Electroencephalographic Activity in Response to Procedural Pain in Preterm Infants Born at 28 and 33 Weeks Gestational Age

OBJECTIVES:: Preterm infants undergo frequent painful procedures in the neonatal intensive care unit. Electroencephalography (EEG) changes in reaction to invasive procedures have been reported in preterm and full-term neonates. Frontal EEG asymmetry as an index of emotion during tactile stimulation shows inconsistent findings in full-term infants, and has not been examined in the context of pain in preterm infants. Our aim was to examine whether heel lance for blood collection induces changes in right-left frontal asymmetry, suggesting negative emotional response, in preterm neonates at different gestational age (GA) at birth and different duration of stay in the neonatal intensive care unit. MATERIALS AND METHODS:: Three groups of preterm infants were compared: set 1: group 1 (n=24), born and tested at 28 weeks GA; group 2 (n=22), born at 28 weeks GA and tested at 33 weeks; set 2: group 3 (n=25), born and tested at 33 weeks GA. EEG power was calculated for 30-second artifact-free periods, in standard frequency bandwidths, in 3 phases (baseline, up to 5 min after heel lance, 10 min after heel lance). RESULTS:: No significant differences were found in right-left frontal asymmetry, or in ipsilateral or contralateral somatosensory response, across phases. In contrast, the Behavioral Indicators of Infant Pain scores changed across phase (P

Focused attention, heart rate deceleration, and cognitive development in preterm and full-term infants

The majority of children who are born very preterm escape major impairment, yet more subtle cognitive and attention problems are very common in this population. Previous research has linked infant focused attention during exploratory play to later cognition in children born full-term and preterm. Infant focused attention can be indexed by sustained decreases in heart rate (HR). However there are no preterm studies that have jointly examined infant behavioral attention and concurrent HR response during exploratory play in relation to developing cognition. We recruited preterm infants free from neonatal conditions associated with major adverse outcomes, and further excluded infants with developmental delay (Bayley Mental Development Index [MDI?

Physiological correlates of memory recall in infancy:vagal tone, cortisol, and imitation in preterm and full-term infants at 6 months

We examined the role of physiological regulation (heart rate, vagal tone, and salivary cortisol) in short-term memory in preterm and full-term 6-month-old infants. Using a deferred imitation task to evaluate social learning and memory recall, an experimenter modeled three novel behaviors (removing, shaking, and replacing a glove) on a puppet. Infants were tested immediately after being shown the behaviors as well as following a 10-min delay. We found that greater suppression of vagal tone was related to better memory recall in full-term infants tested immediately after the demonstration as well as in preterm infants tested later after a 10-min delay. We also found that preterm infants showed greater coordination of physiology (i.e., tighter coupling of vagal tone, heart rate, and cortisol) at rest and during retrieval than full-term infants. These findings provide new evidence of the important links between changes in autonomic activity and memory recall in infancy. They also raise the intriguing possibility that social learning, imitation behavior, and the formation of new memories are modulated by autonomic activity that is coordinated differently in preterm and full-term infants.

Contingency Learning and Reactivity in Preterm and Full-Term Infants at 3 Months

Learning difficulties in preterm infants are thought to reflect impairment in arousal regulation. We examined relationships among gestational age, learning speed, and behavioral and physiological reactivity in 55 preterm and 49 full-term infants during baseline, contingency, and nonreinforcement phases of a conjugate mobile paradigm at 3 months corrected age. For all infants, negative affect, looking duration, and heart rate levels increased during contingency and nonreinforcement phases, whereas respiratory sinus arrhythmia (RSA, an index of parasympathetic activity) decreased and cortisol did not change. Learners showed greater RSA suppression and less negative affect than nonlearners. This pattern was particularly evident in the preterm group. Overall, preterm infants showed less learning, spent less time looking at the mobile, and had lower cortisol levels than full-term infants. Preterm infants also showed greater heart rate responses to contingency and dampened heart rate responses to nonreinforcement compared to full-term infants. Findings underscore differences in basal and reactivity measures in preterm compared to full-term infants and suggest that the capacity to regulate parasympathetic activity during a challenge enhances learning in preterm infants.

Maternal stress and behavior modulate relationships between neonatal stress, attention, and basal cortisol at 8 months in preterm infants

There is evidence that the developmental trajectory of cortisol secretion in preterm infants is altered, with elevated basal cortisol levels observed postnatally through at least 18 months corrected age (CA). This alteration is possibly due to neonatal pain-related stress. High cortisol levels might contribute to greater risk of impaired neurodevelopment. Since maternal factors are important for the regulation of infant stress responses, we investigated relationships between infant (neonatal pain-related stress, attention, cortisol) and maternal (stress, interactive behaviors) factors at age 8 months CA. We found that interactive maternal behaviors buffered the relationship between high neonatal pain-related stress exposure and poorer focused attention in mothers who self-reported low concurrent stress. Furthermore, in preterm infants exposed to high concurrent maternal stress and overwhelming interactive maternal behaviors, higher basal cortisol levels were associated with poor focused attention. Overall, these findings suggest that maternal factors can influence the cognitive resilience at 8 months of preterm infants exposed to early life stress.

Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding

To compare the disposition of fluoxetine and norfluoxetine enantiomers in the mother, foetus and infant.

Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU

Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty-seven preterm infants were studied at 32 (+/-1 week) postconceptional age (PCA). Infants who received analgesia or sedation in the 72 h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born

Specific Newborn Individualized Developmental Care and Assessment Program movements are associated with acute pain in preterm infants in the neonatal intensive care unit

The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) is widely used in neonatal intensive care units and comprises 85 discrete infant behaviors, some of which may communicate infant distress. The objective of this study was to identify developmentally relevant movements indicative of pain in preterm infants.

Are there developmentally distinct motor indicators of pain in preterm infants?

The aims of this study were to examine preterm infant reactions to pain in detail over prolonged time periods using multiple measures, and to assess the value of including specific body movements of the Neonatal Individualized Developmental Care and Assessment Program (NIDCAP) system to evaluate pain. Ten preterm infants born at 31 weeks mean gestational age (GA) and mean birth weight 1676 g were studied during a routine blood collection in a Level III neonatal intensive care unit (NICU). At 32-week post-conceptional age, computerized physiologic and video recordings were obtained continuously for 60 min (prior to, during and after lance). Motor and facial behaviors were coded independently, using the NIDCAP and the NFCS (Neonatal Facial Coding System), respectively, and compared with heart rate (HR) and oxygen saturation responses. Of the movements hypothesized to be stress cues in the NIDCAP model, extension of arms and legs (80%) and finger splay (70%) were the most common following lance. Contrary to the model, most infants (70%) had lower incidence of twitches and startles post-lance compared to baseline. Whereas all infants showed some NFCS response to lance, for three infants, the magnitude was low. HR increased and oxygen saturation decreased post-lance. Infants with more prior pain exposure, lower Apgar, and lower GA at birth, displayed more motor stress cues but less facial activity post-lance. Extension of extremities and finger splay, but not twitches and startles, from the NIDCAP, appear to be stress cues and show promise as clinical pain indicators to supplement facial and physiological pain measures in preterm infants.

Early pain in preterm infants. A model of long-term effects

There are multiple lines of evidence suggesting that in vulnerable prematurely born infants, repeated and prolonged pain exposure may affect the subsequent development of pain systems, as well as potentially contribute to alterations in long-term development and behavior. Multiple factors cumulatively contribute to altered developmental trajectories in such infants. These include characteristics of the developing organism (low tactile threshold, sensitization, rapid brain development), characteristics intrinsic to the infant (gestation, illness severity), characteristics of the experience in the neonatal intensive care unit (pain exposure and cumulative stress), and characteristics of the caregivers within their family and social context. This article provides a model for examining long-term effects of pain in the newborn period embedded in a developmental context framework.

Behavior, pain perception, and the extremely low-birth weight survivor

This article explores the literature concerning responses to pain of both premature and term-born newborn infants, the evidence for short-term and long-term effects of pain, and behavioral sequelae in individuals who have experienced repeated early pain in neonatal life as they mature. There is no doubt that pain causes stress in babies and this in turn may adversely affect long-term neurodevelopmental outcome. Although there are methods for assessing dimensions of acute reactivity to pain in an experimental setting, there are no very good measures available at the present time that can be used clinically. In the clinical setting repeated or chronic pain is more likely the norm rather than infrequent discrete noxious stimuli of the sort that can be readily studied. The wind-up phenomenon suggests that, exposed to a cascade of procedures as happens with clustering of care in the clinical setting in an attempt to provide periods of rest for stressed babies, an infant may in fact perceive procedures that are not normally viewed as noxious, as pain. Pain exposure during lifesaving intensive medical care of ELBW neonates may also affect subsequent reactivity to pain in the neonatal period, but behavioral differences are probably not likely to be clinically significant in the long term. Prolonged and repeated untreated pain in the newborn period, however, may produce a relatively permanent shift in basal autonomic arousal related to prior NICU pain experience, which may have long-term sequelae. In the long run, the most significant clinical effects of early pain exposure may be on neurodevelopment, contributing to later attention, learning, and behavior problems in these vulnerable children. Although there is considerable evidence to support a variety of adverse effects of early pain, there is less information about the long-term effects of opiates and benzodiazepines on the developing central nervous system. Current evidence reviewed suggests that judicious use of morphine for adjustment to mechanical ventilation may ameliorate the altered autonomic response. It may be very important, however, to distinguish stress from pain. Animal evidence suggests that the neonatal brain is affected differently when exposed to morphine administered in the absence of pain than in the presence of pain. Pain control may be important for many reasons but overuse of morphine or benzodiazepines may have undesirable long-term effects. This is a rapidly evolving area of knowledge of clear relevance to clinical management likely to affect long-term outcomes of high-risk children.

Long-term effects of pain in infants

Pain and stress have been shown to induce significant physiological and behavioral reactions in newborn infants, even in those born prematurely. Infants who are born prematurely or seriously ill are commonly exposed to multiple painful and stressful events as part of their prolonged hospitalizations and required medical procedures. There is now evidence that these early events not only induce acute changes, but that permanent structural and functional changes may also result. This article reviews the growing body of evidence of likely long-term effects of early pain and stress on the human infant. It is hoped that a better understanding of this literature will promote more responsive and sensitive management of infants and young children during their encounters with the medical community and will ultimately facilitate the healthy growth and development of all children.

Bedside application of the Neonatal Facial Coding System in pain assessment of premature neonates

Assessment of infant pain is a pressing concern, especially within the context of neonatal intensive care where infants may be exposed to prolonged and repeated pain during lengthy hospitalization. In the present study the feasibility of carrying out the complete Neonatal Facial Coding System (NFCS) in real time at bedside, specifically reliability, construct and concurrent validity, was evaluated in a tertiary level Neonatal Intensive Care Unit (NICU). Heel lance was used as a model of procedural pain, and observed with n = 40 infants at 32 weeks gestational age. Infant sleep/wake state, NFCS facial activity and specific hand movements were coded during baseline, unwrap, swab, heel lance, squeezing and recovery events. Heart rate was recorded continuously and digitally sampled using a custom designed computer system. Repeated measures analysis of variance (ANOVA) showed statistically significant differences across events for facial activity (P <0.0001) and heart rate (P <0.0001). Planned comparisons showed facial activity unchanged during baseline, swab and unwrap, then increased significantly during heel lance (P <0.0001), increased further during squeezing (P <0.003), then decreased during recovery (P <0.0001). Systematic shifts in sleep/wake state were apparent. Rise in facial activity was consistent with increased heart rate, except that facial activity more closely paralleled initiation of the invasive event. Thus facial display was more specific to tissue damage compared with heart rate. Inter-observer reliability was high. Construct validity of the NFCS at bedside was demonstrated as invasive procedures were distinguished from tactile. While bedside coding of behavior does not permit raters to be blind to events, mechanical recording of heart rate allowed for an independent source of concurrent validation for bedside application of the NFCS scale.

Judging pain in infants:behavioural, contextual, and developmental determinants

Caretakers intuitively use various sources of evidence when judging infant pain, but the relative importance of salient cues has received little attention. This investigation examined the predictive significance for judgements of painful discomfort in preterm and full-term neonates of behavioural (facial activity and body movement), contextual (invasiveness of the procedure), and developmental (gestational age) information. Judges viewed videotapes showing infants varying in the foregoing characteristics undergoing heel incisions for routine blood sampling purposes. Findings indicated all but the contextual information contributed uniquely to judgements of pain, with facial activity accounting for the most unique variance (35%), followed by bodily activity and gestational age, each accounting for 3% and 1% of the judgmental variance, respectively. Generally, 71% of the variance in ratings of pain could be predicted using facial activity alone, compared to 30% of the variance using bodily activity alone, 19% by relying on context alone, and 8% by referring to gestational age alone. Noteworthy was the tendency to judge early preterm infants to be experiencing less pain even though they were subjected to the same invasive procedure as the older infants. This finding also runs counter to evidence from developmental neurobiology which indicates that preterm newborns may be hypersensitive to invasive procedures.

Issues of assessment of pain and discomfort in neonates

Pain assessment in neonates often presents problems. The problem of inadequate or inaccurate assessment is complicated by issues related to the nature, consistency, and variability of the infant's physiologic and behavioral responses; the reliability, validity, specificity, sensitivity, and practicality of existing neonatal pain measures or measurement approaches; ethical questions about pain research in infants; and uncertainty about the responsibilities of health care professionals in managing pain in clinical settings. Despite these many issues, neonates need to be comfortable and as free of pain as possible to grow and develop normally. Valid and reliable assessment of pain is the major prerequisite for attaining this goal. Issues embodied in neonatal pain responses, measurement, ethical, and clinical considerations are explored. Suggestions for resolving some of these problems are presented.