Researchers are using brain activity measured on electroencephalography (EEG) to determine when babies are in pain.
They have identified and validated a template of nociceptive brain activity that is also sensitive to the administration of analgesics in infants.
Because babies can’t use words or numeric scales to describe and rate their pain, it’s important to develop a surrogate means of determining when these young patients are in pain, lead author, Caroline Hartley, PhD, postdoctoral researcher, University of Oxford, United Kingdom, told Medscape Medical News.
“Using this template is a useful way to get an objective, quantifiable measure of pain-related brain activity that could be used to test analgesic efficacy,” she said.
But Dr Hartley doesn’t think this template would be used any time soon in everyday clinical practice. “I think it would be used in research studies and clinical trials to test drugs.”
The research was published online May 3 in Science Translational Medicine.
The new analyses included 72 infants across five studies. The infants had no history of neurologic problems, were clinically stable, and were not receiving analgesics.
The researchers noted that the infants were studied during a heel lance that was performed only if clinically required to get a blood sample.
In 18 term infants, researchers recorded and characterized electrophysiologic brain activity in response to noxious (the heel lance) and non-noxious stimuli to derive a template of nociceptive brain activity. The highest-amplitude activity was recorded at the Cz electrode site.
Such a template has several advantages over other means of trying to determine whether a baby is in pain, such as changes in physiology (eg, heart rate) and such behaviors as crying or facial grimaces.
“Babies cry for lots of reasons — for example, when they need a nappy change or when they’re hungry — so these measures may not be sensitive enough, particularly if we’re thinking about testing pain-relieving drugs,” said Dr Hartley.
Researchers tested the specificity of the template in an independent sample of 14 term infants. They recorded EEG activity during a period of background activity (when the baby’s foot was gently held but no stimulation was applied) and in response to auditory (various sound tones), visual (flashes of light), tactile (a modified tendon hammer sending a trigger pulse), and experimental noxious (where a device was used to prick the infant’s heel but without piercing the skin; the sensation is described as being similar to being poked with a blunt pencil) stimuli that were applied in random order.
The template was projected onto the individual trials at the Cz electrode site in the 400- to 700-ms post-stimulation time window. The magnitude of the template was calculated for each trial and compared across stimulus modality.
The suitability of the template for premature infants aged 34 to 36 weeks’ gestation was demonstrated in a sample of 12 infants. This age group was chosen because previous data suggested that after about 34 weeks’ gestation, noxious-specific evoked activity is likely to be generated.
“We were able to show that this template could be used in these babies to identify pain-related brain activity,” said Dr Hartley.
In a fourth study, researchers considered how the magnitude of the noxious-evoked brain activity characterized by the template compared with the evoked changes in pain-related behavior in 28 infants age 34 to 42 weeks’ gestation, where a clinically required heel lance was performed.
There was a significant correlation between the magnitude of noxious-evoked brain activity and pain-related facial expression (P = .038), but in 45% of the infants in whom pain-related behavioral changes were not observed, there was still a significant increase in noxious-evoked brain activity.
Overall, 11 of 12 preterm infants had a significant increase in noxious-evoked brain activity. Pain-related behavioral changes were recorded in nine of these infants.
Finally, in a fifth study, researchers tested the template sensitivity in 12 term-born infants, maximum age 28 days, requiring topical local anesthetic to be applied to the dorsal surface of either foot before medically required venipuncture.
When the experimental noxious stimuli were applied to the untreated foot, the noxious-evoked activity was significantly greater than background activity (P < .001), whereas when the experimental noxious stimuli were applied to the foot treated with topical local anesthetic, the evoked activity was not significantly different from the background activity (P = .026) and was significantly lower from the activity evoked in the untreated foot.
“We found that the pain-related brain activity was reduced by the local anesthetic,” said Dr Hartley. “We hope that the template will be used to test other pain-relieving drugs in babies and to identify the optimal dose of these drugs.”
Dr Hartley and her colleagues are already using the template to test whether morphine is an effective pain reliever in babies who must undergo painful examinations.
The researchers concluded that the specificity and sensitivity of the template are “reasonably high.”
Contributing Factors
The evoked brain activity characterized by the template can’t be interpreted as a direct measure of infant pain but rather quantifies the degree of the noxious input that is reaching the infant’s brain, the authors write.
Genetic and environmental factors contribute to an individual’s nociceptive sensitivity and may explain why noxious-evoked brain activity and behavioral changes were not observed in all participants, they said.
The template of pain-related brain activity isn’t validated for use in individual infants, noted Dr Hartley.
“It’s not sensitive enough to be able to tell when an individual baby is in pain. The most important use we see for this template at the moment is to test whether or not pain-relieving drugs are working.”
In the absence of language, the template represents a surrogate measure of infant pain, “which we can add to behavioral and physiological measures to get a composite picture,” said Dr Hartley.
Lynn Webster, MD, vice president of scientific affairs at PRA Health Sciences, Raleigh, North Carolina, and past president of the American Academy of Pain Medicine, commented on the research for Medscape Medical News.
Dr Webster said that he’s not sure that this is “a very practical or affordable way to assess analgesia in drug development” but that “it does offer an objective measurement that often does not occur in clinical trials.”
He stressed that pain is the sum of affective as well as nociceptive input. “I don’t see how this technique takes into account the rapidly developing affective component of pain perception in a neonate.”
Nevertheless, the researchers’ approach to assessing analgesia in the neonate “should be applauded,” said Dr Webster.
“It may only measure the nociceptive stimuli that reaches the brain, but this alone may be an important objective measurement.”
The authors have disclosed no relevant financial relationships.
Sci Transl Med. Published online May 3, 2017. Abstract
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