Discussion
The use of pupillometry as an objective method to measure pain and
analgesic response has proven to be a useful modality in a variety of
populations; however, establishing normative values for select
populations is still evolving as variables such as age, ethnicity, or
certain comorbidities have shown variability in comparative
measurements.1-3 This study suggests that when using
pupillometry as a clinical tool in pediatric patients with sickle cell
disease, it is reasonable to use the normative values established in
previous studies of healthy participants with similar age and race.
Previous studies have shown significant differences in measurements when
comparing age groups of healthy participants. With age, pupil size and
dilation velocity increase slightly while maximum constriction velocity
decreases. These changes with age are fairly correlated with changes in
eye size but may also be influenced by developmental changes of the
pupillary reflex.1,5 In the study by Brown et al.,
there were also significant differences in pupil size and maximum
constriction velocity when comparing healthy black to their respective
white cohorts. Our results also reflect a variation amongst races as our
data showed no significant change when comparing children with sickle
cell disease to healthy black children of a similar age, but did show a
significant difference amongst our participants in contrast to their
white cohorts in the aforementioned study.
When comparing various comorbidities to baseline values obtained from
healthy participants of similar age and race, some disease processes
have reflected significant changes, making it difficult to use
previously established normative values for those specific populations.
For example, children with ADHD have been shown to have higher pupillary
velocity values in correlation with changes in thickness of the retinal
nerve fiber layer and anxiety has been correlated with increased pupil
sizes.6,7 Specific disease processes affecting the
retina, such as diabetic retinopathy, have expectedly shown progressive
changes in pupillary dynamics with increasing disease
severity.8 Given the lack of a significant difference
in our data when contrasted with Brown et al.’s black participants, our
study supports the use of previously established normative values when
using pupillometry in the assessment of children with sickle cell
disease, as it does not appear to influence pupil dynamics.
Our data was obtained during outpatient clinic visits when participants
were presumed to be at their baseline state of health and without
significant pain or recent opioid use. This was done to first ensure
that sickle cell disease did not lead to baseline changes in pupil
dynamics prior to future investigations regarding changes during an
acute vaso-occlusive pain crisis and its associated management with
narcotics.
Vaso-occlusive crisis is unique to the sickle cell and is a major
contributor to disease morbidity that is often difficult to treat
appropriately. These crises are characterized by nociceptive pain and
associated inflammation which can lead to severe sequelae such as
multiorgan failure and even death.9 Opioids are a
cornerstone of treatment during an acute pain crisis, but the assessment
of pain and treatment efficacy is challenging as current measurements
rely on subjective measurements that are not all encompassing and
difficult for younger or non-verbal children to utilize. Due to concern
of inadequate pain treatment and concern for adverse effects of opioids,
pain is often under or over treated, hence the need for a reliable,
objective method of pain measurement in this
population.9
In a recent study by Connelly et al. self-reported pain levels in
healthy children undergoing surgical procedures showed significant
associations with several measures of pupillary response. Amongst these
measures, maximum pupillary constriction velocity, a dynamic measurement
of pupil response to a light stimulus, showed the most promise as a
surrogate marker of pain. Their data showed an increase of 2 or more on
the validated visual analog scale (VAS) was associated with a change of
≥ 0.22mm/sec in maximum constriction velocity. As expected, an
association between drug dose (in morphine equivalents) and pupil size
was observed; however, when controlled for opioid effect, an independent
effect of pain on pupil response persisted.10 Despite
the known effect of opioids on pupil size, changes in dynamic pupil
parameters have continued to be observed following titration of opioid
dose to a level that elicits respiratory depression, and
intraoperatively, changes in pupillary reflex dilation in children have
occurred prior to significant changes in heart rate or blood pressure,
suggesting that pupillometry could be a valid tool in not just initial
assessment of pain level, but also when evaluating analgesic
response.11,12
Patients with a history of stroke or other neurological deficits were
not included therefore normative values found in this study cannot be
extended to that particular population. Another limitation to this study
was that every patient was black. As the population become more
interracial, there needs to be further studies looking at their specific
normative pupillometry values.
In conclusion, black pediatric patients with sickle cell disease have no
significant difference in pupil size and reactivity compared to black
pediatric patients without sickle cell disease but have a significant
difference compared to white participants in the Brown et al study.
Pupillometry studies are needed in pediatric patients with sickle cell
disease in an acute vaso-occlusive crisis and are currently in progress
at our institution.