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.