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1.  Randomised controlled trial of paracetamol for heel prick pain in neonates 
AIM—To evaluate the effectiveness of paracetamol in decreasing the pain from heel prick.
METHODS—A prospective randomised double blind placebo controlled trial was conducted of 75 term neonates undergoing heel prick. Sixty to 90 minutes before the procedure neonates received paracetamol orally in a dose of 20 mg/kg (group 1) or an equal volume of placebo (group 2). Heel prick was performed in a standardised manner. Pain assessments were made using per cent facial action (brow bulge, eye squeeze, and nasolabial fold (range 0-300%) and per cent of time spent crying (range 0-100%).
RESULTS—Thirty eight neonates were enrolled in group 1 and 37 neonates in group 2. There were no significant differences in the demographic characteristics between groups. Mean gestational age was 39 (SD 1.4) vs 39.4 (SD 1.2) weeks, p=0.86, mean birthweight 3.45 (SD 0.45) vs 3.44 (SD 0.42) kg; p=0.31 for groups 1 and 2, respectively. Facial action pain scores did not differ between groups (143.5(SD 54.2)% vs 131.1 (SD 59.6)%; p=0.38). Cry scores also did not differ (29.4 (SD 19.9)% vs 26.8 (SD 20.2)%; p=0.60). No adverse effects were observed.
CONCLUSION—Paracetamol is ineffective for decreasing the pain from heel prick in term neonates.


PMCID: PMC1720857  PMID: 10194994
2.  Body Movements: An Important Additional Factor in Discriminating Pain From Stress in Preterm Infants 
The Clinical journal of pain  2005;21(6):491-498.
Objectives
To describe developmentally appropriate, specific body movements and other biobehavioral responses of preterm infants to a group of routine care giving tasks (Clustered Care), and to compare responses to acute pain with those of Clustered Care.
Methods
In a randomized design, 54 preterm infants were assessed at 32 weeks gestational age during 3 phases of blood collection (Baseline, Lance/squeeze, Recovery) and of diaper changing, measuring abdominal girth and axillary temperature, and mouth care (Baseline, Clustered Care, Recovery) in a neonatal intensive care unit. The Newborn Individualized Developmental Care and Assessment Program and 1 facial action from the Neonatal Facial Coding System, Brow Bulge, were coded from separate continuous bedside video recordings. Heart rate and oxygen saturation were also acquired continuously.
Results
Brow Bulge, heart rate, and a subset of 9 Newborn Individualized Developmental Care and Assessment Program movements increased and oxygen saturation decreased significantly to Lance/squeeze compared to Baseline. Similar facial and physiological changes occurred during Clustered Care, but with less intensity. However, infants showed greater frequencies and variety of Newborn Individualized Developmental Care and Assessment Program stress cues during Clustered Care than during Lance/squeeze. Stress cues persisted after Clustered Care, whereas the infants returned to Baseline following Lance/squeeze.
Discussion
Changes in facial activity and heart rate remain the most sensitive markers of pain in preterm infants. Tactile procedures, such as diaper changing, produce lower intensity facial and physiological responses than pain procedures, but greater body reactions. Also, the effects from tactile procedures appear to last longer. Adding observations of a small number of specific body movements to the assessment of pain and stress provides complementary information particularly for those infants who may show dampened facial reactivity as a result of repeated pain exposure.
PMCID: PMC1852478  PMID: 16215334
preterm infant; pain; NIDCAP®; NICU; stress
3.  Postnatal Temporal, Spatial and Modality Tuning of Nociceptive Cutaneous Flexion Reflexes in Human Infants 
PLoS ONE  2013;8(10):e76470.
Cutaneous flexion reflexes are amongst the first behavioural responses to develop and are essential for the protection and survival of the newborn organism. Despite this, there has been no detailed, quantitative study of their maturation in human neonates. Here we use surface electromyographic (EMG) recording of biceps femoris activity in preterm (<37 weeks gestation, GA) and term (≥37 weeks GA) human infants, less than 14 days old, in response to tactile, punctate and clinically required skin-breaking lance stimulation of the heel. We show that all infants display a robust and long duration flexion reflex (>4 seconds) to a single noxious skin lance which decreases significantly with gestational age. This reflex is not restricted to the stimulated limb: heel lance evokes equal ipsilateral and contralateral reflexes in preterm and term infants. We further show that infant flexion withdrawal reflexes are not always nociceptive specific: in 29% of preterm infants, tactile stimulation evokes EMG activity that is indistinguishable from noxious stimulation. In 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes. Infant flexion reflexes are also evoked by application of calibrated punctate von Frey hairs (vFh), 0.8–17.2 g, to the heel. Von Frey hair thresholds increase significantly with gestational age and the magnitude of vFh evoked reflexes are significantly greater in preterm than term infants. Furthermore flexion reflexes in both groups are sensitized by repeated vFh stimulation. Thus human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults. Reflex magnitude and tactile sensitivity decreases and nociceptive specificity and spatial organisation increases with gestational age. Strong, relatively non-specific, reflex sensitivity in early life may be important for driving postnatal activity dependent maturation of targeted spinal cord sensory circuits.
doi:10.1371/journal.pone.0076470
PMCID: PMC3790695  PMID: 24124564
4.  Kangaroo mother care diminishes pain from heel lance in very preterm neonates: A crossover trial 
BMC Pediatrics  2008;8:13.
Background
Skin-to-skin contact, or kangaroo mother care (KMC) has been shown to be efficacious in diminishing pain response to heel lance in full term and moderately preterm neonates. The purpose of this study was to determine if KMC would also be efficacious in very preterm neonates.
Methods
Preterm neonates (n = 61) between 28 0/7 and 31 6/7 weeks gestational age in three Level III NICU's in Canada comprised the sample. A single-blind randomized crossover design was employed. In the experimental condition, the infant was held in KMC for 15 minutes prior to and throughout heel lance procedure. In the control condition, the infant was in prone position swaddled in a blanket in the incubator. The primary outcome was the Premature Infant Pain Profile (PIPP), which is comprised of three facial actions, maximum heart rate, minimum oxygen saturation levels from baseline in 30-second blocks from heel lance. The secondary outcome was time to recover, defined as heart rate return to baseline. Continuous video, heart rate and oxygen saturation monitoring were recorded with event markers during the procedure and were subsequently analyzed. Repeated measures analysis-of-variance was employed to generate results.
Results
PIPP scores at 90 seconds post lance were significantly lower in the KMC condition (8.871 (95%CI 7.852–9.889) versus 10.677 (95%CI 9.563–11.792) p < .001) and non-significant mean differences ranging from 1.2 to1.8. favoring KMC condition at 30, 60 and 120 seconds. Time to recovery was significantly shorter, by a minute(123 seconds (95%CI 103–142) versus 193 seconds (95%CI 158–227). Facial actions were highly significantly lower across all points in time reaching a two-fold difference by 120 seconds post-lance and heart rate was significantly lower across the first 90 seconds in the KMC condition.
Conclusion
Very preterm neonates appear to have endogenous mechanisms elicited through skin-to-skin maternal contact that decrease pain response, but not as powerfully as in older preterm neonates. The shorter recovery time in KMC is clinically important in helping maintain homeostasis.
Trial Registration
(Current Controlled Trials) ISRCTN63551708
doi:10.1186/1471-2431-8-13
PMCID: PMC2383886  PMID: 18435837
5.  Does Prone or Supine Position Influence Pain Responses in Preterm Infants at 32 Weeks Gestational Age? 
The Clinical journal of pain  2004;20(2):76-82.
Objective: The purpose of this study was to examine the influence of prone and supine position in preterm infants during acute pain of blood collection.
Setting: Level III Neonatal Intensive Care Unit (NICU).
Study Design: Thirty-eight preterm infants (birthweight 1339 [590–2525] g, GA 29 [25–32] wks) were in 2 groups depending on their position in the isolette prior to and during heel lance at 32 weeks post-conceptional age. The study design was a comparison between groups (Prone, Supine) during 2 events (Baseline, Heel lance).
Outcome Measure: Pain measures were multidimensional, including behavioral (sleep–wake state and facial activity) and physiological (heart rate) responses measured continuously prior to (Baseline) and during blood collection (Lance).
Results: Both groups of infants displayed statistically significant shifts in sleep–wake state to greater arousal, and increased facial activity and heart rate, from Baseline to Lance. Prone position was associated with significantly more deep sleep during Baseline, compared with Supine position, but there were no differences in sleep-wake state during Lance. Minor increased facial activity was shown in some time segments of Baseline for infants in Supine compared with Prone, but did not differ overall between positions. Prone and Supine position did not affect heart rate significantly during Baseline or Lance events.
Conclusions: Prone position promotes deep sleep in preterm neonates at 32 weeks post-conceptional age when they are undisturbed. However, placement in prone position is not a sufficient environmental comfort intervention for painful invasive procedures such as heel lance for blood sampling in the NICU. Neonates require other environmental supports to promote coping with this stressful event.
PMCID: PMC1351381  PMID: 14770046
pain; position; premature neonates; facial activity; heart rate
6.  Reduction of pain response in premature infants using intraoral sucrose. 
The potential of sucrose to reduce the pain response in a group of healthy premature infants was investigated. Fifteen infants of 32-34 weeks postmenstrual age were tested in a blind crossover manner on two separate occasions no more than two days apart. Either 1 ml of 25% sucrose solution or sterile water was syringed into the baby's mouth 2 minutes before routine heel lancing. Response to the painful stimuli was measured by duration of cry and by facial expression (pain score). There was a significant reduction in the duration of first cry, the percentage of time spent crying in the 5 minutes after heel prick, and the pain score in the sucrose treated group. It is concluded that sucrose has analgesic effects in healthy premature infants.
PMCID: PMC2528545  PMID: 8777660
7.  Kangaroo Care Modifies Preterm Infant Heart Rate Variability in Response to Heel Stick Pain: Pilot Study 
Early human development  2009;85(9):561-567.
Background
Heel stick is the most common painful procedure for preterm infants in neonatal intensive care units. Resultant pain causes adverse physiological effects in major organ systems. Kangaroo Care (KC), involving mother-infant skin-to-skin contact is a promising analgesic for infant pain; however, the effect of KC on the autonomic nervous system's response to pain is unknown.
Aim
To determine if KC results in improved balance in autonomic responses to heel stick pain than the standard method where infants remain in an incubator care (IC) for the heel stick.
Study Design
A randomized cross-over trial.
Subjects
Fourteen preterm infants, 30-32 weeks gestational age and less than 9 days postnatal age.
Outcome Measures
Infant behavioral state, heart rate, heart rate variability (HRV) indices including low frequency (LF) and high frequency (HF) power, and the LF/HF ratio measured over Baseline, Heel Warming, Heel Stick, and Recovery periods in KC and IC conditions.
Results
HRV differences between KC and IC were that LF was higher in KC at Baseline (p<.01) and at Heel Stick (p< .001), and HF was higher in KC at Baseline than in the IC condition (p< .05). The LF/HF ratio had less fluctuation across the periods in KC than in IC condition and was significantly lower during Recovery in KC than in IC (p< .001).
Conclusions
Infants experienced better balance in response in KC than IC condition as shown by more autonomic stability during heel stick. KC may be helpful in mediating physiologic response to painful procedures in preterm infants.
doi:10.1016/j.earlhumdev.2009.05.012
PMCID: PMC2742959  PMID: 19505775
Pain; Heel Stick; Kangaroo Care; Heart Rate Variability; Preterm Infants
8.  The analgesic effect of sucrose in full term infants: a randomised controlled trial. 
BMJ : British Medical Journal  1995;310(6993):1498-1500.
OBJECTIVE--To evaluate the effects of different sucrose concentrations on measures of neonatal pain. DESIGN--Randomised, double blind, placebo controlled trial of sterile water (control) or one of three solutions of sucrose--namely, 12.5%, 25%, and 50% wt/vol. SETTING--Postnatal ward. PATIENTS--60 healthy infants of gestational age 37-42 weeks and postnatal age 1-6 days randomised to receive 2 ml of one of the four solutions on to the tongue two minutes before heel prick sampling for serum bilirubin concentrations. MAIN OUTCOME MEASURE--Duration of crying over the first three minutes after heel prick. RESULTS--There was a significant reduction in overall crying time and heart rate after three minutes in the babies given 50% sucrose as compared with controls. This was maximal one minute after heel prick in the 50% sucrose group and became statistically significant in the 25% sucrose group at two minutes. There was a significant trend for a reduction in crying time with increasing concentrations of sucrose over the first three minutes. CONCLUSION--Concentrated sucrose solution seems to reduce crying and the autonomic effects of a painful procedure in healthy normal babies. Sucrose may be a useful and safe analgesic for minor procedures in neonates.
PMCID: PMC2549876  PMID: 7787595
9.  Specific Newborn Individualized Developmental Care and Assessment Program Movements Are Associated With Acute Pain in Preterm Infants in the Neonatal Intensive Care Unit 
Pediatrics  2004;114(1):65-72.
Objective. The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) is widely used in neonatal intensive care units and comprises 85 discrete infant behaviors, some of which may communicate infant distress. The objective of this study was to identify developmentally relevant movements indicative of pain in preterm infants.
Methods. Forty-four preterm infants were assessed at 32 weeks' gestational age (GA) during 3 phases (baseline, lance/squeeze, and recovery) of routine blood collection in the neonatal intensive care unit. The NIDCAP and Neonatal Facial Coding System (NFCS) were coded from separate continuous bedside video recordings; mean heart rate (mHR) was derived from digitally sampled continuous electrographic recordings. Analysis of variance (phase × gender) with Bonferroni corrections was used to compare differences in NIDCAP, NFCS, and mHR. Pearson correlations were used to examine relationships between the NIDCAP and infant background characteristics.
Results. NFCS and mHR increased significantly to lance/squeeze. Eight NIDCAP behaviors also increased significantly to lance/squeeze. Another 5 NIDCAP behaviors decreased significantly to lance/squeeze. Infants who had lower GA at birth, had been sicker, had experienced more painful procedures, or had greater morphine exposure showed increased hand movements indicative of increased distress.
Conclusions. Of the 85 NIDCAP behaviors, a subset of 8 NIDCAP movements were associated with pain. Particularly for infants who are born at early GAs, addition of these movements to commonly used measures may improve the accuracy of pain assessment.
PMCID: PMC1249525  PMID: 15231909
10.  Effect of Kangaroo Care (skin contact) on crying response to pain in preterm neonates 
Objectives
When preterm infants experience heel stick, crying commonly occurs and has adverse physical effects. A reduction in crying is desired. Kangaroo Care, skin contact between mother and infant, reduces pain as measured by the Premature Infant Pain Profile, and may reduce crying time. The purpose of the pilot was to test Kangaroo Care's effect on the preterm infant's crying response to heel-stick.
Methods
A prospective cross-over study with 10 prematures 2-9 days old (30-32 weeks postmenstrual age) was conducted. Infants were randomly assigned to two sequences (Day 1 heel stick in Kangaroo Care [after 30 minutes of prone skin contact upright between maternal breasts] and Day 2 heel stick in incubator [inclined, nested and prone] or the opposite sequence) was conducted. Video tapes of Baseline, Heel Warming, Heel Stick, and Recovery phases were independently scored for audible and inaudible crying times by two research assistants. The audible and inaudible crying times for each subject in each phase were summed and the mean between the scorer's values was analyzed by repeated measures ANOVA.
Results
Subject characteristics did not differ between those in the two sequences. Crying time differed between the study phases on both days (p ≤ 0.001). When in Kangaroo Care as compared to the incubator, crying time was less during the Heel stick (p = 0.001) and Recovery (p = 0.01) phases.
Conclusion
Because Kangaroo Care reduced crying in response to heel stick in medically stable preterm infants who were 2-9 days old, a definitive study is recommended.
doi:10.1016/j.pmn.2007.11.004
PMCID: PMC2647362  PMID: 18513662
11.  Venepuncture is preferable to heel lance for blood sampling in term neonates 
Background: The analgesic effect of oral sucrose in newborn infants undergoing painful procedures is generally accepted. For blood sampling, some studies have shown that venepuncture (VP) is less painful than heel lance (HL).
Objective: To determine the least painful and most effective method among blood sampling by VP or HL with or without sucrose.
Design: Randomised, double blind, placebo controlled trial.
Subjects: A total of 100 healthy, full term newborn infants being screened for inborn errors of metabolism were randomly allocated to one of four experimental groups (25 infants in each).
Intervention and outcome measure: Seven specially trained nurses took turns to carry out blood sampling two minutes after administration of oral sucrose or water. Neonatal pain was assessed by the neonatal facial coding system (NFCS), as well as by crying.
Results: Without sucrose, the NFCS score was higher in the HL group than the VP group during blood sampling (median 58 v 23, p<0.001). Oral sucrose significantly reduced the score of the HL group (58 v 47, p<0.01) and also tended to reduce the score of the VP group (23 v 2, p<0.1). However, the HL with sucrose group still had a higher score than the VP without sucrose group (47 v 23, p<0.01). Crying and the total procedure time showed the same trends as the NFCS score.
Conclusions: VP is less painful and more effective than HL for blood sampling in newborn infants. Although oral sucrose may have an additive analgesic effect, it is not necessarily required if VP is used for blood sampling.
doi:10.1136/adc.2004.069328
PMCID: PMC1721952  PMID: 15871991
12.  Can topical lignocaine reduce behavioural response to heel prick? 
In a randomised, double blind, controlled study the ability of 5% lignocaine ointment to reduce the behavioural response to heel lance in 30 healthy neonates was assessed. Five per cent lignocaine ointment applied to the heel under an occlusive dressing for one hour before heel prick did not reduce the infants' behavioural response to the heel prick procedure.
PMCID: PMC2528406  PMID: 7743286
13.  Behavioral Responses to Pain Are Heightened After Clustered Care in Preterm Infants Born Between 30 and 32 Weeks Gestational Age 
The Clinical journal of pain  2006;22(9):757-764.
Objective
To compare biobehavioral pain responses of preterm infants born at differing gestational ages (GAs) when pain was preceded by a rest period or by a series of routine nursing interventions.
Methods
In a randomized, within subjects, cross-over design, facial (Neonatal Facial Coding System), sleep/wake state and heart rate (HR) responses of 43 preterm infants [mean birth weight: 1303 g (range 590 g to 2345 g); mean GA at birth: 30 weeks (range 25 to 32)] were examined across 3 phases of blood collection (Baseline, Lance, and Recovery) under 2 conditions: pain after a 30-minute rest period versus pain after a series of routine nursing interventions (clustered care). Infant behavioral responses were coded from continuous bedside videotapes. HR was analyzed using custom physiologic signal processing software.
Results
Infants born at earlier GA (<30 wk) had equally intense facial responses during the Lance phase regardless of condition. However, later born infants (≥ 30 wk GA) showed heightened facial responses indicative of sensitized responses during blood collection when it was preceded by clustered care (P = 0.05). Moreover, later born infants had significantly lower facial (P = 0.05) and HR (P = 0.04) reactivity during Recovery when blood collection followed clustered care.
Discussion
Earlier born preterm infants showed heightened states of arousal and poor ability to modulate HR during Recovery when an invasive procedure was preceded by routine tactile nursing procedures. Alternatively, later born infants exhibited sensitized responses when clustered care preceded blood collection. Our findings support the importance of cue based individualized approaches to care.
doi:10.1097/01.ajp.0000210921.10912.47
PMCID: PMC1851898  PMID: 17057556
preterm infant; pain; clustered care
14.  Alleviation of the pain of heel prick in preterm infants. 
The hypothesis that the variability of physiological parameters may indicate pain or stress in the neonate was examined. Four parameters (heart rate, respiratory rate, transcutaneous oxygen tension, and carbon dioxide tension) were examined over a 2 minute epoch in response to a heel prick in an attempt to measure stress/pain in 35 preterm newborn infants (26-34 weeks' gestation) half of whom were receiving intensive care. The change in absolute values of these parameters did not discriminate a dummy procedure without prick from the actual procedure containing the prick (paired t test), but the variability of the parameters during an epoch showed significant discrimination. Three procedures were evaluated to reduce this distress using unpaired t test. The use of local anaesthetic cream was not successful. The components of the mixture cause vasoconstriction that would reduce blood flow to the heel and lead to more squeezing which is likely to be painful in the presence of tissue damage. A nurse comforting the infant with tactile and vocal stimulation was slightly helpful but the use of a spring loaded lance was most successful in reducing the distress. The use of spring loaded lances may be more humane for heel pricks.
PMCID: PMC1061036  PMID: 8198410
15.  Topical amethocaine gel for pain relief of heel prick blood sampling: a randomised double blind controlled trial 
BACKGROUND—Heel prick blood sampling is a commonly performed and painful procedure in the newborn infant. Use of a topical local anaesthetic does not relieve this pain. A 4% w/w amethocaine gel (Ametop) reduces the pain of venepuncture in the newborn but has not been tried with heel pricks.
AIM—To investigate the effect of topical amethocaine gel on the pain of heel prick in the newborn infant.
DESIGN—Randomised, double blind, placebo controlled trial.
SUBJECTS—Sixty newborn infants, gestation 28-42 weeks (median 36), postnatal age 1-16 days (median 5) undergoing routine heel prick blood sampling.
METHODS—A 1.5 g portion of 4% w/w amethocaine gel or placebo was applied to the skin under occlusion for one hour, then wiped away. Heel prick blood sampling with a spring loaded lance was performed five minutes later. The procedure was videotaped and pain assessed at one second intervals using an adaptation of the neonatal facial coding system (NFCS). No or minimal pain was defined as a cumulative score of less than 5 (out of 15) in the three seconds after firing of the lance and as lack of a cry in the first five seconds.
RESULTS—In terms of a low NFCS core and lack of cry (p = 0.12) 20 of 30 (67%) in the amethocaine group and 13 of 29 (45%) in the placebo group had no or minimal pain in response to the heel prick. The median cumulative NFCS score over the three seconds after firing the lance was 3 (interquartile range 0-6) in the amethocaine group compared with 5 (interquartile range 1-10) in the placebo group (p = 0.07). These differences are not significant.
CONCLUSIONS—Topical amethocaine gel does not have a clinically important effect on the pain of heel prick blood sampling and its use for this purpose cannot therefore be recommended. Alternative approaches to the relief of pain from this procedure should be explored.


doi:10.1136/fn.84.1.F56
PMCID: PMC1721197  PMID: 11124928
16.  Electrophysiological Measurements and Analysis of Nociception in Human Infants 
Pain is an unpleasant sensory and emotional experience. Since infants cannot verbally report their experiences, current methods of pain assessment are based on behavioural and physiological body reactions, such as crying, body movements or changes in facial expression. While these measures demonstrate that infants mount a response following noxious stimulation, they are limited: they are based on activation of subcortical somatic and autonomic motor pathways that may not be reliably linked to central sensory processing in the brain. Knowledge of how the central nervous system responds to noxious events could provide an insight to how nociceptive information and pain is processed in newborns.
The heel lancing procedure used to extract blood from hospitalised infants offers a unique opportunity to study pain in infancy. In this video we describe how electroencephalography (EEG) and electromyography (EMG) time-locked to this procedure can be used to investigate nociceptive activity in the brain and spinal cord.
This integrative approach to the measurement of infant pain has the potential to pave the way for an effective and sensitive clinical measurement tool.
doi:10.3791/3118
PMCID: PMC3369648  PMID: 22214879
Neuroscience;  Issue 58;  pain;  infant;  electrophysiology;  human development
17.  Skin conductance and the stress response from heel stick in preterm infants 
AIM—To evaluate whether spontaneous skin conductance activity is an objective method for measuring the stress response to painful stimuli in premature infants. The number and amplitude of the waves and the baseline increase with the activity of the sympathetic nervous system.
METHODS—In 20 preterm infants of gestational age ⩾ 29 weeks, behavioural state and spontaneous skin conductance activity variables were measured for three minutes before, during, and for three minutes after heel stick.
RESULTS—The number of waves (p < 0.001), the amplitude of the waves (p = 0.001), and the level of the behavioural state (p < 0.001) increased during heel stick, and then decreased to levels found before the procedure. The baseline increased both during (p < 0.001) and after heel stick (p < 0.001), compared with levels before.
CONCLUSION—Spontaneous skin conductance activity reflects the stress response to heel stick in premature infants from at least 29 weeks of gestational age.

doi:10.1136/fn.83.2.F143
PMCID: PMC1721148  PMID: 10952711
18.  Randomised controlled trial of eutectic mixture of local anaesthetics cream for venepuncture in healthy preterm infants 
AIM—To assess the safety and efficacy of EMLA cream (eutectic mixture of local anaesthetics) used to induce surface anaesthesia for venepuncture in healthy preterm infants.
METHODS—Nineteen infants, median gestational age 31 weeks (range 26-33 weeks) were assessed in a randomised, double blind, placebo controlled, cross-over trial. Changes in physiological variables (heart rate, blood pressure, oxygen saturation) and behavioural responses (neonatal facial coding system score, crying time) before and after venepuncture with EMLA cream were compared with those obtained with a placebo cream to assess efficacy. Toxicity was assessed by comparing methaemoglobin concentrations at 1 hour and 8 hours after application.
RESULTS—There was no significant difference in efficacy between EMLA and placebo creams in physiological and behavioural responses. There was no significant difference in methaemoglobin concentrations one hour after the cream had been applied. At eight hours, however, concentrations were significantly higher after EMLA than placebo (p=0.016). There was no evidence of clinical toxicity.
CONCLUSION—This study does not support the routine use of EMLA for venepuncture in healthy preterm infants.


PMCID: PMC1720755  PMID: 9577286
19.  Developmental Changes in the Responses of Preterm Infants to a Painful Stressor 
Infant behavior & development  2008;31(4):614-623.
The purpose of this investigation was to examine longitudinally gestational age and developmental differences in preterm infants' self-regulatory abilities in response to a painful stressor, as well as associations between behavioral and cardiovascular responses. Participants included 49 healthy premature infants. Behavioral and cardiovascular responses to a heel stick blood draw were compared between infants of 28–31 and 32–34 weeks gestational age at birth. Both gestational age groups displayed behavioral and cardiovascular indications of stress in response to the blood draw. However, both shortly after birth and several weeks later, infants born at younger gestational ages (28–31 weeks) were more physiologically reactive. Evidence that the behavioral stress responses of 28–31 weeks gestational age group preterm infants do not reflect their physiological responses suggests that evaluation of preterm infants’ experiences and risk require assessments of both physiology and behavior. The greater stress vulnerability of the 28–31 relative to the 32–34 week gestation infants and the implications of this for subsequent development are discussed.
doi:10.1016/j.infbeh.2008.07.004
PMCID: PMC2668509  PMID: 18778857
Stress; Prematurity; Self-regulation; Physiological reactivity
20.  How Well Do Clinical Pain Assessment Tools Reflect Pain in Infants? 
PLoS Medicine  2008;5(6):e129.
Background
Pain in infancy is poorly understood, and medical staff often have difficulty assessing whether an infant is in pain. Current pain assessment tools rely on behavioural and physiological measures, such as change in facial expression, which may not accurately reflect pain experience. Our ability to measure cortical pain responses in young infants gives us the first opportunity to evaluate pain assessment tools with respect to the sensory input and establish whether the resultant pain scores reflect cortical pain processing.
Methods and Findings
Cortical haemodynamic activity was measured in infants, aged 25–43 wk postmenstrual, using near-infrared spectroscopy following a clinically required heel lance and compared to the magnitude of the premature infant pain profile (PIPP) score in the same infant to the same stimulus (n = 12, 33 test occasions). Overall, there was good correlation between the PIPP score and the level of cortical activity (regression coefficient = 0.72, 95% confidence interval [CI] limits 0.32–1.11, p = 0.001; correlation coefficient = 0.57). Of the different PIPP components, facial expression correlated best with cortical activity (regression coefficient = 1.26, 95% CI limits 0.84–1.67, p < 0.0001; correlation coefficient = 0.74) (n = 12, 33 test occasions). Cortical pain responses were still recorded in some infants who did not display a change in facial expression.
Conclusions
While painful stimulation generally evokes parallel cortical and behavioural responses in infants, pain may be processed at the cortical level without producing detectable behavioural changes. As a result, an infant with a low pain score based on behavioural assessment tools alone may not be pain free.
Rebeccah Slater and colleagues show that although painful stimulation generally evokes parallel cortical and behavioral responses in infants, pain may produce cortical responses without detectable behavioral changes.
Editors' Summary
Background.
Pain is a sensory and emotional experience. It is normally triggered by messages transmitted from specialized receptors (nociceptors) in the body to integrative centers in the spinal cord and brainstem and on to the brain, where it undergoes higher sensory and cognitive analysis, allowing the body to respond appropriately to the stimuli. While the experience of pain may be considered to be unpleasant, it is a useful tool in communicating to us and to others that there is something wrong with our bodies. Ultimately, these responses help restrict further damage to the body and start the process of healing.
In a clinical setting, the ability to communicate about pain allows an individual to seek strategies to ease the pain, such as taking analgesics. Being unable to effectively communicate one's experience of pain leaves the individual vulnerable to prolonged suffering. One such vulnerable group is infants.
Ignored and untreated pain in infants has been shown to have immediate and long-term effects as a result of structural and physiological changes within the nervous system. For example, the body responds to untreated pain by increased release of stress hormones, which may be associated with increased morbidity and mortality in the short term. Long-term effects of pain may include altered pain perception, chronic pain syndromes, and somatic complaints such as sleep disturbances, feeding problems, and inability to self-regulate in response to internal and external stressors. It has been proposed that attention deficit disorders, learning disorders, and behavioral problems in later childhood may be linked to repetitive pain in the preterm infant.
Why Was This Study Done?
Until as recently as the 1990s, newborns in some clinical centres underwent surgery with minimal anesthesia. Also, newborns received little or no pain management postoperatively or for painful procedures such as lumbar punctures or circumcisions. Since then, there has been growing awareness amongst clinicians that pain may be experienced from the earliest stages of postnatal life and that inadequate analgesia may lead to the type of long-term consequences mentioned above. However, gauging how much pain infants and young children are experiencing remains a substantial challenge. The researchers in this study wanted to assess the association between cortical pain responses in young infants and currently used tools for the assessment of pain in these infants. These current tools are based on behavioral and physiological measures, such as change in facial expression, and it is possible that these tools do not give an adequate measure of pain especially in infants born preterm.
What Did the Researchers Do and Find?
Twelve clinically stable infants were studied on 33 occasions when they required a heel lance to obtain a blood sample for a clinical reason. The researchers examined the relationship between brain activity and a clinical pain score, calculated using the premature infant pain profile (PIPP) in response to a painful event. Activity in the somatosensory cortex was measured noninvasively by near-infrared spectroscopy, which measures brain regional changes in oxygenated and deoxygenated hemoglobin concentration. The PIPP is a well-established pain score that ascribes a value to infant behavior such as change in facial expression.
They found that changes in brain activity in response to a painful stimulus were related to the PIPP scores. These changes were more strongly linked to the behavioral components of the PIPP, e.g., facial expression, than physiological components, e.g., heart rate. They also found that a positive brain response could occur in the absence of any facial expression.
What Do These Findings Mean?
Behaviors to communicate pain require motor responses to sensory and emotional stimuli. The maturity of this complex system in infants is not clearly understood. The results of this study raise further awareness of the ability of infants to experience pain and highlight the possibility that pain assessment based on behavioral tools alone may underestimate the pain response in infants.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050129.
Important papers on pain in human neonates are discussed in the open access Paediatric Pain Letter with links to original articles
The Institute of Child Health in London has a Web site describing a three-year international project on improving the assessment of pain in hospitalized children, with many useful links
The International Association for the Study of Pain (IASP) provides accurate and up-to-date information and links about pain mechanisms and treatment
doi:10.1371/journal.pmed.0050129
PMCID: PMC2504041  PMID: 18578562
21.  Ultrasound study of heel to calcaneum depth in neonates 
AIM—To investigate whether it would be safe to extend the currently recommended area of sampling to the whole heel in neonates.
METHODS—Eighty newborn infants were studied, weight range 0.56 to 4.34 kg, gestation 24 to 42 weeks. Ultrasound scanning was used to measure the shortest distance between the skin and the perichondrium of the calcaneum.
RESULTS—The shortest depth of perichondrium was in the centre of the heel and ranged from 3 to 8 mm. In 78 of the 80 infants the distance was 4 mm or more. There was a small but significant positive correlation with weight.
CONCLUSIONS—Standard automated lancets for preterm use that puncture to a depth of 2.4 mm may be safely used anywhere over the plantar surface of the heel. The posterior aspect of the heel should be avoided. Reducing the density of heel pricks should reduce the associated pain.


PMCID: PMC1720928  PMID: 10212093
22.  Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures 
Background
Sucrose is widely used to manage procedural pain in term newborns despite a lack of evidence of its effectiveness for different procedures and infant populations. Our objectives were to evaluate the effectiveness and safety of sucrose in newborns undergoing various medical procedures within 2 days of birth.
Methods
We performed a double-blind, randomized controlled trial. We included newborns (≥ 36 weeks gestation) of diabetic mothers and nondiabetic mothers. Each newborn received 2 mL of a 24%-sucrose or placebo solution before all procedures. We used the Premature Infant Pain Profile to assess pain during intramuscular injection of vitamin K, venipuncture for the newborn screening test and the first 3 heel lances for glucose monitoring (newborns of diabetic mothers only). Scores ranged from from 0 (no pain) to 18 (maximum pain).
Results
We included 240 newborns (120 from diabetic mothers, 120 from nondiabetic mothers). The overall mean pain score was lower among newborns who received sucrose than among those who received a placebo (mean difference –1.3, 95% confidence interval [CI] –2.0 to –0.6). We found that pain scores during intramuscular injection did not differ significantly between the sucrose and placebo groups for newborns of diabetic or nondiabetic mothers (newborns of nondiabetic mothers: mean difference –1.1, 95% CI –2.4 to 0.2; newborns of diabetic mothers: mean difference –1.0, 95% CI –2.4 to 0.4). During venipuncture, newborns who received sucrose had lower pain scores compared with those who received a placebo (newborns of nondiabetic mothers: mean difference –3.2, 95% CI –4.6 to –1.8; newborns of diabetic mothers: mean difference –2.4, 95% CI –3.8 to –1.0). Among newborns of diabetic mothers, there was no difference in pain during the first 3 heel lances or mean glucose levels between the sucrose and placebo groups (p = 0.94 and p = 0.29 respectively).
Interpretation
We found a modest reduction of pain in newborns of both diabetic and nondiabetic mothers when sucrose was used for all medical procedures performed in the first 2 days after birth. However, when each procedure was analyzed separately, we found that the effectiveness of sucrose was limited to venipuncture for the newborn screening test. (http://Clinicaltrials.gov trial register no. NCT00213213.)
doi:10.1503/cmaj.071734
PMCID: PMC2464480  PMID: 18591525
23.  Heart Rate Variability in Response to Pain Stimulus in VLBW Infants Followed Longitudinally During NICU Stay 
Developmental psychobiology  2009;51(8):638-649.
The objective of this longitudinal study, conducted in a neonatal intensive care unit, was to characterize the response to pain of high-risk very low birth weight infants (< 1500 g) from 23 through 38 weeks post-menstrual age (PMA) by measuring heart rate variability (HRV). Heart period data were recorded before, during, and after a heel lanced or wrist venipunctured blood draw for routine clinical evaluation. Pain response to the blood draw procedure and age-related changes of HRV in low-frequency and high-frequency bands were modeled with linear mixed-effects models. HRV in both bands decreased during pain, followed by a recovery to near-baseline levels. Venipuncture and mechanical ventilation were factors that attenuated the HRV response to pain. HRV at the baseline increased with post-menstrual age but the growth rate of high-frequency power was reduced in mechanically ventilated infants. There was some evidence that low-frequency HRV response to pain improved with advancing PMA.
doi:10.1002/dev.20399
PMCID: PMC2936240  PMID: 19739134
pain; respiratory sinus arrhythmia; vagal tone; very low birth weight infants; spectral analysis; mechanical ventilation; growth curve; heel lance; venipuncture; frequency domain measures
24.  Skin to calcaneus distance in the neonate 
Background: Current recommendations for obtaining blood from neonates advise avoidance of the midline area of the heel and are based on postmortem studies.
Objective: Because of the potential pain and tissue damage from repeated heel pricking in the same area, to investigate using ultrasonography whether the distance from skin to calcaneus is less at the midline than at the borders.
Methods: One hundred consecutive healthy preterm and 105 consecutive healthy term neonates were studied 48–72 hours after delivery. The skin to perichondrium distance (SPD) was measured on two occasions by ultrasound at the external, midline, and internal areas of the heel.
Findings: Mean SPD was 0.2 mm less at the midline than at the other sites. The proportion of measurements <3 mm at any of the three sites was the same. Depth was <3 mm in less than 3% of the term and ∼20% of the preterm infants. The SPD correlated only with gestational age. Of children <33 weeks gestational age, 38% had an SPD <3 mm compared with 8% of older preterm infants. The proportions of preterm infants of ⩾33 weeks gestation and term infants with an SPD <3 mm were similar (8% v 3%).
Interpretation: With the use of automated lancets of 2.2 mm length or less, the whole heel plantar surface is safe for obtaining blood in term and preterm infants of ⩾33 weeks gestation. This means that soft tissue damage and pain from repeated pricking in the same area can be reduced.
doi:10.1136/adc.2004.068064
PMCID: PMC1721910  PMID: 15871987
25.  Skin-to-Skin Contact Analgesia for Preterm Infant Heel Stick. 
AACN clinical issues  2005;16(3):373-387.
Objectives
The purpose of the study was to compare a heel stick conducted during skin-to-skin contact with the mother to a heel stick in an incubator in reducing premature infant physiologic and behavioral pain responses.
Study Design
24 premature infants in a University-based NICU were recruited and randomized to two sequences: Sequence A group received three hours of skin-to-skin contact with a heel stick in skin-to-skin followed by three hours in an incubator with a heel stick in the incubator. Sequence B group had incubator care and heel stick before skin contact care and heel stick. Heart rate, respiratory rate, oxygen saturation, crying time and behavioral state were measured before, during, and after heel stick. Repeated measures ANOVA and Mann Whitney U statistics were performed.
Results
Heart rate and crying responses to pain were significantly reduced during the skin-to-skin contact and skin contact heel stick as compared to incubator care and incubator heel stick. Three infants did not cry at all during the skin contact heel stick. Infants slept more during skin-to-skin contact than in the incubator.
Conclusion
Skin-to-skin positioning before and during a heel stick is a simple and inexpensive intervention to ameliorate pain in medically stable premature infants.
PMCID: PMC1890009  PMID: 16082239
Pain; premature infant; skin-to-skin contact; heel stick; analgesia

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