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Is a nappy change stressful to neonates?
Early Human Development (2006) 82, 669 — 676
available at www.sciencedirect.com
www.elsevier.com/locate/earlhumdev
Is a nappy change stressful to neonates? ¨relius a,*, Lena Hellstro ¨m-Westas b, Catarina Carle Evalotte Mo ´n b, Elisabeth Norman b, Nina Nelson a a
¨ping University Hospital, Department of Molecular and Clinical Medicine/Division of Paediatrics, Linko ¨ping, Sweden SE-581 85 Linko b Department of Paediatrics, Lund University Hospital, Lund, Sweden Accepted 22 December 2005
KEYWORDS Cortisol; Infant; Newborn; Neonatal intensive care; Pain measurement; Stress
Abstract Objectives: Infants in neonatal intensive care (NICU infants) are often cared for in a stressful environment that includes potentially painful or stressful interventions. The aim was to investigate whether NICU infants have different pattern of stress and pain responses than healthy newborns when challenged by a non-painful everyday care routine. Methods: NICU infants born at 23—38 weeks gestation (n = 39) were compared to healthy fullterm newborns (n = 30). Cortisol concentrations in saliva were determined before and 30 min after a standardised nappy change. The premature infant pain profile (PIPP) and the neonatal infant pain scale (NIPS) were evaluated before, during, directly after, 3 min after, and 30 min after the nappy change. The investigation was performed on two different occasions, first between postnatal days 2—7 and then between postnatal days 10—18. Results: NICU infants had higher median baseline salivary cortisol levels compared to full-term newborns on both occasions (17.1 nmol/L vs. 6.2 nmol/L p b 0.01 and 8.5 nmol/L vs. 2.4 nmol/L p b 0.01, respectively). Salivary cortisol decreased in response to the second nappy change in NICU infants ( p = 0.01). NICU infants had higher PIPP scores during both nappy changes ( p b 0.001 for both occasions) and more sustained increases in PIPP and NIPS up to 30 min after the nappy changes compared to full-term newborns. Conclusions: NICU infants have higher baseline salivary cortisol than healthy full-term newborns. There is a change in baseline cortisol by age in both groups. Full-term infants as well as NICU infants show an increased pain response to a standardised nappy change. D 2006 Elsevier Ireland Ltd. All rights reserved.
Abbreviations: ACTH, adrenocorticotropic hormone; CPAP, continuous positive airway pressure; CRIB, clinical risk index for babies; CRH, corticotropin-releasing hormone; GA, gestational age, HPA axis, hypothalamic—pituitary—adrenal axis; IVH, intraventricular haemorrhage; NICU, neonatal intensive care unit; NICU b 30, infants born before 30 weeks gestational age; NICU z 30, infants born at or above 30 weeks gestational age; NIPS, neonatal infant pain scale; PIPP, premature infant pain profile; q1, first quartile; q3, third quartile; SaO2, oxygen saturation. * Corresponding author. Tel.: +46 13 221378. E-mail address: [email protected] (E. Mo ¨relius). 0378-3782/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2005.12.013
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1. Introduction
2. Material and methods
Neonatal intensive care involves many painful and potentially stressful procedures [1,2]. In addition, the baby’s medical condition and the neonatal intensive care environment itself can be stressful, despite efforts to reduce unnecessary stimuli. While some stress may be advantageous for the baby at birth, excessive stress may cause long-term sequelae and sensitise the child to pain and stress later in life [3—6]. The fetal hypothalamic—pituitary—adrenal system (HPA axis) functions from at least the beginning of the second trimester [7,8]. Extremely low birth weight infants show a pituitary response to corticotropin-releasing hormone (CRH) and an adrenal response to adrenocorticotropic hormone (ACTH) stimulation [9]. Measurement of cortisol in saliva is feasible and valuable when studying the adrenal response to different stressors in early life [10]. Salivary cortisol responses have previously been studied in preterm babies both during painful [11—14] and presumably pleasant procedures [15,16]. Two studies report increased salivary cortisol in response to heel stick in preterm infants at or above 30 weeks of gestational age (GA) [11,13], and one study reports a decreased salivary cortisol in response to skin-to-skin care [15]. Three studies investigate heel stick [12], massage [15], and skin-to-skin care [16] included infants below 30 weeks GA. In each of these studies, both increased and decreased salivary cortisol responses were found. No previous study has compared salivary cortisol responses to an everyday care routine in infants in a neonatal intensive care unit with fullterm healthy newborns. One example of an everyday care routine is the nappy change. A nappy change is performed several times a day in both healthy and sick infants. A few studies have therefore investigated the nappy change as a possible stressor in neonatal intensive care, finding increased pain scores [17] and elevated heart rate [18]. Our hypothesis is that a nappy change may be stressful for infants in intensive care but not for full-term healthy newborns at home. The aim of the present study was to investigate whether infants treated in neonatal intensive care have a different pattern of cortisol and pain response compared to full-term healthy infants when challenged with an everyday care routine, in this case a standardised nappy change.
2.1. Participants
Table 1
2.1.1. NICU infants The study was carried out at the neonatal intensive care unit (NICU) of Linko ¨ping University Hospital, Sweden, from January 2001 to April 2004. The NICU with an average of 450 intakes a year includes 17 beds, nine for intensive and intermediate care and eight for conventional and rooming-in care. Consecutively admitted infants aged 2 days or older were considered for the NICU infant group. Infants treated with cortisone, diagnosed with intraventricular haemorrhage (IVH) or having neurological symptoms were excluded. Thirty-nine babies participated, 23 boys and 16 girls. The babies’ gestational ages ranged from 23 to 37 weeks and birth weights ranged from 505 to 3070 g. At the time of the first nappy change, 20 babies were on CPAP and six on a ventilator. The severity of illness was estimated by the clinical risk index for babies (CRIB) [19] (Table 1). Eleven babies were excluded from the second nappy change because they were discharged from intensive care (n = 8), referred to their home county hospitals (n = 2), or deceased (n = 1). The NICU infants were also divided into two subgroups depending on GA. Twenty-three babies were born before 30 weeks GA (b 30) and 16 were born at or above 30 weeks GA (z 30) (Table 1). 2.1.2. Full-term healthy newborns, controls Healthy newborn infants aged 2 days or older, born in the maternity ward of the University Hospital in Linko ¨ping between August 2002 and March 2003, were considered for the control group. The University Hospital has approximately 2400 deliveries a year. Approximately 54% of mothers giving birth in Linko ¨ping are discharged from the hospital within 48 h of delivery. Inclusion criteria were met if (1) the baby was not discharged before 2 days of age and (2) the family lived in urban Linko ¨ping. Thirty full-term babies were included, 17 boys and 13 girls, with birth weights ranging from 2780 to 3725 g (Table 1).
Clinical data of participating babies during 1st nappy change
Variable Mode of delivery Caesarean section/normal/assisted Birth weight, grams median (range) Gestational age at birth, weeks median (range) Apgar score at 5 min median (range) Postnatal age, days median (range) Boys/girls CPAP/ventilator CRIB mean (SD)
Controls, n = 30
NICU infants, n = 39
NICU infants b 30 weeks, n = 23
NICU infants z 30 weeks, n = 16
9/17/4 3595 (2780—3725) 40 (38—42)
29/9/1 1155 (505—3070) 30 (23—37)
17/5/1 940 (505—1600) 28 (23—29)
9/7/0 1850 (1135—3070) 32 (30—37)
10 (9—10) 2 (2—3) 17/13 0/0
8 (1—10) 5 (2—7) 23/16 20/6 2.8 (3.0)
7 (1—10) 5 (2—7) 14/9 16/5 3.9 (3.2)
9 (5—10) 3.5 (3—5) 9/7 4/1 1.2 (1.8)
Values indicate number of babies unless stated otherwise. NICU infants are divided in two groups based on gestational age at birth.
Is a nappy change stressful to neonates?
2.2. Standardised nappy change In order to evaluate a routine handling procedure to which all babies, sick or healthy, are exposed we chose the response to a nappy change. All nappy changes were performed using a standardised protocol. The protocol included placing the baby on his/her back, removing the used nappy, using a paper towel and lukewarm water without soap to gently clean the skin with seven strokes irrespective of nappy content, putting on a new nappy, and replacing the baby in his/her previous position. Apart from the standardised nappy change there was no other human touch involved in the procedure.
2.3. Salivary cortisol To investigate the cortisol response, saliva was collected before (baseline) and 30 min after the nappy change (response). Saliva was collected using cotton buds, as described previously [10]. Because of components that can disturb the salivary cortisol analysis, saliva was collected at least 1 h after the baby was fed. After collection the saliva was centrifuged, frozen at 22 8C, and stored at 70 8C. A radioimmunoassay for cortisol was used to analyse the cortisol concentrations in the saliva. Samples were run neat in duplicate, and all samples from each individual were run in the same assay. Intra-assay coefficients of variation were 12% at 2.0 nmol/L and 6% at 10.0 nmol/L [10].
2.4. Pain profiles The Premature Infant Pain Profile (PIPP) [20] and the Neonatal Infant Pain Scale (NIPS) [21] were used to measure pain at the bedside. PIPP comprises three behavioural variables (time of brow bulge, eye squeeze, and nasolabial furrow, respectively), two physiological variables (changes in heart rate and oxygen saturation), and two contextual variables (gestational age and behavioural state). Each variable is scored on a scale from zero to three. The minimum PIPP score is zero (no pain) and the maximum score 21. The authors suggest that a PIPP score of six or less means minimal or no pain, and 12 and above indicates moderate to sever pain [20]. Heart rate and oxygen saturation (SaO2) were measured with a cardiorespiratory monitor (Hewlett Packard, Bo ¨blingen, Germany) for NICU infants and with a transportable monitor (Nellcore Puritan Bennett, NPB-40, Pleasanton, CA, USA) for controls. NIPS comprises five behavioural variables (facial expression, cry, arm movements, leg movements, and behavioural state) and one physiological variable (breathing pattern). Each variable is scored on a scale from zero to one or (for cry) two. The minimum NIPS score is zero (no pain) and the maximum seven. PIPP and NIPS have documented reliability and validity for full-term and preterm infants [20,21] and have previously been used in parallel in stress research of preterm infants [16].
2.5. Procedure The research ethics committee of Linko ¨ping University approved the study and informed consent was obtained
671 from all parents. The investigation was performed once between postnatal days 2 and 7 (1st nappy change) and was repeated between postnatal days 10 and 18 (2nd nappy change). All nappy changes for NICU infants were performed in their incubators. The first nappy change for the controls was performed in their cots at the maternity ward and the second nappy change was performed at home. The study sequence was always the same: PIPP and NIPS were scored at baseline (nurse 1 for controls and nurse 3 for NICU infants) and saliva was collected (nurse 2). Thereafter, the standardised nappy change was performed (nurse 2) at the same time as PIPP and NIPS were rated (by nurse 1 and 3, respectively) during the first 30 s of the nappy change, starting when the nappy was opened. Ratings of PIPP and NIPS were repeated as soon as the baby was repositioned, 3 min after and 29 min after the nappy change. A second saliva sample was collected 30 min after the nappy change (nurse 2) to reflect the cortisol response. The interrater reliability for nurses 1 and 3 was 0.86 and 0.95 for NIPS and PIPP, respectively (interclass correlation coefficient).
2.6. Statistics Data were analysed using the statistical program SPSS (version 11.5). Friedman and Wilcoxon signed ranks tests were used to analyse differences in paired data. Kruskal— Wallis test and Mann—Whitney U test were used to test differences between independent samples. In some cases, data were absent because of an insufficient amount of saliva. When this was the case, the infant was excluded from paired analyses but included in other, non-paired analyses. Therefore, the numbers of subjects for each analysis differ slightly. Correlation coefficients were analysed using Spearman’s rho. A univariate analysis of variance (ANOVA) was used to analyse background characteristics as possible mediating factors for the changes in cortisol and pain scores. An increase or decrease in salivary cortisol response is defined as a change in cortisol level from baseline at 10% or more based on intra-assay coefficients of variation of the radioimmunassay [10].
3. Results 3.1. First nappy change 3.1.1. Salivary cortisol Sufficient amounts of saliva for analysis of cortisol were collected in 91% of the babies during the first nappy change. Saliva was sufficient for paired analyses at both baseline and response in 87% and 85% of controls and NICU infants, respectively. The NICU infants had significantly higher baseline salivary cortisol compared to controls ( p b 0.01) (Table 2). NICU infants b30 weeks GA had significantly higher baseline and response salivary cortisol compared to controls ( p b 0.001 and p b 0.001, respectively) and NICU infants z 30 weeks GA ( p b 0.001 for both comparisons) (Fig. 1). After the nappy change, salivary cortisol increased in 13 of the 33 NICU infants, decreased in 15, and was unchanged in five. The median cortisol level for NICU infants decreased by 25% after
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Table 2 Salivary cortisol, nmol/L (baseline and response) and pain profiles (PIPP and NIPS) before, during, after, 3 min after, and 30 min after 1st nappy change for controls and NICU infants, and for NICU infants b 30 and z 30 weeks GA, respectively Controls, n = 30 Cortisol baseline Cortisol response PIPP baseline During After 3 min after 30 min after NIPS baseline During After 3 min after 30 min after
6.2 7.7 3 3 3 2 3 0 4 2 0 0
(4.1—11.1) (3.7—13.1) (1—3) (1.75—6.25)c (2—5)c (0—3.25) (2—4) (0—1) (1—6)c (0—5)c (0.75) (0—0)
NICU infants, n = 39 17.1 12.8 4 8 7 6 5 0 4 1 1 1
(5.8—32.2) (4.9—23.9) (4—5)a (7—11)a,c (4—8)a,c (3—7)a,c (4—5)a (0—1) (2—6)c (1—3)c (1—2)a,c (0—1)a
a
NICU b 30 weeks, n = 23 20.2 18.6 5 9 8 6 5 1 4 2 1 1
a
(14.7—40.3) (11.7—36.2)a (4—6)a (7—12)a,c (5—10)a,c (5—8)a,c (4—6)a (0—1)a (3—6)c (1—3)c (1—3)a,c (0—2)a
NICU z 30 weeks, n = 16 5.8 (3.9—15.9)b 4.4 (3.3—12.0)b 4 (3—4)a,b 8 (6.25—8)a,b,c 4 (3.25—6.5)a,b,c 3 (3—6)a,b 4 (4—5)a,b 0 (0—1) 4 (2—5)c 1 (0—2)b,c 1 (0—1)a,b,c 0 (0—1)a
Values are given in median (first quartile—third quartile). a p b 0.05, significant difference from controls. b p b 0.05, significant difference from NICU infants b30 weeks. c p b 0.05, significant difference from baseline.
the nappy change (Table 2). Among the 26 control infants, salivary cortisol increased in eight, decreased in 14, and was unchanged in four. The median cortisol level for controls increased by 24% after the nappy change (Table 2). There was no correlation between changes in salivary cortisol levels and changes in pain score. Furthermore, there was no correlation between changes in salivary cortisol levels and pain scores at different measuring points in relation to the first nappy change (baseline, during, directly after, 3 min after, and 30 min after). 3.1.2. Premature infant pain profile, PIPP Both NICU infants and controls had a significant increase in PIPP score during nappy change compared to baseline ( p b 0.001 and p b 0.01, respectively). NICU infants had significantly higher PIPP scores at baseline and throughout all measuring points compared to controls ( p b 0.001 for all comparisons) (Table 2). The NICU infants had a sustained high PIPP score lasting until the 3 min measuring point compared to baseline (during: p b 0.001, after: p b 0.001, and 3 min after: p b 0.05) (Fig. 2). In the NICU infant group, there was a significant difference in PIPP
Figure 1 Median salivary cortisol (nmol/L) in NICU infants b 30 weeks (white bars), NICU infants z 30 weeks (striped bars), and controls (grey bars) at baseline and in response to the first and second nappy change, respectively.
scores at all measuring points between babies born before and after 30 weeks GA, with babies born at lower GA showing higher scores (baseline: p b 0.001, during: p b 0.05, after: p b 0.001, 3 min after: p b 0.01, and 30 min after: p b 0.05) (Table 2). 3.1.3. Neonatal infant pain scale, NIPS Both NICU infants and controls showed a significant increase in NIPS score during nappy change compared to baseline ( p b 0.001 for both comparisons) (Fig. 2). The NICU infants had a sustained high NIPS score lasting until the 3 min measuring point compared to baseline (during: p b 0.001, after: p b 0.001, and 3 min after: p b 0.01) (Table 2). The NICU infants born before 30 weeks GA had a significantly higher NIPS score at the 3 min measuring point compared to babies born after 30 weeks GA ( p b 0.01) (Table 2). There was a moderate, but significant, linear correlation between PIPP and NIPS at all time points: baseline: r = 0.29 ( p b 0.05), during: r = 0.29 ( p b 0.05), after: r = 0.31 ( p b 0.05), 3 min after: r = 0.53 ( p b 0.001), and 30 min after: r = 0.36 ( p b 0.01).
3.2. Second nappy change 3.2.1. Salivary cortisol Sufficient amounts of saliva for analysis of cortisol were collected in 89% of the babies during the second nappy change. Saliva was sufficient for paired analyses at both baseline and after the nappy change in 87% and 82% of controls and NICU infants, respectively. The NICU infants had a significantly higher baseline salivary cortisol at the second nappy change compared to controls ( p = 0.001) (Table 3). After the nappy change, three out of 24 NICU infants showed an increase in cortisol levels, 16 showed a decrease, and four did not change. In NICU infants the median salivary cortisol decreased by 42% ( p = 0.01) (Table 3). The decrease was most pronounced in NICU infants b30 weeks (Fig. 1). There was a significant difference in baseline cortisol between babies born before and after 30 weeks GA in the NICU infant group ( p b 0.01)—the more preterm the infant, the higher the cortisol levels (Fig. 1). Among the
Is a nappy change stressful to neonates?
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Median PIPP 2nd nappy change
Median PIPP 1st nappy change
10
8
6
4
2
0 Baseline
During
4
2
3 minutes after
After
During
5
30 minutes after
3 minutes after
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Median NIPS 2nd nappy change
Median NIPS 1st nappy change
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0 Baseline
30 minutes after
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4
3
2
1
0 Baseline
After
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30 minutes after
3 minutes after
4
3
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Figure 2 Median values for pain scores (PIPP and NIPS) at baseline, during, directly after, 3 min after, and 30 min after the first and second nappy change, respectively. Solid black lines represent NICU infants b 30 weeks GA, broken black lines represent NICU infants z 30 weeks GA, grey dotted lines represent controls.
control infants, 12 out of 26 showed an increase in cortisol levels, 11 showed a decrease, and three did not change. The median salivary cortisol level for controls increased 75% after the nappy change (Table 3). In both groups, baseline and response salivary cortisol levels were significantly lower at the second nappy change compared to the first nappy change (NICU infants: p b 0.01 for both baseline and response; controls: p b 0.01 and p b 0.05 at baseline and response, respectively). There was no correlation between changes in salivary cortisol levels and changes in pain score. Furthermore, there was no correlation between changes in salivary cortisol levels and pain scores at different measuring points in relation to the second nappy change (baseline, during, directly after, 3 min after, and 30 min after). 3.2.2. Premature infant pain profile, PIPP The PIPP score increased significantly from baseline during the nappy change in both NICU infants and controls ( p b 0.001 and p b 0.05, respectively). Compared to baseline, the NICU infants had a sustained rise in PIPP score lasting until the 3 min measuring point (during: p b 0.001,
directly after: p b 0.01, and 3 min after: p b 0.05 (Table 3). NICU infants had significantly higher PIPP scores at baseline and at all measuring points compared to controls ( p b 0.001 for all comparisons), with babies born at lower GA showing higher scores (Fig. 2). 3.2.3. Neonatal infant pain scale, NIPS The NIPS score increased significantly from baseline during the nappy change in both NICU infants and controls ( p b 0.001 and p b 0.01, respectively) (Fig. 2). The NICU infants had sustained high NIPS scores at the 30 min measuring point compared to baseline ( p b 0.05) (Table 3). There was a small but significant linear correlation between PIPP and NIPS at three time points, during: r = 0.39 ( p b 0.01), after 3 min: r = 0.27 ( p b 0.05), and after 30 min: r = 0.31 ( p b 0.05). ANOVA was used to test environmental milieu (NICU vs. home), mode of delivery, dexamethasone given to the mother prior to delivery, gender of the baby, severity of illness (CRIB score, and need for mechanical ventilation), and postnatal days as possible explanations for the magnitude of change in cortisol levels and change in pain scores.
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Table 3 Salivary cortisol, nmol/L (baseline and response) and pain profiles (PIPP and NIPS) before, during, after, 3 min after, and 30 min after 2nd nappy change for controls and NICU infants, and for NICU infants b 30 and z 30 weeks gestational age, respectively Controls, n = 30 Cortisol baseline Cortisol response PIPP baseline During After 3 min after 30 min after NIPS baseline During After 3 min after 30 min after
2.4 4.2 2 2 1 1 2.5 0 4 1 0 0
(1.8—4.5) (2.0—11.0) (0—3) (1—5.25)c (0—4) (0—3) (1—3) (0—2.25) (1.75—6)c (0—5) (0—3) (0—1)
NICU infants, n = 28 8.5 4.9 5 8.5 6 4 5 0 4 1 1 0.5
a
(3.9—12.8) (2.8—12.7)c (4—5)a (6.25—10.75)a,c (5—8)a,c (3—5)a,c (4—6)a (0—0.75) (1.25—5)c (0.25—3)c (0—1) (0—1)c
NICU b 30 weeks, n = 20 10.6 6.9 5 10 7 4 6 0 4 1 0.5 1
(5.1—16.8) (3.8—15.2) (4—5)a (8—12)a,c (5—9)a,c (3—5)a (5—7)a (0—1) (2—6)c (1—3)c (0—1) (0—1.75)
a
NICU z 30 weeks, n = 8 3.6 3.2 4 6 4.5 3 3.5 0 2.5 1 1 0
(2.1—8.4)b (2.5—7.1) (3.25—4)a,b (4—9.5)a,b,c (2.25—6)a,b (1—4.5) (3—4)a,b (0—0) (0.25—4)c (0—2.75)c (0—1.75)c (0—0)
Values are given in median (first quartile—third quartile). a p b 0.05, significant difference from controls. b p b 0.05, significant difference from NICU infants b30 weeks. c p b 0.05, significant difference from baseline.
These analyses did not reveal any statistical significance neither for the first nor the second nappy change.
4. Discussion Our study shows that infants in neonatal intensive care have higher baseline salivary cortisol levels than full-term healthy babies. In agreement with other studies, we found significantly lower baseline salivary cortisol at older postnatal ages (during the second nappy change) in both controls and NICU infants [16,22,23]. However, at 10—18 days postnatal age (the second nappy change), the baseline salivary cortisol level was still higher in the NICU infants than in the controls. This could be an early sign of a disturbance in the HPA axis, in accordance with the results in a recent published study showing higher baseline salivary cortisol and response to novel stimuli in preterm infants at 8 months as compared with full-term controls [6]. Miller et al. has recently showed that stress at delivery may influence the HPA axis response [24]. They found that infants born vaginally mounted greater cortisol responses during vaccination at the age of 2 months. We did not find any support for this in our study. However, that could be an effect of that preterm infants commonly are delivered by caesarean section. In our study 74% of the NICU infants were delivered by caesarean section and only 30% of the controls. Earlier studies have shown that infants do not have the same diurnal rhythm in cortisol levels as adults [25,26]. Cortisol levels increase in relation to delivery but stabilise 2 days after birth, i.e., before inclusion in the present study [27]. Therefore, the lower cortisol values, at an older age, may be either an effect of postnatal age or a result of a stabilised medical condition in the NICU infants. However, lower cortisol values also in our controls at older postnatal age suggest that postnatal age rather than medical circumstances has a large influence on cortisol levels even for NICU infants. In agreement with other studies, we found salivary cortisol brespondersQ as well as bnon-respondersQ in both
groups [12,15,16]. The brespondersQ either increased or decreased after the standardised nappy change, while the bnon-respondersQ did not show any change in cortisol secretion. We know from the study by Hanna and colleagues [9] that even preterm infants have the ability to increase cortisol secretion when given ACTH. Moreover, Gitau et al. found that the fetal HPA axis can mount cortisol responses from the 20th week [28]. In our study, the cortisol response differed between individuals when exposed to the same stressor, a nappy change. It is possible that compared to infants with lower baseline levels, infants with high baseline cortisol levels do not have the same ability to increase cortisol levels further when exposed to a stressor [29,30]. However, it remains unclear whether a decreased cortisol response, as found in NICU infants during the second nappy change, is 1) a sign of a lower degree of stress, 2) a question of immaturity in the HPA axis, or 3) an effect of suppressed adrenal activity due to longstanding and/or repetitive high stress load. A nappy change is usually repeated several times a day and is a potentially stressful procedure for a sick baby. A healthy full-term baby, on the other hand, being more stable, is more likely to habituate to [31—33] or even appreciate a nappy change. Additionally, although the intervention was principally the same in each group, a nappy change may in fact represent a much more intense intervention in a sick infant, involving the stimulus of CPAP/ventilator movements, as well as repositioning of wires, probes or other technology. Even breplacing the baby in his/her previous positionQ is a more complicated procedure for a sick infant. Thus, an intervention, which is theoretically the same, may have different side effects in practice. Our NICU infants had a slightly different pain pattern than controls. The NICU infants had a peak during the nappy change and returned to baseline very slowly (3 to 30 min). However, the controls also showed a peak during nappy change—though not as high as the NICU infants—on the other hand they returned to baseline more quickly. One limitation in our study is, however, the absence of measuring points between 3 and
Is a nappy change stressful to neonates? 30 min after the nappy change. Several measuring points may have revealed further dynamics. The pain scales are also used in a slightly modified manner (repeated observations in relation to stimulus) in order to assess the state of the baby, in relation to changes in salivary cortisol, 3 and 30 min after the nappy change. Even though a nappy change is not considered a painful intervention, the pain scores increased in the present investigation. One could wonder if the pain instruments (i.e., NIPS and PIPP) do measure pain exclusively. It is difficult, or perhaps even impossible, to distinguish stress from pain in infants. Pain is a stressor and as such may cause a stress response, which may be harmful to an already seriously ill and unstable infant. However, a stress response was not verified by increased salivary cortisol in the present study. In agreement with earlier studies, we did not find any correlation between pain scores and salivary cortisol levels [14,16]. Even though pain is a stressor that could potentially trigger the HPA axis, the behavioural expression of pain is not necessarily comparable to a hormonal stress response. Therefore, a baby’s increase in pain score does not necessarily correspond to the cortisol response. The interpretation of the pain scales also needs to include the suggestion from the authors that scores at or below six are not considered to be pain [20]. But the question still remains: is a nappy change stressful to neonates? Or, is it even painful in some sick and very preterm infants? The preterm infant may be more vulnerable and sensitive to disturbance and may have greater difficulty to stabilise and to cope with various strains—it is thus more likely that the preterm baby needs more time to stabilise and return to baseline. This is supported by the findings of pronounced and sustained pain scores in the most preterm infants. Clinically these findings lend further support to individual handling of the baby [34]. It is important to reduce the number of stressors in neonatal intensive care [1,2]. As we found the nappy change to cause a behavioural pain response this should be performed with caution and gently especially in preterm/severely ill infants. It is perhaps sensible to individualise, and in certain cases reduce, the numbers of nappy changes according to the baby’s need rather than to a predetermined schedule.
5. Conclusions Infants in neonatal intensive care have higher baseline salivary cortisol levels during their first days of life compared to healthy full-term infants. The highest cortisol values were found in infants below 30 weeks GA. A significant decrease in salivary cortisol was found in NICU infants after the second nappy change. Both healthy fullterm infants and infants in neonatal intensive care have lower baseline salivary cortisol at an older age (during the second standardised nappy change). Infants in neonatal intensive care expressed a high and prolonged pain response to the standardised nappy change compared to healthy full-term infants who expressed a high but short pain response. The pain scores were more pronounced in the most preterm infants.
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Acknowledgements We are grateful to Professor Elvar Theodorsson for his valuable contribution to methodological issues. We would also like to thank the nurses, Christine Rose´n, Anne Sandehed, and Lisbeth deJonge for their excellent assistance with data collection. This research was supported by ¨ stergo grants from the County of O ¨tland, Sweden, the Swedish Society of Nursing, the Perinatal Foundation, Linko ¨ping, the Sven Jerring Foundation, the South Sweden Society of Nursing, the Swedish Medical Research Council (grant 0037), and Lund University Hospital Funds.
References [1] Barker DP, Rutter N. Exposure to invasive procedures in neonatal intensive care unit admissions. Arch Dis Child 1995;72:F47 – 8. [2] Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003;157:1058 – 64. [3] McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol 1995;5:205 – 16. [4] Porter FL, Grunau RE, Anand KJ. Long-term effects of pain in infants. J Dev Behav Pediatr 1999;20:253 – 61. [5] Sapolsky RM. Why stress is bad for your brain. Science 1996;273:749 – 50. [6] Grunau RE, Weinberg J, Whitfield MF. Neonatal procedural pain and preterm infant cortisol response to novelty at 8 months. Pediatrics 2004;114:e77. [7] Pepe GJ, Albrecht ED. Regulation of the primate fetal adrenal cortex. Endocr Rev 1990;11:151 – 76. [8] Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and B-endorphin response to intrauterine needling. Lancet 1994;344:77 – 81. [9] Hanna CE, Keith LD, Colasurdo MA, Buffkin DC, Laird MR, Mandel SH, et al. Hypothalamic pituitary adrenal function in the extremely low birth weight infant. J Clin Endocrinol Metab 1993;76:384 – 7. [10] Mo ¨relius E, Nelson N, Theodorsson E. Salivary cortisol and administration of concentrated oral glucose in newborn infants: improved detection limit and smaller sample volumes without glucose interference. Scand J Clin Lab Invest 2004;64:113 – 8. [11] Magnano CL, Gardner JM, Karmel BZ. Differences in salivary cortisol levels in cocaine-exposed and noncocaine-exposed NICU infants. Dev Psychobiol 1992;25:93 – 103. [12] Boyer K, Johnston C, Walker C-D, Filion F, Sherrard A. Does sucrose analgesia promote physiologic stability in preterm neonates? Biol Neonate 2004;85:26 – 31. [13] Davis EP, Townsend EL, Gunnar MR, Georgieff MK, Guiang SF, Ciffuentes RF, et al. Effects of prenatal betamethasone exposure on regulation of stress physiology in healthy premature infants. Psychoneuroendocrinology 2004;29:1028 – 36. [14] Herrington CJ, Olomu IN, Geller SM. Salivary cortisol as indicators of pain in preterm infants. Clin Nurs Res 2004;13: 53 – 68. [15] Gitau R, Modi N, Giannakoulopoulos X, Bond C, Glover V, Stevenson J. Acute effects of maternal skin-to-skin contact and massage on saliva cortisol in preterm babies. J Reprod Infant Psychol 2002;20:83 – 8. [16] Mo ¨relius E, Theodorsson E, Nelson N. Salivary cortisol and mood and pain profiles during skin-to-skin care for an unselected group of mothers and infants in neonatal intensive care. Pediatrics 2005;116:1105 – 13.
676 [17] Blauer T, Gerstmann D. A simultaneous comparison of three neonatal pain scales during common NICU procedures. Clin J Pain 1998;14:39 – 47. [18] Wang Y-W, Chang Y-J. A preliminary study of bottom care effects on premature infants’ heart rate and oxygen saturation. J Nurs Res 2004;12:161 – 7. [19] The international neonatal network: the CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. Lancet 1993;342:193 – 8. [20] Stevens B, Johnston C, Petryshen P, Taddio A. Premature infant pain profile: development and initial validation. Clin J Pain 1996;12:13 – 22. [21] Lawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw 1993;12:59 – 66. [22] Spangler G, Scheubeck R. Behavioral organization in newborns and its relation to adrenocortical and cardiac activity. Child Dev 1993;64:622 – 33. [23] Scott SM, Watterberg KL. Effect of gestational age, postnatal age, and illness on plasma cortisol concentrations in premature infants. Pediatr Res 1995;37:112 – 6. [24] Miller NM, Fisk NM, Modi N, Glover V. Stress responses at birth: determinants of cord arterial cortisol and links with cortisol response in infancy. BJOG 2005;112:921 – 6. [25] Antonini SRR, Jorge SM, Moreira AC. The emergence of salivary cortisol circadian rhythm and its relationship to sleep activity in preterm infants. Clin Endocrinol 2000;52:423 – 6.
E. Mo ¨relius et al. [26] Huysman MWA, Hokken-Koelega ACS, DeRidder MAJ, Sauer PJJ. Adrenal function in sick very preterm infants. Pediatr Res 2000;48:629 – 33. [27] Stahl F, Amendt P, Dorner G. Total and free cortisol plasma levels in pre- and postnatal life. Endokrinologie 1979;74: 243 – 6. [28] Gitau R, Fisk NM, Teixeira JMA, Cameron A, Glover V. Fetal hypothalamic—pituitary—adrenal stress responses to invasive procedures are independent of maternal responses. J Clin Endocrinol Metab 2001;86:104 – 9. [29] Lacey JI. The evaluation of autonomic responses: toward a general solution. Ann N Y Acad Sci 1956;67:125 – 63. [30] Wilder J. The law of initial value in neurology and psychiatry; facts and problems. J Nerv Ment Dis 1957;125:73 – 86. [31] Gunnar MR. Adrenocortical activity and behavioral distress in human newborns. Dev Psychobiol 1988;21:297 – 310. [32] Gunnar MR, Connors J, Isensee J. Lack of stability in neonatal adrenocortical reactivity because of rapid habituation of the adrenocortical response. Dev Psychobiol 1989;22:221 – 33. [33] Gunnar MR, Hertsgaard L, Larson M, Rigatuso J. Cortisol and behavioral responses to repeated stressors in the human newborn. Dev Psychobiol 1992;24:487 – 505. [34] Als H, Duffy FH, McAnulty GB, Rivkin MJ, Vajapeyam S, Mulkern RV, et al. Early experience alters brain function and structure. Pediatrics 2004;113:846 – 57.
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Is a nappy change stressful to neonates? ¨relius a,*, Lena Hellstro ¨m-Westas b, Catarina Carle Evalotte Mo ´n b, Elisabeth Norman b, Nina Nelson a a
¨ping University Hospital, Department of Molecular and Clinical Medicine/Division of Paediatrics, Linko ¨ping, Sweden SE-581 85 Linko b Department of Paediatrics, Lund University Hospital, Lund, Sweden Accepted 22 December 2005
KEYWORDS Cortisol; Infant; Newborn; Neonatal intensive care; Pain measurement; Stress
Abstract Objectives: Infants in neonatal intensive care (NICU infants) are often cared for in a stressful environment that includes potentially painful or stressful interventions. The aim was to investigate whether NICU infants have different pattern of stress and pain responses than healthy newborns when challenged by a non-painful everyday care routine. Methods: NICU infants born at 23—38 weeks gestation (n = 39) were compared to healthy fullterm newborns (n = 30). Cortisol concentrations in saliva were determined before and 30 min after a standardised nappy change. The premature infant pain profile (PIPP) and the neonatal infant pain scale (NIPS) were evaluated before, during, directly after, 3 min after, and 30 min after the nappy change. The investigation was performed on two different occasions, first between postnatal days 2—7 and then between postnatal days 10—18. Results: NICU infants had higher median baseline salivary cortisol levels compared to full-term newborns on both occasions (17.1 nmol/L vs. 6.2 nmol/L p b 0.01 and 8.5 nmol/L vs. 2.4 nmol/L p b 0.01, respectively). Salivary cortisol decreased in response to the second nappy change in NICU infants ( p = 0.01). NICU infants had higher PIPP scores during both nappy changes ( p b 0.001 for both occasions) and more sustained increases in PIPP and NIPS up to 30 min after the nappy changes compared to full-term newborns. Conclusions: NICU infants have higher baseline salivary cortisol than healthy full-term newborns. There is a change in baseline cortisol by age in both groups. Full-term infants as well as NICU infants show an increased pain response to a standardised nappy change. D 2006 Elsevier Ireland Ltd. All rights reserved.
Abbreviations: ACTH, adrenocorticotropic hormone; CPAP, continuous positive airway pressure; CRIB, clinical risk index for babies; CRH, corticotropin-releasing hormone; GA, gestational age, HPA axis, hypothalamic—pituitary—adrenal axis; IVH, intraventricular haemorrhage; NICU, neonatal intensive care unit; NICU b 30, infants born before 30 weeks gestational age; NICU z 30, infants born at or above 30 weeks gestational age; NIPS, neonatal infant pain scale; PIPP, premature infant pain profile; q1, first quartile; q3, third quartile; SaO2, oxygen saturation. * Corresponding author. Tel.: +46 13 221378. E-mail address: [email protected] (E. Mo ¨relius). 0378-3782/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2005.12.013
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1. Introduction
2. Material and methods
Neonatal intensive care involves many painful and potentially stressful procedures [1,2]. In addition, the baby’s medical condition and the neonatal intensive care environment itself can be stressful, despite efforts to reduce unnecessary stimuli. While some stress may be advantageous for the baby at birth, excessive stress may cause long-term sequelae and sensitise the child to pain and stress later in life [3—6]. The fetal hypothalamic—pituitary—adrenal system (HPA axis) functions from at least the beginning of the second trimester [7,8]. Extremely low birth weight infants show a pituitary response to corticotropin-releasing hormone (CRH) and an adrenal response to adrenocorticotropic hormone (ACTH) stimulation [9]. Measurement of cortisol in saliva is feasible and valuable when studying the adrenal response to different stressors in early life [10]. Salivary cortisol responses have previously been studied in preterm babies both during painful [11—14] and presumably pleasant procedures [15,16]. Two studies report increased salivary cortisol in response to heel stick in preterm infants at or above 30 weeks of gestational age (GA) [11,13], and one study reports a decreased salivary cortisol in response to skin-to-skin care [15]. Three studies investigate heel stick [12], massage [15], and skin-to-skin care [16] included infants below 30 weeks GA. In each of these studies, both increased and decreased salivary cortisol responses were found. No previous study has compared salivary cortisol responses to an everyday care routine in infants in a neonatal intensive care unit with fullterm healthy newborns. One example of an everyday care routine is the nappy change. A nappy change is performed several times a day in both healthy and sick infants. A few studies have therefore investigated the nappy change as a possible stressor in neonatal intensive care, finding increased pain scores [17] and elevated heart rate [18]. Our hypothesis is that a nappy change may be stressful for infants in intensive care but not for full-term healthy newborns at home. The aim of the present study was to investigate whether infants treated in neonatal intensive care have a different pattern of cortisol and pain response compared to full-term healthy infants when challenged with an everyday care routine, in this case a standardised nappy change.
2.1. Participants
Table 1
2.1.1. NICU infants The study was carried out at the neonatal intensive care unit (NICU) of Linko ¨ping University Hospital, Sweden, from January 2001 to April 2004. The NICU with an average of 450 intakes a year includes 17 beds, nine for intensive and intermediate care and eight for conventional and rooming-in care. Consecutively admitted infants aged 2 days or older were considered for the NICU infant group. Infants treated with cortisone, diagnosed with intraventricular haemorrhage (IVH) or having neurological symptoms were excluded. Thirty-nine babies participated, 23 boys and 16 girls. The babies’ gestational ages ranged from 23 to 37 weeks and birth weights ranged from 505 to 3070 g. At the time of the first nappy change, 20 babies were on CPAP and six on a ventilator. The severity of illness was estimated by the clinical risk index for babies (CRIB) [19] (Table 1). Eleven babies were excluded from the second nappy change because they were discharged from intensive care (n = 8), referred to their home county hospitals (n = 2), or deceased (n = 1). The NICU infants were also divided into two subgroups depending on GA. Twenty-three babies were born before 30 weeks GA (b 30) and 16 were born at or above 30 weeks GA (z 30) (Table 1). 2.1.2. Full-term healthy newborns, controls Healthy newborn infants aged 2 days or older, born in the maternity ward of the University Hospital in Linko ¨ping between August 2002 and March 2003, were considered for the control group. The University Hospital has approximately 2400 deliveries a year. Approximately 54% of mothers giving birth in Linko ¨ping are discharged from the hospital within 48 h of delivery. Inclusion criteria were met if (1) the baby was not discharged before 2 days of age and (2) the family lived in urban Linko ¨ping. Thirty full-term babies were included, 17 boys and 13 girls, with birth weights ranging from 2780 to 3725 g (Table 1).
Clinical data of participating babies during 1st nappy change
Variable Mode of delivery Caesarean section/normal/assisted Birth weight, grams median (range) Gestational age at birth, weeks median (range) Apgar score at 5 min median (range) Postnatal age, days median (range) Boys/girls CPAP/ventilator CRIB mean (SD)
Controls, n = 30
NICU infants, n = 39
NICU infants b 30 weeks, n = 23
NICU infants z 30 weeks, n = 16
9/17/4 3595 (2780—3725) 40 (38—42)
29/9/1 1155 (505—3070) 30 (23—37)
17/5/1 940 (505—1600) 28 (23—29)
9/7/0 1850 (1135—3070) 32 (30—37)
10 (9—10) 2 (2—3) 17/13 0/0
8 (1—10) 5 (2—7) 23/16 20/6 2.8 (3.0)
7 (1—10) 5 (2—7) 14/9 16/5 3.9 (3.2)
9 (5—10) 3.5 (3—5) 9/7 4/1 1.2 (1.8)
Values indicate number of babies unless stated otherwise. NICU infants are divided in two groups based on gestational age at birth.
Is a nappy change stressful to neonates?
2.2. Standardised nappy change In order to evaluate a routine handling procedure to which all babies, sick or healthy, are exposed we chose the response to a nappy change. All nappy changes were performed using a standardised protocol. The protocol included placing the baby on his/her back, removing the used nappy, using a paper towel and lukewarm water without soap to gently clean the skin with seven strokes irrespective of nappy content, putting on a new nappy, and replacing the baby in his/her previous position. Apart from the standardised nappy change there was no other human touch involved in the procedure.
2.3. Salivary cortisol To investigate the cortisol response, saliva was collected before (baseline) and 30 min after the nappy change (response). Saliva was collected using cotton buds, as described previously [10]. Because of components that can disturb the salivary cortisol analysis, saliva was collected at least 1 h after the baby was fed. After collection the saliva was centrifuged, frozen at 22 8C, and stored at 70 8C. A radioimmunoassay for cortisol was used to analyse the cortisol concentrations in the saliva. Samples were run neat in duplicate, and all samples from each individual were run in the same assay. Intra-assay coefficients of variation were 12% at 2.0 nmol/L and 6% at 10.0 nmol/L [10].
2.4. Pain profiles The Premature Infant Pain Profile (PIPP) [20] and the Neonatal Infant Pain Scale (NIPS) [21] were used to measure pain at the bedside. PIPP comprises three behavioural variables (time of brow bulge, eye squeeze, and nasolabial furrow, respectively), two physiological variables (changes in heart rate and oxygen saturation), and two contextual variables (gestational age and behavioural state). Each variable is scored on a scale from zero to three. The minimum PIPP score is zero (no pain) and the maximum score 21. The authors suggest that a PIPP score of six or less means minimal or no pain, and 12 and above indicates moderate to sever pain [20]. Heart rate and oxygen saturation (SaO2) were measured with a cardiorespiratory monitor (Hewlett Packard, Bo ¨blingen, Germany) for NICU infants and with a transportable monitor (Nellcore Puritan Bennett, NPB-40, Pleasanton, CA, USA) for controls. NIPS comprises five behavioural variables (facial expression, cry, arm movements, leg movements, and behavioural state) and one physiological variable (breathing pattern). Each variable is scored on a scale from zero to one or (for cry) two. The minimum NIPS score is zero (no pain) and the maximum seven. PIPP and NIPS have documented reliability and validity for full-term and preterm infants [20,21] and have previously been used in parallel in stress research of preterm infants [16].
2.5. Procedure The research ethics committee of Linko ¨ping University approved the study and informed consent was obtained
671 from all parents. The investigation was performed once between postnatal days 2 and 7 (1st nappy change) and was repeated between postnatal days 10 and 18 (2nd nappy change). All nappy changes for NICU infants were performed in their incubators. The first nappy change for the controls was performed in their cots at the maternity ward and the second nappy change was performed at home. The study sequence was always the same: PIPP and NIPS were scored at baseline (nurse 1 for controls and nurse 3 for NICU infants) and saliva was collected (nurse 2). Thereafter, the standardised nappy change was performed (nurse 2) at the same time as PIPP and NIPS were rated (by nurse 1 and 3, respectively) during the first 30 s of the nappy change, starting when the nappy was opened. Ratings of PIPP and NIPS were repeated as soon as the baby was repositioned, 3 min after and 29 min after the nappy change. A second saliva sample was collected 30 min after the nappy change (nurse 2) to reflect the cortisol response. The interrater reliability for nurses 1 and 3 was 0.86 and 0.95 for NIPS and PIPP, respectively (interclass correlation coefficient).
2.6. Statistics Data were analysed using the statistical program SPSS (version 11.5). Friedman and Wilcoxon signed ranks tests were used to analyse differences in paired data. Kruskal— Wallis test and Mann—Whitney U test were used to test differences between independent samples. In some cases, data were absent because of an insufficient amount of saliva. When this was the case, the infant was excluded from paired analyses but included in other, non-paired analyses. Therefore, the numbers of subjects for each analysis differ slightly. Correlation coefficients were analysed using Spearman’s rho. A univariate analysis of variance (ANOVA) was used to analyse background characteristics as possible mediating factors for the changes in cortisol and pain scores. An increase or decrease in salivary cortisol response is defined as a change in cortisol level from baseline at 10% or more based on intra-assay coefficients of variation of the radioimmunassay [10].
3. Results 3.1. First nappy change 3.1.1. Salivary cortisol Sufficient amounts of saliva for analysis of cortisol were collected in 91% of the babies during the first nappy change. Saliva was sufficient for paired analyses at both baseline and response in 87% and 85% of controls and NICU infants, respectively. The NICU infants had significantly higher baseline salivary cortisol compared to controls ( p b 0.01) (Table 2). NICU infants b30 weeks GA had significantly higher baseline and response salivary cortisol compared to controls ( p b 0.001 and p b 0.001, respectively) and NICU infants z 30 weeks GA ( p b 0.001 for both comparisons) (Fig. 1). After the nappy change, salivary cortisol increased in 13 of the 33 NICU infants, decreased in 15, and was unchanged in five. The median cortisol level for NICU infants decreased by 25% after
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Table 2 Salivary cortisol, nmol/L (baseline and response) and pain profiles (PIPP and NIPS) before, during, after, 3 min after, and 30 min after 1st nappy change for controls and NICU infants, and for NICU infants b 30 and z 30 weeks GA, respectively Controls, n = 30 Cortisol baseline Cortisol response PIPP baseline During After 3 min after 30 min after NIPS baseline During After 3 min after 30 min after
6.2 7.7 3 3 3 2 3 0 4 2 0 0
(4.1—11.1) (3.7—13.1) (1—3) (1.75—6.25)c (2—5)c (0—3.25) (2—4) (0—1) (1—6)c (0—5)c (0.75) (0—0)
NICU infants, n = 39 17.1 12.8 4 8 7 6 5 0 4 1 1 1
(5.8—32.2) (4.9—23.9) (4—5)a (7—11)a,c (4—8)a,c (3—7)a,c (4—5)a (0—1) (2—6)c (1—3)c (1—2)a,c (0—1)a
a
NICU b 30 weeks, n = 23 20.2 18.6 5 9 8 6 5 1 4 2 1 1
a
(14.7—40.3) (11.7—36.2)a (4—6)a (7—12)a,c (5—10)a,c (5—8)a,c (4—6)a (0—1)a (3—6)c (1—3)c (1—3)a,c (0—2)a
NICU z 30 weeks, n = 16 5.8 (3.9—15.9)b 4.4 (3.3—12.0)b 4 (3—4)a,b 8 (6.25—8)a,b,c 4 (3.25—6.5)a,b,c 3 (3—6)a,b 4 (4—5)a,b 0 (0—1) 4 (2—5)c 1 (0—2)b,c 1 (0—1)a,b,c 0 (0—1)a
Values are given in median (first quartile—third quartile). a p b 0.05, significant difference from controls. b p b 0.05, significant difference from NICU infants b30 weeks. c p b 0.05, significant difference from baseline.
the nappy change (Table 2). Among the 26 control infants, salivary cortisol increased in eight, decreased in 14, and was unchanged in four. The median cortisol level for controls increased by 24% after the nappy change (Table 2). There was no correlation between changes in salivary cortisol levels and changes in pain score. Furthermore, there was no correlation between changes in salivary cortisol levels and pain scores at different measuring points in relation to the first nappy change (baseline, during, directly after, 3 min after, and 30 min after). 3.1.2. Premature infant pain profile, PIPP Both NICU infants and controls had a significant increase in PIPP score during nappy change compared to baseline ( p b 0.001 and p b 0.01, respectively). NICU infants had significantly higher PIPP scores at baseline and throughout all measuring points compared to controls ( p b 0.001 for all comparisons) (Table 2). The NICU infants had a sustained high PIPP score lasting until the 3 min measuring point compared to baseline (during: p b 0.001, after: p b 0.001, and 3 min after: p b 0.05) (Fig. 2). In the NICU infant group, there was a significant difference in PIPP
Figure 1 Median salivary cortisol (nmol/L) in NICU infants b 30 weeks (white bars), NICU infants z 30 weeks (striped bars), and controls (grey bars) at baseline and in response to the first and second nappy change, respectively.
scores at all measuring points between babies born before and after 30 weeks GA, with babies born at lower GA showing higher scores (baseline: p b 0.001, during: p b 0.05, after: p b 0.001, 3 min after: p b 0.01, and 30 min after: p b 0.05) (Table 2). 3.1.3. Neonatal infant pain scale, NIPS Both NICU infants and controls showed a significant increase in NIPS score during nappy change compared to baseline ( p b 0.001 for both comparisons) (Fig. 2). The NICU infants had a sustained high NIPS score lasting until the 3 min measuring point compared to baseline (during: p b 0.001, after: p b 0.001, and 3 min after: p b 0.01) (Table 2). The NICU infants born before 30 weeks GA had a significantly higher NIPS score at the 3 min measuring point compared to babies born after 30 weeks GA ( p b 0.01) (Table 2). There was a moderate, but significant, linear correlation between PIPP and NIPS at all time points: baseline: r = 0.29 ( p b 0.05), during: r = 0.29 ( p b 0.05), after: r = 0.31 ( p b 0.05), 3 min after: r = 0.53 ( p b 0.001), and 30 min after: r = 0.36 ( p b 0.01).
3.2. Second nappy change 3.2.1. Salivary cortisol Sufficient amounts of saliva for analysis of cortisol were collected in 89% of the babies during the second nappy change. Saliva was sufficient for paired analyses at both baseline and after the nappy change in 87% and 82% of controls and NICU infants, respectively. The NICU infants had a significantly higher baseline salivary cortisol at the second nappy change compared to controls ( p = 0.001) (Table 3). After the nappy change, three out of 24 NICU infants showed an increase in cortisol levels, 16 showed a decrease, and four did not change. In NICU infants the median salivary cortisol decreased by 42% ( p = 0.01) (Table 3). The decrease was most pronounced in NICU infants b30 weeks (Fig. 1). There was a significant difference in baseline cortisol between babies born before and after 30 weeks GA in the NICU infant group ( p b 0.01)—the more preterm the infant, the higher the cortisol levels (Fig. 1). Among the
Is a nappy change stressful to neonates?
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Median PIPP 2nd nappy change
Median PIPP 1st nappy change
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8
6
4
2
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During
4
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3 minutes after
After
During
5
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Median NIPS 2nd nappy change
Median NIPS 1st nappy change
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3
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30 minutes after
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4
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Figure 2 Median values for pain scores (PIPP and NIPS) at baseline, during, directly after, 3 min after, and 30 min after the first and second nappy change, respectively. Solid black lines represent NICU infants b 30 weeks GA, broken black lines represent NICU infants z 30 weeks GA, grey dotted lines represent controls.
control infants, 12 out of 26 showed an increase in cortisol levels, 11 showed a decrease, and three did not change. The median salivary cortisol level for controls increased 75% after the nappy change (Table 3). In both groups, baseline and response salivary cortisol levels were significantly lower at the second nappy change compared to the first nappy change (NICU infants: p b 0.01 for both baseline and response; controls: p b 0.01 and p b 0.05 at baseline and response, respectively). There was no correlation between changes in salivary cortisol levels and changes in pain score. Furthermore, there was no correlation between changes in salivary cortisol levels and pain scores at different measuring points in relation to the second nappy change (baseline, during, directly after, 3 min after, and 30 min after). 3.2.2. Premature infant pain profile, PIPP The PIPP score increased significantly from baseline during the nappy change in both NICU infants and controls ( p b 0.001 and p b 0.05, respectively). Compared to baseline, the NICU infants had a sustained rise in PIPP score lasting until the 3 min measuring point (during: p b 0.001,
directly after: p b 0.01, and 3 min after: p b 0.05 (Table 3). NICU infants had significantly higher PIPP scores at baseline and at all measuring points compared to controls ( p b 0.001 for all comparisons), with babies born at lower GA showing higher scores (Fig. 2). 3.2.3. Neonatal infant pain scale, NIPS The NIPS score increased significantly from baseline during the nappy change in both NICU infants and controls ( p b 0.001 and p b 0.01, respectively) (Fig. 2). The NICU infants had sustained high NIPS scores at the 30 min measuring point compared to baseline ( p b 0.05) (Table 3). There was a small but significant linear correlation between PIPP and NIPS at three time points, during: r = 0.39 ( p b 0.01), after 3 min: r = 0.27 ( p b 0.05), and after 30 min: r = 0.31 ( p b 0.05). ANOVA was used to test environmental milieu (NICU vs. home), mode of delivery, dexamethasone given to the mother prior to delivery, gender of the baby, severity of illness (CRIB score, and need for mechanical ventilation), and postnatal days as possible explanations for the magnitude of change in cortisol levels and change in pain scores.
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Table 3 Salivary cortisol, nmol/L (baseline and response) and pain profiles (PIPP and NIPS) before, during, after, 3 min after, and 30 min after 2nd nappy change for controls and NICU infants, and for NICU infants b 30 and z 30 weeks gestational age, respectively Controls, n = 30 Cortisol baseline Cortisol response PIPP baseline During After 3 min after 30 min after NIPS baseline During After 3 min after 30 min after
2.4 4.2 2 2 1 1 2.5 0 4 1 0 0
(1.8—4.5) (2.0—11.0) (0—3) (1—5.25)c (0—4) (0—3) (1—3) (0—2.25) (1.75—6)c (0—5) (0—3) (0—1)
NICU infants, n = 28 8.5 4.9 5 8.5 6 4 5 0 4 1 1 0.5
a
(3.9—12.8) (2.8—12.7)c (4—5)a (6.25—10.75)a,c (5—8)a,c (3—5)a,c (4—6)a (0—0.75) (1.25—5)c (0.25—3)c (0—1) (0—1)c
NICU b 30 weeks, n = 20 10.6 6.9 5 10 7 4 6 0 4 1 0.5 1
(5.1—16.8) (3.8—15.2) (4—5)a (8—12)a,c (5—9)a,c (3—5)a (5—7)a (0—1) (2—6)c (1—3)c (0—1) (0—1.75)
a
NICU z 30 weeks, n = 8 3.6 3.2 4 6 4.5 3 3.5 0 2.5 1 1 0
(2.1—8.4)b (2.5—7.1) (3.25—4)a,b (4—9.5)a,b,c (2.25—6)a,b (1—4.5) (3—4)a,b (0—0) (0.25—4)c (0—2.75)c (0—1.75)c (0—0)
Values are given in median (first quartile—third quartile). a p b 0.05, significant difference from controls. b p b 0.05, significant difference from NICU infants b30 weeks. c p b 0.05, significant difference from baseline.
These analyses did not reveal any statistical significance neither for the first nor the second nappy change.
4. Discussion Our study shows that infants in neonatal intensive care have higher baseline salivary cortisol levels than full-term healthy babies. In agreement with other studies, we found significantly lower baseline salivary cortisol at older postnatal ages (during the second nappy change) in both controls and NICU infants [16,22,23]. However, at 10—18 days postnatal age (the second nappy change), the baseline salivary cortisol level was still higher in the NICU infants than in the controls. This could be an early sign of a disturbance in the HPA axis, in accordance with the results in a recent published study showing higher baseline salivary cortisol and response to novel stimuli in preterm infants at 8 months as compared with full-term controls [6]. Miller et al. has recently showed that stress at delivery may influence the HPA axis response [24]. They found that infants born vaginally mounted greater cortisol responses during vaccination at the age of 2 months. We did not find any support for this in our study. However, that could be an effect of that preterm infants commonly are delivered by caesarean section. In our study 74% of the NICU infants were delivered by caesarean section and only 30% of the controls. Earlier studies have shown that infants do not have the same diurnal rhythm in cortisol levels as adults [25,26]. Cortisol levels increase in relation to delivery but stabilise 2 days after birth, i.e., before inclusion in the present study [27]. Therefore, the lower cortisol values, at an older age, may be either an effect of postnatal age or a result of a stabilised medical condition in the NICU infants. However, lower cortisol values also in our controls at older postnatal age suggest that postnatal age rather than medical circumstances has a large influence on cortisol levels even for NICU infants. In agreement with other studies, we found salivary cortisol brespondersQ as well as bnon-respondersQ in both
groups [12,15,16]. The brespondersQ either increased or decreased after the standardised nappy change, while the bnon-respondersQ did not show any change in cortisol secretion. We know from the study by Hanna and colleagues [9] that even preterm infants have the ability to increase cortisol secretion when given ACTH. Moreover, Gitau et al. found that the fetal HPA axis can mount cortisol responses from the 20th week [28]. In our study, the cortisol response differed between individuals when exposed to the same stressor, a nappy change. It is possible that compared to infants with lower baseline levels, infants with high baseline cortisol levels do not have the same ability to increase cortisol levels further when exposed to a stressor [29,30]. However, it remains unclear whether a decreased cortisol response, as found in NICU infants during the second nappy change, is 1) a sign of a lower degree of stress, 2) a question of immaturity in the HPA axis, or 3) an effect of suppressed adrenal activity due to longstanding and/or repetitive high stress load. A nappy change is usually repeated several times a day and is a potentially stressful procedure for a sick baby. A healthy full-term baby, on the other hand, being more stable, is more likely to habituate to [31—33] or even appreciate a nappy change. Additionally, although the intervention was principally the same in each group, a nappy change may in fact represent a much more intense intervention in a sick infant, involving the stimulus of CPAP/ventilator movements, as well as repositioning of wires, probes or other technology. Even breplacing the baby in his/her previous positionQ is a more complicated procedure for a sick infant. Thus, an intervention, which is theoretically the same, may have different side effects in practice. Our NICU infants had a slightly different pain pattern than controls. The NICU infants had a peak during the nappy change and returned to baseline very slowly (3 to 30 min). However, the controls also showed a peak during nappy change—though not as high as the NICU infants—on the other hand they returned to baseline more quickly. One limitation in our study is, however, the absence of measuring points between 3 and
Is a nappy change stressful to neonates? 30 min after the nappy change. Several measuring points may have revealed further dynamics. The pain scales are also used in a slightly modified manner (repeated observations in relation to stimulus) in order to assess the state of the baby, in relation to changes in salivary cortisol, 3 and 30 min after the nappy change. Even though a nappy change is not considered a painful intervention, the pain scores increased in the present investigation. One could wonder if the pain instruments (i.e., NIPS and PIPP) do measure pain exclusively. It is difficult, or perhaps even impossible, to distinguish stress from pain in infants. Pain is a stressor and as such may cause a stress response, which may be harmful to an already seriously ill and unstable infant. However, a stress response was not verified by increased salivary cortisol in the present study. In agreement with earlier studies, we did not find any correlation between pain scores and salivary cortisol levels [14,16]. Even though pain is a stressor that could potentially trigger the HPA axis, the behavioural expression of pain is not necessarily comparable to a hormonal stress response. Therefore, a baby’s increase in pain score does not necessarily correspond to the cortisol response. The interpretation of the pain scales also needs to include the suggestion from the authors that scores at or below six are not considered to be pain [20]. But the question still remains: is a nappy change stressful to neonates? Or, is it even painful in some sick and very preterm infants? The preterm infant may be more vulnerable and sensitive to disturbance and may have greater difficulty to stabilise and to cope with various strains—it is thus more likely that the preterm baby needs more time to stabilise and return to baseline. This is supported by the findings of pronounced and sustained pain scores in the most preterm infants. Clinically these findings lend further support to individual handling of the baby [34]. It is important to reduce the number of stressors in neonatal intensive care [1,2]. As we found the nappy change to cause a behavioural pain response this should be performed with caution and gently especially in preterm/severely ill infants. It is perhaps sensible to individualise, and in certain cases reduce, the numbers of nappy changes according to the baby’s need rather than to a predetermined schedule.
5. Conclusions Infants in neonatal intensive care have higher baseline salivary cortisol levels during their first days of life compared to healthy full-term infants. The highest cortisol values were found in infants below 30 weeks GA. A significant decrease in salivary cortisol was found in NICU infants after the second nappy change. Both healthy fullterm infants and infants in neonatal intensive care have lower baseline salivary cortisol at an older age (during the second standardised nappy change). Infants in neonatal intensive care expressed a high and prolonged pain response to the standardised nappy change compared to healthy full-term infants who expressed a high but short pain response. The pain scores were more pronounced in the most preterm infants.
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Acknowledgements We are grateful to Professor Elvar Theodorsson for his valuable contribution to methodological issues. We would also like to thank the nurses, Christine Rose´n, Anne Sandehed, and Lisbeth deJonge for their excellent assistance with data collection. This research was supported by ¨ stergo grants from the County of O ¨tland, Sweden, the Swedish Society of Nursing, the Perinatal Foundation, Linko ¨ping, the Sven Jerring Foundation, the South Sweden Society of Nursing, the Swedish Medical Research Council (grant 0037), and Lund University Hospital Funds.
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