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).
Abstract
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.
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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.
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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."
http://www.medscape.com/viewarticle/880849
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