,25 30 minutes,14,26,28 80 min,13,14 or 3
1
2
Skin-to-Skin Contact and Preterm Infant Pain
The Journal of Pain
Enrollment
Assessed for eligibility
N = 33
Could not reach mom: n = 3
Refused to participate: n = 1
Non-English speaking: n = 1
Analysis
Follow up
Allocation
Randomized
N = 28
Allocated to sequence A*
(KC30 – KC15 – IC)
n=9
Complete data: n = 6
Missing all data†: n= 1
Missing IC data‡: n = 2
Allocated to sequence B*
(KC15 – IC – KC30)
n = 10
Completed data: n = 6
Missing all data†: n=1
Missing KC30 data‡: n =2
Missing IC & KC30‡: n= 1
Allocated to sequence C*
(IC – KC30 – KC15)
n=9
Completed data: n = 8
Missing KC15 & KC30‡:
n= 1
Subjects in the final analysis (excluding 2 subjects†): N = 26
Completed data in all conditions: n = 20
KC30 data: n = 22
KC15 data: n = 25
IC data: n = 23
Figure 1. CONSORT diagram of enrollment, allocation, follow-up, and data analysis. *Sequence A: the consecutive study conditions
were KC30, KC15, and then IC; Sequence B: the consecutive study conditions were KC15, IC, and then KC30; Sequence C: the consecutive study conditions were IC, KC30, and then KC15. yNo data were collected in all 3 study conditions. zEarly termination of the data
collection.
hours36 before and through the heel stick, have been
studied; all durations have been shown to be effective
in reducing behavioral and physiological pain responses.
However, the autonomic responses to different
durations of KC are unknown, and studies determining
the most effective duration of KC for maximum pain
reduction in young preterm infants have not been
reported.
Physiological responses to painful stimuli in infants
include increases in heart rate, respiratory rate, blood
pressure, intracranial pressure, and palmar sweating,
and decreases in transcutaneous oxygenation saturation,
vagal tone, and peripheral and cerebral blood
flow.39,47,54,60 Although most infants show both
behavioral and physiological responses to pain, young
preterm infants often respond to pain without
concordant behavioral and physiologic measures.
Behavioral responses may diminish when acute pain
abates, but physiological responses may remain
elevated when stress continues.5,54 Therefore,
behavioral and physiological indicators should be
distinctly measured as pain outcomes in preterm
infants. In addition to monitoring infants’ behavioral
responses, the measure of KC’s pain reduction ability
can be established by determining KC’s effects on
autonomic responses. One such autonomic response—
heart rate variability (HRV)—is the variation in the
R-to-R, or beat-to-beat interval. It is a noninvasive measure of autonomic regulation of heart rate (HR) and is
a sensitive index of stress due to pain reactivity. The spectral analysis of HRV is used to determine the frequency
content of the fluctuating HR. The spectral power of
the low-frequency (LF) band (.04–.15 Hz) primarily represents sympathetic activity with some parasympathetic activity, while the high-frequency (HF) band (.15–1.0 Hz) is
related to respiratory sinus arrhythmia and reflects parasympathetic activity. The LF/HF ratio reflects the balance
of sympathetic and parasympathetic activities. HRV is
a recommended indicator to be examined in response
to painful events shortly after birth.20,59 The purpose of
this study was to examine the effect on autonomic pain
responses in preterm infants of longer and shorter
durations of KC before, during, and after heel stick
compared to the standard incubator care.
Methods
Design
A randomized cross-over design was used to determine the effect of a longer KC condition (30 minutes of
KC before and throughout heel stick; KC30) and a shorter
KC condition (15 minutes of KC before and throughout
heel stick; KC15) compared with standard incubator
care (IC) during heel stick. Mother-infant dyads were randomly assigned to 1 of the 3 sequences of the intervention order: Sequence A with KC30, KC15, and then IC;
Sequence B with KC15, IC, and then KC30; and Sequence
Cong et al
C with IC, KC30, and then KC15 (CONSORT, Fig 1). A
list of randomization codes with 4 subjects in each randomization block was developed by the statistician (the
third author). The list of random codes consisted of the
subject’s number and assignment to sequence; assignments were kept in sealed envelopes and opened in front
of the mother after consent was obtained. Infants served
as their own controls for demographic and health factors. While carryover effect from 1 condition to the
next is a concern with any crossover design, previous research has shown that physiological and behavioral state
effects of KC disappear within 3 hours of KC cessation.8
One study42 reported that KC’s blunting effects on
plasma and salivary cortisol were not sustained a day
later. Therefore, a 24- to 72-hour washout period was applied between each study condition. Painful procedures
during the washout period were measured to determine
their relationship to outcome measures even though
they were likely to occur randomly and equivalently
across the 3 comparison conditions.
Subjects
The study was conducted in a level III NICU in a university health center in the Northeast US. The study had the
university and hospital institutional review board approvals. The mothers gave written informed consent. Inclusion criteria were infants: 1) who were 28 0/7 to 32 6/7
weeks gestational age and less than 14 days old when recruited to partially control for previous pain experiences;
2) who were cared for in an incubator; 3) who were either NPO or on bolus feeds to control for feeding effects
on HRV;58 and 4) whose mothers were >18 years old and
English speaking. Exclusion criteria were infants: 1) with
known congenital anomalies; 2) with severe periventricular/intraventricular hemorrhage ($Grade III); 3) who
had undergone minor or major surgery; 4) who were receiving sedation or vasopressors or analgesics to control
for the effect of sedative medication on pain responses;
5) whose mothers had positive drug abuse history during
pregnancy to control for the effects on pain responses;
and 6) with any signs of tissue breakdown or inflammation/necrosis of either heel, because tissue damage increases pain responsiveness.52 Tissue breakdown was
measured by the Neonatal Skin Condition Score.38 Infants with a score of 5 or above were excluded from
the study. The sample size estimate was calculated in
the Power Analysis and Sample Size (PASS) software
package v.8.0.6 (NCSS, Kaysville, UT) with formulae appropriate to comparisons of means between KC and IC
conditions using paired observations. Based on our previous findings13 of a medium effect size of KC compared
with incubator care on autonomic responses (LF and HF
power, and LF/HF ratio) during heel stick procedure, 26
subjects were needed to detect the effect of KC on modifying heart rate variability indices (effect size = .50), with
a = .05 and power = .80.
Outcome Measures
HRV indices were measured using ANX3.0 (Ansar, Inc.,
Philadelphia, PA), a portable noninvasive, real-time HRV
The Journal of Pain
3
monitor that assesses autonomic nervous responses.
Three electrodes were placed on the infant’s chest to
conduct an electrocardiogram signal and rhythmic respiratory activity (chest wall impedance) from a cardiorespiratory monitor to a laptop with the HRV software. The R
waves of the QRS complex were identified and the R-to-R
intervals were measured in milliseconds. The heart beat
interval data were interpolated at 4 Hz to generate instantaneous HR. The instantaneous HR and respiratory
activity was then transformed into the frequency spectrum using continuous wavelet transforms, which were
recalculated every 32 seconds. The analysis of the transformed data generates 2 components of clinical interest:
the low frequency area (LFa) in the LF spectrum (.04 to
.15 Hz), which reflects sympathetic activity, and respiratory frequency area (RFa) within the HF region (.15 and
.4 Hz), which reflects parasympathetic activity. The system can also adjust for respiratory effects on power spectral analysis of HRV by performing a spectral analysis of
the respiratory signal to develop the respiratory activity
spectrum. The respiratory activity spectrum measures
the changes in the respiratory cycle, which reflect
parasympathetic modulation and influence HRV. The ratio of the LF-to-HF frequency spectra is also measured as
an index of sympathetic-parasympathetic balance.
Movement and artifact were eliminated by comparing
amplitude (height) of the R-wave included with the amplitude of the last acceptable R-wave.
Infant Behavioral State was measured using the Anderson Behavioral State Scoring System (ABSS)7 because behavioral state may influence HRV during painful
procedures.45 The ABSS has 12 categories: 1 = very quiet
sleep, 2 = quiet sleep, 3 = active sleep, 4 = very active
sleep, 5 = drowsy, 6 = alert inactive, 7 = quiet awake, 8
= active awake, 9 = very active awake, 10 = fussy crying,
11 = crying, and 12 = hard crying. For each assessment,
an infant was observed for 30 seconds, and the number
of the highest behavioral state observed was recorded
with 1 exception: alert inactivity. The desirable but relatively rare state of alert inactivity was recorded when it
occurred, even if a higher numbered state also occurred
during the same assessment.21 The researcher (first author) and 1 research assistant who was blind to the purpose of the study observed and coded behavioral states
once every minute from the Baseline to the end of Recovery. Discrepancies in coding were resolved by discussion.
The inter-rater reliability reached 95%. In the final analysis, we calculated infant behavioral state in percent time
of the following 6 categories: quiet sleep (state 1 and 2),
active sleep (state 3 and 4), drowsy (state 5), alert awake
(state 6 and 7), active awake (state 8 and 9), and crying
(state 10, 11, and 12). Content validity of the ABSS was
supported by review of a panel of neonatal nurse clinicians/researchers and a developmental pediatrician.40
Infants’ severity of illnesses and the number of previous pain procedures were also measured because both
can influence an infant’s pain responses. Severity of illness can affect the infant’s ability to mount a response
to pain.43 It was measured by the Score for Neonatal
Acute Physiology Version II (SNAP-II).50 The SNAP-II is
a simplified neonatal illness severity score that measures
4
Skin-to-Skin Contact and Preterm Infant Pain
The Journal of Pain
6 physiologic variables during the first 12 hours of life.
Total scores can range from 0 (normal) to 115 (life-threatening) points. The data were obtained from the infants’
medical records after recruitment.
tions, except that the heel stick was conducted with
the infant in the incubator. All heel sticks were conducted by the nurse who cared for the infant in the study.
Data Analysis
Data Collection Procedure
Only heel stick blood draws that were clinically warranted and ordered by health care providers were used
as the painful procedures in the study. Data collection included 4 phases in each of the 3 study conditions, KC30,
KC15, and IC: 1) Baseline (BL), 30 minutes for KC30; 15
minutes for KC15; and 15 minutes for IC; 2) Heel Warm
(HW) with a warm pack for 5 minutes; 3) Heel Stick
(HS), an estimate of .5 to 5.0 minutes of stick and squeeze
for blood collection, and the end point of the HS was the
adhesive bandage application immediately after all
blood was procured; and 4) Recovery (RC), 20 minutes
from the bandage application. The duration of Heel Stick
phase varied at each study occasion because the blood
sampling was ordered for different clinical purposes
and a varied amount of blood was needed. All equipment for data collection were checked and calibrated
by the biomedical engineer. A video camera was
mounted on a tripod and focused on the infant’s face
to record facial actions, and the videotapes were later reviewed and scored.
To control for potential circadian influences on heart
rate patterns and infant behavioral states, data collection occurred at approximately the same time, 9:00 to
12:00 am for each infant and each of the 3 study conditions (KC30, KC15, and IC). The procedure was conducted
as follows: 1) KC30 condition: The mother moved to the
La Fuma recliner chair, and, after she was seated, the
chair was reclined. The infant was transferred by the
researcher from the incubator into KC position. The
diaper-clad infant was placed on his/her mother’s chest,
skin-to-skin, in a prone and an upright position at an incline of 30 to 40 . The infant was covered across the back
with a blanket and with the mother’s cover gown. The
mother was encouraged to keep her hands clasped behind the infant’s back and allow her infant to sleep. KC
intervention began at Baseline (30 minutes before the
heel stick) and continued throughout Heel Warm, Heel
Stick and blood collection, and Recovery phases. For
Heel Warm, the infant’s foot was retracted from beneath
the blanket as the infant remained in KC. The heel stick
was conducted using a standardized protocol18 on the
retracted foot. When all needed blood had been collected, a Band-Aid was placed on the lancet site, and
the foot was placed beneath the blanket. KC was continued throughout the Recovery phase. 2) KC15 condition:
The only difference in this condition from the KC30
was that KC lasted 15 minutes before the heel stick during Baseline rather than 30 minutes. 3) IC condition: The
infant, wearing only a diaper and covered with a blanket,
was placed prone in the incubator at a 30 to 40 incline to
resemble the KC position and remained in this position
until the end of data collection. Data collection began
15 minutes before the heel stick, and all other data collection procedures were the same as for the KC condi-
SPSS v.17.0 software package was used in data analysis
(SPSS Inc., Chicago, IL). In order to minimize bias, a research assistant who was blind to the purpose of the
study helped analyze the data. Mean instantaneous HR
changes from Baseline (last 5 minutes) to Heel Warm,
Heel Stick, and Recovery in all 3 study conditions (KC30,
KC15, and IC) were compared. The majority (68%) of
the Heel Stick phase were done within 3 minutes of onset. Data were analyzed in the 30-second epoch from
the instant of stick until the first 3 minutes of Heel Stick
and the 30-second epoch of the first 5 minutes of Recovery. Means of LF, HF, and LF/HF ratio were calculated during Baseline (last 5 minutes), Heel Warm (5 minutes),
Heel Stick (first 3 minutes), and Recovery (first 5 minutes)
in 3 study conditions. To determine painful procedureinduced autonomic responses, the repeated-measures
analysis of variance (RM-ANOVA) was conducted to compare HRV indices across Baseline, Heel Stick, and Recovery phases in each study condition, respectively. To
examine the effect of 2 KC conditions compared with
IC on pain responses during each study phase, the Randomized Blocks ANOVA using the General Linear Model
procedure in SPSS was conducted, with HR changes and
HRV indices as the dependent variables and 3 study conditions as the repeated factor. When 1 or more subjects
has a missing observation, the Randomized BlocksANOVA includes the partial data from a subject rather
than dropping it. In the randomized blocks scheme,
each subject is considered a block, and each condition
(KC30, KC15, or IC) is viewed as assigned to the block in
a random order. Logarithmic transformation of HRV variables was applied before the analysis, because the HRV
data were not normally distributed.
Results
Twenty-eight stable male and female preterm infants
and their mothers were enrolled. Two infants did not
have any heel sticks ordered by the health provider after
recruitment and did not provide any data; therefore,
they are not included in the final sample. In the final sample of 26 infants, the majority were white (73%), nonHispanics (77%), and with Cesarean section birth (89%). The
majority of mothers were married (62%), high school
graduates (89%), full-time employed (54%), and had
no KC experience before the study (62%). The demographic and medical characteristics are described in
more detail in Table 1, and no significant differences of
these characteristics were found among the random assigned study sequences. After randomized allocation
and data collection initiation, early termination of the
data collection occurred in 6 infants because 5 infants
did not have further heel sticks ordered within the study
period, and 1 infant had a grade 2 intraventricular hemorrhage (Fig 1).
Cong et al
The Journal of Pain
Demographic and Medical
Characteristics (N = 26)
significant differences of absolute HR changes were
found among 3 conditions during the first 5 minutes
of Recovery.
Table 1.
CHARACTERISTICS
FREQUENCY (%)
Gender: Male
Female
Race: White
African American
2 or more
Hispanic: No
Yes
GA at birth (wk)
PNA (days) at: KC30 (n = 22)
KC15 (n = 25)
IC (n = 23)
Birth weight (g)
APGAR score at: 1 min
5 min
Severity of illness (SNAPII)
Prior number of pain experiences
Prior number of heel sticks
Mothers’ age
13 (50%)
13 (50%)
19 (73%)
6 (23%)
1 (4%)
20 (77%)
6 (23%)
5
MEAN (SD)
Heart Rate Variability (HRV) Indices
30 13 (2.2)
14.5 (6.3)
13.8 (5.6)
13.5 (5.6)
1444.6 (379.0)
5.7 (2.6)
8.0 (1.3)
5.5 (8.8)
34.4 (14.5)
17.4 (8.4)
29.2 (6.3)
Abbreviations: GA, gestational age; PNA, postnatal age.
The mean number of previous painful procedures
was 34.4 6 14.5 with a range of 14 to 72 before the
first day of study; heel sticks accounted for 49% of
the total painful procedures. No correlation was found
between previous painful experiences with outcome
measures, including heart rate and heart rate variability
indices, in all 3 study conditions. The time of heel stick
blood sampling procedure (Heel Stick phase) was not
different with 3 conditions, 245 6 125 seconds in
KC30, 217 6 110 seconds in KC15, and 280 6 206 seconds in IC.
Heart Rate
Mean heart rates were not different during Baseline
among KC30 (154 6 11 bpm), KC15 (156 6 14 bpm),
and IC (155 6 12 bmp) conditions. HR changes during
Heel Stick phase from Baseline were found in 2 directions, either increased or decreased. HR decrease during
Heel Stick phase occurred in a small group of infants in
all study conditions, but more decreases happened in IC
than KC30 and KC15 at 60 seconds of Heel Stick, c2 (2) =
8.00, P < .05 (Table 2). The absolute values of HR change,
increase or decrease, from Baseline to Heel Warming,
Heel Stick, and Recovery are presented in Fig 2. A trend
showed that infants in the IC condition have more HR
changes than infants in the KC30 and KC15 conditions
during the Heel Stick phase. Randomized Blocks ANOVA
showed that HR changes were significantly different
among 3 conditions during Heel Stick at 30 seconds
(F(2, 67) = 3.17, P < .05) and at 120 seconds (F(2, 60) =
3.01, P < .05). Pairwise comparisons showed that infants’
HR changes were more in IC condition than in both
KC30 and KC15 at 30 seconds (22.40 6 15.42 versus
13.77 6 9.30 and 14.36 6 15.41 bmp, P < .05 respectively), and at 120 seconds (20.08 6 10.98 versus 14.05
6 8.67 and 13.2768.76 bpm, P < .05 respectively). No
Means of HRV indices across 4 study phases, Baseline
(last 5 minutes), Heel Warming (5 minutes), Heel Stick
(first 3 minutes), and Recovery (first 5 minutes) in each
study condition are shown in Figs 3A–3C, and Table 3.
Low Frequency Area (LF)
In the IC condition, LF values significantly changed
from Baseline to Heel Stick and Recovery phases, F (2, 44)
= 3.45, P < .05, while LF was higher in the Heel Stick phase
than in Baseline, P < .05 and in Recovery, P < .05 (Table 3).
No significant changes in LF across study phases were
found in the KC30 and KC15 conditions. When comparing LF among the 3 conditions (Fig 3A), there were no significant differences in LF during Baseline and Heel
Warming. During Heel Stick phase, LF values were significantly different among KC30, KC15, and IC, F (2, 42) =
3.55, P < .05, and post hoc comparisons showed that LF
was significantly higher in IC than in KC30 during Heel
Stick phase, P < .05.
High Frequency Area (HF)
In the IC condition, HF values significantly changed
from Baseline to Heel Stick and Recovery phases, F(2, 44)
= 7.24, P < .01, while HF was higher in the Heel Stick
phase than in Baseline, P < .01 and in Recovery, P < .01
(Table 3). No significant changes in HF across study
phases were found in 2 KC conditions. When comparing
HF among the 3 conditions (Fig 3B), HF values did not differ during Baseline and Heel Warming. During Heel Stick,
HF values were significantly different among KC30,
KC15, and IC, F (2, 42) = 3.51, P < .05, and post hoc comparisons showed that HF was significantly higher in IC than
in KC30, P < .05.
LF/HF Ratio
LF/HF ratio decreased from Baseline to Heel Stick and
increased from Heel Stick to Recovery in all 3 conditions,
KC30 (F (2, 42) = 10.90, P < .01), KC15 (F (2, 48) = 4.59, P < .05),
and IC (F (2, 44) = 5.41, P < .01) (Table 3). When comparing
LF/HF ratio among 3 study conditions, no significant differences were found during Baseline, Heel Warming,
Heel Stick, and Recovery phases (Fig 3C).
Infant Behavioral State
During the last 5 minutes of Baseline, infants had different quiet sleep time in KC30 (86%), KC15 (76%), and
IC (52%), c2(2) = 6.51, P < .05, while in both KC30 and
KC15 conditions infants spent more time in quiet sleep
than in IC, P < .05 respectively. During the first 3 minutes
of Heel Stick, infants cried 48% of the time in KC30, 49%
in KC15, and 60% of time in IC; the differences were not
significant.
6
Skin-to-Skin Contact and Preterm Infant Pain
The Journal of Pain
Table 2.
Mean Instantaneous Heart Rate Changes From Baseline to the First 3 Minutes of Heel Stick
KC30 (N = 22)
HR CHANGES
(BPM)
HS 30 s:
HR inc
HR dec
HS 60 s:
HR inc
HR dec
HS 90 s:
HR inc
HR dec
HS 120 s:
HR inc
HR dec
HS 150 s:
HR inc
HR dec
HS 180 s:
HR inc
HR dec
N
(%)
KC15 (N = 25)
M (SD)
N
(%)
M (SD)
IC (N = 23)
N
(%)
M (SD)
19 (86%)
3 (14%)
13.93 (8.53)
12.75 (15.83)
21 (84%)
4 (16%)
11.91 (12.47)
27.17 (11.53)
18 (78%)
5 (22%)
20.5 (11.69)
29.25 (25.48)
22 (100%)
0*
16.09 (10.18)
23 (96%)
1 (4%)*
14.95 (9.74)
23.4
18 (78%)
5 (22%)*
20.59 (11.54)
17.68 (11.47)
21 (95%)
1 (5%)
16.41 (13.33)
9.18
22 (92%)
2 (8%)
12.86 (10.33)
24.06 (26.93)
18 (82%)
4 (18%)
17.8 (13.08)
21.44 (5.01)
18 (82%)
3 (18%)
17.4 (13.51)
9.59 (10.63)
21 (95%)
1 (5%)
13.99 (9.8)
.4
18 (90%)
2 (10%)
21.06 (14.36)
16.5 (6.62)
19 (90%)
1 (10%)
19.28 (14.2)
.13
13 (65%)
6 (35%)
14.16 (13.54)
17.65 (22.02)
15 (83%)
3 (17%)
18.55 (11.27)
20.09 (31.82)
13 (76%)
4 (24%)
14.89 (12.25)
10.39 (13.89)
13 (93%)
1 (7%)
20.88 (7.78)
2.47
17 (100%)
0
16.2 (14.78)
Abbreviations: HR inc, HR increase; HR dec, HR decrease.
NOTE. HS 30s to HS 180s = every 30 seconds during Heel Stick.
*Comparison of numbers of infants having HR decrease among KC30, KC15, and IC, c2 (2) = 8.00, P < .05. There were missing data in every time epoch except the first
30-second one because the blood testing was ordered for different clinical purposes; therefore, the duration of the HS duration varied from .5 minute to 5 minutes.
Discussion
Absolute HR Changes (bmp)
Our study is the first to determine the effects of different durations of maternal KC and standard incubator
care on autonomic response to the painful heel stick procedure in young preterm infants. Results demonstrated
that infants’ HR changes during the Heel Stick phase
were less in both longer KC (KC30) and short KC (KC15)
than in IC. Longer duration of maternal KC significantly
affected infants’ sympathetic and parasympathetic responses during heel stick compared to standard incubator care. When in both the longer and shorter KC
conditions, infants had more quiet sleep state than in incubator care during the baseline phase.
In the standard incubator care, the data from HR
changes, HRV indices, and behavioral state clearly
KC30
KC15
IC
Study Phases / Time
Figure 2. Absolute heart rate changes across from Baseline (BL)
to Heel Warm (HW), Heel Stick (HS), and Recovery (RC) in 3 study
conditions (KC30, KC15, and IC). HS30s to HS180s = every 30 seconds of the first 3 minutes of HS; Error bar shows the standard
error of the mean. *P < .05, significantly different among 3 conditions of KC30, KC15 and IC.
showed that pain responses were caused by the heel stick
without pain treatment. In the incubator, from Baseline
to Heel Stick, infants had HR changes of more than 20
bpm and LF and HF power increased, and crying was
the most common state. HR changes and changes in sympathetic and parasympathetic activities are commonly
associated with acute painful stimuli in neonates.32,44
These findings are consistent with the body of
neuroanatomical, neurochemical, and biobehavioral
evidence that young preterm infants possess the
ability to detect, perceive, and respond to painful
procedures.2,15,53 The consequences of untreated heel
stick pain are detrimental. Unmitigated pain responses,
such as increased or decreased heart rate, decreased
oxygen saturation, and alterations in blood pressure
are precursors to intraventricular hemorrhage.39 The
finding of bidirectional HR changes during the Heel Stick
phase might be a biphasic transient response, which is
characterized by a marked deceleration followed by
a subsequent acceleration or by an acceleration followed
by deceleration.31,51 An older study was the first to
report HR decelerations followed by accelerations in
full-term infants undergoing immunization.27 The biphasic response was more common in the placebo group
than in the intervention group in studies of heel lance in
term newborns and of immunization in 3-month-old infants.31,32 Our observation was the first in preterm
infants that is consistent with previous studies showing
that infants had more HR decelerations in IC than in KC
conditions. The biphasic response pattern is associated
with the fear paralysis reflex, characterized by
a sympathetic inhibition together with a vagal
bradycardia, which can be triggered by a sudden noise
and pain stimuli in infants.29 The sharp fall in HR can
Cong et al
The Journal of Pain
41
Low Frequence Spectra
LF (bmp2/Hz)
100
KC30
KC15
IC
80
60
40
20
0
BL
HW
HS
RC
Study Phase / Time
HF (bmp2/Hz)
High Frequence Spectra
35
30
25
20
15
10
5
0
KC30
KC15
IC
BL
HW
HS
RC
Study Phase / Time
LF/HF Ratio
LF/HF ratio
KC30
KC15
IC
BL
HW
HS
RC
Study Phase / Time
Figure 3. Heart rate variability responses. BL = the last 5 minutes of Baseline, HW = 5 minutes of Heel Warm, HS = the first
3 minutes of Heel Stick, RC = the first 5 minutes of Recovery. Error bar shows the standard error of the mean. *P < .05, significantly different among 3 conditions of KC30, KC15, and IC.
lead to reduced cerebral blood flow and even fainting or
dying.51
In the incubator care condition, compared with Baseline levels, infants had HR changes associated with increased LF and HF power during the first 3 minutes of
the Heel Stick phase. Increased HRV power indicates
pain-induced central stress response activating both sympathetic (LF) and parasympathetic (HF) activities, which is
consistent with our previous study.13 The literature of autonomic responses to pain using spectral analysis of HRV
measures in preterm infants is still inconsistent. Lindh
et al33 reported that HR increased and total HRV and LF
power reduced during blood sampling, and Grunau
et al23 and Padhye et al47 reported that both LF and HF
power decreased during blood collection and increased
in the recovery period. However, other studies did not
show the correlation of HRV to pain.22,54 An early
7
study involving preterm infants reported an increase
in total HRV during a 5-minute period heel prick, a finding that contrasts to those of later studies but is in agreement with the findings reported here. Note that the
frequency limits of the LF and HF bands varied between
studies, which could account for variations in the findings. Furthermore, differences in factors and units of
measurement of band powers make quantitative comparisons of HRV between studies a difficult task. Extrinsic
factors, such as variation in stimulus intensity, and infant
behavioral states and supine33 or prone13 position also
cannot be excluded. Parasympathetic and sympathetic
coactivation may be characteristic of a different type of
pain response behavior, sometimes called tonicimmobility or hypervigilance.48 In this type of response,
sympathetic activation is initially constrained by parasympathetic activation, but is available if subsequently
necessary for disinhibition of sympathetic activation
from parasympathetic activity for fight/flight.48 LF/HF ratio was found to have dropped significantly from Baseline to Heel Stick and increased from Heel Stick to
Recovery phase, which is consistent with the findings of
other studies23,60 that painful procedures without pain
intervention can be detrimental for young preterm
infants and can be a cause of loss of sympatheticparasympathetic balance.
The infant’s response to painful procedures in the NICU
can lead to a profound disruption of the autonomic homeostasis. Two defense responses to painful stimuli have
been found in animals and humans: an active fight or
flight response, or a passive response manifested by
freezing or paralysis.48 The response of HR acceleration,
in which the infant has the primitive impulse to escape
injury, was a fight-flight response that includes preparation for action and dominance of sympathetic activation.
The HR deceleration response might be coactivation
of a fight-flight response with a parasympatheticmediated conservation-withdrawal response.
In marked contrast to the incubator condition, both
longer and shorter Kangaroo Care interventions reduced
infants’ autonomic pain responses. Compared to IC, infants had fewer HR changes during Heel Stick phase in
both KC30 and KC15, which is consistent with previous
studies.13,14,25,35 Both LF and HF values were almost
unchanged across Baseline, Heel Stick, and Recovery
phases in KC30 and KC15 (Figs 3A and 3B), indicating
less or no significant stressful autonomic responses induced by the heel stick procedure. We also found that
LF/HF ratio showed a trend of lower values (more parasympathetic dominant) in the 2 KC conditions than in
IC, although the significant differences were not reached
(Fig 3C). The current results partially differ from our previous study13 in which KC was conducted 80 minutes before the heel stick began. The early study showed that
both LF and HF power were higher at Baseline and LF
was higher at Heel Stick in KC compared to the IC condition, while in the current study, both LF and HF were
lower during Heel Stick in KC30 condition than in IC.
One explanation for inconsistent results may be related
to the different duration of KC intervention prior to
the heel stick. In our study in 2009,13 80 minutes KC
8
Skin-to-Skin Contact and Preterm Infant Pain
The Journal of Pain
Table 3.
Mean Heart Rate Variability Indices Through Baseline to Recovery
KC30 (N = 22)
KC15 (N = 25)
IC (N = 23)
AMONG CONDITIONS
HRV
(BPM2/HZ)
M (SD)
M (SD)
M (SD)
P
LF BL
HS
RC
Across phases: P
HF BL
HS
RC
Across phases: P
LF/HF BL
HS
RC
Across phases: P
12.51 (20.66)
13.40 (24.28)*
15.50 (22.76)
NS
5.92 (21.24)
4.76 (12.03)*
3.93 (9.70)
NS
43.46 (41.84)y
17.70 (14.35)y
39.92 (33.84)y
<.01
49.45 (64.75)
52.42 (75.44)
38.98 (60.12)
NS
25.33 (42.27)
21.08 (31.05)
13.49 (28.15)
NS
41.57 (64.64)y
20.06 (25.57)y
49.12 (68.34)y
<.05
49.22 (109.60)y
69.84 (102.08)y,*
34.24 (55.82)y
<.05
9.10 (12.88)y
24.04 (40.90)y,*
11.66 (28.34)y
<.01
57.72 (59.03)y
23.98 (21.39)y
62.23 (76.46)y
<.01
NS
<.05
NS
NS
<.05
NS
NS
NS
NS
Abbreviations: LF, low frequency area; HF, high frequency area; LF/HF, low frequency to high frequency ratio; BL, baseline phase; HS, heel stick phase; RC, recovery
phase.
*P < .05, comparisons among study conditions of KC30, KC15, and IC.
yP < .05–.01, comparisons across study phase of BL, HS and RC.
was selected to give infants at least 1 full cycle of sleep
before the heel stick. At the end of 80 minutes of KC followed by the heel stick, infants may be more arousal and
disruptive in the second circle of sleep than they are
being awakened after 30 minutes of KC.14,37 Anxious
arousal may result in autonomic activation’s
manifesting as increased HRV power. Therefore, 80
minutes of KC may not be as effective as 30 minutes of
KC in reducing autonomic pain responses. To compare
KC30 versus KC15, 30 minutes of KC likely provides
more adequate time for the mother and her infant to
adapt the KC position, increases infant exposure to KC’s
analgesic effects, and induces more quiet sleep
episodes in the infant. Further investigation of
different durations of KC and the role of sleep state on
pain response is indicated.
KC’s action as a pain treatment is through multisensory
stimulation input, activation of the neuro-chemical system, and modulation of the stress regulation system
involved in pain experience.13,28 Although animal
studies suggest that younger infants (less than 32 weeks
gestational age) may not have the endogenous
mechanism that could be evoked to decrease pain
compared to older infants,17 nonpharmacologic interventions such as KC clearly trigger some endogenous
mechanism and have analgesic effects in preterm infants.
The skin-to-skin, chest-to-chest contact between the parent and a preterm infant provides a multisensory stimulation including continual nonphasic and full body touch as
well as the parent’s warmth, heartbeat, chest respiratory
movements, body odor, and voice. These components of
KC act in a uniquely interactive fashion between the parent and the infant, and they serve as soothing stimulations for infants under invasive procedures. KC may also
activate the C-afferents system to produce a faint sensation of pleasant touch. Although KC has been practiced
and studied for more than 3 decades, the basic mechanism is still not clear. Oxytocin release in both the parent
and the infant during KC is suggested as 1 mediator for
these effects.57 Oxytocin is released from nerve terminals
in brain areas, such as the amygdala, and is involved in
the control of stress, anxiety, and autonomic functions.57
The autonomic nervous system is a hierarchically controlled, bidirectional, body-brain interface integrating
afferent bodily inputs with central motor outputs for
homeostatic-emotional processes. Oxytocin release can
influence the reactivity of the autonomic nervous system
with increased parasympathetic tone, and can induce
analgesia and facilitate wound healing by down regulating or buffering the response to stressors.56
Generalization of findings is limited by the small sample size and insufficient power. While not statistically
significant, the average heel stick phase in IC was found
to be 30 to 60 seconds longer than KC15 or KC30. KC
could affect the heel stick length because of the
mother’s warmth and the incline position, but the
power may be not sufficient to detect this difference
as the differences seem clinically meaningful and the intragroup variability was high. Another limitation is that
the data collection and infant behavioral state coding
procedure could not be completely blind to KC conditions because maternal respiratory movements may
move the infant’s face up and down in the video, as reported by other researchers.25,36 Potential biases caused
by these limitations have to be considered, and fully
powered and blind studies are needed. Our study
adds to the continuing evidence for KC as
a nonpharmacologic intervention to alleviate preterm
infant pain responses related to the heel stick. This
study’s HRV findings of autonomic stability in the
longer KC conditions during heel stick for preterm
infants lend further support to other studies that
demonstrate that KC decreases HR, crying, and
grimacing during painful procedures.
Acknowledgments
We would like to thank the participating mothers and
their babies and the NICU nurses in the University of Connecticut Health Center.
Cong et al
References
1. Abdulkader HM, Freer Y, Garry EM, FleetwoodWalker SM, McIntosh N: Prematurity and neonatal noxious
events exert lasting effects on infant pain behaviour. Early
Hum Dev 84:351-355, 2008
2. Anand KJ: Effects of perinatal pain and stress. Prog Brain
Res 122:117-129, 2000
3. Anand KJ: Analgesia for skin-breaking procedures in
newborns and children: What works best? CMAJ 179:
11-12, 2008
4. Anand KJ, Anderson BJ, Holford NH, Hall RW, Young T,
Shephard B, Desai NS, Barton BA: Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates:
Secondary results from the NEOPAIN trial. Br J Anaesth
101:680-689, 2008
5. Anand KJ, Aranda JV, Berde CB, Buckman S, Capparelli EV,
Carlo W, Hummel P, Johnston CC, Lantos J, Tutag-Lehr V,
Lynn AM, Maxwell LG, Oberlander TF, Raju TN, Soriano SG,
Taddio A, Walco GA: Summary proceedings from the neonatal pain-control group. Pediatrics 117:S9-S22, 2006
6. Anand KJ, Hall RW: Love, pain, and intensive care. Pediatrics 121:825-827, 2008
7. Anderson GC, Behnke M, Gill NE, Cohen M, Mearel C,
McDonie TE: Self-regulatory gauge to bottle feeding for
preterm infants: Effect on behavioral state, energy, expenditure, and weight gain, in Funk FG, Turnquist MT,
Champagne LA, Coop RA, Wiere T (eds): Key Aspects of Recovery: Nutrition, Rest, and Mobility. New York, NY,
Springer, 1990, pp 93-97
8. Bohnhorst B, Heyne T, Peter CS, Poets CF: Skin-to-skin
(kangaroo) care, respiratory control, and thermoregulation.
J Pediatr 138:193-197, 2001
The Journal of Pain
9
16. Ferber SG, Makhoul IR: Neurobehavioural assessment of
skin-to-skin effects on reaction to pain in preterm infants: A
randomized, controlled within-subject trial. Acta Paediatr
97:171-176, 2008
17. Fitzgerald M, Walker SM: Infant pain management: A
developmental neurobiological approach. Nat Clin Pract
Neurol 5:35-50, 2009
18. Folk LA: Guide to capillary heelstick blood sampling in
infants. Adv Neonatal Care 7:171-178, 2007
19. Freire NB, Garcia JB, Lamy ZC: Evaluation of analgesic effect of skin-to-skin contact compared to oral glucose in preterm neonates. Pain 139:28-33, 2008
20. Gibbins S, Stevens B, McGrath PJ, Yamada J, Beyene J,
Breau L, Camfield C, Finley A, Franck L, Johnston C,
Howlett A, McKeever P, O’Brien K, Ohlsson A: Comparison
of pain responses in infants of different gestational ages.
Neonatology 93:10-18, 2008
21. Gill NE, Behnke M, Conlon M, McNeely JB, Anderson GC:
Effect of nonnutritive sucking on behavioral state in preterm infants before feeding. Nurs Res 37:347-350, 1988
22. Grunau RE, Holsti L, Haley D, Oberlander T, Weinberg J,
Solimano A, Whitfield MF, Fitzgerald C, Yu W: Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain 113:293-300, 2005
23. Grunau RE, Oberlander TF, Whitfield MF, Fitzgerald C,
Lee SK: Demographic and therapeutic determinants of
pain reactivity in very low birth weight neonates at 32
weeks’ postconceptional age. Pediatrics 107:105-112, 2001
24. Hohmeister J, Kroll A, Wollgarten-Hadamek I, Zohsel K,
Demirakca S, Flor H, Hermann C: Cerebral processing of pain
in school-aged children with neonatal nociceptive input: An
exploratory fMRI study. Pain 150:257-267, 2010
9. Byrd PJ, Gonzales I, Parsons V: Exploring barriers to pain
management in newborn intensive care units: A pilot survey
of NICU nurses. Adv Neonatal Care 9:299-306, 2009
25. Johnston CC, Filion F, Campbell-Yeo M, Goulet C, Bell L,
McNaughton K, Byron J, Aita M, Finley GA, Walker CD: Kangaroo mother care diminishes pain from heel lance in very
preterm neonates: A crossover trial. BMC Pediatr 8:13, 2008
10. Carbajal R, Lenclen R, Jugie M, Paupe A, Barton BA,
Anand KJ: Morphine does not provide adequate analgesia
for acute procedural pain among preterm neonates. Pediatrics 115:1494-1500, 2005
26. Johnston CC, Stevens B, Pinelli J, Gibbins S, Filion F,
Jack A, Steele S, Boyer K, Veilleux A: Kangaroo care is effective in diminishing pain response in preterm neonates. Arch
Pediatr Adolesc Med 157:1084-1088, 2003
11. Carbajal R, Rousset A, Danan C, Coquery S, Nolent P,
Ducrocq S, Saizou C, Lapillonne A, Granier M, Durand P,
Lenclen R, Coursol A, Hubert P, de Saint Blanquat L,
Boelle PY, Annequin D, Cimerman P, Anand KJ,
Breart G: Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 300:
60-70, 2008
27. Johnston CC, Strada ME: Acute pain response in infants:
A multidimensional description. Pain 24:373-382, 1986
12. Castral TC, Warnock F, Leite AM, Haas VJ, Scochi CG: The
effects of skin-to-skin contact during acute pain in preterm
newborns. Eur J Pain 12:464-471, 2008
29. Lagercrantz H, Edwards D, Henderson-Smart D,
Hertzberg T, Jeffery H: Autonomic reflexes in preterm infants. Acta Paediatrica Scandinavica 79:721-728, 1990
13. Cong X, Ludington-Hoe SM, McCain G, Fu P: Kangaroo
Care modifies preterm infant heart rate variability in response to heel stick pain: Pilot study. Early Hum Dev 85:
561-567, 2009
30. Lago P, Guadagni A, Merazzi D, Ancora G, Bellieni CV,
Cavazza A: Pain management in the neonatal intensive
care unit: A national survey in Italy. Paediatr Anaesth 15:
925-931, 2005
14. Cong X, Ludington-Hoe SM, Walsh S: Randomized crossover trial of kangaroo care to reduce biobehavioral pain
responses in preterm infants: A pilot study. Biol Res Nurs
13:204-216, 2011
31. Lindh V, Wiklund U, Blomquist HK, Hakansson S: EMLA
cream and oral glucose for immunization pain in 3-monthold infants. Pain 104:381-388, 2003
15. Evans JC, McCartney EM, Lawhon G, Galloway J: Longitudinal comparison of preterm pain responses to repeated
heelsticks. Pediatr Nurs 31:216-221, 2005
32. Lindh V, Wiklund U, Hakansson S: Heel lancing in term
new-born infants: An evaluation of pain by frequency
domain analysis of heart rate variability. Pain 80:143-148,
1999
28. Kostandy
RR,
Ludington-Hoe
SM,
Cong
X,
Abouelfettoh A, Bronson C, Stankus A, Jarrell JR: Kangaroo
Care (skin contact) reduces crying response to pain in preterm neonates: Pilot results. Pain Manag Nurs 9:55-65, 2008
10
The Journal of Pain
Skin-to-Skin Contact and Preterm Infant Pain
33. Lindh V, Wiklund U, Sandman PO, Hakansson S: Assessment of acute pain in preterm infants by evaluation of facial
expression and frequency domain analysis of heart rate variability. Early Hum Dev 48:131-142, 1997
47. Padhye NS, Williams AL, Khattak AZ, Lasky RE: Heart rate
variability in response to pain stimulus in VLBW infants followed longitudinally during NICU stay. Dev Psychobiol 51:
638-649, 2009
34. Losacco V, Cuttini M, Greisen G, Haumont D, PallasAlonso CR, Pierrat V, Warren I, Smit BJ, Westrup B, Sizun J:
Heel blood sampling in European neonatal intensive care
units: Compliance with pain management guidelines. Arch
Dis Child Fetal Neonatal Ed 96:F65-F68, 2011
48. Paine P, Kishor J, Worthen SF, Gregory LJ, Aziz Q: Exploring relationships for visceral and somatic pain with autonomic control and personality. Pain 144:236-244, 2009
35. Ludington-Hoe S, Anderson GC, Swinth JY, Thompson C,
Hadeed AJ: Randomized controlled trial of kangaroo care:
Cardiorespiratory and thermal effects on healthy preterm
infants. Neonatal Netw 23:39-48, 2004
36. Ludington-Hoe S, Hosseini R, Torowicz DL: Skin-to-skin
contact (Kangaroo Care) analgesia for preterm infant heel
stick. AACN Clin Issues 16:373-387, 2005
37. Ludington-Hoe S, Johnson MW, Morgan K, Lewis T,
Gutman J, Wilson PD, Scher MS: Neurophysiologic assessment of neonatal sleep organization: Preliminary results of
a randomized, controlled trial of skin contact with preterm
infants. Pediatrics 117:e909-e923, 2006
38. Lund CH, Osborne JW: Validity and reliability of the neonatal skin condition score. JOGNN 33:320-327, 2004
39. Mainous RO, Looney S: A pilot study of changes in cerebral blood flow velocity, resistance, and vital signs following
a painful stimulus in the premature infant. Adv Neonatal
Care 7:88-104, 2007
40. McCain GC: Facilitating inactive awake states in preterm
infants: A study of three interventions. Nurs Res 41:157-160,
1992
41. McIntosh N, Van Veen L, Brameyer H: The pain of heel
prick and its measurement in preterm infants. Pain 52:
71-74, 1993
42. Modi N, Glover V: Non-pharmacological reduction of hypercortisolaemia in preterm infants. Infant Behav Dev 21:86,
1998
43. Morison SJ, Holsti L, Grunau RE, Whitfield MF,
Oberlander TF, Chan HW, Williams L: Are there developmentally distinct motor indicators of pain in preterm infants?
Early Hum Dev 72:131-146, 2003
44. Oberlander TF, Grunau RE, Whitfield MF, Fitzgerald C,
Pitfield S, Saul JP: Biobehavioral pain responses in former extremely low birth weight infants at four months’ corrected
age. Pediatrics 105:e6, 2000
45. Oberlander TF, Saul JP: Methodological considerations
for the use of heart rate variability as a measure of pain
reactivity in vulnerable infants. Clin Perinatol 29:427-443,
2002
46. Ozawa M, Kanda K, Hirata M, Kusakawa I, Suzuki C: Influence of repeated painful procedures on prefrontal cortical pain responses in newborns. Acta Paediatr 100:198-203,
2011
49. Pillai Riddell RR, Racine NM, Turcotte K, Uman LS,
Horton RE, Din Osmun L, Ahola Kohut S, Hillgrove Stuart J,
Stevens B, Gerwitz-Stern A: Non-pharmacological management of infant and young child procedural pain. Cochrane
Database Syst Rev, CD006275, 2011
50. Richardson DK, Corcoran JD, Escobar GJ, Lee SK: SNAP-II
and SNAPPE-II: Simplified newborn illness severity and mortality risk scores. J Pediatr 138:92-100, 2001
51. Ritz T, Meuret AE, Ayala ES: The psychophysiology of
blood-injection-injury phobia: looking beyond the diphasic response paradigm. Int J Psychophysiology 78:50-67,
2010
52. Ruda MA, Ling QD, Hohmann AG, Peng YB, Tachibana T:
Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 289:628-631, 2000
53. Slater R, Worley A, Fabrizi L, Roberts S, Meek J, Boyd S,
Fitzgerald M: Evoked potentials generated by noxious stimulation in the human infant brain. Eur J Pain 14:321-326,
2010
54. Stevens B, Franck L, Gibbins S, McGrath PJ, Dupuis A,
Yamada J, Beyene J, Camfield C, Finley GA, Johnston C,
O’Brien K, Ohlsson A: Determining the structure of acute
pain responses in vulnerable neonates. Can J Nurs Res 39:
32-47, 2007
55. Stevens B, McGrath P, Gibbins S, Beyene J, Breau L,
Camfield C, Finley A, Franck L, Howlett A, McKeever P,
O’Brien K, Ohlsson A, Yamada J: Procedural pain in newborns
at risk for neurologic impairment. Pain 105:27-35, 2003
56. Uvnas-Moberg K: Oxytocin may mediate the benefits of
positive social interaction and emotions. Psychoneuroendocrinology 23:819-835, 1998
57. Uvnas-Moberg K, Arn I, Magnusson D: The psychobiology of emotion: The role of the oxytocinergic system. Int J
Behav Med 12:59-65, 2005
58. Veerappan S, Rosen H, Craelius W, Curcie D, Hiatt M,
Hegyi T: Spectral analysis of heart rate variability in premature infants with feeding bradycardia. Pediatr Res 47:
659-662, 2000
59. Walter-Nicolet E, Annequin D, Biran V, Mitanchez D,
Tourniaire B: Pain management in newborns: From prevention to treatment. Paediatr Drugs 12:353-365, 2010
60. Weissman A, Aranovitch M, Blazer S, Zimmer EZ: Heellancing in newborns: Behavioral and spectral analysis assessment of pain control methods. Pediatrics 124:e921-e926,
2009