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Volume 13, Issue 1, December 2015 . Research Manuscript. 1-8. Effects of Medications on Pupillometry
Measurements of Sedation in the
Intensive Care Unit!

Johlee Schinetsky, Jeffrey Quach, Ashlynn
Volpe, Natalie Tran and Samantha Gaffney
Faculty Mentor: Dr. Jessica Johnson, Pharmacy
Abstract
Administration of sedatives and opioid analgesics to hospitalized
patients in the Intensive Care Unit (ICU) is a common event as
part of the usual process of care. Accidental over-sedation leads to
increased patient harm, prolonged ICU length of stay, and
increased healthcare costs. Thus, clinicians must find efficient, objective ways to monitor patients' neurologic status and the Primary author Johlee Schinetsky is effects of sedating medications. The Pupillary Light Reflex (PLR) a Doctor of Pharmacy candidate and pupil size have traditionally been used for this clinical from Kenner, LA. After graduating in May 2016, she plans to complete assessment. Digital Video Pupillometry, or Digital Pupillometry a PGY1 and PGY2 training in (DP), is emerging as a potential mechanism for more objective pharmacy practice. Her research monitoring of analgesia and depth of sedation. DP provides rapid interests include critical care and precise electronic measurements of baseline and constricted pupillary diameters, velocity of contraction, and latency time pharmacy curriculum development between light exposure and onset of contraction reflex. Further and remediation policies. She has research on the many effects of medication on PLR is needed in also served on several scholarly order to continue researching the utility of DP for reliable projects, such as: the Pupillometry monitoring of ICU sedation. In this paper, we will discuss the Study, Student Perceptions of the known effects of various medication classes on pupillary COP's Current Remediation Policy, musculature as reported in the current literature. and Quality Blue Primary Care Quality Measures. !
Key Terms:
Digital Video Pupillometry • Pupillary Light Reflex Pain and Sedation Assessment

J. Schinetsky et al. Background
been difficult to objectively quantify. Standard manual clinical assessments of pupil size and For nonverbal patients such as small reactivity conducted using a penlight have a high children, intubated intensive care unit (ICU) rate of error and inter- and intra-observer patients, and those with neurologic deficits, it is variability (Teasdale & Knill-Jones, 1978; often challenging to assess pain responses and Wilson, Amling, Floyd, & McNair, 1988). sedation levels. Researchers and clinicians have become increasingly aware of the urgent need to The development of the portable, develop and enhance ways of monitoring cordless, handheld digital pupillometer has sympathetic and parasympathetic neurologic activity via pupil responses. Digital Pupillometry measurements of PLR and pupil size, potentially (DP) is emerging as a potential mechanism of increasing the clinical utility of the assessment. objective monitoring of analgesia and depth of The digital pupillometer utilizes a standard light sedation, though further studies are needed to source intensity to stimulate the PLR. The device fully understand how commonly administered then records the size of the pupil, the latency of therapeutic medications may affect this response to light, the rate of change (velocity) of pupillary diameter, and the minimum and maximum diameters of the pupil (PLR The autonomic nervous system is amplitude) (Fountas et al., 2006; Martínez- responsible for regulating pupillary musculature, Ricarte et al., 2013). DP is more sensitive than thus controlling the amount of light that enters the unaided human eye, and studies have shown the eye. Respectively, the sympathetic and the digital pupillometer to identify minimal PLR parasympathetic branches of this system dilate that might otherwise mistakenly be considered and constrict the pupil through specific muscle "non-reactive" (Larson & Muhiudeen, 1995). innervation in the eye. The pupillary light reflex pathway involves signal transmission between The new science of DP might offer a the retinal ganglion cells, optic nerve, midbrain, more objective measure of pain or analgesia, and short ciliary post-ganglionic nerves especially in settings where postoperative pain (Chanques et al., 2006). To begin this process, can be difficult to communicate. For example, in light is perceived by the photosensitive retinal the ICU, many patients will relate pain scores ganglion cells. The optic nerve then receives this that are inconsistent with their behavior which information and refers the message to the can lead to under- or over-sedation (Larson & midbrain. In response, outward stimulation Sessler, 2012). Adverse effects of untreated through post-ganglionic ciliary nerves contracts post-operative acute pain include limited the circular muscle of the eye [Figure 1]. mobility, impaired ventilation, and increased stress hormones. Conversely, overtreatment can Pupillary Light Reflex (PLR) and pupil lead to respiratory toxicity and aggravates size have been traditionally used as clinical opioid-induced side effects such as nausea and assessments of neurologic status. In standard vomiting, ileus, sedation, and hyperalgesia clinical practice, the PLR is estimated using (Larson & Sessler, 2012). terms like "brisk," "sluggish," or "non-reactive," where generally, a decrease in a patient's level of To clarify, pupillary dilation response is arousal is associated with a decrease in pupil not specific for pain, but rather it is related to any diameter and PLR response velocity (Martínez- stimulus that is strong enough to increase the Ricarte et al., 2013). Pupillometry has, until now, level of arousal. Numerous clinical conditions, XULAneXUS: Xavier University of Louisiana's Undergraduate Research Journal

Me lations asureme hips !medications, and variables, such as the patient's concentrations leading to more profound effects wakefulness, level of ambient light, and time of on pupil dilation. Several studies have utilized day that a procedure is performed, may alter pupillometry to demonstrate the aforementioned pupillometry data collection. In order to validate effects of opioids. the dependency of these methods, clinicians must consider that pupil size and pupillary response to pain are influenced by various pupillometry to study the pharmacodynamic factors besides pain. effects of tramadol, an opioid-like drug, on PLR. In the study, the polymorphism of CYP2D6, a In this paper, we will discuss the effects member of the cytochrome P450 enzymes of certain medication classes on pupillary light involved in the metabolism of drugs, was reflexes, focusing mostly on opiates and analyzed in each participant (n=26) because this sedatives. Based on a review of literature enzyme mediates the active O-demethylated exploring the effects of medications on PLR in metabolite of tramadol, which is responsible for controlled environments, it is clear that DP providing its analgesic. Once healthy participants technology will require health professionals to were labeled as extensive metabolizers (EM), better understand the limitations and potential intermediate metabolizers (IM), or poor extraneous variables that may affect its metabolizers (PM), they received oral doses of measurements. This information is foundational 150 mg, 100 mg, or 50 mg tramadol and placebo, to future studies of potential applications, patient respectively. DP then captured the amplitude, care benefits, and advanced pharmacotherapy in latency, and duration of reaction to light pre-dose uncontrolled environments like the ICU. Opioids and opioid-like medications have pupillometry, and the CYP2D6 genotype highly the ability to affect pupillary diameter, influenced these responses. The miotic reaction specifically by producing miosis of the eye and was observed in all participants. However, there latency in the PLR. Opioids produce miosis by were differences in the extent of miosis observed between the differing metabolizers. The parasympathetic innervation of the pupil maximum mean differences between placebo and (Fleigert, Kurth, & Göhler, 2005). When light tramadol doses given to PM, IM, and EM were hits the retina of the eye, it elicits a response that reported as -0.5 mm, -0.8 mm, and -1.1 mm, must go through neural pathways in order to respectively (Fleigert et al., 2005). The lack of reach the brain for interpretation [Figure 1]. The miosis in the PM compared to EM can be Edinger-Westphal nucleus is one of those attributed to the fact that there is a lack of pathways. It is a nucleus of neurons that formation of the active O-demethylated regulates parasympathetic signals to the iris metabolite of tramadol. muscles. Parasympathetic signals in the iris will result in miosis. Opioids suppress the inhibitory Furthermore, parameters of dynamic tract of this nucleus, resulting in more of an pupillometry were also studied. For both EM and excitatory response that leads to what can be PM, a decrease of amplitude, velocity of seen as pupil constriction. Furthermore, opioid constriction, and reaction duration occurred, induced miosis occurs in a dose-dependent while an increase in latency was observed. fashion, with higher levels of plasma However, the EM experienced these effects for a XULAneXUS: Xavier University of Louisiana's Undergraduate Research Journal J. Schinetsky et al. much longer time period than the PM, 24 and 8 were noted to have pupillary miosis occurring, hours respectively (Fleigert et al., 2005). with diameters of less than 3mm at the point of Therefore, these effects would be important to maximal desaturation (Rollins et al., 2014). consider when using a DP to assess patients Furthermore, the light reflex of the pupil was receiving tramadol in a clinical setting. significantly diminished compared with pre-drug administration baseline measures. As the PCO2 While the aforementioned studies have levels increased, there was a decrease in PLR. confirmed that opioids are capable of inducing This relationship shows that as CNS depression miosis of the pupils and delaying response of the increases, the pupils are not as responsive to light reflex, one particular study questioned changes in light. Therefore, Rollins' study was whether these effects would continue during able to establish that even during high-doses of opioid-induced toxicity. Rollins, Feiner, Lee, opioid administration, parasympathetic effects of Shah, and Larson examined the effects of the pupil remain, which allows for pupillary significant opioid-induced respiratory depression examination and evaluation of PLR to remain with accompanying hypercarbia and hypoxia. useful for neurologic assessment during opioid The sympathetic nervous system is activated during states of hypercarbia and hypoxia. Theoretically, this would cause the pupils to be GABA Agonists
overcome by sympathetic activation as well, causing mydriasis (dilation) of the pupils. In the ICU, benzodiazepines (e.g. lorazepam, diazepam, and midazolam) have Rollins' study was designed to determine traditionally been used to induce sedation in whether or not the sympathetic nervous system patients, especially as adjunct therapy in predominates, which would signify if the light anesthesia. When combined with an opiate reflex remains quantifiable during opioid toxicity analgesic to achieve anesthesia, benzodiazepines with associated hypercarbia and hypoxia run the risk of causing major respiratory (defined as less than 85% Oxygen saturation). depression, which calls for careful titration of the Ten healthy volunteers received remifentanil, a dose and constant monitoring of respiratory rate. potent short-acting opioid analgesic as a gradually increasing infusion rate followed by Hou, Samuels, Langley, Szabadi, and intermittent boluses until an oxyhemoglobin Bradshaw (2007) performed one DP study using saturation of 85% or less was reached, signifying either an orally administered placebo or hypoxia and hypercarbia had been reached. diazepam 10mg, with either a sympatholytic or Arterial blood gases and pupillary measures were parasympatholytic eye drop, to observe the effect taken before opioid administration, at maximal of benzodiazepines on the PRL and concluded desaturation, and fifteen minutes after recovery that diazepam has no effect on pupillary reflexes. (Rollins et al., 2014). Another study performed by the same team compared pupillary function as affected by Rollins' results demonstrated that during diazepam and diphenhydramine, again finding this time, respiratory rate was profoundly that diazepam has no significant effect on depressed and as expected, evidence of pupillary response (Hou et al., 2006). sympathetic activation was present, indicated by significant increases in heart rate (p- Propofol is another common GABA value=<0.0001). However, parasympathetic agonist agent used for induction and activation of the pupil remained, and all subjects maintenance of sedation in the ICU. When dosed XULAneXUS: Xavier University of Louisiana's Undergraduate Research Journal Me lations asureme hips !correctly, patients achieve a significant level of controlled pump set to a target plasma sedation with a rapid rate of recovery due to the concentration of 0.6 ng/ml to ensure adequate drug's pharmacokinetic profile. A study sedation. Measurements on pupil diameter and performed by Odras-Banderas et al. (2014) light reflexes were taken every two minutes examining pupillary response in patients where starting thirty minutes before the administration they were all sedated with propofol showed of dexmedetomidine until the discontinuation of varied results. In post-operative heart surgery dexmedetomidine after 45 minutes. patients, all sedated with propofol, about half of the sample presented with no pupillary response Compared to the data collected pre- during sedation. Neurological examination was infusion, dexmedetomidine did not affect resting normal in 80% of the sampled patients after pupil diameter significantly, with pre- and post- sedation. The study concluded that propofol does demedetomidine pupil sizes measuring 2.0 + alter neurological and pupillary response and 0.36 and 2.0 + 0.32 respectively. However, suggested that these DP examinations should not dexmedetomidine increased the amplitude of the be used to make clinical decisions on sedation pupillary light reflex from 0.30 + 0.14mm to management in patients on propofol. 0.37 + 0.12mm compared to pre-infusion values. Adrenergics
dexomedetomidine on humans in the University of California's study did not coincide with Dexmedetomidine, previously seen pupillary effects in mice and rats adrenoceptor agonist, is a relatively new sedative given an alpha-2 agonist (Koss, 1986). agent gaining popularity due to its unique Researchers concluded that pupillary effects of property of only producing mild cognitive dexomedetomidine in human subjects should be impairment (Larson & Talke, 2001). Studies on studied further and cannot be explained via the animal subjects have found that alpha-2 pathway of alpha-2 inhibition from the locus adrenoceptor agonists reduce tonic inhibitory coeruleus to the pupilloconstrictor nucleus as tone of cell bodies on the pupilloconstrictor seen in animal subjects. neurons and inhibit the pupilloconstrictor nucleus via an alpha-2 adrenergic mechanism Other Influences
[Figure 1]. Although two opposing actions are occurring, the predominant effect of the Documentation on external factors pupilloconstrictor nucleus causes mydriasis to causing variations on pupillary reflexes can be occur in both rat and cat subjects. The same found dated as far back as 1943, when Skoglund mechanism of action occurs in humans with one wrote about how alcohol dilates the pupil in difference: the effects of the pupilloconstrictor proportion to blood alcohol levels. Hess and Polt nucleus are not dominant to the effects of (1966) found that pleasant taste induces pupil autoreceptors in human subjects; therefore, dilation. Loud noises have also been found to instead of mydraisis the subjects may experience increase pupil diameter due to activation of the miosis (Koss, 1986). sympathetic pathway. Barlett, Faw, and Leibert (1967) discovered alertness in an individual The Department of Anesthesia and presented with pupillary constriction, whereas Perioperative Medicine at the University of relaxation was suggested by pupillary dilation California tested this hypothesis on eight healthy (Sarbin & Slagle, 1979). The Federal University control subjects (Larson & Talke, 2001). of Maranhao (Brazil) found that men and women Dexmedetomidine was infused via a computer- with moderate to severe anxiety had greater pupil XULAneXUS: Xavier University of Louisiana's Undergraduate Research Journal J. Schinetsky et al. dilation than those with mild to no anxiety, sympathetic activation to external stimuli also though there was no difference in pupil dilation play a critical role in interpreting sedation levels. between the genders (Bertrand, Garcia, Viera, Therefore, clinicians should be vigilant and use Santos, & Bertrand, 2013). clinical judgment as we learn more about DP. Further research is vital in order to establish the When assessing pain in nonverbal potential of implementing the use of DP to patients in a realistic setting, it may be difficult supplement current sedation scales, such as the to control external factors such as taste, anxiety, Richmond agitation sedation scale, and to aid light level, and noise. Thus, it is important to clinicians in objectively measuring sedation investigate and understand patients' conditions levels and neurologic status in the critically ill. and medications, along with the many other external factors that can affect a pupillometry References
reading, in future studies and clinical practices. Barrett K. E., Barman S. M., Boitano S, Brooks Conclusion
H. L. (2016). Vision. In Barrett K.E., Barman S.M., Boitano S, Brooks H.L. While sedation is frequently required for (Eds), Ganong's Review of Medical critically ill patients during routine procedures or Physiology, 25e. Retrieved November 26, to alleviate pain and anxiety, over-sedation has become a common and unfortunate occurrence. Many negative outcomes are associated with over-sedation, such as cardiovascular instability, immunosuppression, decreased gut motility, increased risk of thromboembolic events, and Bertrand, A. L., Garcia, J. B. S., Viera, E. B., prolonged ICU stays. Unfortunately, a subjective Santos, A. M., & Bertrand, R. H. (2013). scoring tool is currently used to monitor sedation Pupillometry: The influence of gender levels, which has the potential to leave critically and anxiety on the pain response. Pain ill patients over-sedated and at risk. Physician,16(3), E257-E266. Digital pupillometry is a promising tool Chanques G, Jaber S, Barbotte E, Violet S, that potentially is able to objectify the process of Sebbane M, Perrigault P, et al. (2006). monitoring the depth of sedation levels in Impact of systematic evaluation of pain patients by relying on pupil diameter and and agitation in an intensive care unit. pupillary light reflexes as markers of sedation Crit Care Med, 06;34(6):1691-9. levels. Before implementing the routine use of DP, it is important to consider any and all factors Fliegert, F, Kurth, B, & Göhler, K. (2005). The that may affect patients' pupil diameters and effects of tramadol on static and dynamic PLR. Medications that are commonly used to pupillometry in healthy subjects--the achieve sedation include general anesthetics, relationship between pharmacodynamics, opiates, and benzodiazepines. Through previous pharmacokinetics studies, it has been shown that while opiates and metaboliser status. European Journal of anesthetics, such as propofol, do have significant Clinical Pharmacology, 61(4), 257-266. benzodiazepines do not. Unique factors to drug Fountas, K. N., Kapsalaki, E. Z., Machinis, T. molecule such as metabolism and patient specific G., Boev, A. N., Robinson, J. S., & XULAneXUS: Xavier University of Louisiana's Undergraduate Research Journal Me lations asureme hips Troup, E. C. (2006). Clinical implications Perez, M. L., & Porta-Etessam, J. (2014). of quantitative infrared pupillometry in Neurological examination in patients neurosurgical patients. Neurocritical undergoing sedation with propofol: a Care, 5(1), 55-60. descriptive study. Revista De Neurologia, 58(12), 536-540. Hess, E. H, & Polt, J. M. (1966). Changes in pupil size as a measure of taste Rollins, M, Feiner, J, Lee, J, Shah, S, Larson, M difference. Perceptual and Motor Skills, (2014). Pupillary effects of high-dose pupillometry. American Society of Hou, R. H., Samuels, E. R., Langley, R. W., Anesthesiologists 2014. Szabadi, E, & Bradshaw, C. M. (2007). Arousal and the pupil: Why diazepam- Sarbin, T. R., & Slagle, R. W. (1979). Hypnosis induced sedation is not accompanied by and Psychophysiological Outcomes. In E. miosis. Psychopharmacology, 195(1), 41- Fromm & R. E. Short (Eds.), Hypnosis: Developments in Research and New Perspectives (pp. 296). Piscataway, New Hou, R. H., Scaife, J, Freeman, C, Langley, R. Jersey: Rutgers. W., Szabadi, E, & Bradshaw, C. M. (2006). Relationship between sedation Teasdale G, Knill-Jones R, van dS. (1978). and pupillary function: Comparison of diazepam and diphenhydramine. British impaired consciousness and coma. J Journal of Clinical Pharmacology, 61(6), Neurosurg Psychiatry, 07;41(7):603-10. Larson M. D., & Muhiudeen I. (1995). Wilson, S. F., Amling, J. K., Floyd, S. D., & Pupillometric analysis of the ‘absent light McNair, N. D. (1988). Determining reflex'. Arch Neurol. 04;52(4):369-72. assessments of pupillary size and Larson, M. D., & Sessler, D. I. (2012). reaction. The Journal of Neuroscience Pupillometry to guide postoperative Nursing: Journal of the American analgesia. Anesthesiology, 116(5), 980- Association of Neuroscience Nurses, 20(3), 189-192. Martínez-Ricarte F, Castro A, Poca M. A., Sahuquillo J, Expósito L, Arribas M, et al. (2013). Infrared pupillometry. basic principles and their application in the non-invasive monitoring of neurocritical patients. Neurologia. 01/20;28(1):41-51. Ordas-Bandera, C. M., Sanchez-Marcos, C, Janeiro-Lumbreras, D, Jimenez-Martin, M. J., Muniz-Castrillo, S, Cuadrado- XULAneXUS: Xavier University of Louisiana's Undergraduate Research Journal J. Schinetsky et al.
Figure 1: Pupillary Light Reflex Mechanism
(Illustration by Jeffrey Quach; adapted from Barrett, Barman, Boitano, & Brooks, 2016)
Special thanks to our research mentor, Dr. Jessica Johnson, for her constant This work is licensed under the Creative encouragement and leadership. Also, thank you Commons Attribution-Noncommercial-No to the physicians and fellows of the Louisiana Derivate Works 3.0 License. To view a copy of State University School of Medicine, Section of this license, visit: Pulmonology and Critical Care Medicine, for their partnership in project design. XULAneXUS: Xavier University of Louisiana's Undergraduate Research Journal

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