SECTION 5 measurement of pain 354 Care and Assessment (NIDCAP) program with a central focus on the social processes involved in protecting and maintaining the stability of the infant within a particular external envi ron- ment has evolved from this theory. Th e Assessment of Preterm Infants \200\231 Behavio r (APIB) instrument (Als et al., 1982 ) provides a systematic profi le for assessing the in dividual infant \200\231s behavioral cues as a measure of their system capacity and regulat ory abilities. Preventing and/or minimizing stressful procedures, assisting the infant to m aintain and regulate organized behavioral state and instituting developmentally specifi c s trategies to mitigate the eff ects of stressful events are hallmark interventions. Th ese p hysical (e.g. positioning, bundling), tactile (e.g. kangaroo care, non-nutritive sucking), and behavioral (e.g. distraction) strategies are also used as pain-relieving interventions. determining behavioral and physiological responses; multidimen- sional and composite measur es are almost exclusively comprised of indicators from acute pain studies. A typical behavi oral response depicting the behavioral facial action acute pain response in infants is show n in Figure 35.1 . Chronic pain is frequently defi ned as pain that has persisted beyond th e normal tissue healing time. However, the temporal delineation of \200\230healing time \200\231 is debated as somewhere between 3 and 6 months. Th e temporal delineation presents additional dilemmas when consider- ing prolonged pain in infants. In addition to the issue of total life span, which may be less than 3 or 6 months, infants have limited time com- p rehension abilities and cannot fully appreciate past, present, and future or process inform ation in a moment by moment fashion. Researchers have largely ignored chronic pain assessme nt and its complexities in infants focusing almost exclusively on acute pain, with only a f ew meas- ures addressing this more prolonged phenomenon (see Table 35.1 ). Th e social communication model of pain Th e SCM (Craig, 2009 ) promotes understanding of t he complex interactions between biological, psychological, and social features of pain. Cra ig asserts that pain is a sequence of complex interde- pendent stages, characterized by fee dback loops among sequential stages. Assessing infant pain is construed as a dynamic, inter active process between child and caregiver (e.g. health professional, fam- ily or others) w ho are uniquely infl uenced by family, community, and culture. Infants almost invariably re act to acute tissue stress and damage in a manner that distinguishes \200\230pain \200\231 from \200\230non-pain \200\231 states. Th ese reactions provide a means for caregivers to decode the pain expression and infer the infant \200\231s subjective state from biologi- c al and behavioral correlates. Unidimensional versus multidimensional Infant pain measures can also be classifi ed as eith er unidimensional (one global item or a multiple items within a single domain) or multidime nsional (multiple items with multiple domains/compos- ite measures) where dimension refers to an aspect of a phenomenon and domain is the set of possible dimensions within the phenom e- non. Applying these defi nitions to pain, unidimensional single item measures capture on e dimension of the experience (e.g. visual ana- logue scale capturing pain intensity) where as unidimensional sin- gle domain measures include: (1) multiple items (e.g. brow bulge, ey e squeeze) from a single domain (e.g. facial expression) within a single dimension (e.g. be havioral), for example, the Neonatal Facial Coding System (Grunau and Craig 1987 ); or (2) multiple items (e.g. brow bulge, hand movement, high pitch cry) from mul- tiple domains (e. g. facial expression, movement, cry) within a sin- gle dimension (e.g. behavioral), for exa mple, Douleur Aigue du Nouveau-ne (Carbajal et al., 1997 ). Th is model is unique in its focus on interaction with the caregiver encompassing their cog nitive and aff ective capabilities that support complex social interactions and processes. Once pain is expressed by the infant, caregivers interpret that the infant is in pain. Th i s attribution of pain is infl uenced by the caregiver \200\231s (1) sensitivities, (2) know ledge level (e.g. of the specifi c child or alternatives to dis- tress), (3) attitudes and beliefs, and (4) prior relationship to the child. Th e stage is then set for implementing a nd evaluating pain- relieving interventions. Multidimensional (composite) measures include multiple items (e.g. brow bulge, heart rate, gestational age) from multiple domains (e.g. facial expression, biomarker,) within multiple dimensions (e.g. behavioral, physiological,), such as the Premature Infant Pain Profi le ( Stevens et al., 1996 ). Th e issue of combining dimensions in multi- dimensional measures i s frequently raised by measurement critics, who suggest mixing poorly correlated dimensions in total scores is unjustifi ed and may lead to ineff ective or incomplete management. Con versely, proponents suggest dissociation between indicators is common in a complex entity a nd therefore taking all dimensions into account is necessary to capture the full scope of t he phenomenon for well-informed decision-making (McDowell, 2006 ). While the SCM of infant pain addresses the broader context of pain, our current knowledge i s primarily centered on acute tissue- damaging or nociceptive pain, with little clarity on the infant \200\231s experience and expression of more prolonged acute (e.g. postoper- ativ e), persistent (e.g. recurrent), or chronic pain. Th is understand- ing is important as the basis for the development and validation of pain assessment indicators and measures in the se domains. A more detailed exploration of the SCM is provided by Pillai Riddell et al. ( C hapter 9 , this volume). Existing neonatal and infant pain measures Approximately four dozen measures have been deve loped to assess pain in neonates and infants over the past three decades. Several have been extensively validated, although their feasibility and clinical utility are infrequently ad dressed. Th e most well-validated measures are multidimensional behavioral indicators or co mpos- ite measures. Only a few measures incorporate individual infant characteristics or co ntextual factors. Furthermore, the current body of neonatal pain measures is comprised of a narrow and fi nite cadre of behavioral and physiological items. Recommendations to expand this repertoire and to explore potential new indicators Pain assessment measures and indicators Acute versus chronic Neonatal and infant pain asses sment measures have been devel- oped for both acute and chronic pain. Acute pain signals a specifi c nociceptive event, injury, or illness, is usually of sudden onset, and is limited to a short period of time. Acute pain typically subsides with eff ective management aft er the painful event (e.g. heel lance) or when the illness or injury resolves; it can be pers istent and re- occur in multiple episodes over time. Most research on infant pain assessmen t has used tissue damaging stimuli as the paradigm for CHAPTER 35 neonatal and infant pain assessment 355 (a) (b) (c) (d) Figure 35.1 Example of a typical behavioral response depicting the behavioral facial action acute pain response in infants. (e.g. cortical indices) or biomarkers (e.g. cortisol) and their rela- tionship to observed behavioral indicators have only recently been considered. A critical appraisal of unidimens ional and multi- dimensional neonatal and infant pain measures with demonstrated reliabilit y and validity is summarized in Table 35.1 . Heart rate variability (HRV) is another biomarker that has been substantially studied, espe cially in the extremely low birth weight infant population. For example, Grunau and colleag ues (2001) demonstrated a heightened cardiac sympathetic activity dur- ing heel lance where the most signifi cant factors associated with altered behavioral and autonomic pain reacti vity at 32 weeks PCA (greater number of previous invasive procedures since birth and GA at birth) were related to a dampened response. Aft er controlling for these variables, exogeno us steroid exposure independently con- tributed to the behavioral and autonomic pain scores , also damp- ening the response. A summary of recent studies on biomarkers in infant pain i s included in Table 35.2 . Individual pain indicators Given the issues associated with observation of behavioral and p hysiological pain indicators in neonates and infants, researchers have begun to investigate potential biomarkers and neurocogni- tive/physiological indicators. Biomarkers Several researchers have conducted studies examining the use of cortisol as a bi omarker of stress as a pain indicator during/aft er an invasive procedure. While some repor ted an increases of cortisol (Franck et al., 2011 ; Grunau et al., 2010 ), others found no diff er- ences (Cignacco et al., 2009 ; Gibbins et al., 2008a ). Th ese confl icting result s may be associated with the heterogeneity of study designs, sample size, intensity of the painful procedure, severity of illness, and method of cortisol collection. Cortical indicators Th ere is growing interest on the role of the brain in pain mecha- nism and transmission of noxious stimuli from the periphery to the central nervous system. Th e majority of research has been con- ducted with animals. However, newer non-invasive neuroi maging techniques including electrophysical methods (electroencephalo- gram \200\224EEG), r adiological methods (positron emission tomogra- phy \200\224PET), magnetic resonance techni ques (magnetic resonance SECTION 5 measurement of pain 356 Table 35.1 Unidimensional and multidimensional composite measures for acute pain and persis tent/ prolonged/ chronic pain Pain scale Dimension/ domain Type of pain Age level Indicators Psychometric properties Unidimensional single-domain measures ABC Scale (Bellieni et al., 2005, 2007) Behavioral Acute (procedural) Preterm/full- term infants Cry: (a) Pitch of \201 rst cry (b) Rhythmicity of bout of crying (c) Cry constancy Term infants: Interrater reliability: (Cohen \200\231s K = 0.83) Intrarater reliability: (C ohen \200\231s K = 0.85) Speci \201 city: analgesic/non-analgesic (P <0.0001); pain/ sham (P <0.0001) Sensitivity: high correlation between ABC and DAN Concurrent validity: (Spearma n r = 0.91) Internal consistency: (Cronbach \200\231s alpha = 0.76) Practicality: nurses sc ored as \200\230good \200\231 Preterm infants: Interrater reliability (K = 0.70) Concurren t validity: (r = 0.68; r2 = 0.45; p <0.0001) between ABC and PIPP Neonatal Facial Coding System (NFCS) (Grunau and Craig, 1987) Behavioral Acute (procedural and postoperative) > 25 weeks GA \200\224term infants Facial actions Brow bulge Eye squeeze Naslabial furrow Open lips Horizontal mouth Vertical mouth Lips pursed Taut tongue Chin quiver Tongue protrusion Acute pain: Interrater reliability: (r = 0.60 \200\2231.00) Intrarater reliability: (r = 0. 88) Content and face validity Construct validity: (r = 0.79, P <0.001; Lilley et al., 1997) Postoperative pain: Interrater reliability: (r = 0.84 \200\2231.0) Concurrent validity wit h VAS and COMFORT-B scale: (with VAS (P <0.001) and COMFORT-B (P <0.001). With HR mean (P < 0.001), BP mean (P <0.001), HRV (P <0.001), and BPV (P= 0.007) (Peters et al., 2003) Unidimensional multiple-domains measures Behavioral Indicators of Infant Pain (BIIP) Scale (Holsti and Grunau, 2007a) Behavioral Acute (procedural) 23 \200\22332 weeks GA State Facial actions Hand actions Internal consistency: (r = 0.82) Interrater reliability: (r = 0.80 \200\2230.92) Construct validity: (F[1, 86] = 85.9, p <0.0001) Concurrent validity with NIPS: (earlier born <29 wee ks (EB) r = 0.64, p < 0.0001; later born 29 \200\22332 weeks (LB) r = 0.60, p <0001). Corre lations between the BIIP and mean heart rate (EB r = 0.33, p <0.05; LB r = 0.50, p <0.001) Bernese Pain Scale for Neonates (BPSN) (Cignacco et al., 2004) Behavioral Acute (procedural) 27 \200\22341 weeks GA with/ without ventilation Alertness Duration of crying Time to calm Skin color, Eyebrow bulge with eye squeeze, Postu re Breathing pattern Interrater reliability: (r = 0.86 \200\2230.97) Intrarater reliability: (r = 0.98 \200\2230.99) Construct validity: (P <0.0001) Concurrent and convergent validity: BPSN compared to VAS and PIPP (r = 0.86, and r = 0.91, P <0.0001, respectively) Birth \200\2234 years Crying Facial expression Posture of trunk and legs Motor restlessness Internal consistency: (>1 year) (Cronbach \200\231s alpha = 0.96) Interrater reliability: ( >3 years) (r = 0.64 \200\2230.77) Content validity Construct and concurrent validity in old er subsample (P <0.001) Children \200\231s and Infants \200\231 Postoperative Pain Scale (CHIPPS) (B \213 ttner an d Finke, 2000) Behavioral Prolonged (postoperative) (Continued) CHAPTER 35 neonatal and infant pain assessment 357 Table 35.1 (Continued) Pain scale Dimension/ domain Type of pain Age level Indicators Psychometric properties Douleur Aigue du Nouveau-ne (DAN) (Carbajal et al., 1997, 2005) Behavioral Acute (procedural) 24 \200\22341 weeks GA Facial expression Limb movement Vocalizations/ attempt at vocalizations Internal consistency: (Cronbach \200\231s alpha = 0.88) Interrater reliability: (r = 0.91) Content validity Face, Legs, Activity, Cry, Consolability (FLACC) scale (Manworren and Hynan, 2003; Merkel e t al., 1997) Behavioral Acute (procedural) Birth to adolescents (also for children with disabilities) Face Legs Activity Cry Consolability Interrater reliability (K = 0.61) Content validity Concurrent validity (P <0.001) Modi \201 ed Behavioral Pian Scale (MBPS) (Taddio et al., 1995) Behavioral Acute (procedural) 2 \200\2236 months Facial expression Cry Body movement Interrater reliability: (ICC = 0.95) Internal consistency: (r = 0.55 \200\2230.66) Test-res t reliability: (r = 0.95) Content validity Construct validity: (P <0.01) Concurrent validit y: (r = 0.68 \200\2230.74) Multidimensional composite measures Cardiac Analgesic Assessment Scale (CAAS) (Suominen et al., 2004) Behavioral, Physiological Prolonged (postoperative) Birth \200\223mean age = 2.5 years Papillary size Heart rate Blood pressure Respiratory and motor response Interrater reliability: (r = 0.86 \200\2231.0) Content validity Convergent validity: (K = 0 .33; P <0.05 pre-post bolus) Convergent validity (with PIPP and VAS) Concurrent validity: with NIPS and CHIPPS (range r = 0.30 \200\2230.38) Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) Scale (Krechel and Bi ldner, 1995) Behavioral, physiological Prolonged (postoperative) 28 weeks GA \200\2236 years Crying Requires O 2 Increased vital signs Expression Sleep (CRIES) Scale (Krechel and Bildner, 1995) Increased vital signs Expression Sleepless Construct validity and predictive validity: (sensitivity and speci \201 city >90%) Interra ter reliability: (r = 0.98) Feasibility: global rating for routine use was low (20%) Rated as moderately feasible for clinical practice COMFORT scale (Ambuel et al., 1992) Behavioral, physiological Acute, acute (prolonged), chronic and level of sedation 0 \200\22317 years Alertness, calmness respiratory response Crying Physical movement Muscle tone Facial tensio n Blood pressure (MAP) baseline Heart rate baseline VAS Interrater reliability: (Kappa = 0.54- 0.93) Internal consistency: (Cronbach \200\231s = 0.92, ICC = 0.82 \200\223 0.85, r = 0.90 \200\2230.92) Concurrent validity (r = 0.75, P <0 .01) Content validity Convergent validity: with clinician judgment (r = 0.89 \200\2230.96) Concurrent validity: with VAS (r = 0.44 \200\2230.96) Echelle Douleur Inconfort Nouveau-n (EDIN) (Debillon et al., 2001) Behavioral, physiological Prolonged (postoperative) 26 \200\22336 weeks GA Facial expression Movement Sleep Consoliability Interrater reliability: (k = 0.69, r = 0.59 \200\2230.74) Internal consistency: (Cronbach \200\231s = 0.92) Content validity Construct validity: (P <0.000) (Continued) SECTION 5 measurement of pain 358 Table 35.1 (Continued) Pain scale Dimension/ domain Type of pain Age level Indicators Psychometric properties EVENDOL (Moreaux, 2010) Behavioral, physiological Acute (pain in emergency) 1 month \200\223 6 years Complaint Grimace Movements Postures Interaction with surroundings Interrater reliability: (r >0.9, weighted kappa 0.7 to 0.9) Construct validity: before /aft er nalbuphine (p < 0.0001), at mobilization (p = 0.0011) Concurrent validity: between VAS a nd EVENDOL > 0.8 (p < 0.0001); between EVENDOL and other scales (EDIN, CHEOPS, FLACC, TPPPS ): 0.5 to 0.93 Content validity: (Cronbach coe \203 cient = 0.83 to 0.92). Faceless acute neonatal pain scale (FANS) (Milesi et al., 2010) Behavioral, physiological Acute (procedural) Preterm infants Heart rate variation Acute discomfort Limb movements Vocal expressions Inter-rater agreement: (r = 0.92) Internal consistency: (Cronbach \200\231s = 0.72) Conc urrent validity: FANS and DAN (ICC = 0.88) Hartwig Score (H nseler et al., 1991) Behavioral, physiological Acute Infants Motor response Grimacing Eyes Respiration Aspiration Interrater reliability: (ICC = 0.934) Internal consistency: all items (Cronbach \200\231s a lpha = 0.867) Concurrent validity: between Hartwig Score and VAS: mean of the di \200 eren ces of 0.77 (0.77); 95% CI of 0.508 \200\2231.03 (0.411; 1.129) and levels of agreement fro m \210\2221.76 to 3.23 ( \210\2221.74 to 3.0); between Hartwig Score and Comfort scale: me an di \200 erences of 0.15 (0.34); 95% CI of 0.013 \200\2230.287 (0.104; 0.576) and levels of agreement from \210\2221.49 to 1.77 ( \210\2221.13 to 1.82) (H nseler et al., 2011) Liverpool Infant Distress Scale (LIDS) (Horgan and Choonara, 1996; Horgan et al., 2002) Behavioral, physiological Prolonged (postoperative) Neonates Facial expression Sleep pattern Cry quantity and quality, Spontaneous movement and excitabi lity Flexion of \201 ngers, toes, Tone Internal consistency: (r = 0.84 \200\2230.94) Interrater reliability: (r = 0.74 \200\2230.8 8) Intrarater reliability: (r = 0.1 = 0.96) Content validity Discriminant validty: (P = 0.0 04 \200\2230.0000) Multidimensional Assessment of Pain Scale (MAPS) (Ramelet et al., 2007a, 2007b) Behavioral, physiological Prolonged (postoperative) 0 \200\22331 months Vital signs Breathing pattern Facial expressions Body movement State of arousal Internal consistency: (Cronbach \200\231s alpha = 0.62 at baseline, 0.80 at 15 min, 0.37 at 30 min, 0.26 at 60 min. When \200\230vital signs \200\231 was deleted, internal consisten cy at baseline, 15, 30, and 60 min improved r = 0.64, 0.79, 0.67, and 0.71) Concurrent vali dity: between MAPS and FLACC: mean of di \200 erences 0.44 (CI: 0.18 \200\2230.71); limits of agreement = \210\2221.22 to 2.09; between MAPS and VAS: mean of di \200 erences 0.25 (CI of 0.02 \200\2230.49); limits of agreement \210\2221.24 to 1.74 Clinical utility: repo rted as useful in preverbal children (median 2, IQR1) and moderately simple (median 2, IQR 0). Median observation time was 2 min (IQR 4) and mean assessment time was 35.3 ( 26) se c Modi \201 ed Infant Pain Scale (MIPS) (Buchholz et al., 1998) Behavioral, physiological Prolonged (postoperative) 4 \200\22330 weeks PNA Sleep Facial expression Quality of cry Spontaneous motor activity, Excitability/ responsive ness to stimulation, Flexion \201 ngers/toes, Interrater reliability: (r = 0.85) Content validity Convergent validity: in dichotomous rat ing (P <0.0001) (Continued) CHAPTER 35 neonatal and infant pain assessment 359 Table 35.1 (Continued) Pain scale Dimension/ domain Type of pain Age level Indicators Psychometric properties Sucking Overall tone, Consolability, Sociability, Change in HR, BP Fall in O 2 saturation S leep Facial expression Sucking Hyper-reactivity Agitation Hypertonicity Toes/ \201 ngers \202 exion Consolability Modi \201 ed Postoperative Comfort Score (Guinsburg et al., 1998) Behavioral, physiological Prolonged (mechanical ventilation) < 32 weeks GA Convergent validity: in bedside (P <0.00001) and laboratory video coding (P = 0.02) Content validity Divergent validity: placebo and analgesic samples (P <0.05) Modi \201 ed Postoperative Comfort Score (Guinsburg et al., 1998) Behavioral, physiological Prolonged (postoperative) Preterm infants Sleep Facial expression Activity Tone Consolibility Cry Sociability Content validity Discriminant validity: (P <0.0001) Napean Neonatal Intensive Care Unit Pain Assessment Tool (NNICUPAT) (Marceau, 2003) Behavioral, physiological, and contextual Acute (procedural) Ventilated infants 25 \200\22336 weeks GA Facial expression Body movement Color Saturation Respiration Heart rate Nurse perception of pain Content validity Interrater reliability: before and during procedure (r = 0.88) Interrater reliability: after procedure (r = 0.48) Concurrent validity: during procedure ( 0.01) Neonatal Infant Pain Scale (NIPS) (Lawrence et al., 1993) Behavioral, physiological Acute (procedural) Preterm and full-term Facial expression Cry Breathing patterns Arm movement Leg movement State of arousal Interrater reliability: (r = 0.92 \200\2230.97) Internal consistency: (0.87 \200\2230.95) C ontent validity Concurrent validity: (r = 0.53 \200\2230.83) Interrater reliability: (r = 0.85 \200\2230.95) Intrarater reliability: (Spearman \200\231s rho r = 0.874, P <0.0001). Construct (discriminate) validity: (Z=-6.429, P <0.0001) Intern al consistency: (Cronbach \200\231s alpha = 0.84 \200\2230.89) Convergent validity: with PI PP (r = 0.83 with high pain scores, r = 0.61 with low pain scores) Neonatal Pain, Agitation and Sedation Scale (N-PASS) (Hummel et al., 2003, 2008, 2010) Behavioral, physiological Acute (procedural) and prolonged (mechanical ventilation) 23 \200\22340 weeks GA Crying/irritability Behavioral state Facial expression Extremities/tone Vital signs (HR, RR , BP, O 2 saturation) Riley Infant Pain Scale (RIPS) (Schade et al., 1996) Behavioral, physiological Prolonged (postoperative) <3 years or children unable to verbalize pain Facial expression Body movement Sleep Verbal/vocal Consolability Response to movement/touch Interrater reliability: (ICC = 0.53 \200\2230.83; lower <1 month age group) Internal consis tency: (r = 0.73 \200\2230.88) Content validity Discriminant validity: (P<0.001) (Continued) SECTION 5 measurement of pain 360 Table 35.1 (Continued) Pain scale Dimension/ domain Type of pain Age level Indicators Psychometric properties Content validity Concurrent validity: (r = 0.93) Pain Assessment in Neonates Scale (PAIN) (Hudson- Barr et al., 2002) Behavioral, physiological Acute (procedural) 26 \200\22347 weeks GA Facial expression Cry Breathing patterns Extremity movement State arousal O 2 saturation In creased heart rate Pain Assessment Tool (PAT) (Hodgkinson et al., 1994) Interrater reliability: (r = 0.85) Content validity Convergent validity: (r = 0.38) Concurr ent validity: (r = 0.76) (Spence et al., 2005) Behavioral, physiological and contextual Prolonged (postoperative) 27 weeks to full-term Posture/tone Sleep pattern Expression Color Cry Respirations Heart rate O 2 saturations Blo od pressure Nurse perception Postoperative Pain Score (POPS) for Infants (Barrier et al., 1989) Behavioral, physiological Prolonged (postoperative) 1 \200\2237 months Infant sleep during the preceding hour Facial expression Cry Interrater reliability: (r = 0.79 \200\2230.88) Content validity Discriminant validity: (P < 0.0001) Motor activity Excitability Flexion Sucking Tone Consolability Interrater reliability: (r >0.89 for total score) Intrarater reliability scores: (r = 0.95) Internal consistency: (alpha = 0.59 \200\2230.76) Construct validity: (P <0.05) Convergent validity: between PIPP and CRIES: (r=0.447; P <0.001; r = 0.292 to 0.472; P <0.005, respec tively; ICC=0.6139; 95% CI: 0.4 \200\2230.76); between PIPP and FLACC: (r=0.462 to 0.521; P <0.01); between PIPP and N-PASS: (r = 0.81 to 0.83) during severe pain and (r=0.61) for mi nimal-to-moderate pain. Feasibility: sta \200 nurses able to use after a brief explanation and practice session. (Jonsdottir and Kristjansdottir, 2005). Clinical utility: Schiller ( 1999) examined the PIPP and the CRIES. Both measures were rated as clinically useful: PIPP rated higher on acceptability and the CRIES rated higher on completion time and cost. Premature Infant Pain Pro \201 le (PIPP) (Stevens et al., 1996) Behavioral, physiological, and contextual Acute (procedural) Term and preterm neonates GA Behavioral state Heart rate O 2 saturation Brow bulge Eye squeeze Nasolabial furrow Premature Infant Pain Pro \201 le \200\223 Revised (PIPP \200\223R) (Gibbins, 2008b; Steve ns et al., 2012) Behavioral, physiological, and contextual Acute (procedural) Term and preterm neonates Same as PIPP but GA and behavioral state scored only when subtotal score of behavioral and physiological indicators > 0 Convergent validity: between PIPP and PIPP \200\223R: (R 2 = 0.93, p <0.0001) for ELBW infa nts during diaper change (R 2 = 0.91, p <0.0001) and heel lance (R 2 = 0.98, p <0.0001) con ditions. PIPP and PIPP-R scores were highly correlated (R 2 = 0.98, p <0.001) for infants 2 5 \200\22341 weeks GA (Continued) CHAPTER 35 neonatal and infant pain assessment 361 Table 35.1 (Continued) Pain scale Dimension/ domain Type of pain Age level Indicators Psychometric properties Construct validity: PIPP \200\223R scores were signi \201 cantly lower during diaper chang e [mean 8.3(SD = 2.9)] compared to heel lance [mean 9.9 (SD= 3.1); (t (95) = 4.51, p = 0.03 6)]. Feasibility: Mean scores on each feasibility scale (median of 4/of 5). Scale for Use in Newborns (SUN) (Blauer and Gerstmann, 1998) Behavioral, physiological (movement, facial expression biomarkers, biomarkers) Prolonged (excluded postoperative) 24 \200\22340 weeks GA Central nervous system state Breathing Movement Tone, face Heart rate Mean blood pressure Content validity Discriminant validity: (p < 0.05 \200\2230.01) Table 35.2 Biomarker indicators of neonatal/ infant pain Indicator(s) Reference Study design/methods Main results Cortisol Behavioral Biochemical Cignacco et al., 2009 Single group, exploratory repeated measures design exploring the variability in pain respon se in preterm infants who received sucrose during routine heel stick (n = 9) 72 \200\22394% within-subject variability No signi \201 cant di \200 erences in cortisol before and after the heel sticks (p = 0.55). A general gradual decrease of cortisol levels across time Behavioral Physiological Biochemical Franck et al., 2011 Prospective observational study comparing indices of pain in critically ill full-term neona tes following cardiac surgery (n = 81) A 27% di \200 erence in COMFORT scores between tissue damaging and non-tissue damaging pro cedures (P <0.001). COMFORT score and the high-frequency HRV showed inverse correlations wi th opioid dose and plasma levels over the \201 rst 48 h postoperatively; after accounting for clinical variables, only COMFORT score remained signi \201 cant (P <0.001). Both beha vioral and physiological variables accounted for 45% and 15% respectively of the variance i n COMFORT scores (P <0.001). Plasma cortisol increased postoperatively but no change in uri nary cortisol Physiological Behavioral Biochemical Gibbins et al., 2008a Prospective crossover design comparing physiological, behavioral and biochemical responses to painful and non-painful procedures in ELGA infants (n = 50) Facial actions \200\224brow bulge (t = \210\2224.6, p <0.001), eye squeeze (t = \210\2223 .5, p <0.002), nasolabial furrow (t = \210\2223.3, p <0.002) and vertical mouth stretch (t = \210\2222.6, P <0.01), increased post heel lance. No changes in physiology, body moveme nt, or cortisol following the heel lance Behavioral Physiological Biochemical Grunau et al., 2010 Prospective cohort study examining cortisol reactivity during immunization in preterm (n = 99) and full-term (n = 39) infants at corrected age 4 months Cortisol (P = 0.011), facial activity (P <0.0001), and HR increased (P <0.0001) during immu nizations. Cortisol was lower in preterm ELGA and VLGA boys, compared with full-term boys ( P = 0.006) Behavioral Biochemical Holsti et al., 2007b Randomized cross-over design examining facial responses, adrenocorticotropic hormone (ACTH) and cortisol levels in preterm infants during routine nursing procedures (n = 90 preterm i nfants: extremely low gestational age (ELGA: 28 weeks); very low gestational age (VLGA: 29 \200\22331 weeks)) Facial actions increased signi \201 cantly from baseline during clustered care (p = 0.001) , and continued during the recovery phase. Th e correlation between ACTH and cortisol di \200 ered signi \201 cantly between the two GA groups. During clustered care, ELGA infants showed no relationship between ACTH and cortisol, whereas VLGA infants showed a signi \201 cant correlation (r = 0.62, p = 0.0001) Biochemical Scha \200 er et al., 2009 Prospective cohort study comparing salivary cortisol and cortisone levels during rest and a pain-induced stress event in small for gestational age (SGA) and appropriate for gestation al age (AGA) neonates 34 weeks of gestation (n = 58) In AGA neonates, salivary cortisol and cortisone levels signi \201 cantly increased after the stress event (P <0.05) while SGA infants exhibited a blunted response (Continued) SECTION 5 measurement of pain 362 Table 35.2 (Continued) Indicator(s) Reference Study design/methods Main results Biochemical Yamada et al., 2007 Prospective cohort study to determine di \200 erences between (a) hair cortisol levels in term and preterm infants exposed to stress in the NICU and (b) hair cortisol levels and sev erity of illness (n = 60 infants >25 weeks GA) No signi \201 cant di \200 erences between the hair cortisol levels in hospitalized term and preterm infants. Hospitalized infants had signi \201 cantly higher hair cortisol level s than healthy term infants (t (76) = 2.755, p = 0.004) Term NICU infants showed a statisti cally signi \201 cant association between total number of ventilator days and hair cortiso l levels: for every extra day on the ventilator, hair cortisol levels increased on average by 0.2 mol/g (p = 0.03) Heart rate variability (HRV) Behavioral Physiological Faye et al., 2010 Prospective cohort study exploring HRV to pain in the full-term newborn (n = 28). Postopera tive pain assessed using EDIN scale at the end of the 2 h recording period Mean EDIN scores were 2 1 and 7 2 in respectively the groups \200\230Low EDIN \200\231 and \200\230High EDIN. \200\231 HFVI was signi \201 cantly lower in the \200\230High EDIN \200\231 group than in the \200\230Low EDIN \200\231 (0.7 0.2 vs. 1.2 0.3, respectively; P <0.01). An HFVI <0.9 predicted an EDIN score 5, with a sensitivity of 90%, and a speci \201 city of 75% Physiological Padhye et al., 2009 Prospective repeated measures cohort study to characterize the HRV response of high-risk ve ry low birth weight infants (<1500 g) from 23 \200\22338 weeks GA (n = 38 infants) to heel lance procedure and venepuncture HRV in both bands decreased during pain (P<0.001), followed by a recovery to near-baseline levels (P = 0.166). Venepuncture and mechanical ventilation attenuated the HRV response to pain (P= 0.024 and P=0.001 respectively). HRV at the baseline increased with GA but the gro wth rate of high-frequency power was reduced in mechanically ventilated infants Physiological Behavioral Stevens et al., 2007 Prospective observational cohort study comparing pain responses to heel lance from infants at high (Cohort A, n = 54), moderate (Cohort B, n = 45) and low (Cohort C, n = 50) risk for NI (n = 149) A signi \201 cant cohort by phase interaction for total facial action (F(6, 409) = 3.50, p = 0.0022) and 4 individual facial actions existed; with Cohort C demonstrating the most fa cial action. A signi \201 cant Phase e \200 ect existed for increased maximum HR (F(3, 43 1) = 58.1, p = 0.001), minimum HR (F(3, 431) = 78.7, p = 0.001), maximum O 2 saturation (F( 3, 425) = 47.6, p = 0.001), and minimum O 2 saturation (F(3, 425) = 12.2, p = 0.001) with n o cohort di \200 erences Cohort B had signi \201 cantly higher minimum (F(2, 79) = 3.71, p = 0.029), and mean (F(2, 79) = 4.04, p = 0.021) fundamental cry frequencies A signi \201 cant phase e \200 ect for low/high-frequency HRV ratio (F(2, 216) = 4.97, p = 0.008) was found with the greatest decrease in Cohort A. Signi \201 cant cohort by phase interactions existed for low- and high-frequency HRV measures in appropriate designs are needed. For example, for rand- omized controlled trials , a measure of methodological quality such as the CONsolidated Standards of Reporting Trial s (CONSORT, 2010) statement that includes whether a validated measure, appro- priate random ization, and follow-up of outcomes are used should be incorporated as a guideline for repor ting the methodological quality of published studies and responsible external generalizatio n of the results. imaging \200\224MRI), and near-infrared spectroscopy (NIRS), have been explored to try and better understand structural, biochemical, or functional neuronal activity in the brain \200\231s response to noxious stimulation. A summary of the most recent studies are include d in Table 35.3 . Recently, Brummelte et al. ( 2012 ), using MRI, three-dimensional magnetic resonance spectr oscopic imaging, and diff usion ten- sor imaging demonstrated that greater numbers of skin- break- ing procedural pain indicators may contribute to impaired brain development in prete rm infants. Fabrizi and colleagues ( 2011 ) systematically mapped the maturation of tactile and nociceptive activity in the developing human brain using EEG signals. Specifi c neural circuits for discrimination between touch and nociception emerged from 35 to 37 weeks GA i n the human brain. Current clinical practice guidelines, policies, and procedures An important aspect of impro ving clinical outcomes is to ensure that the most recent evidence is eff ectively translate d into clinical practice. Th is translation needs to be supported by inclusion of rec- omme ndations for pain assessment within wider pain management guidelines. To date, several publ ished guidelines from professional organizations have included recommendations on pain asse ss- ment and management (see Table 35.4 ). Th e majority do not focus on children, although there are a few that are specifi c to children Although, biomarkers, cortical indicators and cognitive mapping provide novel and objective means to exploring the infant \200\231s response to pain, decoding their complex and varia ble patterns and compar- ing them to behavioral pain indicators and composite measures has not been suffi ciently explored. Carefully designed measure- ment studies comparing cogniti ve indicators with established CHAPTER 35 neonatal and infant pain assessment 363 Table 35.3 Cognitive indicators of neonatal/infant pain Indicator Reference Study design/methods Main results Magnetic resonance imaging (MRI) Brummelte et al., 2012 Prospective cohort study (n = 86 preterm infants 24 \200\22332 weeks GA) to examine relatio nship between procedural pain and early brain development Greater numbers of painful procedures were associated with reduced white matter (p = 0.028) and reduced subcortical gray matter (p = 0.004) after adjusting for multiple clinical fact ors Electro- encephalography (EEG) Fabrizi et al., 2011 Prospective cohort study (N = 18 infants 37 \200\22345 weeks GA; and N = 41 infants 28 \200 \22345 weeks GA (born at 24 \200\22341 weeks GA)) comparing touch or heel lance Occurrence in the preterm infants was signi \201 cantly less than in the full-term infants (p = 0.01tactile potential; p = 0.01 nociceptive-speci \201 c potential). Latencies of ta ctile and nociceptive-speci \201 c potentials were shorter in full-term infants than in pr emature infants. Neuronal bursts were signi \201 cantly greater in preterm infants than te rm infants whether evoked by touch (p = 0.048) or noxious lance (p <0.001) Neural circuits for discrimination between touch and nociception emerge from 35 \200\22337 weeks GA in the human brain Slater et al., 2010 Pilot prospective cohort study to determine whether cortical neurons are speci \201 cally activated by noxious stimuli in newborns (N = 10 infants 35 \200\22339 weeks PMA) using EEG recording following a routine heel lance Th e potential was observed in the central electrodes and characterized by a positivity tha t occurs at approximately 560 msec post-stimulus Th e magnitude of the nociceptive-speci \201 c potential was not dependent on sleep state, whereas an earlier potential, which was sleep-state dependent, was evoked by both noxious and non-noxious stimulation Researchers r eport that results provide the \201 rst direct evidence of speci \201 c noxious-evoked n eural activity in the infant brain Electro- myography (EMG) Schasfoort et al., 2008 Prospective cohort study to determine the feasibility of long-term, objective, and continuo us measurement of peripheral motor parameters to discriminate between pain and no pain in h ospitalized pre-verbal infants during (a) acute painful procedure: n = 9 (5 \200\223175 day s of age): and (b) postoperative pain: n = 14 infants (age range 45 \200\223400 days for ag e) measured for prolonged periods (mean 7 h) using acceleration sensors on one arm and both legs, and two muscle activity parameters derived from EMG sensors Acute painful procedure: the accelerometry-based parameters legs activity and overall extre mity activity (i.e. mean of arm and legs) was signi \201 cantly higher during heel lance t han before or after lance (p \211 0.001) Post-operative pain: relationships existed betwe en accelerometry-based overall extremity activity and COMFORT scale (r = 0.76, p <0.001), a nd between EMG-based wrist \202 exor activity and COMFORT (r = 0.55, p <0.001, for a subg roup of 7 infants) Researchers conclude that long-term, objective, and continuous measureme nt of peripheral motor parameters is feasible, has high potential, and is promising to asse ss pain in preverbal hospitalized infants Tactile stimulation produced no changes in HR or SaO 2 HR increased in the \201 rst 20 se c (p < 0.001), while SaO 2 decreased during the 40 sec after venepuncture (p <0.0001). Foll owing tactile or painful stimulation, [HbO 2 ] increased bilaterally (p <0.0001) Pain-induc ed [HbO 2 ] increases in the contralateral somatosensory cortex (p <0.05) were not mirrored in the occipital cortex (p >0.1) Pain-related [HbO 2 ] increases were signi \201 cantly m ore pronounced in male neonates, inversely correlated with GA and directly correlated with PNA. Researchers concluded that painful and tactile stimuli elicit speci \201 c haemodynam ic responses in the somatosensory cortex, implying conscious sensory perception in preterm neonates Near-infrared spectroscopy (NIRS) Bartocci et al., 2006