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Multi-modal pain assessment: are near-infrared spectroscopy, skin conductance, salivary cortisol, physiologic parameters, and Neonatal Facial Coding System interrelated during venepuncture in healthy, term neonates?
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Abstract
Background
Improving pain and stress assessments in neonates remains important in preventing
the short- and long-term consequences. We aimed to identify the relationships between
different pain assessment parameters by simultaneously measuring changes in cortical,
autonomic, hormonal, physiological, and behavioral evoked responses to venepuncture
in healthy, full-term neonates.
Methods
This observational, prospective study (ancillary to the ACTISUCROSE trial) included
113 healthy, 3-day old, full-term neonates who underwent venepuncture for systematic
neonatal screening, from July to October 2013, in a tertiary-level maternity ward
of a university hospital. During venepuncture, we simultaneously measured the cortical
single-channel near-infrared spectroscopy (NIRS) signals, foot skin conductance, salivary
cortisol, physiological responses, and behavioral (Neonatal Facial Coding System [NFCS])
evoked responses.
Results
Regarding the NIRS analysis, the highest correlation was between the NFCS at venepuncture
and the change in NIRS integrated values of total hemoglobin (
r=0.41,
P<0.001) or oxygenated hemoglobin (
r=0.27,
P<0.001). The NFCS at venepuncture was moderately positively correlated with changes
in salivary cortisol (
r=0.42,
P<0.001) and skin conductance (
r=0.29,
P<0.001). Salivary cortisol and skin conductance changes were not correlated; the latter
parameters were not correlated with heart rate, respiratory rate, or SpO2.
Conclusion
During venepuncture, NFCS was mildly or moderately correlated with salivary cortisol,
skin conductance, and cortical NIRS changes.
Procedural pain in the neonatal intensive care unit triggers a cascade of physiological, behavioral and hormonal disruptions which may contribute to altered neurodevelopment in infants born very preterm, who undergo prolonged hospitalization at a time of physiological immaturity and rapid brain development. The aim of this study was to examine relationships between cumulative procedural pain (number of skin-breaking procedures from birth to term, adjusted for early illness severity and overall intravenous morphine exposure), and later cognitive, motor abilities and behavior in very preterm infants at 8 and 18 months corrected chronological age (CCA), and further, to evaluate the extent to which parenting factors modulate these relationships over time. Participants were N=211 infants (n=137 born preterm 32 weeks gestational age [GA] and n=74 full-term controls) followed prospectively since birth. Infants with significant neonatal brain injury (periventricular leucomalacia, grade 3 or 4 intraventricular hemorrhage) and/or major sensori-neural impairments, were excluded. Poorer cognition and motor function were associated with higher number of skin-breaking procedures, independent of early illness severity, overall intravenous morphine, and exposure to postnatal steroids. The number of skin-breaking procedures as a marker of neonatal pain was closely related to days on mechanical ventilation. In general, greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months CCA, however, specific protocols for morphine administration were not evaluated. Lower parenting stress modulated effects of neonatal pain, only on cognitive outcome at 18 months.
The prevention of pain in neonates should be the goal of all caregivers, because repeated painful exposures have the potential for deleterious consequences. Neonates at greatest risk of neurodevelopmental impairment as a result of preterm birth (ie, the smallest and sickest) are also those most likely to be exposed to the greatest number of painful stimuli in the NICU. Although there are major gaps in our knowledge regarding the most effective way to prevent and relieve pain in neonates, proven and safe therapies are currently underused for routine minor yet painful procedures. Every health care facility caring for neonates should implement an effective pain-prevention program, which includes strategies for routinely assessing pain, minimizing the number of painful procedures performed, effectively using pharmacologic and nonpharmacologic therapies for the prevention of pain associated with routine minor procedures, and eliminating pain associated with surgery and other major procedures.
Results Characterization of Tactile and Noxious-Specific Brain Activity in Full-Term Infants To investigate the emergence of specific neural activity evoked by tactile and noxious stimulation in the developing human infant brain, we first defined this activity in full-term infants. Principal component analysis (PCA) was used to identify tactile and nociceptive-specific potentials following time-locked touch or noxious lance of the heel (clinically required for blood samples) of 18 infants, aged 37–45 weeks gestational age (GA) (born at 37–41 weeks GA). The electroencephalogram (EEG) activity, recorded using a modified international 10/20 electrode placement system (Figure 1A), showed that full-term infants display distinct and separable responses to tactile and noxious stimuli recorded at the midline (CPz; Figures 1B–1D), as previously reported [6]. The tactile potential was defined by the first principal component (PC) in the EEG at CPz between 50 and 300 ms after stimulation because the weight of this component was significantly larger following touch compared to the background EEG (one-way analysis of variance [ANOVA]: F2.66 = 3.72, p 37 weeks). The aim was to understand how and when the circuitry required for touch and pain discrimination emerges in the human brain. The importance of this study lies not only in deepening our understanding of early human brain somatosensory function but also in the insight it provides about the onset of specific nociceptive processing, most likely required for pain perception, in the central nervous system. We show here that neural activation by peripheral tactile and noxious stimulation occurs from an early preterm stage but that there is a change in the pattern and specificity of the response with age. At early stages of brain development, less than 35 weeks gestation, the dominant response to both touch and noxious lance of the heel is an increased incidence of nonspecific neuronal bursts. At later stages of brain development, after 35–37 weeks gestation, the dominant response is quite different. Touch and noxious lance of the heel now evoke characteristic somatosensory potentials, maximal at the central electrodes, which are completely separable in timing and morphology for the two modalities of stimulation. Thus, specific somatosensory tactile and nociceptive potentials appear to emerge from a transient, nonspecific neuronal bursting activity. Synchronized neuronal bursting activity has been reported in numerous immature neuronal circuits in both man and laboratory animals. This endogenous neuronal activity during prenatal and early postnatal brain development is thought to be a key factor in the organization of functional cortical neuronal networks by guiding synapse formation, elimination, and rearrangement [9, 10]. Such transient spontaneous neuronal bursting activity has been recorded with EEG in premature and very young infants at different developmental stages [11–14] and used for clinical prognosis because their persistence at full term or absence during development is correlated with brain abnormality [15–18]. The neuronal bursting activity that we report was defined as delta brushes [11, 13] consisting of fast frequency ripples of 8–25 Hz superimposed on a slow wave of 0.3–1.5 Hz [3, 8, 19, 20]. Delta brushes increase in frequency and amplitude with maturity, becoming most prominent and frequent at 32–34 weeks postmenstrual age (PMA) and decrease by 42 weeks PMA. Before 28 weeks PMA, they are mostly expressed in central areas of the brain, whereas from 28 weeks to near term they spread also to the temporal, frontal, and occipital areas [8]. Our finding that delta brushes were triggered by touching the heel is consistent with previous reports of activation by spontaneous hand and foot movements and tactile stimulation [20]. Delta brushes are similar in terms of developmental profile, frequency characteristic, and topography to the spindle bursts recorded in the cortex of neonatal rats, which are also triggered by sensory stimulation and correlated with spontaneous sleep-related myoclonic twitches through sensory feedback [21, 22]. Here we show that noxious stimulation of the body also triggers the same neuronal bursting activity but with greater incidence than after tactile stimulation. The fact that neuronal bursts can be triggered by a wide range of sensory stimuli across broad areas of the brain [3, 4] suggests that the higher incidence of bursts triggered by heel lance reflects the intensity of the input rather than any specific discrimination of stimulus modality. The somatosensory evoked potentials that we recorded in older infants were the same as described previously from EEG recording in response to touch and noxious lance of the heel [6, 23]. The characteristics of the tactile potential reported here are similar in morphology and topography to the vertex potentials evoked by electrical stimulation and time-locked tapping of tendons and muscles [24, 25], auditory click [26], and, to a certain extent, to those evoked by visual stimulation in full-term newborns [25, 26]. A similar potential has also been recorded in adults following visual, auditory, nonnoxious, and noxious laser stimulation [27]. Although we have used the term “tactile potential” to describe the potential evoked by both the nonnoxious and noxious stimulation, we do not know what aspect of neuronal processing this potential represents. It may be directly related to the tactile input or reflect a nonmodality-specific process, such as attention or arousal. On the other hand, the characteristics of the infant nociceptive-specific response, which was only evoked in response to the noxious stimulus, are strikingly similar in polarity and topography to cerebral potentials evoked by “painful” mechanical stimulation in adults [28]. The clearly defined specific noxious-evoked potentials recorded in older infants in response to heel lance, in contrast to the nonspecific increase in neuronal bursts characteristic of early prematurity, are therefore likely to reflect the maturation of the functional brain circuitry that enables the human brain to discriminate noxious stimuli from other forms of sensory input. Neuronal bursts are more evenly distributed across electrode sites than the evoked potentials, as might be expected if the neuronal bursts represent activity in more immature networks across the brain. This activity may contribute to the previously reported hemodynamic activity recorded in the contralateral somatosensory cortex following noxious stimulation from 25 weeks gestation [29]. We do not know which features of the evoked neuronal activity drove the change in total hemoglobin concentration; however, the occurrence of the neuronal bursts shows a slight prevalence on the contralateral side. In contrast, the nociceptive-specific and tactile potentials were maximal at the midline region of the brain, consistent with observation in adult studies [28]. The transition from predominantly nonspecific neuronal bursts to specific evoked potentials occurs at 35–37 weeks gestation, which is just before an infant would normally be born. Several mechanisms have been proposed to underlie neuronal bursting activity in developing circuits, including depolarizing GABA, extrasynaptic glutamate, gap junctions, and transient connections [2]. In the somatosensory cortex, bursting develops in vitro, emphasizing its intrinsic nature, but is strongly modulated by sensory inputs [22] and interhemispheric connections in vivo [30]. The transition from neuronal bursts to evoked potentials in the somatosensory and nociceptive processing at 35–37 weeks gestation in the human brain is consistent with previous reports [25] and is in concurrence with a similar shift in the visual system [4]. The transition in the processing of peripheral stimuli may be related to the structural development of thalamocortical connections and the formation of callosal and association pathways at around this time [31]. Our findings are in line with the idea that neuronal bursts represent the activation of neuronal circuits, which can spontaneously fire or may be triggered by peripheral activation, such as spontaneous retinal waves or somatosensory input that may occur in utero. However, the 35-week-GA human infant would not normally be exposed to noxious stimulation and therefore it is unlikely that noxious sensory input is a requirement for early cortical pain circuit development. A key role may be played by the pacemaker neurons that have been recently discovered within the maturing lamina I of the spinal cord and provide an endogenous drive to the developing pain circuitry [32]. Repeated noxious stimulation of the kind used in this study is a feature of neonatal intensive care [33]. Our finding that noxious heel lance increases neuronal bursting activity in the brain from the earliest age raises the possibility that excess noxious input may disrupt the normal formation of cortical circuits and that this is a mechanism underlying the long-term neurodevelopmental consequences and altered pain behavior in ex-preterm children [34–36]. In the adult, pain is a complex, subjective experience with sensory and affective components involving multiple brain regions [37, 38]. We propose that the transition from nonspecific neuronal bursts to specific evoked potentials is a first stage in the development of central pain processing. The timing of this change marks the functional maturation of cortical circuitry such that the human brain can discriminate noxious sensory input from other nonnoxious sensory stimulation. Experimental Procedures Subjects Forty-six infants, recruited from the intensive care unit, special care baby unit, and postnatal ward at the Elizabeth Garrett Anderson and Obstetric Hospital, participated in this study. Three infants were studied on more than one occasion. GA was determined from antenatal ultrasound scans taken at 19–20 weeks gestation or from the maternal report of the last menstrual period. This is equivalent to PMA. Table 1 gives the demographic characterization of the subjects. Medical charts were reviewed and, at the time of study, infants were assessed as clinically stable. Infants were not eligible for inclusion in the study if they were (1) receiving analgesics, sedatives, or other psychotrophic agents; (2) showing signs of tissue damage on the lower limbs; (3) born to diabetic mothers or opioid users; (4) asphyxiated at birth; or (5) born with congenital malformations or other genetic conditions. Ethical approval was obtained from the University College Hospital ethics committee, and informed written parental consent was obtained prior to each study. The study conformed to the standards set by the Declaration of Helsinki guidelines. EEG Recording Recording electrodes (disposable Ag/AgCl cup electrodes) were positioned according to the modified international 10/20 electrode placement system at F7, F8, Cz, CPz, C3, C4, CP3, CP4, T3, T4, T5, T6, O1, and O2. A reduced number of electrodes were used if access to the infant was limited. Reference and ground electrodes were placed at FCz and the chest, respectively. The impedance of the electrode-skin interface was kept to a minimum by rubbing the skin with an EEG prepping gel, and conductive EEG paste was used to optimize contact with the electrodes. Electrodes were held in place by an elastic net and leads were tied together to minimize electrical interference. EEG activity, from DC (or 0.05 Hz in eight cases) to 70 Hz, was recorded using the Neuroscan (Scan 4.3) SynAmps2 EEG/EP recording system. Signals were digitized with a sampling rate of 2 kHz and a resolution of 24 bit. Experimental Protocol The noxious stimulus was a clinically required heel lance performed to collect a blood sample. No heel lances were performed solely for the purpose of the study. Tactile stimulation was applied by lightly tapping a tendon hammer against the heel of the infants. The EEG recordings were automatically marked at the time of the stimulus in order to select EEG epochs in correspondence of the events for analysis. Tactile and noxious stimulation were performed on the same foot for each infant. EEG Epoch Analysis The tactile and nociceptive-specific potentials were defined from the EEG recordings at CPz of 18 term infants born at term (GA: mean = 40.58 weeks; range = 37.71–45.28 weeks). 1.7 s EEG epochs, starting 0.6 s before the event, corresponding to noxious heel lances (n = 23), touches of the heel (n = 23), and no stimulation (background EEG, n = 23), were considered. PCA was used to characterize the evoked activity following time-locked touch and lance of the heel (see Supplemental Experimental Procedures available online). The neuronal bursts (delta brushes) were defined in the EEG recordings at any electrode site of 21 preterm infants (GA: mean = 34.36 weeks; range = 28.43–36.86 weeks). Six-second EEG epochs, starting 3 s before the event, corresponding to noxious heel lances (n = 30), touches of the heel (n = 30), and no stimulation (background EEG, n = 30) were considered. Delta brushes were identified in accordance to their characteristic frequency, polarity, amplitude, and duration (see Supplemental Experimental Procedures). The occurrence of tactile and nociceptive-specific potentials and of delta brushes was assessed on 60 EEG recordings following time-locked touch or noxious lance of the heel of 41 infants, aged 28–45 weeks GA (born at 24–41 weeks GA). These infants included the 18 term infants born at term and the 21 preterm infants mentioned above (3 of which were also studied at term), plus 2 infants born prematurely and studied at term. Age at birth was not considered as a variable in this analysis. The occurrence of the tactile and nociceptive-specific potentials was evaluated at Cz rather than CPz because it was an independent electrode site not used to define the potentials, where similar tactile and nociceptive-specific potentials were recorded as at CPz (Figure S1) [6]. Statistical independence here refers to properties of the measurement errors. The maturation of neuronal bursts into tactile and nociceptive-specific potentials was evaluated as changes in their occurrence in respect to each other across infant gestational age. All the EEG epochs considered in this analysis were baseline corrected by subtracting the mean baseline signal and high-pass filtered at 0.1 Hz (fourth-order bidirectional Butterworth filter). In 17 test occasions, the heel-lancing procedure was performed twice to collect the required blood sample; for these infants, two epochs corresponding to tactile stimulation and background control EEG were also analyzed. A total of 68 noxious heel lances were analyzed; of these, 3 were excluded from analysis because automatic event marking of the EEG did not occur and 5 because of the presence of movement artifacts in the EEG recording. Epochs corresponding to tactile and background control EEG in these test occasions were also not analyzed.
[3
]Inserm CIC 1412, Centre for Clinical Investigation, Brest University Hospital, Brest,
France
Author notes
Correspondence: Jean-Michel Roué, Service de Réanimation Néonatale et Pédiatrique,
Hôpital Morvan, 2 Avenue Foch, 29609, Brest, France, Tel +33 29 822 3667, Email
jean-michel.roue@
123456chu-brest.fr
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