Friday, June 2, 2017

Nociceptive brain activity as a measure of analgesic efficacy in infants

Hartley C, Duff EP, Green G, Mellado GS, Worley A, Rogers R, Slater R. Nociceptive brain activity as a measure of analgesic efficacy in infants. Sci Transl Med. 2017 May 3;9(388).

Pain in infants is undertreated and poorly understood, representing a major clinical problem. In part, this is due to our inability to objectively measure pain in nonverbal populations. We present and validate an electroencephalography-based measure of infant nociceptive brain activity that is evoked by acute noxious stimulation and is sensitive to analgesic modulation. This measure should be valuable both for mechanistic investigations and for testing analgesic efficacy in the infant population.

From the article

We identified the template by contrasting the patterns of brain activity evoked by noxious and non-noxious stimulation in 18 term infants. The noxious stimulation was either a clinically required heel lance or an experimental noxious stimulus, which was the application of a weighted noxious probe applied to the surface of the foot (128 mN). The non-noxious stimulation was either a heel lance control procedure or tactile stimulation of the heel (see Materials and Methods). The topography and time course of the response were established by considering activity across all electrodes in the 1000-ms poststimulation period. Noxious-evoked activity was maximal at Cz, which is the vertex electrode positioned on the midline of the scalp. At this electrode site, noxious-evoked activity was significantly different from the activity evoked by the non-noxious stimuli in the time window 446 to 611 ms after stimulation [P = 0.003, cluster-corrected nonparametric test . To obtain a representative waveform of the noxious-evoked brain activity, principal component analysis was applied in this time window (400 to 700 ms after stimulation) at Cz. A principal component was identified that was significantly greater in response to the noxious stimuli compared with the non-noxious stimuli and background activity (P < 0.01). This principal component is comparable to that identified in previous research investigating noxious-evoked brain activity in infants  and was defined as the template of nociceptive brain activity. The template is scaled so that a magnitude of 1 represents the average response evoked by a clinically required heel lance performed in these term infants. Activity evoked by the milder experimental noxious stimuli and in younger infants is expected to be smaller in magnitude…

Here, a template representing the temporal pattern of nociceptive brain activity in infants has been characterized at the Cz electrode site and validated across a range of studies. The template was derived using principal component analysis, which is an approach that has previously been used in multiple publications to characterize infant nociceptive brain activity. Predefining a template has several important advantages over current methodology. First, it provides a more robust analytical approach because of the independence of the data sample. This avoids previous study limitations, where noxious-evoked brain activity has been characterized and evaluated within the same population, and is particularly important in randomized controlled trials, where the precedent is to predefine outcome measures. Second, using a predefined template prevents the need for the evoked activity to be recharacterized in a subset of data within each new study. This will directly benefit smaller-scale investigations where there is less power to robustly characterize the evoked activity across a range of infant demographics and stimulus conditions. Moreover, using all the available data to address questions pertaining to infant pain is of particular importance because of practical and ethical considerations, whereby data collection primarily relies on the need for clinically essential painful procedures to be performed in study participants. Third, defining a template of nociceptive activity allows for a standardized approach to be adopted and will facilitate comparisons between future research investigations and study populations.

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.

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 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…

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…

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…

"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."

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