Measurement of neonatal responses to painful stimuli: A research review

lebl. 14 No. 6 December 1997

Journal of Pain and Symptom Management 343

Review Article

Measurement of Neonatal Responses to Painful Stimuli: A Research Review L i n d a Sturla Franck, RN, P h D a n d Christine Miaskowski, RN, PhD, FAAN

D@artment of Family Health Care Nursing (L.S.E ), and Department of Physiological Nursing (C.M.), University of California-San Francisco, San Francisco, Cal!fornia, USA

Abstract The measurement of neonatal responses to painful stimuli remains a significant clinical problem. Although nunwro~ measures have beer~ evaluated, instruments that are valid, reliable, and clinically feasib~ are not yet available. The purpose of this paper is to critique the studies that have been done using biochemical, physiological, and behavioral measures to evaluate neonatal responses to painful stimuli. Spec~c issues regarding measurement in [nemature and critically ill neonates are emphasized. The intent of this review and critique of the literature is to stimulate additional research into the assessmerit of neonatal pain. J Pain S)~nptom Manage 1997;14:343-378. © U.S. Cancer Pain Reli~" Committee, 199Z

Key Words Neonates, pain ruecL~urement, asses~'ment

Introduction The m e a s u r e m e n t of a multidimensional p h e n o m e n o n , like pain, is extremely complex. Therefore, the selection of appropriate instruments to measure responses to painful stimuli must be based on consideration of n u m e r o u s factors, including (a) the reliability and validity of the instrument for a specific age group; (b) t h e p u r p o s e a n d c o n t e x t o f t h e measurement; (c) the appropriateness of the instrument for the stimulus being studied; and (d) the versatility of the instrument and its feasibility for clinical use.1 Factors that can affect measurement of responses to painflfl stimuli in all humans include interpretation of verbal

Address ~pt4nt ~quests to: Linda Sturla Franck, RN, PhD, Department of Family Health Care Nursing, University of California-San Francisco, Box 0606, N411Y, San Francisco, CA 94143.

Accepted,/br publication: l'?bruarv 10, 1997. © U.S. Cancer Pain Relief Committee, 1997 Published bv ElsevieJ, New "~rk, New x,])rk

a n d n o n v e r b a l r e s p o n s e s , v a r i a b i l i t y in responses due to individual characteristics, the effects of intercurrent illness, and the plasticity of the central nervous system's responses to painflll stimuli. 2':~ There are n u m e r o u s methodological chall e n g e s in the m e a s u r e m e n t of" n e o n a t a l responses to painful stimuli: (a) neonates are n o t capable o f d e s c r i b i n g their subjective experience; (b) there is a dispariD: between the accelerated development of the sensory systems and immature m o t o r capabilities of neonates, I which leads to stereotypic behavioral r e s p o n s e s to b o t h painful and n o n painful stimuli; (c) habituation of neonatal behavioral a n d physiological responses to painful stimuli can occur ~' and impede detection of these responses; (d) central nervous system (CNS) development is rapid and dramatic during late gestation and in the early postnatal period, ~ making comparisons and ()885-3924/97/$[ 7.09 PII S0885-3924(97)00222-4

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generalization of findings of neonatal studies difficult; and (e) the u n c o n t r o l l e d intensity" and quality of painful stimuli to which neonates are subjected are difficult to measure. Responses to painful stimuli that occur during the course of neonatal care are generally evaluated in research studies because of the ethical constraints regarding the use of experimentally induced pain in xaflnerable populations, such as neonates. These stimuli are presumed to be painful in neonates because they are painful in o l d e r c h i l d r e n a n d adults. Despite many of these methodological obstacles, there is a growing literature that describes instruments to measure neonatal responses to painful stimuli. A l t h o u g h the studies presented below clearly show that neonatal responses to painful stimuli can be measured, the clinical significance of the measured responses and the usefulness o f the instruments in the care of the critically ill or premature neonate remain to be definitively established. The purpose of this paper is to provide a systematic review and critique of the methods used to measure neonatal responses to painful stimuli. A Medline search was done for the years 1966 to the present to obtain a list of all research studies, written in English, that measured neonatal responses to painful stimuli. Additional papers were identified in the reference lists of the articles found through the Medline search. T h r e e classes of measures were identified--biochemical measures, physiological measures, and behavioral m e a s u r e s - from the re~4ew of the studies. In addition, studies that c o m b i n e d one or more class of measures were reviewed. Each of the classes of measures are evaluated in terms of their validity and reliability, their appropriateness for the neonatal population, and their feasibility for use as a clinical or a research tool. Specific issues regarding the m e a s u r e m e n t of pain in p r e m a t u r e a n d critically ill n e o n a t e s are emphasized, It should be noted that much of the research regarding m e a s u r e m e n t of neonatal responses to painful stimuli was coupled with the testing of interventions to attenuate those responses. Only studies that investigated interventions using a control group, in which measurements of unaltered responses to painful stimuli were performed, are included in this review. In addition, only those measures

Vol. 14 No. 6 December 1997

that were tested on infants in the neonatal period, from birth to 1 m o n t h of age, will be discussed.

Biochemical Responses of Neonates to Painful Stimuli The most direct m e a s u r e m e n t of the stress response is the biochemical assay of the hormones and metabolites of the hypothalamicpituitary-adrenal (HPA) axis. The neonatal n e u r o e n d o c r i n e stress response consists of a complex pattern of catabolic h o r m o n e release characterized by increases in cortisol, epinephrine (E), n o r e p i n e p h r i n e (NE), growth hormone, and endorphins, as well as suppression a n d / o r peripheral resistance to insulin. 7 Several laboratory techniques, specifically high pressure liquid c h r o m a t o g r a p h y with electrochemical detection (HPLC-ED), radioimmunoassay (RIA), a n d r a d i o e n z y m a t i c assay (PEA) permit detection of stress h o r m o n e s from relatively small volumes of blood (that is, 0.1-1.5 mL). However, the availability of these assays is not widespread and limited data exist on normal ranges of these h o r m o n e s in neonates u n d e r basal and stressed conditions. This discussion will be limited to studies that measured cortisol and the catecholamines, E, and NE, because these h o r m o n e s were most f r e q u e n t l y assayed in n e o n a t e s (Table 1). Because pain is a significant stressor to the neonate, m e a s u r e m e n t of changes in cortisol, E, and NE shonld represent a biochemical response to a painful stimulus.

Cortisol

Cortisol levels reflect activity of the HPA axis. In infants, cortisol is most c o m m o n l y measured using RIA. RIA is sensitive for the range of cortisol detected in neonates at rest (approximately 3 p g / d L ) s'q and when stressed (approximately 25.5 p g / d L ) . 1°'11 The meas u r e m e n t o f p l a s m a cortisol in n e o n a t e s became more feasible with the development of a technique to p e r f o r m RIA using very small amounts of blood spotted on filter paper, v-''~:~ Recently, a technique for measuring salivary cortisol in infants was developed. H ' ~ This technique measures only u n b o u n d cortisol, whereas plasma cortisol levels reflect both

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b o u n d and u n b o u n d fractions. G u n n a r and colleagues ns c o n c u r r e n t l y m e a s u r e d plasma and salivary cortisol in lull term neonates and demonstrated a relatively constant ratio up to levels of 16 p g / d L . At this level, the ratio of salivary-to-plasma cortisol increases dramatically. G u n n a r 14 proposed that plasma cortisol levels greater than 16 p g / d L should be conside r e d r e p r e s e n t a t i v e o f a stress r e s p o n s e . Increases in cortisol levels up to 16 p g / d L may only represent the variability in cortisol levels related to behavioral state changes iv and may not be indicative of a response to stress. In tifll-term neonates, cortisol increases significantly with crying, 17'18 illness, 19 a n d in response to nonpainful stimuli such as physical examination, s'l~''16 Increased cortisol levels were detected in full-term neonates within 20-30 min following painful stimuli such as circumcision, m'u°'m heelstick, 2z and surgery. ~:~ In one study, the cortisol response to circumcision was significantly decreased with the use of a 1% lidocaine dorsal penile nerve block (DPNB), c o m p a r e d to saline injection or no injection. 94 However, Williamson and Evans ~~' were unable to demonstrate a reduction in cortisol levels with DPNB during circumcision, perhaps due to overall higher baseline cortisol levels in the study sample or the stress of blood sampling prior to the maximal analgesic effect. 94 G u n n a r 26 compiled data from several studies to demonstrate that cortisol levels increase in a graded m a n n e r with increasingly invasive stimuli. For example, cortisol levels increased threefold following a discharge exam, sixfold following circumcision by an experienced ph p sician, and eightfold following circumcision by a resident physician, as c o m p a r e d to levels during undisturbed rest. s'~ ~.~4,26 Habituation of the cortisol response in neonates (that is, decreased responsiveness with repeated stimulation) was demonstrated after n o n p a i n f u l stimuli such as r e p e a t e d handling. 14 However, lack of habituation or even sensitization (that is, increased magnitude of response with repeated stimulation) was demonstrated with painful procedures, such as heelstick. 27 Drug exposure 21 and health status 2 7 may also influence cortisol responses to painful stimuli. While the level of behavioral arousal is often associated with the magnitude of cortisol increase, behavioral arousal does

Vol. 14 No. 6 December 1997

not consistently predict increases in cortisol levels. 9s A low correlation was demonstrated between changes in physiological measures and cortisol response during heelstick in fullterm neonates, despite a modest correlation between cortisol response and level of behavioral arousal. ~9 In full-term neonates, operative stress results in significantly increased cortisol levels at 6 and 12 hr postoperatively. However, postoperative cortisol levels are decreased when anesthesia is used during surgery. :~° Postoperative cortisol levels were f o u n d to be significantly h i g h e r in n e o n a t e s who received n i t r o u s o x i d e / o x y g e n (N20/O~)) a n e s t h e s i a comp a r e d to neonates who received h a l o t h a n e anesthesia ~1 and in neonates who u n d e r w e n t o p e n h e a r t surgery u n d e r light anesthesia (that is, halothane and morphine) c o m p a r e d to n e o n a t e s who received d e e p anesthesia (that is, sufentanil at 35-40 p g / k g ) . :~9 A few studies measured cortisol levels in preterm infants. In ill premature neonates, who were exposed to frequent painful stimuli such as arterial and venous cannulation and endotracheal (ET) suctioning, serum cortisol levels increased over the first few days of life and peaked by day 5. ~9 In a n o t h e r study, :~~ Pokela measured changes in cortisol levels of ill premature neonates following ET suctioning or daily nursing care procedures, such as bathing or weighing. O n e group of neonates received m e p e r i d i n e p r i o r to the p r o c e d u r e a n d a n o t h e r g r o u p received a saline injection. In the meperidine g r o u p , c o r t i s o l levels decreased from baseline within 2 hr following the procedure, whereas in the placebo group, cortisol levels r e m a i n e d elevated. U n f o r t u nately, data for ET suctioning and daily care procedures were combined, perhaps obscuring differences in responses to the two different types of stinmli. In a n o t h e r study of p r e m a t u r e neonates u n d e r g o i n g patent ductus arteriosus (PDA) ligation, 34 plasma cortisol levels did not differ between the experimental group (that is, neonates who received NzO/Oe, curare, and fentanyl) and the control g r o u p (that is, neonates who received N 9 0 / O e and curare). However, c o r t i c o s t e r o n e a n d l l - d e o x y c o r t i s o l levels ( p r e c u r s o r steroid h o r m o n e s ) were significantly elevated in the control group. The lack

Vol. 14 No. 6 Dec~nber 1997

Measut~ment of Pain in Neonates

of cortisol response may reflect immaturi W of steroid biosynthesis in the premature neonate. Cortisol and o t h e r steroid h o r m o n e s are t h o u g h t to a u g m e n t rather than initiate the s t r e s s r e s p o n s e . 7'34 Therefore, m e a s u r e m e n t of precursors of cortisol may more accurately reflect the stress response of premature neonates to painfid stimuli. Specific and sensitive assays for measuring changes in cortisol levels in the neonate in response to painfifl stimuli are available. However, changes in cortisol levels are influenced by n u m e r o u s factors in the neonate. Therefore, the m e a s u r e m e n t of this b i o c h e m i c a l r e s p o n s e to p a i n f u l stimuli requires additional research before its clinical utility can be established. Catecholamines Catecholamines are believed to be the primary mediators of the neuroendocrine response to stress 7'33'35 and tile most reliable indicators of the acute stress response. ~6 Measurement of plasma catecholamine levels is a valid and reliable, although indirect, method of measuring s~Tnpathetic activity:~7 In the fetus and neonate, catecholamines (predominately NE) are prod u c e d in s y m p a t h e t i c nerves, the a d r e n a l medulla, a n d extra-adrenal c h r o m a f f i n tissue. :*s':~:~Norepinephrine is detected in the fetus as early as 16 weeks' gestation, and E is detected by 22 weeks' gestation. 3s Surgical procedures performed on premature neonates, such as thoracotomy for PDA ligation, induce dramatic hormonal and metabolic stress responses 2s'~9'4° that may contribute to postoperative morbidity and mortality. :~°'34 In one study, 4° plasma E and NE levels increased dramatically by the end of surgery but returned to baseline levels within 6 hr postoperatively. .Mtbough catecholamine levels may not remain elevated for as many hours postoperatively in the neonate compared to the adult, the increase is believed to play a significant role in stimulating the exu-eme metabolic aberrations noted postoperatively in neonates. 4~ N o r e p i n e p h r i n e and E levels are closely correlated with the intensity and duration of the surgical stimulus ~~'31 and the catecholamine response to surgical stress appears similar in both preterm and full-term neonates. 4° However, increases in catecholamine levels are not specific to surgical stressors. O t h e r painful procedures such as chest physiotherapy and

351

ET sucrioning are also associated with large increases in p l a s m a E levels a n d smaller increases in NE levels. 42'43 Hypoxia and acidosis also lead to substantial increases in plasma E and NE levels in neonates. "~4'45 Table 1 summarizes the results of studies that measured E and NE levels in premature a n d full-term n e o n a t e s f o l l o w i n g p a i n f u l s t r e s s o r s . :~°-32'40-43'46 Opioids have been shown to attenuate E and NE responses to varying degrees. 31'33'46'47 A l t h o u g h neonates clearly demonstrate catecholamine responsiveness to painful stimuli, there is marked variability in both the baseline values and the degree of change in plasma E and NE levels associated with pain. The sources of the variability in responses were not identified. Therefore, additional research is warranted to determine how useful the m e a s u r e m e n t of E and NE will be in evaluating and managing neonates' responses to painful stimuli.

Physiological Responses of Neonates to Painful Stimuli Physiological responses to painful stimuli include changes in heart rate, respiratory rate, blood pressure, transcutaneous oxygen levels (tcPOz), transcutaneous carbon dioxide levels (tcPCO2), oxygen saturation (SaO2), intracranial pressure (ICP), and measures o f vagal t o n e , skin b l o o d flow, a n d p a l m a r sweat. Research studies evaluating neonatal responses to painful stimuli have generally included measurement of multiple physiological responses. However, changes in physiological responses are difficult to interpret because these responses are influenced by other nonnoxious stimuli, particularly in the ill or premature infant. 4s Studies that evaluated physiological responses o f n e o n a t e s to painfnl stimuli are smmnarized in Table 2. Vital Signs Vital signs, such as heart rate, respiratory rate, blood pressure, and oxygenation levels (that is, tcPO,, or SaO~) can be m e a s u r e d directly and easily from m o n i t o r i n g equipm e n t readily available in the intensive care setring. Significant decreases in oxygen levels and oxygen saturation, and increases in heart rate and b l o o d pressure were d e m o n s t r a t e d in healthy n e o n a t e s d u r i n g circumcision. 4~-~s However, in one study, 54 a significant increase

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in tcPO~ was observed following circumcision and was attributed to the improved minute ventillation that resulted from crying. Comfort measures, such as pacifiers, tactile stimulation, and music, appear to have little effect on the physiological responses to circumcision. A c e t o m i n o p h e n had no effect on physiological responses to c i r c u m c i s i o n . ~'~ However, topical local anesthetics ~'2'5<~7 and DPNB "~1'5:~'5s significantly reduced the physiological responses of neonates to circumcision. Many studies have examined the physiological responses of neonates to heelstick. Studies in h e a l t h y a n d ill p r e t e r m a n d fnll t e r m infants >)-71 demonstrate significant increases in heart rate and decreases in oxygenation (tcPO2, SaO2) during the lancing phase of the procedure, c o m p a r e d to baseline levels. Significant decreases in the partial pressure of arterial oxygen (PaOg) and increases in heart rate during heel stimulation (that is, without lancing) were also d o c u m e n t e d in neonates r e c o v e r i n g f r o m r e s p i r a t o r y distress syndrome. 79 The decreases in oxygenation persisted for at least 12 ntin post-procedure. Increases in skin conductance ~s and palmar sweat >`) were also demonstrated in full-term (but not preterm) neonates following heelstick. Decreases in heart rate variability and increases in blood pressure and intracranial pressure were reported in premature neonates following heelstick. (~5'67-v° In several of these studies, Stevens (~'69 and J o h n s t o n TM f o u n d that severity of illness had no influence on the physiological responses of premature neonates to heelstick. A few studies r e p o r t e d similar changes in physiologic parameters following arterial puncture, venipuncture, and intravenous line (IV) insertion. 67'73'v4 Norris and colleaDms 57 examined changes in tcPO9 during several nursing procedures (that is, suctioning, repositioning, and heelstick) in p r e t e r m n e o n a t e s with respiratory distress. Although decreases in o ~ g e n a t i o n were seen with all three procedures, the decreases in tcPO 2 were statistically significant only with suctioning and repositioning. The recovery time to baseline tcPO9 levels was not related to the length of the procedure. Heart rate, blood pressure, oxygenation, and intracranial pressure were all found to increase significantly during suctioning. 7~-7v

Vol. 14 No. 6 December 1997

These responses decreased xdth the use of phenobarbital. 77 C o r f f et al. 7L f o u n d that the h e a r t rate response and the a m o u n t of crying could be reduced by holding a preterm neonate in a tucked position during heelstick. Miller and A n d e r s o n 74 also d e m o n s t r a t e d a decreased heart rate response and decreased crying during IV insertion with the use of nonnutritive sucking. Field and Goldson >) found that nonnutritive sucking m o d e r a t e d heart rate and respiratory rate increases in healthy preterm neonates but not in ill preterm neonates. One study evaluated the effects of subcutaneous lidocaine on vital sign changes of ill premature neonates u n d e r g o i n g l u m b a r puncture. TM P o s i t i o n i n g f o r l u m b a r p u n c t u r e p r o d u c e d significant instability, i n c l u d i n g increases in heart rate and decreases in heart rate variability, respiratory rate and tcPO,,, in both the experimental and control groups. S u b c u t a n e o u s l i d o c a i n e i n j e c t i o n did n o t attenuate the alterations in vital signs produced by positioning. In addition, no differe n c e s in vital sign c h a n g e s were n o t e d between the experimental group and the control group during the lmnbar puncture. These results suggest that handling of an ill premature infant is a significant stressor and lhat a local anesthetic is not sufficient to attenuate vital sign instability caused by either the handling or the lumbar puncture. In another study, 7~) neonates who received intraoperative local anesthetic in addition to anesthesia during pyloromyotomy had similar postoperative heart rates and respiratory rates during the postoperative period as those neonates who received anesthesia alone. However, a more p o t e n t intervention, fentanyl anesthesia, attenuated heart rate and blood pressure e l e v a t i o n s in n e o n a t e s d u r i n g PDA ligation, s°'ul and improved p u l m o n a r y flmction in n e o n a t e s following d i a p h r a g m a t i c h e r n i a repair, s~ Vital sign measurements are readily available in the clinical setting and are important parameters for the clinical m a n a g e m e n t of critically ill neonates. Vital signs, particularly heart rate and oxygenation levels, do change in response to acute, discrete painful stimuli, such as circumcision or heelstick. However, vital signs change in response to nonpainful stimuli as well. Therefore, these measures, by

~/bl. 14 No. 6 December1997

Measurement o[ Pain in Neonates

themselves, may not be specific e n o u g h to distinguish b e t w e e n painflfl a n d n o n p a i n f u l stimuli, or determine the efficacy of interventions to reduce neonatal responses to painful stimuli in the presence of multiple, repeated, or prolonged painful stimuli such as occurs in the care of the critically ill premature neonate. Vagal 7bne l n d e x O n e m e t h o d that may provide an accurate and reliable measure of the neonatal stress response to painful stimnli is vagal tone. A widely used index of vagal tone employs a time series signal processing technique to measure the variation in heart period pattern occurring within the frequency band associated with spontaneous respiration. Vagal tone is believed to specifically reflect parasympathetic influence (via the vagus nerve) on heart rate and is t h e r e f o r e a s s u m e d to r e p r e s e n t a CNSmediated response, s:<~4 Vagal tone index (VFI) is normally distributed in h e a l t h y filll-term and ill p r e t e r m neonates, s:'-s7 However, VTI is significantly decreased in premature neonates less than 32 weeks' gestation and in ill neonates as compared to healthy full-term neonates, s~>-ss Vagal tone index appears to be sensitive to differences in stimulus intensity and m W discriminate between the responses of neonates to painful and nonpainful stimuli. For example, in fitllterm neonates, decreases in VTI following restraint were smaller than decreases following circumcision, s9 In addition, pre-circumcision VTI was predictive of the magnitude of the change in \ ~ I follow4ng the procedure, whereas heart period was not. Neonates w4th higher baseline VFI values had larger decreases in ~q'I fob lowing circumcision. Measurement of VFI should provide accurate estimates of respiratory sinus arrhythmia (RSA) a m p l i t u d e for n e o n a t e s r e c e i v i n g assisted ventilation, as long as the total respiratory rate (that is, spontaneous and mechanical breaths) is within the respiratory frequency specified in the \ ~ I algorithm. 9° However, few studies have been c o n d u c t e d to evaluate VTI or other measures of R S A 91''~'-) in mechanically ventilated neonates. No studies have evaluated measures of vagal tone in mechanically ventilated neonates during acute painful stimuli. In neonates, VTI may provide better specificity and sensitivity in detecting the parasynr-

361

p a t h e t i c r e s p o n s e to painful stimuli than either heart rate or heart period variability. Research findings suggest that \rTI is sensitive to differences in stimulus intensity and may discriminate between responses to painful and n o n p a i n f u l stmluh. " . s,~ " F u r t h e r r e s e a r c h is required to determine the stability of vagal tone measures over repeated measurements, '~3 across gestational ages, and in neonates who have different severities of illness. P a l m a r Sweat Water loss across the skin of the palmar surface was shown to occur in neonates at 37 weeks' gestation or older following physiologic arousal. '~4 Pahnar sweat is accurately and reliably measured using an evaporimeter to quantitate transepidermal water loss. 95 In flfll-term neonates, palmar sweat increased following painful stimuli such as heelst~ck. ~" Harpin and Rutter '~ demonstrated a reduction in palmar sweat using a mechanical lance compared to manual lancing of the heel. Changes in palmar sweat are positively correlated x~fith changes in heart rate and negatively correlated with changes in respiratory rate and oxygen saturation. ~7 In addition, significant changes in skin conductance were demonstrated during heelstick. '~5 Unfortunately, neit h e r p a h n a r sweat n o r c h a n g e s in skin c o n d u c t a n c e can be detected in p r e m a t u r e infants and the measures are, therefore, of limited use in measuring neonatal responses to painful stimuli. •

t)"

Skin Blood Flow In two studies, ~s'~'~ skin blood flow, measured by laser doppler, was used to evaluate neonatal responses to painful procedures. In these studies, significant increases in skin blood flow were demonstrated during painful procedures (for example, heelstick, suctioning, chest physiotherapy, percutaneous catheter insertion). However, increases in skin blood flow were attenuated when m o r p h i n e was administered prior to the procedures. '~''J9 Physiological changes tend to occur concurrently in response to painfi~l stimuli, but variation in responses occurs between and within individuals. In healthy infants, physiological responses may be dramatic, but are usually brief and not clinically significant. However, premature a n d / o r ill infants often have clinically significant responses, even to stimuli con-

362

Franck and Miaskowski

sidered nonpainful in the healthy term infant (for example, handling). The sensitivity, of the ill or extremely immature neonate to painful a n d n o n p a i n f u l stimuli u n d e r s c o r e s the importance of interventions to prevent physiological compromise. While vital signs (that is, heart rate, blood pressure, and oxygenation, primarily) are responsive to a wide range of stimuli and treatments, parameters such as vagal tone or skin blood flow that specifically reflect neural activi~' may prox4de more accurate data o n the n e o n a t e ' s p h y s i o l o g i c a l response to painful stimuli.

Behavioral Responses of Neonates to Painful Stimuli Changes in n e o n a t e s ' behavior are con> monly used as indices of their responses to painful stimuli. Behavioral changes that can be measured include vocalization, facial expression, behavioral state, gross m o t o r movement, and flexor reflex threshold. Studies that evaluated behavioral responses of neonates to painful stimuli are summarized in Table 3. Vocalization

The temporal characteristics of the neonatal cry (that is, cry length, n u m b e r of episodes, interval between episodes, and percent of time spent crying) in response to painful stimuli have been measured in healthy, full-term neonates. In one of the first studies of neonatal pain response to be reported, '°° n e o n a t e s cried significantly longer and their cries contained m o r e vocalizations a n d less pauses between vocalizations in response to increased force of a r u b b e r b a n d snap against their heels. While the length of the cry episode, n u m b e r of vocalizations, and interval between vocalization were shown to vary widely a m o n g infants and across postnatal age (increasing and decreasing at various times within the first year of life), the latency from application of a painful stimulus to the onset of cry appears to be less variable a m o n g infants and exhibits a relatively consistent pattern across postnatal age m°-m2 and stimulus intensity, l°° More invasire stimuli such as heelstick or circumcision result in increased crying time, m:~'m4 and cry duration, and decreased cry latency, 62,64A°~-ms as c o m p a r e d to nonpainfifl stimuli. However,

I,bl. 14 No. 6 December I 9 9 7

preterm neonates may not always exhibit cry behavior. 7° The acoustic features (that is, pitch and harmonics) of neonatal cries elicited by painful stimuli can be evaluated using spectral analysis of r e c o r d e d cries. " 56s,)106 . . . . . . ~09 ~10 Significantly higher pitch, distinctive harmonics, shorter cry cycles, and increased crying time were demonstrated during circumcision c o m p a r e d to pre- and post-circumcision handling, s9 The h i g h e r pitch and shorter d u r a t i o n of cries associated with painful stimuli are similar to the cries of medically c o m p r o m i s e d infants. 111 Comfort measures, 71''°s nonnutritive sucking alone, 59"74 and nonnutritive sucking with sucrose l°s were shown to decrease the crying time of healthy full-term and both ill and healthy preterm neonates in response to painful stimuli. 74'm7 Neonates who received local anesthetic during circumcision demonstrated reduced crying times as c o m p a r e d to neonates who did not receive local anesthetic. 1°'')4'49'515:~,5~; H o w e v e r , in o n e study, 119 t o p i c a l lidocaine did not reduce crying in response to heelstick. M e a s u r e m e n t o f acoustic a n d t e m p o r a l characteristics are valid and reliable methods to describe infant cry and distinguish cries elicited by painful stimuli from those elicited by nonpainful stimuli, ll~ However, recent data suggest that the acoustic characteristics of cry alone may not ahvays discriminate between painflfl and nonpainful stimuli, and that physiological or behavioral data may need to be evaluated. ~~4 Cry is believed to be at least partially u n d e r neural control 11:~ and differences in cry characteristics may reflect activation of the neur o e n d o c r i n e stress response. Is'~15 However, the absence of cry does not necessarily indicate absence of a response to a painful stimulus. Furthermore, m e a s u r e m e n t of cry in the intensive care setting is problematic. Recording e q u i p m e n t and c o m p u t e r programs for spectral analysis are costly and the quality of the recordings may be compromised by the noisy environment. Metabolic or neurologic pathology may affect cry acoustics as well. '~6 Most importantly, intubated neonates, who may experience the most frequent and intense painful stimuli, are unable to cry. While analyses of the temporal or acoustic characteristics of cry may be useful for measuring responses

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of heahhy neonates, these lechniques may not be appropriate tbr measuring the responses of critically ill n e o n a t e s to painflll stimuli.

k ?wial t'~xpre,s~sion I n f a n t s display a relatively s t e r e o t y p i c constellation o f facial m o v e m e n t s in r e s p o n s e to a c u t e p a i n f u l stimuli. I jr T h e n e o n a t e ' s l)-l ~ I M e a s u r e m e n t o f reaction t i m e ( t h a t is, t h e t i m e f r o m a p p l i c a t i o n o f the s t i m u l u s to t h e d e t e c t i o n o f m o v e m e n t ) by d i r e c t o b s e r v a t i o n I'-'° o i p h o t o g r a m m e t r i c

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t e c h n i q u e s m:' allows m o r e p r e c i s e quantification o f b o d y m o v e m e n t . However, these m e t h ods have only b e e n u s e d to d e s c r i b e t h e gross m o t o r m o v e m e n t s in less t h a n 20 h e a l t h ) , fullterm neonates. The body movements of premature neon a t e s in r e s p o n s e to p a i n f u l stimuli have n o t b e e n p r e c i s e l y d e s c r i b e d , b u t a p p e a r to b e reduced when compared to full-term inPants. 12] O n e s t u d y u s e d a " s t r u g g l i n g s c o r e " to q u a n t i 6 , t h e d e g r e e o f gross m o t o r movement associated with lumhar puncture."-"-' P r e t e r m a n d full-term n e o n a t e s w h o r e c e i v e d s u t ) c u t a n e o u s l i d o c a i n e p r i o r to lumb a r p u n c t u r e s t r u g g l e d less d u r i n g t h e p r o c e d u r e t h a n t h o s e w h o d i d n o t receive l i d o c a i n e . D e s p i t e the difficuhies in c o n t r o l l i n g stimuIns i n t e n s i l y o r b e h a v i o r a l state a n d the lack o f o b j e c t i v e m e a s u r e m e n t , m a n y r e s e a r c h e r s conc l u d e t h a t t h e gross m o t o r r e s p o n s e s o f neonates a r e less specific a n d less i n t e n s e t h a n r e s p o n s e s m a d e by (alder infants, c h i l d r e n , o r adnhs, and interpret decreased responsiveness to mean that neonates perceixe less pain. l'-'<]e:~'~'-'4 However, the studies d o n e to d a t e can o n l y b e u s e d to c h a r a c t e r i z e gross m o t o r r e s p o n s e s a n d s h o u l d n o l b e used to i n t e r t h e intensity o f a p a i n f u l stimulus. Furt h e r m o r e , o t h e r factors such as d e g r e e o f illness, t h e p l a c e m e n t o f invasive a n d noninwtsire monitoring devices, and the use of c h e m i c a l o r physical restraints limit o b s e r v a tion o f total b o d y m o v e m e n t in t h e intensive c a r e setting. Vide() t a p e r e c o r d i n g o f movem e n t s t o t l a t e r analysis p r o v i d e s for m o r e a c c u r a t e m e a s u r e m e n t , b u t may n o t b e feasible in t h e clinical setting. T h e r e l o r e , gross m o t o r m o v e m e n t may n e e d to b e u s e d with o t h e r m e a s n r e s to assess n e o n a t e s ' r e s p o n s e s to p a i n f u l stimuli.

Flexor Reflex Threshold T i l e f l e x o r reflex o f t h e n e o n a t e is a clear, distinct withdrawal of the leg that can be e v o k e d by a s t i m u l u s to t h e heel. It is s i m i l a r to that o b s e r v e d in a d u l t s in r e s p o n s e to electrical s t i m u l a t i o n o f t h e sural n e r v e . l ~ T h e n e o n a t a l f l e x o r r e f l e x t h r e s h o l d (FRT) c a n b e m e a s u r e d by a p p l y i n g g r a d e d m e c h a n i c a l s t i m u l a t i o n , u s i n g von Frey tilaments, to t h e sole o f a n i n f a n t ' s f o o t a n d r e c o r d i n g t h e s m a l l e s t g r a m fi~rce r e q u i r e d to e l i c i t t h e retlex.Je(~ S t u d i e s with a d u h s d e m o n s t r a t e d

l~{d. 14 No. 6 December 1997

Measurement oJ Pain in Neonates

that the reflex is evoked only by stimuli perceived as painful a n d that stimulus intensity, threshold, a n d responsiveness to analgesia parallel p e r c e p t i o n o f pain. 127''127'1zs T h e FRT is discrete a n d r e p r o d u c i b l e in b o t h the n e o n a tal h u m a n a n d animal, but is evoked by stimuli o f m u c h lower intensity than in the adult. Iz~ T h e FRT response in h e a h h y a n d m o d e r ately ill neonates, 25-42 weeks' gestation, has b e e n d e s c r i b e d . L2a'le9 I n t h e s e two s t u d ies, 19<12'~ the FRT r a n g e d f r o m 0.2 to 1.0 a n d 0.5 to 2.0 g, respectively. T h e FRT increased significantly with gestational age but was n o t related to postnatal age. R e p e a t e d stimulation (with the same force a d m i n i s t e r e d at 5-sec intervals) p r o d u c e d sensitization in the prem a t u r e infant less than 30 weeks' gestation, such that rhythmic flexion a n d extension or c h r o n i c flexion o f the limb o c c u r r e d , a n d m o v e m e n t was also n o t e d in the o t h e r leg a n d torso. Sensitization d e c r e a s e d with increasing gestational age a n d habituation (that is, diminished responsivity to r e p e a t e d stimulation) was o b s e r v e d in most infants at 32-35 weeks' gestation. 1~, l ~., T h e effect o f tissue d a m a g e to the heel ( i n d u c e d by r e p e a t e d heelsticks over a p e r i o d o f 1-4 weeks) o n the FRT o f p r e m a t u r e neonates was described a n d c o m p a r e d to the FRT of the uninjured heel of the same neonates, l:~°'l:u A h h o u g h there was wide variabilfly in FRT f r o m day to da B a lower FRT was consistently d e m o n s t r a t e d in the injured heel as c o m p a r e d with the intact heel. lz"'l:~l T h e h y p e r s e n s i t i v i t y o f t h e i n j u r e d h e e l was reversed with application o f a topical local anesthetic, l:-11 In c o n t r a s t to tissue d a m a g e , contralateral tactile stiinulation resulted in a significant i n c r e a s e in FRT in the i n j u r e d heel. l'-''~ T h e s e data suggest a clear organization o f spinal sensory processing a n d a high level o f excitability within the d e v e l o p i n g spinal c o r d o f the p r e m a t u r e n e o n a t e . Von Frey filaments are n o t s t a n d a r d equipm e n t in intensive care settings, but are relatively i n e x p e n s i v e , h a t e r - r a t e r reliability in m e a s u r i n g the flexor reflex threshold has n o t b e e n reported. However, because the flexor reflex is a distinct "all or n o t h i n g " response, a h i g h d e g r e e o f c o n s i s t e n c y a m o n g testers would be expected. A l t h o u g h the n e o n a t e ' s lower limb m o v e m e n t may be restricted d u e to m o n i t o r i n g de~4ces or intravenous catheters, it

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is u n c o m m o n that b o t h legs are restricted simultaneously, or for p r o l o n g e d periods. Tile FRT is a valuable r e s e a r c h tool f o r e x a m i n i n g n e o n a t e s ' sensitivity a n d variability in sensitivity w h e n c u t a n e o u s s t i m u l i are applied to the infants' heel. T h e FRT may be useful in assessing the sensitivity o f n e o n a t e s to potentially painful events a n d their responses to pain m a n a g e m e n t interventions. T h e usefulness o f the FRT with a b r o a d range o f clinical conditions requires f u r t h e r investigation. Behavioral

States

Behavioral states are a cluster o f discrete behavioral and physiologic elements representing the infant's level of arousal, l:~Z.l:~:-1Behaxioral states are stable, o c c u r in regular cycles, and influence the inf~ant's abili~ ~ to respond to both internal and external stimulation. 1:~:-1They can be measured by direct observation or polygraph r e c o r d i n g o f r e s p i r a t o r y p a t t e r n , eye movements, gross m o t o r movement, and sleep/wake activity. Perturhations in state regulation are often associated xdth illness, neurological disorders, or prematurity. T M For example, premature inf~ants spend a greater a m o u n t o f time in active sleep than fifll-term infants and do not display behavioral state cycles until approximately 32 weeks' gestation. As infants mature, behavioral state cycles b e c o m e well-defined, m o r e stable, a n d less easily d i s r u p t e d by e n v i r o n m e n t a l s tim uli. 1:-/5,I:-11~ Painfifl stimuli can evoke measurable shortand long-term changes in beha~fioral state cycles in full-term inf~ants. In one stud}; an approximate 10% increase in quiet non-rapid eye movem e n t (non-REM) sleep and a c o r r e s p o n d i n g decrea~se in active (REM) sleep were observed during the night following circumcision, m7 In a n o t h e r stud,~, T M during the h o u r immediately following circumcision, an increase in wakefillhess followed by a decrease in latency to REM sleep alter the first post-circumcision feeding was observed, c o m p a r e d to the pre-circumcision state. However, no change in the proportion o f REM to non-REM sleep was found. G u n n a r and colleagues m observed behavioral state d u r i n g and 30 rain after circmncision and f o u n d a significant increase in wakefulness during the procedure and a significant increase in light sleep after the p r o c e d u r e c o m p a r e d with the neonate's pre-circumcision state. Brief procedures such as heelstick were shown to increase the

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behavioral state level to active a n d / o r crying during and after the p r o c e d u r e in healthy fullterm neonates a n d healthy and ill p r e t e r m neonates. 59 Behavioral state changes are generally measured by subjective assessment. Most clinicians in the intensive care setting are familiar with the c o n c e p t and assessment o f behavioral state. In o r d e r to detect subtle c h a n g e s in behavioral state, however, extensive training is required. P o l y g r a p h r e c o r d i n g o f r e s p i r a t o r y a n d eye movements, a~s well as electroencephalograms, can improve the accuracy o f beha~fioral state measurement. Behavioral state must be considered in all measurements of neonatal responses to painful stimuli because o f the potential influence of baseline beha~4oral state level on the neonate's responsiveness to these stinmli. ~~9 O t h e r researchers have m e a s u r e d c h a n g e s in the infant's interactive b e h a v i o r following painful stimuli using the Brazelton N e o n a t a l Assessment Scale (BNAS). 14° This scale measures neurological reflex f u n c t i o n a n d interactive responses to e n v i r o n m e n t a l stimuli, with a particular emphasis o n behavioral state regulation. P e r f o r m a n c e on the BNAS was f o u n d to be significantly different in n e o n a t e s circunlcised at 2 days o f age c o m p a r e d to controls (that is, n e o n a t e s n o t c i r c u m c i s e d until 3 weeks of age). HI T h e behavioral differences persisted in 33% of the n e o n a t e s until 22 h r fi)llowing c i r c u m c i s i o n . However, the alterations in behavioral state were diverse, with some infants becoming drowsy and other infants b e c o m i n g m o r e irritable. I n a r e l a t e d s t u d y , 14~ 2 - d a y - o l d i n f a n t s t e n d e d to be less available (that is, less receptive to e n v i r o n m e n t a l stimuli), have less feeding behavior, a n d d e m o n s t r a t e qualitatively different mother-infant interactions during the first 24 h r postoperatively following circ u m c i s i o n . D i x o n a n d c o l l e a g u e s 14:~ f o u n d infants undergoing circumcision without DPNB h a d less attention, p o o r e r self-soothing ability, a n d greater m o t o r acti~qty (hypertonicity a n d tremulousness), as m e a s u r e d by the BNAS, u p to 24 hr p o s t - c i r c u m c i s i o n c o m p a r e d to infants who received DPNB. Overall, BNAS scores, ti)r b o t h groups, were within the range o f n o r m a l b e h a v i o r for full term newb o r n infants. 'An acceptable level of inter-rater reliability using the BNAS requires extensive training.

l,'bl. 14 No. 6 December 1997

T h e r e f o r e , this m e t h o d is n o t practical for m e a s u r i n g responses to painful stimuli in the intensive care setting. In addition, behavioral e v a l u a t i o n is e x t r e m e l y p r o b l e m a t i c in the critically ill o r p r e t e r m n e o n a t e b e c a u s e b e h a v i o r may already be altered d u e to illness or immaturiD, a n d the BNAS exam c a n n o t be p e r f o r m e d on the ventilated n e o n a t e .

Correlation o f B e h a v i o r a l M e a s u r e s

A t t e m p t s to correlate different behavioral measures o f responses to painful stilnuli have p r o d u c e d equivocal results. O b s e r v a t i o n s o f full-term infants following heelstick l°~''19°'l~l clearly i n d i c a t e t h a t the healthy, full-term response o f n e o n a t e s consists o f a c o m b i n a tion o f vocalization, facial g r i m a c i n g , b o d y m o v e m e n t s , a n d d i s r u p t i o n in b e h a v i o r a l state. H o w e v e r , m o r e specific a s s o c i a t i o n s a m o n g behavioral r e s p o n s e p a r a m e t e r s may n o t be consistent. For example, G r u n a u a n d Craig, lls in a large study o f full-term infants d u r i n g heelstick, f o u n d that facial expression was related to behavioral state (with a w a k e / alert infants having the m o s t facial activity) a n d also to cry d u r a t i o n a n d latency'. However, n o c o r r e l a t i o n was f o u n d b e t w e e n facial expression a n d cry pitch or h a r m o n i c s , m < ~ s While it is reasonable to suggest that behavioral responses to painful stimuli s h o u l d be c o r r e l a t e d , a n a l t e r n a t i v e h y p o t h e s i s to explain the lack of c o r r e l a t i o n a m o n g measures is t h a t these d i f f e r e n t b e h a v i o r s ( t o t example, facial expression, cry) r e p r e s e n t distinct d i m e n s i o n s o f the pain e x p e r i e n c e or diff e r e n t response systems. Failure to discriminate between responses to painful a n d nonpainflfl stimuli is a c o m m o n weakness o f m o s t o f the behavioral measures currently available. Large interindividual variability' in n e o n a t a l responses to painful stimuli suggests that n e o n a t e s s h o u l d be used as their own controls to detect c h a n g e s in responses to p a i n f u l stimuli. P o r t e r 144 suggests t h a t the interindividual v a r i a b i l i t y in b e h a v i o r a l responses may indicate the early d e v e l o p m e n t o f individual c o p i n g styles. S o m e o f the variability, seen in n e o n a t a l responses to painful stimuli may be due to differences in baseline b e h a v i o r a l state d u r i n g the s t u d y p e r i o d s which may influence the d e g r e e o f responsiveness to the stimuli. T h e b e h a v i o r o f n e o n a t e s

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Measurement of Pain in Neonates

3 71

becomes more organized and under inhibit o r y c o n t r o l with i n c r e a s i n g age a n d h e a l t h . 545 The accurate interpretation of behavioral r e s p o n s e s to p a i n f u l stimuli r e m a i n s p r o b l e m atic. L a c k o f c o n t r o l s , l a c k o f d e f i n i t i o n o f r e s p o n s e p a r a m e t e r s , a n d lack o f s t a n d a r d i z a t i o n o f m e a s u r e m e n t m e t h o d s l i m i t t h e usefulness o f m o s t c u r r e n t l y a v a i l a b l e b e h a v i o r a l m e a s u r e s ] 46 F u r t h e r m o r e , m e t h o d s to reliably a c c o u n t f o r t h e a l t e r a t i o n s in b e h a v i o r a l r e s p o n s e s to p a i n f u l stimuli d u e to illness o r p r e m a t u r i t y have n o t b e e n d e v e l o p e d . W h i l e c h a n g e s in b e h a v i o r m a y r e f l e c t r e s p o n s e s to p a i n f u l stimuli, c a u t i o n m u s t b e u s e d in inferr i n g t h e a b s e n c e o f a r e s p o n s e to p a i n f u l stimuli from the absence of behavioral responses.

Few s t u d i e s m e a s u r e d b i o c h e m i c a l , physiological, a n d b e h a v i o r a l r e s p o n s e s to a p a i n f u l stimulus. 33'~'7'15° In o n e study, :~:~d e c r e a s e d cortisol levels, d e c r e a s e d l e n g t h o f h y p o x e m i a , and decreased duration of physiologic r e s p o n s e s were s e e n in n e o n a t e s w h o r e c e i v e d m e p e r i d i n e p r i o r to ET s u c t i o n i n g a n d nursi n g care p r o c e d u r e s , as c o m p a r e d to a c o n t r o l g r o u p . In a n o t h e r study, 57 lower [ 3 - e n d o r p h i n levels a n d d e c r e a s e d b e h a v i o r a l state levels were f o u n d in n e o n a t e s w h o r e c e i v e d t o p i c a l l i d o c a i n e p r i o r to c i r c u m c i s i o n , as c o m p a r e d to a c o n t r o l g r o u p , w h e r e a s p h y s i o l o g i c a l parameters were not significantly different b e t w e e n t h e two g r o u p s . U n f o r t u n a t e l y , neit h e r study e x a m i n e d t h e r e l a t i o n s h i p s b e t w e e n the different categories of measures.

Correlation of Biochemical, Physiological, and Behavioral Measures

Multidimensional Measures of Neonatal Responses to Painful Stimuli

T h e use o f m u l t i p l e q u a n t i t a t i v e m e a s u r e s w i t h i n t h e s a m e s t u d y is k n o w n as w i t h i n m e t h o d s triangulation.147 M e t h o d o l o g i c a l tria n g u l a t i o n is u s e d to i m p r o v e t h e i n t e r n a l c o n s i s t e n c y o r r e l i a b i l i t y o f t h e d a t a . 148'149 M a n y studies o f n e o n a t a l r e s p o n s e s to p a i n f u l stimuli r e v i e w e d a b o v e u t i l i z e d m u l t i p l e m e a sures within a single m e a s u r e m e n t class ( t h a t is, m u l t i p l e b e h a v i o r a l m e a s u r e s ) o r across two m e a s u r e m e n t classes ( t h a t is, c o n c u r r e n t m e a surement of physiological and behavioral responses or of biochemical and behavioral responses. F o r e x a m p l e , o n e study, 6z w h i c h m e a s u r e d both behavioral and physiological responses, d e m o n s t r a t e d s i g n i f i c a n t i n c r e a s e s in b o t h p e r c e n t o f t i m e c r y i n g a n d h e a r t r a t e in r e s p o n s e to heelstick. T h e s e were h i g h l y c o r r e lated. In a n o t h e r study, 89 a s i g n i f i c a n t c o r r e l a tion was d e m o n s t r a t e d b e t w e e n c r y a n d VTI. N e o n a t e s with lower VTI h a d h i g h e r p i t c h e d cries in r e s p o n s e to c i r c u m c i s i o n . Skin cond u c t a n c e c h a n g e s were also f o u n d to b e significantly correlated with behavioral state c h a n g e s in f u l l - t e r m n e o n a t e s . ~~'° T h e r e l a t i o n ship between behavioral and biochemical responses was explored in only three studies, t7-m I n c r e a s e d c r y i n g t i m e a n d h i g h e r b e h a v i o r a l state were c o r r e l a t e d with signific a n t i n c r e a s e s in cortisol levels. ~7-m

Recently, several studies have p r o v i d e d d a t a d e m o n s t r a t i n g p r e l i m i n a r y validity a n d reliability o f m u l t i d i m e n s i o n a l s c o r i n g t o o l s to measure neonatal responses to painful s t i m u l i . ~'~-~'~:~ T h e s e s c o r i n g t o o l s a s s i g n p o i n t s to i n d i c a t e t h e p r e s e n c e o f a n d t h e intensity of behavioral or physiological r e s p o n s e s to p a i n f u l s t i m u l i . A c o m p o s i t e score is b e l i e v e d to r e p r e s e n t a m o r e c o m p l e t e p i c t u r e o f t h e n e o n a t e s ' r e s p o n s e s to p a i n t h a n any single m e a s u r e . T h e first t o o l , t h e N e o n a t a l I n f a n t P a i n Scale (NIPS),152 m e a s u r e s six b e h a v i o r a l i t e m s r a t e d o n a two- o r t h r e e - p o i n t scale. T h e NIPS was u s e d in o n e study o f ill t e r m a n d p r e t e r m neonates undergoing capillary, venous, or a r t e r i a l p u n c t u r e s . ~Sz S c o r e s o n t h e N I P S i n c r e a s e d significantly d u r i n g t h e n e e d l e sticks a n d d e c r e a s e d significantly f o l l o w i n g t h e p r o c e d u r e s to n e a r b a s e l i n e levels. O l d e r n e o n a t e s h a d h i g h e r NIPS scores t h a n y o u n g e r n e o n a t e s . N o d i f f e r e n c e s were f o u n d in NIPS s c o r e s a m o n g t h e d i f f e r e n t types o f n e e d l e sticks. T h e i t e m s o n t h e NIPS d e m o n s t r a t e d h i g h i n t e r n a l c o n s i s t e n c y a n d i n t e r - r a t e r reliability scores r a n g e d f r o m 0.92 to 0.97. T h e NIPS scores w e r e h i g h l y c o r r e l a t e d with t h e nurses' assessments of the neonates' responses to n e e d l e s t i c k , w h i c h were r a t e d u s i n g a visual a n a l o g u e scale.

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Measurement of Pain i~ Neonates

A n o t h e r tool, t h e CRIES scale, 15j was develo p e d to m e a s u r e n e o n a t a l r e s p o n s e s to posto p e r a t i v e pain. In o n e study, 151 t h e CRIES scale was c o m p a r e d to t h e O b s e r v a t i o n a l P a i n Score ( O P S ) , w h i c h is a behax4oral score develo p e d to assess p o s t o p e r a t i v e p a i n in infants 1-7 m o n t h s o f age. 1~4'15~ In a g r o u p o f 24 n e o nates 32-40 weeks gestational age, hourly C R I E S a n d O P S s c o r e s w e r e f o u n d to b e h i g h l y c o r r e l a t e d a n d d e c r e a s e d significantly f o l l o w i n g a n a l g e s i c a d m i n i s t r a t i o n . T h e CRIES s c o r e s w e r e also in a g r e e m e n t with n u r s e s ' subjective assessments o f p a i n . T h e m a j o r i t y o f n u r s e s (73%) p r e f e r r e d u s i n g the CRIES s c o r e o v e r t h e OPS. However, n o e x p l a n a t i o n for t h e p r e f e r e n c e was p r o v i d e d in t h e r e p o r t . Most recently, a multidimensional pain a s s e s s m e n t tool was d e v e l o p e d specifically for use with p r e m a t u r e n e o n a t e s . T h e P r e m a t u r e I n i a n t Pain Profile (PIPP) 1"~':~was d e v e l o p e d using data from four studies of neonates u n d e r g o i n g h e e l s t i c k (a total o f 238 subjects) to identify" t h e i n d i c a t o r s f o r a n d e s t a b l i s h b e g i n n i n g validity o f t h e i n s t r u m e n t . T h e PIPP consists o f seven i n d i c a t o r s , i n c l u d i n g gestational age, b e h a v i o r a l m e a s u r e s ( t h a t is, t h r e e facial a c t i o n s a n d b e h a v i o r a l state), a n d physio l o g i c a l m e a s u r e s ( t h a t is, h e a r t rate, o x y g e n saturation). The presence or degree of change in t h e i n d i c a t o r is r a t e d o n a f o u r - p o i n t scale. U s i n g the PIPP, n e o n a t a l r e s p o n s e s to heelstick were distinguished from neonatal r e s p o n s e s to handling.~'~3 Further testing of the inultidimensional i n s t r u m e n t s is n e e d e d to d e t e r m i n e w h e t h e r this a p p r o a c h is m o r e sensitive a n d specific fbr m e a s u r i n g n e o n a t a l r e s p o n s e s to p a i n f u l stimuli t h a n the u n i v a r i a t e m e a s u r e s t h a t have b e e n d e s c r i b e d previously.

373

be evaluated in c o m b i n a t i o n with o t h e r measures to o b t a i n an accurate assessment o f a neon a t e ' s response to painflfl stimuli. W h i l e behavioral m e a s u r e s a r e t h e m o s t c o m m o n l y u s e d m e a s u r e s to evaluate n e o n a t a l responses to painful stinmli, these measures n e e d to be evaluated in light o f the n e o n a t e ' s clinical c o n d i t i o n . T h e absence of behaviors does not indicate the absence o f pain. Because of the degree of interindividual variability in all n e o n a t a l r e s p o n s e s a n d t h e n u m b e r o f u n c o n t r o l l e d stressors in t h e i n t e n sive c a r e setting, studies to e v a l u a t e t h e validity and reliability of measures of neonatal r e s p o n s e s to p a i n f u l s t i m u l i m u s t c o n s i d e r n e o n a t e s ' b a s e l i n e b e h a v i o r a l state. F u r t h e r m o r e , given t h e i n a d e q u a c i e s o f c u r r e n t m e a s u r e m e n t m e t h o d s in d i f f e r e n t i a t i n g b e t w e e n painful and nonpainful responses, triangulation o f m e t h o d s across all t h r e e m e a s u r e m e n t classes, o r m u l t i d i m e n s i o n a l m e a s n r e s , m a y provide more accurate and clinically useful i n f o r m a t i o n to d e t e r m i n e n e o n a t a l r e s p o n s e s to p a i n f n l stimuli.

Acknowledgment T h i s p a p e r was s u p p o r t e d in part by research grants from the American Association o f Critical C a r e Nurses, N e l l c o r M e n t o r s h i p Grant; the School of Nursing, Century Club Fund; and the Pediatric Clinical Research C e n t e r ( N I H g r a n t M O 1 - R R 0 1 2 7 7 1 ) , University o f C a l i f o r n i a , San F r a n c i s c o .

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Conclusions In s u m m a r y , n e o n a t a l r e s p o n s e s to p a i n f u l stimuli have b e e n evaluated using a variety o f measures within t h r e e classes o f responses (that is, biochemical, physiological, a n d behavioral). Plasma c a t e c h o l a m i n e assays may pro~qde the m o s t valid a n d r e l i a b l e m e a s u r e s o f the bioc h e m i c a l r e s p o n s e s o f n e o n a t e s to p a i n f u l stimuli. However, c a t e c h o l a m i n e assays are difficult to o b t a i n in the clinical setting. Physiological responses are potentially the most clinically relevant measures. However, they may n e e d to

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