Doi:10.1016/j.earlhumdev.2004.01.003

Early Human Development 77 (2004) 57 – 65 additive effects on pain reduction in newborns Maria Gradin a,*, Orvar Finnstro¨m b, Jens Schollin a aDepartment of Paediatrics, O¨rebro University Hospital, S-701 85 O¨rebro, Sweden bDepartment of Paediatrics, University Hospital, Linko¨ping, Sweden Aims: The aims of this study were to compare the pain reducing effect of oral glucose with that of being breast-fed shortly before venipuncture in newborns, and also the pain score and cryingtime with parents’ assessment. Design: Randomised, controlled trial. Subjects: 120 full termnewborns undergoing venipuncture randomly assigned to on of four groups: I, Breast-fed and 1-mlplacebo; II, Breast-fed and 1-ml 30% glucose; III, Fasting and 1-ml placebo; and IV, Fasting and1-ml 30% glucose. Outcome measures: Pain during venipuncture was measured with thePremature Infant Pain Profile (PIPP). Crying time was recorded. The parents assessed their babies’pain on a Visual Analogue Scale (VAS). Results: The PIPP score was significantly lower in theinfants receiving glucose, than in those not given glucose ( p = 0.004). There was no significantdifference in PIPP score between the infants who were fed and the fasting infants. The PIPP scorewas lower in group II (median 7) than in group I (md 10). There was a similar difference betweengroup IV (md 9) and group III (md 11). The median crying times during the first 3 min in groupsI, II, III, and IV were 63, 18, 142 and 93 s, respectively. There was low agreement between theparents’ assessment of pain and the PIPP score and crying time. Conclusion: Breast-feedingshortly before venipuncture has no major impact on the pain score but on crying time. Thecombination of oral glucose and breast-feeding shows the lowest pain score and significantlyshorter duration of crying.
Published by Elsevier Ireland Ltd.
Keywords: Neonate; Pain; Glucose; Breast-feeding * Corresponding author. Tel.: +46-19-6026664; fax: +46-19-6023122.
E-mail address: [email protected] (M. Gradin).
0378-3782/$ - see front matter. Published by Elsevier Ireland Ltd.
doi:10.1016/j.earlhumdev.2004.01.003 M. Gradin et al. / Early Human Development 77 (2004) 57–65 Newborns routinely experience pain from invasive procedures such as blood sampling. The sick infant may experience repetitive pain from many diagnostic ortherapeutic procedures. Apart from short-term effects, pain also has long-term effects,which may later affect the newborns neurological development, including reaction topain Various methods are used to reduce procedural pain in the newborn. One of the most frequently studied is oral administration of sugar solutions The pain-reducingeffect of oral sugar solutions is believed to be mediated by two mechanisms: anorotactile stimulation by the intraoral fluid gives an initial effect and an orogustatorystimulation prolongs the effect through release of endogenous opioids In aseries of studies, oral sucrose or glucose has been used to alleviate pain reactionsduring blood sampling, by heel stick or venipuncture Otherinterventions such as non-nutritive sucking skin-to-skin contact andswaddling have also been proposed as means of reducing pain during bloodsampling in newborns.
Throughout history, feeding has been used to calm and comfort infants. Today, many care professionals encourage breast-feeding before a painful procedure to keep the neonatesatisfied and not showing so much pain. Questions have been raised whether breast-feeding could be effective to reduce pain and used instead of oral sweet solutions. Thereare few scientific studies in this field. Gray and colleagues found that among infantsundergoing blood sampling, those who were breast-fed during the procedure showed lesscrying and grimacing than control infants Bilgen et al. reported that breast-feeding during blood sampling was less effective than oral sucrose, on the basis of thecrying time and behavioural variables, and Carbajal et al. found breast-feedingsuperior to water or holding but noted no difference between the effects of breast-feedingduring blood sampling and orally given glucose. Time since feeding is often stated amongbackground characteristics in studies about neonatal pain, indicating this to be importantfor the response to a painful procedure. Whether the time since feeding correlates withpain response is rarely studied. In a study on pain response at 4- or 6-month vaccination,Taddio et al. found that time of last feeding did not correlate significantly with painresponse. Studies looking at pain response in newborns recently fed versus not fed has sofar not been performed.
As pain is a multidimensional phenomenon, a multidimensional measure of pain, combining behavioural and physiological factors with contextual factors such asgestational age and behavioural state, has been found to be superior to other measuresThe Premature Infant Pain Profile (PIPP) fulfils this requirement and is easy to use For research about effectiveness of pain-relieving methods, and in clinical practice, it would also be easier if the parents could assess the infants’ pain by themselves. There arefew studies on parental assessment of neonatal pain. Xavier Balda et al. found thatparents were able to correctly indicate a newborn with pain, when looking at pictures ofdifferent facial expressions. A comparison of symptoms used by mothers and nurses toidentify an infant with colic pain showed some similarities M. Gradin et al. / Early Human Development 77 (2004) 57–65 – to compare the pain-reducing effect of recently being breast-fed with that of oral glucose – to compare the parents’ assessment of their infant’s pain with measurements made with the PIPP score and crying time during the procedure.
The study was undertaken at the maternity ward at O March 2001 and September 2002. It was approved by the Local Ethics Committee andinformed consent was obtained from each parent. One hundred and twenty healthy, termbreast-fed infants undergoing the metabolic screening blood test at the age of 3 – 5 dayswere studied. Babies with feeding problems or with suspicion of any illness were notincluded.
The infants were randomly assigned to one of four study groups using a system of sealed envelopes: Group I, breast-fed and placebo (sterile water); group II, breast-fed and30% glucose (Kabi Pharmacia, Stockholm, Sweden); group III, fasting and placebo; andgroup IV, fasting and 30% glucose.
In the breast-fed groups the infants were breast-fed ad libitum within 45 min prior to blood sampling. The amount of breast milk being consumed was not noted. In the fastinggroups the blood sampling was performed at least 2 h after the last feed. The medianlength of time since feeding was 5 min (range 0 – 25) in group I, 5 min (0 – 40) in group II,135 min (120 – 240) in group III and 130 min (120 – 295) in group IV. Other characteristicsof the studied infants are presented in On the basis of a previous study we calculated that a sample size of 30 infants per group would be required to achieve a statistically reliable difference in pain score with apower of 80% and a p value of < 0.05. We hypothesized a difference of 1.7, a standard Mean gestational age, weeks 39.4 (37 – 42) 3638 (2325 – 4425) 3637 (2700 – 4830) 3442 (2185 – 4560) 3660 (3025 – 4950) M. Gradin et al. / Early Human Development 77 (2004) 57–65 deviation (S.D.) of f 3.0, and added 10% to the sample size to ensure for the use of non-parametric statistics.
The procedure was conducted in a quiet observation room. The babies were placed on a preheated nursing table and connected to a pulseoximeter (Datex Ohmeda 3800, Helsinki,Finland). Any parent wishing to be present during the blood sampling was allowed to doso, but was asked not to talk to or comfort the baby. The infant’s face and thepulseoximeter were filmed during the study period with two cameras (Panasonic DigitalVideo Camera NV-DS15, Panasonic Svenska, Stockholm, Sweden) and mixed into onetape using a mixer (Panasonic Digital AV Mixer WJ-AVE 55, Panasonic Svenska). Anexperienced nurse, trained in this particular project, performed the blood sampling. Thenurse identified an appropriate vein on the dorsal aspect of the hand, and the baseline heartrate, oxygen saturation and behavioural state were then recorded during a period of 15 s.
One millilitre of 30% glucose (Kabi Pharmacia) or sterile water was given by a syringeinto the infant’s mouth by the nurse who did not know the content of the syringes. Oneminute afterwards, the nurse cleaned the skin with a local disinfectant and performed thevenipuncture, using a 21-gauge needle (Terumo, Leuven, Belgium). When the bloodcollection was completed, an adhesive bandage was applied and the infant was leftundisturbed for a 3-min recovery phase.
After the procedure, the parents marked their opinion of their infant’s pain during the skin puncture on a Visual Analogue Scale (VAS) scoring from 0 to 100 (0 = no pain,100 = severe pain) One observer not aware of the assignments to the study groups scored all videotapes.
Pain response was measured with use of the PIPP during the first 30 s after the skinpuncture. PIPP is a seven-indicator composite scale assigning points for three behavioural(facial actions: brow bulge, eye squeeze and nasolabial furrow) two physiological (heartrate and oxygen saturation) and two contextual (gestational age, behavioural state)indicators of pain The infants in this study could reach a maximum PIPP score of18. Crying was measured continuously as the presence of audible distressed vocalization.
The observer’s intercoder reliability for PIPP was 0.847.
The parental assessment of pain was divided into three groups: no or minimal pain (VAS < 33), minor – moderate pain (VAS 34 – 67), and moderate – severe pain (VAS>67),and was compared with the PIPP score, which was divided into no or minimal pain(PIPP < 6), minor pain (PIPP 7 – 12), moderate or severe pain (PIPP>12) and cryingtime divided into crying < 15, 15 – 60 and >60 s.
In some instances, data were missing because of equipment failure, such as losing the signal for heart rate or losing the recording of sound. If data were missing, the infant wasexcluded from that particular analysis, but was included in other analyses that did notinvolve the missing variable. For this reason, the numbers of subjects for each analysisdiffered.
M. Gradin et al. / Early Human Development 77 (2004) 57–65 In comparison of differences between groups, Kruskal – Wallis one-way ANOVA was used for PIPP and for crying within the first 3 min. Significance in comparisons betweentwo groups was assessed by the Mann – Whitney U test with Bonferroni – Holm adjustmentAgreement between parental assessment and PIPP score and crying time, respec-tively, was measured by weighted kappa. The statistical analysis was carried out with theSPSS for Windows software program. A p value < 0.05 was considered significant.
The four groups were comparable in background characteristics. Nine infants were excluded after randomisation; three because the mothers did not want to proceed and sixbecause of technical problems with the video recordings.
The PIPP score was significantly lower in the infants receiving glucose (groups II + IV; median 7) than in those not given glucose (groups I + III; median 11) ( p = 0.004).
There was no significant difference in PIPP score between the infants who were fed (groups I + II; median 9) and the fasting infants (groups III + IV; median 9).
shows the PIPP scores obtained in the four groups. The PIPP score was lower in group II (breast-feeding and glucose; median 7) than in group I (breast-feeding andplacebo; median 10). There was a similar difference between the fasting group receivingglucose (group IV; median 9) and that without glucose (group III; median 11). Analysis ofvariance showed that the median PIPP scores were significantly different ( p = 0.037).
Fig. 1. Bubble plot showing Premature Infant Pain Profile scores for the infants in the four groups undergoingvenipuncture. Horizontal lines indicate median values. Size of the bubble represents number of individuals.
M. Gradin et al. / Early Human Development 77 (2004) 57–65 Pairwise comparisons of median PIPP scores did not reach statistical significance with useof Bonferroni – Holm correction.
The infants not receiving glucose (groups I + III) were more likely to show pain (PIPP>6) than those receiving glucose (groups II + IV) (relative risk [RR] 1.6 95%;confidence interval [CI] 1.2 – 2.0). For the infants that were fasting (groups III + IV)compared to the infants being fed (groups I + II), the corresponding relative risk was 1.1(95% CI 0.9 – 1.5).
The median crying times during the first 3 min in groups I, II, III, and IV were 63, 18, 142 and 93 s, respectively ( p = < 0.0001) Statistical significance was achieved forgroup I (breast-feeding and placebo) versus (group II (breast-feeding and glucose)( p = 0.008) and versus group III (fasting and placebo) ( p = 0.005), and for group III(fasting and placebo) versus group IV (fasting and glucose) ( p = 0.009).
There was also a significant difference in this respect between the breast-feeding and glucose group (group II) and the fasting and placebo group (group III) ( p = < 0.001) andthe fasting and glucose group (group IV) ( p = 0.022).
There was no difference between the groups regarding experience of previous invasive procedures, or the duration of the blood collection procedure. In groups I, II, III and IV,there were 27, 28, 25, and 28 infants having less than five earlier procedures, and meanduration was 94, 83, 84 and 81 s, respectively.
There was low agreement between the parents’ assessment of pain and the PIPP score and crying time during the procedure, with weighted kappa 0.25 (95% CI 0.1 – 0.4) and0.44 (95% CI 0.29 – 0.59), respectively.
Fig. 2. Bubble plot showing the crying times during the first 3 min for the infants in the four groups. Crying timeby different groups. Horizontal lines indicate median values. Size of the bubble represents number of individuals.
M. Gradin et al. / Early Human Development 77 (2004) 57–65 Oral sugar solutions with or without non-nutritive sucking have been shown to be effective for treatment of procedural pain in newborns Very few studiesaddressed the question of pain-reducing effects of breast-feeding before a painfulprocedure. In some recently published studies, breast-feeding the infant during the painfulprocedure has been found to have an effect of the pain reaction In Sweden, as inmany other countries, most hospitals work with a ‘‘Baby Friendly Hospital Initiative’’which implies not interrupting feeding, making painful procedures as blood samplingduring breast-feeding improper.
It is not clear whether feeding of an infant before a painful procedure is of benefit or not. The objective of this study was therefore to investigate the effect on pain in newbornsbeing breast-fed shortly before a procedure and to compare this effect with that of orallyadministered glucose. Our study suggests that if oral glucose is given prior to thevenipuncture, the question of recently being fed or being fasting has no major impacton the pain score but on crying time. A combination of breast-feeding and oral glucoseyielded the lowest pain score and was associated with a significantly shorter duration ofcrying, indicating a combined effect on discomfort due to pain and perhaps hunger.
In our study, we have been looking on the effect of being breast-fed. Whether feeding with bottle or feeding tube and use of formula instead of breast milk will gain a similarresult or not, we do not know.
Crying is not specific for pain, and neonates cry to express several basic needs. Despite this fact, crying has been used in many studies as a measure of pain, especially after apainful procedure The somewhat divergent results in our study between thepain score and the crying time might be explained by the fact that some babies werefasting and cried because of hunger.
Oral glucose given prior to a painful procedure is effective and has as known no side effects when used in term infants. In a recently published study, it was found that preterminfants ( < 31 weeks) receiving sucrose during the first week of life prior to all proceduresthat were assumed to cause pain were at risk for poorer neurobehavioral and physiologicaloutcomes compared to controls. The authors concluded that routine use of sucrose forevery painful event cannot therefore be recommended for preterm infants This needsto be confirmed by further studies.
Unfortunately some infants had to be excluded from the analysis of the PIPP score because of missing data in some part of the analysis, especially in the breast-fed and watergroup (group I) and also in the fasting and water group (group III). These missing datamight have affected the result. To check for this possibility, we used a model thatsubstituted the group median for the missing values (heart rate and oxygen saturation).
Similar results were obtained with use of this model on the PIPP score, indicating that themissing data probably had no or only minor impact on the results.
Recent knowledge favours the use of composite scales including both physiolog- ical and behavioural measures for evaluating pain in newborns. One of the most frequentlyapplied methods is PIPP. This scale was developed to assess acute pain in preterm and fullterm newborns It has been submitted to extensive reliability and validity testingunder controlled research conditions, and has also been found to have good validity and M. Gradin et al. / Early Human Development 77 (2004) 57–65 reliability for use in clinical settings The authors of the PIPP scale states a differenceof 2 in PIPP score to be of clinical importance (Personal communication with CelesteJohnston). In clinical practice it would be useful if parental assessment of their infant’spain could be used instead of scores, such as PIPP. However, in this study the parents’assessment of their infant’s pain during venipuncture was not in accordance with the PIPPscore or crying time. The results of the parental assessment showed a wide range, andother factors such as their own experiences of painful procedures, fear, culture andexperience of newborns might have influenced their assessment. Parental assessment oftheir infant’s pain cannot, in our opinion, replace measurement by pain scores.
Oral glucose reduces the signs of pain from venipuncture in the healthy, term newborn.
When combining oral glucose and breast-feeding shortly before the procedure, thereduction is even greater. We recommend that in full-term neonates, in clinical practice,oral glucose should be given at venipuncture and, if possible, the infant should be breast-fed before. If, for any reason, the infant cannot be fed before the procedure, oral glucoseshould always be used.
This study was supported by grants from the Research Committee of O ¨ rebro University Hospital Research Foundation, and the Sven Johansson Memorial Foundation. We also thank Ewy Conradsson, assistant nurse, for her help andAnders Magnusson for statistical advises.
[1] Porter FL, Grunau RE, Anand KJ. Long-term effects of pain in infants. J Dev Behav Pediatr 1999;20: [2] Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate 1998;73:1 – 9.
[3] Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 1997;349:599 – 603.
[4] Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures (Cochrane Review). Cochrane Library 2002;349(3):1 – 35 [Oxford: Updated Software].
[5] Blass EM, Shah A. Pain-reducing properties of sucrose in human newborns. Chem Senses 1995;20:29 – 35.
[6] Barr RG, Pantel MS, Young SN, Wright JH, Hendricks LA, Gravel R. The response of crying newborns to sucrose: is it a ‘‘sweetness’’ effect? Physiol Behav 1999;66:409 – 17.
[7] Barr R, Young S. A two-phase model of the soothing taste response: implications for a taste probe of temperament and emotion regulation. In: Lewis M, editor. Soothing and stress. New Jersey: ErlbaumAssociates; 1999. p. 109 – 37.
[8] Skogsdal Y, Eriksson M, Schollin J. Analgesia in newborns given oral glucose. Acta Paediatr 1997;86: [9] Eriksson M, Gradin M, Schollin J. Oral glucose and venepuncture reduce blood sampling pain in newborns.
M. Gradin et al. / Early Human Development 77 (2004) 57–65 [10] Guala A, Pastore G, Liverani ME, et al. Glucose or sucrose as an analgesic for newborns: a randomised controlled blind trial. Minerva Pediatr 2001;53:271 – 4.
[11] Johnston CC, Stremler R, Horton L, Friedman A. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates. Biol Neonate 1999;75:160 – 6.
[12] Carbajal R, Chauvet X, Couderc S, Olivier-Martin M. Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term neonates. BMJ 1999;75:1393 – 7.
[13] Abad F, Diaz NM, Domenech E, Robayna M, Rico J. Oral sweet solution reduces pain-related behaviour in preterm infants. Acta Paediatr 1996;85:854 – 8.
[14] Abad F, Diaz-Gomez NM, Domenech E, Gonzalez D, Robayna M, Feria M. Oral sucrose compares favourably with lidocaine-prilocaine cream for pain relief during venepuncture in neonates. Acta Paediatr2001;90:160 – 5.
[15] Gradin M, Eriksson M, Holmqvist G, Holstein A, Schollin J. Pain reduction at venipuncture in newborns: oral glucose compared with local anesthetic cream. Pediatrics 2002;110:1053 – 7.
[16] Franck LS, Lawhon G. Environmental and behavioral strategies to prevent and manage neonatal pain.
[17] Gray L, Watt L, Blass EM. Skin-to-skin contact is analgesic in healthy newborns. Pediatrics 2000;105:1 – 6.
[18] Campos RG. Soothing pain-elicited distress in infants with swaddling and pacifiers. Child Dev 1989;60: [19] Gray L, Miller LW, Philipp BL, Blass EM. Breastfeeding is analgesic in healthy newborns. Pediatrics ¨ zek E, Cebeci D, O¨rs R. Comparison of sucrose, expressed breast milk, and breast-feeding on the neonatal response to heel prick. J Pain 2001;2:301 – 5.
[21] Carbajal R, Veerapen S, Couderc S, Jugie M, Ville Y. Analgesic effect of breast feeding in term neonates: randomised controlled trial. BMJ 2003;326:13.
[22] Stevens BJ, Johnston CC, Gibbins S. Pain assessment in neonates. In: Anand K, Stevens B, McGrath P, editors. Pain in neonates. Amsterdam: Elsevier; 2000. p. 101 – 34.
[23] Stevens B, Johnston C, Petryshen P, Taddio A. Premature infant pain profile: development and initial validation. Clin J Pain 1996;12:13 – 22.
[24] Xavier Balda R, Guinsburg R, de Almeida MF, Peres C, Miyoshi MH, Kopelman BI. The recognition of facial expression of pain in full-term newborns by parents and health professionals. Arch Pediatr AdolescMed 2000;154:1009 – 16.
[25] Field P. A comparison of symptoms used by mothers and nurses to identify an infant with colic. Int J Nurs [26] Huskisson E. Visual analogue scales. In: Melzack R, editor. Pain measurement and assessment. New York: [27] Holm S. A simple sequentially rejective multiple test procedure. Scand J Statist 1979;6:65 – 70.
[28] Gibbins S, Stevens B. Mechanisms of sucrose and non-nutritive sucking in procedural pain management in infants. Pain Res Manag 2001;6:21 – 8.
[29] Baby Friendly Hospital Initiative. Ten steps to successful breastfeeding from WHO/UNICEF. Promoting, and supporting breastfeeding: a special role of maternity service. A joint WHO/UNICEF statement. Geneve:World Health Organization; 1989.
[30] Owens ME, Todt EH. Pain in infancy: neonatal reaction to a heel lance. Pain 1984;20:77 – 86.
[31] Bours G, Abu-Saad H, Hamers J, van Dongen R. Pain assessment in neonates—a state of the art study.
Maastricht: Maastricht University; 1996.
[32] Johnston CC, Filion F, Snider L, et al. Routine sucrose analgesia during the first week of life in neonates younger than 31 weeks’ postconceptional age. Pediatrics 2002;110:523 – 8.
[33] Ballantyne M, Stevens B, McAllister M, Dionne K, Jack A. Validation of the premature infant pain profile in the clinical setting. Clin J Pain 1999;15:297 – 303.

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