PEDIATRICS Vol. 110 No. 3 September 2002, pp. 570-576
Does Parenchymal Brain Injury Affect Biobehavioral Pain Responses in Very Low Birth Weight Infants at 32 Weeks’ Postconceptional Age?
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* Biobehavioral Research Unit, Centre for Community Child Health Research, B.C. Research Institute for Children’s and Women’s Health, Vancouver, British Columbia, Canada
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia, Canada
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective. Children with neurologic impairments have shown diminished pain response compared with control subjects; however, it remains unclear what mechanisms underlie this response or when it develops. If this were also true with premature infants who undergo neonatal intensive care, then infants with parenchymal brain injury (PBI) would be at increased risk of underrecognition and undertreatment of procedural pain. The purpose of this study was to determine whether infants with PBI display altered responses to acute procedural pain at 32 weeks’ postconceptional age (PCA), compared with control subjects.
Methods. We compared responses to blood collection by heel lance at 32 weeks’ PCA in 12 very low birth weight infants (mean [range] birth weight: 876 g [630–1240 g]; gestational age: 26.3 weeks (24–28 weeks) who had sustained PBI in the neonatal period, with 12 control subjects matched for gestational age at birth and gender (838 g [625–990 g]; 26.3 weeks [24–28 weeks[) who had normal neonatal brain imaging. PBI was defined as cerebral parenchymal infarction (grade 4 intraventricular hemorrhage) or cystic periventricular leukomalacia on serial cranial ultrasound scans conducted in the neonatal period. Biobehavioral responses to pain were measured using facial activity (Neonatal Facial Coding System) and measures of heart rate (HR) variability (low-frequency [LF] power [0.04–0.15], high-frequency [HF] power [0.15–0.8 Hz], and LF/HF ratio) as a measure of cardiac autonomic modulation. Neurodevelopmental follow-up was undertaken at 18 months.
Results. The infants with PBI had significantly higher illness severity scores at day 1 compared with day 3 (Score of Neonatal Acute Physiology II: 32.1 vs 19.8) but similar previous pain experiences (109 vs 115) and total morphine exposure (0.29 vs 0.30 mg/kg). Both groups of children mounted similar responses to heel lance at 32 weeks’ PCA with no difference in facial response or HR variability. Mean HR and facial action scores increased from baseline to the lance, whereas LF, HF, and the LF/HF ratio decreased significantly. No group differences were found. The only statistically significant difference between groups was that infants with PBI had more tongue protrusion at lance. Neurodevelopmental follow-up showed 8 of 11 toddlers with PBI had cerebral palsy compared with 0% of control toddlers. Psychomotor Developmental Index score on the Bayley Scales of Infant Development II was significantly lower in the PBI group. Five of 11 toddlers with PBI had Mental Developmental Index score <2 standard deviations below mean compared with 0% of the control toddlers.
Conclusion. Contrary to expectations, we did not find any evidence of an altered pain response pattern in infants with proven brain injury in the neonatal period. Although most infants with PBI developed cerebral palsy, these findings suggest that cerebral injury predominantly to the central white matter leaves brainstem responses intact in the neonatal period. Furthermore, it seems that the injured brain of the preterm infant has not yet expressed the identifiable differences in pain display and the functional impairment observed at later ages.
Key Words: preterm infants • pain reactivity • parenchymal brain injury
Abbreviations: SNI, significant neurologic impairment • IVH, intraventricular hemorrhage • PVL, periventricular leukomalacia • NICU, neonatal intensive care unit • PCA, postconceptional age • PBI, parenchymal brain injury • SNAP, Score of Neonatal Acute Physiology • NFCS, Neonatal Facial Coding System • HR, heart rate • HRV, heart rate variability • ECG, electrocardiogram • LF, low-frequency • HF, high-frequency • ANOVA, analysis of variance
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Recent research suggests that the pain experience in individuals with a significant neurologic impairment (SNI) is blunted or altered.1–3 Pain expression in populations with SNI has been an area of limited investigation. Studies of pain reactivity in preterm infants typically have excluded infants with neurologic lesions, thereby leaving no knowledge of the pain experience in populations of preterm infants with abnormal neurologic function. Emerging evidence suggests that acute pain responses are blunted or diminished among children with developmental delay,4 adolescents with cerebral palsy,1 and the frail elderly with dementia.2 Although the expression of distress in this setting may be ambiguous and nonspecific, there is no evidence to indicate that individuals with communication or cognitive limitations experience less suffering and misery from pain than those who are considered to be neurodevelopmentally intact. Although it remains unclear how such altered pain reactivity is related to an altered underlying neurologic substrate, these findings have raised concerns that severe impairments are associated with an increased likelihood of pain insensitivity (ie, a decreased sensory pain experience) or pain indifference (ie, a decreased emotional response to pain).5 These beliefs may in turn place individuals with brain injury at increased risk for inadequate pain management and substandard health care.
Children who are born at the extremes of prematurity are at particular risk for a combination of significant neurologic injury (eg, intraventricular hemorrhage [IVH], periventricular leukomalacia [PVL]), increased early pain experience, and analgesic exposure at a time of rapid development of the immature brain. Approximately 50 000 infants are born annually in United States with a birth weight of <1500 g, and 85% survive; however, 5% to 15% develop cerebral palsy, and a much larger number have less visible motor, cognitive, behavior, and learning difficulties.6 Advanced care in the neonatal intensive care unit (NICU) has increased survival, but it has also increased exposure to pain and stress and to the medications used to manage pain, principally opiate analgesics and benzodiazepines, at a crucial time of neurologic development.7 Furthermore, recent work has shown that early repeated pain exposure in preterm infants may be associated with altered pain responses in the neonatal period,7,8 later in infancy,9,10 and in childhood.11 Infants who are born extremely prematurely are at substantial risk for increased exposure to pain and, coupled with possible underrecognition of distress, are at risk for undertreatment of pain.12 This situation, combined with the paucity of a detailed understanding of pain reactivity in this setting, highlights the urgency to learn more about the pain experience in this vulnerable infant population. There have been no descriptions of pain reactivity among preterm infants with neurologic impairment.
The present study was undertaken to examine biobehavioral pain reactivity in preterm infants with significant parenchymal lesions. In particular, we wondered whether these lesions that subsequently evolve into motor and sensory impairments (ie, associated with cerebral palsy) later in infancy and childhood were the antecedents of altered pain behaviors that appear in children and adolescents with an SNI. In this study, we examined biobehavioral pain response among infants who were born prematurely (<27 weeks) and had grown to 32 weeks’ postconceptual age (PCA) with an identified significant parenchymal lesion on ultrasound. We hypothesized that pain response would be blunted or altered among preterm infants with significant parenchymal brain injury (PBI; viz cerebral parenchymal infarction [grade 4 IVH] or PVL) when compared with a group of preterm infants with grade 2 or less IVH, matched for gestational age at birth and gender.
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METHODS |
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Subjects
Written informed consent was obtained from the mother or legal guardian of each infant according to a protocol approved by the Clinical Research Ethics Committee of the University of British Columbia. Twelve infants in the present study were part of a continuous series (n = 166) of infants with birth weight
1500 g who were undergoing tertiary level 3 neonatal intensive care in British Columbia’s Children’s Hospital and were recruited to a study of pain response in preterm infants. These 12 infants had PBI identified on routine serial cranial ultrasound scans in the neonatal period and for this reason had been excluded from a larger study of evolution of pain responses because of their high risk of later neurodevelopmental impairment.7 Ten of the infants had cystic PVL, and 2 had cerebral parenchymal infarction (grade 4 IVH). A control group (n = 12) without PBI and with no IVH greater than grade 2 was selected blindly from the larger cohort and matched for gestational age at birth and gender. All infants were studied at 32 weeks’ to 32 weeks 6 days’ PCA. Infants with congenital anomalies were excluded from both study and control groups. Severity of illness was measured on day 1 and day 3 after birth using the Score of Neonatal Acute Physiology II (SNAP II).13,14 Subject characteristics are provided in Table 1.
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Procedures
Infants were recruited in the NICU by a research nurse. Behavioral observations of the Neonatal Facial Coding System (NFCS),15 infant sleep/waking state,16 and finger splay16 were conducted by a trained coder at bedside in real time during routine blood collection following the methods described previously.17 Training of the coder was initially conducted using videotapes played in real time, followed by practice coding in the NICU to achieve interobserver agreement as previously reported.17 Blood collection was performed by a laboratory technician. The behavioral coders were blind to the purpose of the study and medical information about the infants.
The infant’s NICU nurse applied the foot warmer, then the research nurse removed the electrodes from the bedside cardiac monitor cable and switched them to the cable that fed into the study computer for heart rate (HR) data acquisition. HR was recorded continuously during a 200-second baseline, during the blood collection, and for a recovery period of 200 seconds after last contact. Infant sleep/wake state, NFCS, and hand movements were rated during 6 events: baseline, first contact by the laboratory technician to remove the heel warmer, swabbing to cleanse the heel, lance, squeeze, and recovery period of 200 seconds after last contact. Autonomic recordings were conducted simultaneously throughout the study. Analysis of HR variability (HRV) requires relatively prolonged periods of stability, without movement artifacts; therefore, time segments of 2.2 minutes per event were used.
Measures
Infant Sleep/Wake State
Infant state was coded as defined by Als16. Sleep/wake state was coded from 1 to 7 as follows: 1, deep sleep; 2, light sleep; 3, drowsy; 4, quiet awake; 5, active awake; 6, highly aroused, agitated, upset, and/or crying; 7, prolonged respiratory pause >8 seconds. Preterm infants at times seem to go into a transitory state of "collapse" or "withdrawal," characterized by muscular flaccidity and prolonged pause in breathing, which is captured in state 7.
Facial Activity
The 10 facial actions of the NFCS15,18 were coded: brow lowering, eyes squeezed shut, deepening of the nasolabial furrow, open lips, vertical mouth stretch, horizontal mouth stretch, taut tongue (cupping of the tongue), chin quiver (high-frequency vibration of the chin), lip purse (tightening the muscles around the lips to form "oo"), and tongue protrusion (tongue pushed forward). Each face action was coded as 1/0 (occurred/did not occur) during each event.
Hand Movements
Finger splay was coded as it seems to be a stress indicator in preterm infants.16,17,19 Finger splay was defined as backward extension of the fingers.
HR
Continuous electrocardiogram (ECG) was recorded from a single lead of surface ECG (lead II) and digitally sampled at 360 Hz off-line using a specially adapted computer acquisition system and custom physiologic signal processing software.20 R waves were detected from the sampled ECG and used to form a smoothed instantaneous 4-Hz HR time series as described elsewhere.21 Segments of HR (2.2 minutes each) were selected from 1) the resting baseline period within 5 minutes before the lance, 2) a lance period starting within 20 seconds after the finger prick blood collection, and 3) a recovery period within 5 minutes after the lance. The epoch duration of 2.2 minutes was based on the need for stable behavioral state and the absence of gross movement artifact as previously reported.9,22 The epoch selection criteria were based on quantitative signal stationary state, the presence of a stable behavioral state, and the absence of gross movement artifact. Power spectral estimates of HR were quantified using the area (power) of the spectrum in a low-frequency (LF) region (0.04–0.15 Hz) and a high-frequency (HF) region (0.15–0.80 Hz), as well as by the ratio of LF and HF power (LF/HF), as previously described.9,22 These parameters were chose because previous work has shown that, in both humans and animal models, power at frequencies above 0.15 Hz is attributable solely to modulation of cardiac vagal (parasympathetic) activity, primarily by respiratory activity, whereas power at lower frequencies (0.4–0.15 Hz) can be attributable to modulation of both cardiac vagal and sympathetic activity by a variety of stimuli, including LF respiration and arterial baroreflexes.21,23
Neurodevelopmental Assessments
Development was assessed at 18 months’ corrected age and included a conventional neurologic examination and the Bayley Scales of Infant Development24 to generate the Psychomotor Developmental Index and the Mental Developmental Index.
Data Analysis
Behavioral Data
Univariate repeated measures analysis of variance (ANOVA) was conducted separately on facial activity and autonomic reactivity scores across the 6 events and 2 groups (PBI and control). Occurrence of sleep/wake state, finger splay, and individual face actions was compared between the groups using 
2.
Physiologic Data
The mean and standard error of the mean of the HR and power spectra for each data segment were calculated. A repeated measure ANOVA was used to compare outcome measures across study periods and groups. Post hoc comparisons were done, when appropriate, with repeated measures. A difference was considered statistically significant for P < .05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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A group of 12 infants with parenchymal lesions identified by ultrasound were studied at 32 weeks’ PCA and compared with a control group matched for gestational age at birth and gender. All infants underwent a routine heel lance blood collection without complications. Infant state at baseline was examined, and the majority of infants were in state 216 at the outset of the baseline period. Infant characteristics are summarized in Table 1.
Behavioral Data
Sleep/Wake State
Infant state was unchanged from baseline to first contact by the laboratory technician (2 [df 9] = 10.11; P = .34) but then shifted significantly with heel cleansing (2 [df 9] = 46.57; P = .0001), shifted further with heel lance (2 [df 6] = 18.46; P = .005), and shifted further again during squeezing of the heel (2 [df 6] = 16.40; P = .01). Arousal decreased significantly during recovery (2 [df 12] = 27.62; P = .006). There were no statistically significant differences in the pattern of changes in sleep/wake state between the 2 groups. During baseline, 1 of 12 infants (8%) in each group was assessed to be in deep sleep, 9 and 10 were in light sleep, PBI and non-PBI group, respectively, and 1 was drowsy in the control group. In both groups, 7 (58%) of 12 infants were highly aroused or crying during heel lance, and 8 (66%) and 9 (75%), PBI and non-PBI group, respectively, were highly aroused or crying during heel squeezing.
Facial Activity
The individual facial actions to pain were summed to provide a total NFCS pain score for each event with a possible value from 0 to 9; mean facial action scores are presented for each study period in Fig 1. Because of nonoccurrence of lip purse, this facial action was dropped from further consideration. Mean facial activity remained stable in the periods before lance and increased among both groups to lance and squeeze events. Repeated measures ANOVA for facial activity showed a statistically significant main effect across events (F = 16.6; df 1,50; P < .01); however, no significant overall group differences or interactions were found (P > .05). Infants with PBI had significantly higher tongue protrusion at lance (2 df [1] = 4.8; P = .03).
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Finger Splay
Occurrence of finger splay across events is presented in Fig 2. The proportion of infants who displayed finger splay increased in both groups during heel squeezing; however, this change did not reach statistical significance (
2 [1] = 2.40; P = .17). There were no differences between the 2 groups.
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Physiologic Data
Mean HR
Mean HR increased significantly from baseline to lance and decreased in the recovery period (F [1,2] = 57.0; P <.01; Fig 3). No differences between groups were observed.
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Power Spectral Estimates
Power spectral estimates are displayed in Fig 4. In both groups, HF was low at baseline and decreased with the lance event and increased again with recovery, reflecting a decrease in cardiac parasympathetic modulation with the lance and increase with recovery. Overall HF changes were significant (F [2,1] = 3.4; P = .5); however, no group differences were seen. LF decreased significantly from baseline (F [1,2] = 6.157; P < .01) in both groups and increased in recovery. The LF/HF ratio also declined with the lance and increased in recovery (F [1,2] = 5.45; P = .01). The differences in the ratio reflect a greater decrease in LF than in HF power. No group differences were present, suggesting that overall cardiac autonomic responses to the lance were similar among all infants (Table 2).
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Neurodevelopmental Follow-up
Neurodevelopmental follow-up was available at a mean adjusted age of 17.4 months in 11 of the 12 infants with PBI and in 9 of the 12 control infants. Eight of the 11 toddlers with PBI had clear signs of cerebral palsy on neurologic examination compared with 0 of the 9 control toddlers (P = .0014; Fisher exact test), and Psychomotor Developmental Index on the Bayley Scales of Infant Development II was significantly lower in the PBI group (64 ± 18 vs 91 ± 10; P = .0008). Five of the 11 toddlers with PBI had Bayley Mental Developmental Index >2 standard deviations below the mean compared with 0 of the control toddlers (P = .037; Fisher exact test).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Contrary to our initial expectation, the overall pattern of biobehavioral pain reactions was similar between preterm infants with significant neonatal neurologic injury (PBI) and a group of infants without injury, matched for gender and gestational age at birth. The infants in the PBI group were able to mount facial, finger, and cardiac autonomic pain responses, as well as shifts in state of arousal, similar to infants without significant neurologic lesions. It seems that neonatal cerebral parenchymal injury did not alter pain responses at 32 weeks’ PCA.
It remains difficult to explain these findings completely. There is very little in the literature to guide our understanding of pain reactivity in infants and children with neurologic injury. In contrast to previous studies that examined pain response among older children and adults with SNI,1–4 we did not demonstrate substantial blunting of pain response that might be associated with a central neurologic injury. Although children and adolescents with a neurodevelopmental disability seem to be at increased risk for painful events25 and inadequate treatment,26 pain behaviors seem to be nonspecific and difficult to recognize, even by experienced caregivers.27 Parents report that acute pain reactions among children with a wide range of developmental disorders may be blunted and underreported.28 Detailed videotaped analysis of facial expression of adolescents who had an SNI and were undergoing a vaccine injection showed little or no response compared with a mock vaccination or baseline conditions. Similarly, measures of HRV used to quantify cardiac autonomic arousal showed little response to the vaccine1 among adolescents with SNI or the frail elderly with dementia during venepuncture.3 Acute physiologic and behavioral pain responses in the frail elderly is not uniformly blunted and seems to be correlated with levels of cognitive impairment.3,29 It remains unclear how an altered neurologic substrate influences acute pain reactivity or the developmental course behind the altered response. Similar studies of acute pain responses in infants with neurologic injury have not been previously reported.
It is possible that the nature of the neurologic lesions in our study population did not involve central areas that modulate the pain response, or that the original insult had not yet evolved into a lesion that impaired the transmission of appreciation of pain. In the subject group, the nature and extent of the central lesions were heterogeneous. Cerebral parenchymal infarction and PVL result from single or multiple circulatory events, leading to ischemic damage to areas in the cerebral white matter and interrupting ascending and descending pathways. With PVL, ischemic lesions are frequently multiple and bilateral, whereas cerebral parenchymal infarction usually produces a larger unilateral lesion. These lesions may or may not interrupt the motor and sensory connections to the cortex, depending on the extent and location of the lesions. Specific neurologic clinical signs usually are not evident in individual infants at 32 weeks’ PCA, which might explain why an abnormal pain response was not seen in our infants with PBI. Thalamic and pontine lesions are associated with central pain syndromes in adults after strokes30; thus, it is conceivable that infants in our study might develop conditions of persistent or abnormal pain appreciation over time. However, the lesions of the infants in the present study all were cerebral, mostly affecting white matter, and not pontine or thalamic. Lesions in these hemispheres would have an impact on the motor, cognitive, language, and emotional capacity to express and communicate pain, capacities that develop during the course of childhood and are not part of the typical pain expression repertoire of infancy.
It is possible that these infants had not yet "grown" into the functional disabilities associated with their central lesions. Namely, just as motor and cognitive disabilities emerge during the first year of life in infants with PBI, altered pain reactivity, as observed in populations of older children, may also appear with time. This might be supported by our findings of motor and cognitive impairments seen at 18 months of age. Results of neurodevelopmental follow-up in the 2 groups in the second year of life confirmed the high prevalence of neurodevelopmental sequelae in the infants with PBI, anticipated by their overtly abnormal neonatal head ultrasound scans. The neurodevelopmental abnormalities identified in the PBI group confirm that these patients, who, when studied earlier in life before their neurodevelopmental abnormality became apparent, do belong to a category of children with motor impairment in whom others have described blunted pain responses in later life. The inability to show differences in pain responses in the PBI group in this study is not, therefore, attributable to the severity or character of the brain injury. At this point, it is unclear whether what we have observed in this study was a generalized pattern of normal development among infants with PBI that will remain consistent with infants without neurologic impairment or was a phase of transient normality that eventually evolves into a pattern of abnormal pain responses later in infancy along with the motor and other developmental limitations associated with the significant neurologic insults observed in our study group. The long-term developmental course of the effects of a PBI over time on neonatal pain response remains to be studied.
A limitation of this current study is the limited sample size. As this is the first known study to examine facial and heart responses to a noxious event in preterm infants with brain injury, no previous data were available for means and standard deviations for sample size estimates.
The findings in this study have implications for the recognition and management of pain among preterm infants with neurologic injury. These data suggest that even in the presence of a significant neurologic injury, preterm infants are able to mount a clinically recognizable pain reaction that does not differ from noninjured infants, and thereby can be assessed for the presence of pain and receive treatment that is available to all preterm infants.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This initial study of pain in preterm infants with significant neurologic injury did not demonstrate altered biobehavioral pain responses. On follow-up at 18 months, infants with identified PBI in the neonatal period had clear evidence of the motor and cognitive impairments associated with cerebral palsy. Together, these findings suggest that just as infants with PBI grow into their functional limitations, they also may develop blunted or altered pain responses that we have seen in other populations of children with cerebral palsy. Additional detailed work is needed to understand the nature of pain reactivity in neonates with brain injury and the developmental course that unfolds in early childhood that parallels other aspects of their disabilities.
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FOOTNOTES |
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Received for publication Oct 19, 2001; Accepted Mar 22, 2002.
Reprint requests to (T.O.) Centre for Community Child Health Research, 4480 Oak St, Vancouver, British Columbia V6H 3V4, Canada. E-mail: toberlander{at}cw.bc.ca
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