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COMMENTARY |
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
Accurate pain assessment is a key and central issue that confronts clinicians at the bedside of preterm neonates or researchers who study nonverbal subjects.1 Although many validated methods for pain assessment are available,2 none of them are widely accepted or clearly superior to others. Consequently, no "gold standard" can be recommended for broad adoption in clinical practice because of 2 problems that are common to all assessment methods.
First, these methods were developed from studies of neonates who underwent acute painful procedures (heel stick, venipuncture, circumcision). Physiologic or behavioral parameters chosen for inclusion in these methods were those that changed most acutely in response to tissue injury and subsided after painful stimulation was over. These responses were thought to be "specific" for neonatal pain. Subsequent research, however, noted that many infants do not produce "specific" responses when exposed to invasive, skin-breaking procedures.3 Preterm newborns who were more immature, asleep, or exposed to previous painful procedures were less likely to demonstrate specific responses to pain,3 whereas previous physical handling accentuated their responses to acute pain.4
Second, these behavioral and physiologic responses require the subjective evaluation of a clinical observer.5 Significant interobserver variability occurs6,7 and can be reduced but not eliminated by training or greater experience. The need for training creates a significant obstacle for the routine use of these methods. Because physicians or nurses who rotate temporarily through the unit are not trained, most neonates are not assessed for pain, which greatly reduces their likelihood of receiving analgesia.8,9
Most pain measures incorporate specific facial movements associated with pain expression in neonates; comparative studies have noted greater accuracy for these versus other pain parameters.10 Brahnam et al11 have developed a neural network–based learning algorithm trained on a database of 204 photographs, of which 60 were obtained from infants in pain. This system, called the Classification of Pain Expressions (COPE), uses facial-recognition techniques to extract and examine features of an infant's facial expression and was noted to have >90% accuracy. These authors are now working on a follow-up study involving 500 infants and using video images. Moving images should allow these researchers to investigate the dynamic characteristics of pain expressions, affording much greater accuracy and clinical utility.
Despite recent progress in assessing and treating acute pain in infancy, attempts to measure persistent or prolonged pain have been largely unsuccessful. Such infants remain untreated and may experience prolonged suffering, because many of the signs of acute pain are absent. The only tools that measure prolonged pain in infants include the N-PASS (Neonatal Pain, Agitation and Sedation Scale)12 and EDIN (Échelle Douleur Inconfort Nouveau-Né [Neonatal Pain and Discomfort Scale])13 (both of which have unproven construct validity for pain) and the DEGR (Douleur Enfant Gustave Roussy)14 (which has not been tested in preterm neonates). Other than the vital signs, physiologic parameters that represent autonomic activation were not included in pain-assessment methods, perhaps because they lack specificity for pain or because they require specialized equipment at the bedside: heart rate variability15 or sympathetic tone from spectral analyses of heart rate variability,16 changes in palmar sweating17 or skin conductivity,18 and changes in skin blood flow.19 Other methods such as pupillometry20 have not been developed for neonates, whereas measuring salivary cortisol21 or other stress hormone responses22 are not practical for clinical use.
In addition, measures of sensory function were developed by using the tactile stimulation produced by Von Frey filaments,23–25 but these may only reflect hypersensitivity of the pain pathways and, at best, are indirect measures of pain during movement, dressing change, or physical examination. Reflex withdrawal after Von Frey stimulation does not lead to cortical activation either.26
The mismatch between measured parameters for acute versus prolonged pain may be explained by 2 sequential phases in the neonate's behavioral/physiologic responses to pain.27 These 2 phases are remarkably distinct, showing a psychophysiological "activation" or "shutdown," but occur in succession, consistent with the sequential phases of "protest" and "despair" that have been described in studies of maternal separation.28,29 Because of their limited energy reserves, preterm infants cannot maintain the psychophysiological activation triggered by skin-breaking procedures if the pain becomes persistent.27 Consequently, methods of assessment developed from models of acute pain may not apply to patients with prolonged pain.
These difficulties may well be overcome in the near future. From evaluating ventilated preterm neonates who were randomly assigned to receive masked morphine or placebo infusions, Boyle et al30 found that facial expressions of pain, high activity levels, poor responses to handling, and lack of ventilator synchrony specifically identified neonates in the placebo group. These indicators, in addition to those listed above, may provide the initial parameters for specifically measuring persistent pain in neonates. Indicators for morphine analgesia, however, were not identified because clinicians found it easier to identify neonatal discomfort rather than analgesia.30
Although neuroimaging techniques may partially define the supraspinal processing of pain, their subjective importance still has to be inferred.31 Bartocci et al32 used near-infrared spectroscopy to study cortical pain processing in 40 preterm neonates (born at 28–36 weeks of gestation) at 25 to 42 hours of age. Cortical activation was recorded over both somatosensory areas in 29 newborns and over the contralateral somatosensory and occipital areas in 11 newborns. Blood flow to somatosensory areas increased after standardized tactile (skin disinfection) and painful (venipuncture) stimuli but not to the occipital cortex, which implied a functional specificity for this response. Pain-related blood flow increases were more pronounced in male neonates, correlated with increasing postnatal ages and decreasing gestational ages, and appeared more prominent in the left (dominant?) somatosensory cortex.
Slater et al26 also recorded cortical activation after heel sticks in 18 infants between 25 and 45 weeks' gestation. Some neonates were studied repeatedly (1–5 times) between postnatal ages ranging from 5 to 134 days. Robust activation occurred over the contralateral somatosensory cortex, greater in awake than in asleep infants. No cortical response occurred after tactile stimulation of the heel even when accompanied by reflex limb withdrawal.26 Because neonatal responses to acute pain change with increasing exposure to invasive procedures after birth,33–35 these findings may reflect the effects of age-dependent cortical maturation or the cumulative experience of previous invasive procedures.
Taken together, these studies demonstrate robust cortical activation after acute pain in neonates, altered by gender, laterality, gestational age, postnatal age, behavioral state, previous pain experiences, and differences between reflex withdrawal and "pain."26,32 The magnitude of this cortical response was reduced in 2 neonates who received morphine,26 which is the opposite of what may have been expected from their pain-assessment scores.36
But, how can measured neurophysiological events represent a subjective experience? This is the hard problem,31,37 almost insurmountable in fetuses or preterm neonates.38 Yet, these data are important for 3 reasons. First, these nuanced activation responses at the highest level of sensory processing imply that preterm neonates may "consciously" perceive the acute pain of skin-breaking procedures. Second, similar neuroimaging methods or electroencephalography may provide ways of validating the currently available or novel pain-assessment methods that can be easily, reliably, routinely applied at the bedside. Third, newer methods designed to assess prolonged pain must adopt a different paradigm from those developed for invasive procedures. Until then, clinicians will need to estimate the pain that infants experience during neonatal intensive care and attempt to reduce it without altering their respiratory/hemodynamic stability or future brain development.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to K.J.S. Anand, MBBS, DPhil, Arkansas Children's Hospital, 800 Marshall St, Little Rock, AR 72202. E-mail: anandsunny{at}uams.edu
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
The author has indicated he has no financial relationships relevant to this article to disclose.
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