Pupillary Dilation in Research: More than Meets the Eye

Abstract

Pupil dilation is a commonly used procedure in vision research. While often considered a minimal risk procedure, there is the potential for significant adverse effects. Currently, there is variance in practices and protocols among researchers and institutions, perhaps due to a lack of guidelines for safe pupil dilation practices in research settings. In this perspective, we explore variables that can increase the potential for adverse effects and provide suggestions to limit their impact. Prior to dilation, an investigator can assess an individual’s medical status and drug regimen when deciding upon a mydriatic agent to be used. Assessing the angle through a variety of methods (i.e. penlight test, van Herick slit lamp, optical coherence tomography, gonioscopy) can also prevent inappropriate dilation of pupils with concerning anatomical features. During dilation, an investigator should look to limit the potential of infection and use caution in repeat dosing of dilation-resistant pupils. Post-dilation, an investigator should closely monitor eyes with elevated risk factors and improve an individual’s health literacy on angle closure complications. When combined with proper informed consent processes regarding adverse effects, the aforementioned can allow for risk mitigation in studies using pupil dilation.

Introduction

Mydriatic agents are commonly used in vision research for pupil dilation. While this is often viewed as a minimal risk research activity, there is the potential for serious adverse events. According to regulations that govern research in the United States, minimal risk is defined as, “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” ¹ This is important as minimal risk research can undergo expedited review by an IRB. Risk level also determines whether parents give permission for a child to participate in research, if one or both must give permission, and in some cases, whether the IRB can even approve the research in the first place. Nevertheless, a previous study noted significant variation among institutions and vision researchers regarding screening for potential adverse effects prior to dilating participants.² The potential for adverse effects with pupil dilation can stem from both medical and demographic variables.^3–6 For instance, allergic reactions, pregnancies, certain chronic medical conditions and interactions among the drugs used to treat them may lead to an increased propensity for adverse events. Albeit rare, an individual’s specific anatomical characteristics can also increase the likelihood for perhaps the most well-known adverse effect from pupil dilation: acute angle closure.^7–9 Accounting for these variables prior to dilating research participants may lessen the potential for adverse outcomes and keep the procedure in line with minimal risk designations.

Minimizing risks associated with dilation should also incorporate protocols to address potential pitfalls during the administration of dilating agents. This can include the implementation of proper hand hygiene,¹⁰ accounting for the angle at which a dilating drop is applied,¹¹ punctal occlusion to limit systemic absorption,¹² and avoiding multiple instillations with the same mydriatic.^13–15

After dilation, investigators can further minimize dilation risks with post-dilation protocols. For instance, post-dilation practices should ideally include assessment of intraocular pressure and/or anterior chamber assessment, to ensure the absence of angle closure. While the absolute risk of angle closure is low, taking into consideration personal risk factors that increase the relative risk of angle closure is important to help minimize risk. However, this may not be feasible in all research settings. In these instances, an investigator should look to educate research participants on the signs and symptoms of angle closure to allow for faster recognition of angle closure events.^7,16 Regardless of how the angle is assessed post-dilation, having a detailed plan for what to do with any emergent complications is critical to appropriately minimize risks for the participant.

Despite there being established methods to identify individuals at risk for these complications, there are currently no standardized guidelines specifically for researchers to mitigate risk associated with pupillary dilation. While there is some commentary regarding proper administration of eye drops in a clinical setting, these resources lack in-depth discussion of assessing and educating a patient before and after administration.^17,18 Additionally, these recommendations are not tailored to research settings where discussion may be adjusted to reflect varied risk/benefit to the individual. In this perspective, we propose potential practices as a resource for researchers in conducting human participant research involving pupillary dilation. These practices fall into four general categories: 1) identifying individuals at risk for complications prior to dilation, 2) steps for reducing risk associated with the dilation procedure, 3) steps to monitor for possible complications during and following dilation, and 4) materials informing research participants of potential risks associated with pupillary dilation.

Identifying Individuals at Risk for Complications Prior to Dilation

First and foremost, risks can theoretically be minimized by enrolling individuals who would be dilated as a result of a clinic visit (as one would presume that the eye care provider appropriately assessed whether it was safe to dilate the patient in clinic). This would require an adjustment in timing of the informed consent process, as the ability to clearly read informed consent documents would be compromised (as dilation is usually accompanied with the use of cycloplegic drops which affects accommodation). However, the research team still would need to be trained in recognizing signs and symptoms of possible dilation complications regardless of whether individuals were dilated with an eye care provider. That said, exclusively enrolling patients who will already be in a dilated state minimizes risk from the perspective of the research protocol but may decrease eligible participant pools. Another consideration to take with predilated individuals includes logistical concerns of decreased pupil dilation due to the time it takes an individual to present for a study. Minimized risk does not equate to complete absence of risk and certain adverse effects, such as angle closure and/or allergic reaction, may occur several hours post dilation.^7,19 Furthermore, clinically dilated individuals are obviously not an option for studies that do not enroll from clinic populations.

Adverse Effects

To assist a researcher in properly screening individuals for low risk, we created a flowchart that can uncover individuals with the lowest-risk eyes (Figure 1). Individuals with the lowest risk include those without previous history of allergic reaction, those who are not pregnant or nursing, those without medical conditions and medications that may negatively interact with dilation agents, and those without concerning anterior segment anatomy that places them at increased risk for angle closure.^3–6 Eyes with the lowest risk also includes those that have had safe historic dilation. We therefore suggest that lower risk eyes can also include those that have been safely dilated within the past 6 months. The potential for complications between the concerning medical conditions and medications with dilating agents such phenylephrine, cyclopentolate, tropicamide, and atropine is shown in Table 1. This table can be used to aid a researcher through the prescreening flowchart for the lowest-risk eyes. Taking these factors into consideration will allow for the proper selection of a mydriatic agent for a given participant and their individual variables.

Figure 1.

A flowchart depicting an initial screening process to minimize risks associated with pupillary dilation of individuals participating in research studies.

Table 1.

Potential risk factors for commonly used mydriatic agents.

Variable	Phenylephrine	Cyclopentolate	Tropicamide	Atropine
For individuals with the following conditions or variables:
cardiovascular disease	10% preparation contraindicated (a5; c60–62; d63)	Utilize	Utilize	Utilize (b64) with caution (a6; c47; e65; b66)
thyrotoxicosis/hyperthyroidism	10% preparation contraindicated (a5,c61)	Utilize	Utilize	Utilize with caution (c67)
Down syndrome	Utilize	Utilize with caution (a3; b68; f26)	Utilize with caution (b68; f26)	Utilize (g69; b70; c47) with caution (b68, 71; f26)
pediatric age group	10% preparation contraindicated in individuals < 1 year old. (a5; c60,61) Caution in individuals <5 years old. (c61) Microdrop dose in infants. (c45; b72,73)	Precaution or avoidance (a3; b41; e74; d75) when <6 years old, low body mass index (b15). Microdrop dose in infants (b73).	Utilize Microdrop dose in infants (b72).	Avoid when <3 months old (a6). Precaution or avoidance when <7 years old (b41). Low dose in adolescence (b41).
Pregnant or nursing	Avoid (a5)	Avoid (a3)	Avoid (a4)	Avoid (a6)
Previous allergic reaction	Avoid (b21; d19,22)	Avoid (d20)	Avoid (d19)	Avoid (b57)
For individuals taking the following medications:
carbachol	Utilize	Avoid (a3)	Avoid (a4)	Precaution or avoidance (b76)
pilocarpine	Utilize	Avoid (a3)	Avoid (a4)	Precaution or avoidance (b77)
ophthalmic cholinesterase inhibitor	Utilize	Avoid (a3)	Avoid (a4)	Precaution or avoidance (b78)
atropine	Avoid (a5)	Precaution or avoidance (c79)	Precaution or avoidance (c79)	------------
atropine-like drugs	Avoid (a5)	Precaution or avoidance (c79)	Precaution or avoidance (c79)	Avoid (b80,81)
monoamine oxidase inhibitors	Precaution or avoidance(c61,62; f82)	Utilize	Utilize	Avoid (a6)
tricyclic antidepressants	Precaution or avoidance (c61,62; f82; b83)	Utilize	Utilize	Utilize with caution (b84)

Effects are listed with their associated citation. Alphabetical letter designates type of literature as follows: a = drug label package inserts, b = original article, c = literature review, d = case report, e = case series, f = textbook, g = opinion.

The flowchart (Figure 1) begins with an assessment of pregnancy status and previous experiences with mydriatic agents. One approach to minimize the likelihood of allergic reaction would be to exclude anyone with a history of an allergic reaction to mydriatics from studies requiring their use.^20–22 When being used as part of trials/studies that offer potential benefit to the research participant, the overall risk/benefit analysis should be assessed in consultation with a physician and take into account the type and severity of the prior allergic reaction. For women who may be pregnant and/or nursing, the effects that may arise to the mother and/or infant as a result of the dilating agents are unknown. Thus, it would be generally advisable to avoid pupillary dilation of pregnant participants for minimal risk studies or studies that do directly require this population. This can be assessed through self-reporting, provided it is explained to the prospective participant that the risks to their infant are unknown – so an answer of “I am not sure” should be taken as “Yes” and dilation would not be advisable. One caveat about relying on self-reporting comes with studies involving minors. A sexually active 17-year-old female may be reticent to answer such a screening question in front of her parent(s), thus it is important to have a separate assent conversation with the minor as part of the overall consent process.

Certain medical conditions and states have also been seen to contribute to adverse events associated with dilating agents. These include conditions revolving around cardiovascular disease, thyrotoxicosis, Down syndrome, and being a part of a pediatric age group (Table 1). As with any medication, the potential for drug interactions is present. Table 1 also provides the researcher with insight on drugs with the potential to precipitate an adverse event when used with select mydriatics. These include carbachol, pilocarpine, ophthalmic cholinesterase inhibitors, atropine, atropine-like drugs, monoamine oxidase inhibitors and tricyclic antidepressants. Given the availability of various dilating agents and the equal effort required to administer them, screening for these potentially interacting conditions and medications is a practical step to minimizing overall risk. However, such screening was reported as standard practice by only 71% of researchers in a previous study.²

Ocular Risk Factors

The last step of Figure 1 looks for any historical adverse events regarding pupil dilation and considers further anterior segment assessment to determine potential risk. Some researchers may not have the ability to utilize individuals dilated in a clinical setting for their study. In these cases, if an individual has been safely dilated recently (~6 months), it could be assumed that they are not at risk for complications from dilation. If not, then it is important to assess the ocular anatomy (in particular the anterior segment) prior to dilation. Surprisingly, in a recent survey, only 64% of vision researcher respondents reported examining the anterior segment, in any form, prior to dilation.² There are several techniques available for examining the anterior segment, though they range widely in accuracy, complexity, and cost. A proposed screening flowchart for imaging higher risk eyes is shown in Figure 2 and includes addressing traits and anatomical features associated with an increased risk of angle closure. To account for the variable sensitivity and specificity of these methods, we suggest a sequential screening process with lower effort, less accurate methods for individuals without risk factors and more laborious, accurate methods for individuals deemed higher risk. Higher risk pupils can be defined by the presence of risk factors that elevate the risk of an angle closure event such as Asian or Inuit ethnicity, female sex, family history of glaucoma,^8,23 advanced age,^23,24 hypermetropia,²³ cataracts,²⁵ and conditions that predispose to forward lens displacement (i.e. Marfan syndrome or homocystinuria induced ectopia lentis).²⁶

Figure 2.

A flowchart for assessing anterior segment anatomy in the research setting.

The first method of screening is the penlight method, which estimates a narrow angle by observing the shadow cast by a light-source placed temporally and in the horizontal plane of the iris (Figure 3).²⁷ A possible narrow angle can be detected when ≥50% of the nasal iris is in shadow. While easy to utilize in practice, the subjective nature and inconsistent definitions of a “narrow angle” result in variable study sensitivity and specificity. One study²⁸ found the penlight method to have a sensitivity and specificity of 89% and 88% respectively when discerning between eyes with an anterior chamber depth (ACD) of >2 mm or ≤2 mm. Thomas et al.²⁹ found the penlight method to provide a sensitivity and specificity of 45.5% and 82.7% respectively compared to gonioscopy with a custom grading scale. He et al.³⁰ noted a sensitivity and specificity of 76.3% and 80.7% respectively using gonioscopy with a modified Shaffer grading system for reference. Nevertheless, for researchers who do not routinely examine the angle due to lack of access to expensive equipment and/or trained personnel, the penlight method may have value in minimizing risks in individuals without significant risk factors for angle closure and has been suggested as an alternative in the literature.³¹

Figure 3.

An illustration of the penlight test. The pupil is illuminated temporally with a penlight (blue flashlight in the diagrams), and the amount of shadow in the nasal iris can be graded as outlined by Elliott (2014).⁹⁴ (A) An iris without shadow over the nasal iris suggests improbable angle closure (Grade 4). (B) An iris with 25% of the nasal iris in shadow indicates that angle closure is unlikely (Grade 3). (C) An iris with 50% of the nasal iris in shadow indicates possible angle closure (Grade 2). (D) If 75% or more of the nasal iris is in shadow, angle closure is highly likely or certain (Grade 1 or 0). Figure adapted from Elliott (2014).⁹⁴

For individuals with traits that correspond to a higher risk of angle closure, the use of more accurate screening measures should be employed. These methods are illustrated in Figure 4 for an individual with an open angle and an individual with a narrow angle. The current gold standard for determining anterior segment anatomy and the commonly used reference when measuring the accuracy of other methods of screening is gonioscopy.³² For gonioscopy, an individual with a narrow angle can be defined through being unable to visualize at least 180° of 360° of the trabecular meshwork in an individual.³³ This method requires specialized equipment and skilled personnel who use direct applanation and a mirrored gonioscope to examine the angle directly - resources not available to all researchers. The use of a slit lamp with van Herick’s indirect method could provide useful screening in this elevated risk population. Vargas and Drance²⁸ defined a narrow angle as van Herick Grades I and II and noted a sensitivity and specificity of 82% and 84% respectively when using an ACD of ≤2 mm as the reference for shallow chambers. Thomas et al.²⁹ defined a narrow angle as van Herick Grade I and noted a sensitivity and specificity of 61.9% and 89.3% when using gonioscopy with a custom grading scale as reference. Dabasia et al.³⁴ noted a sensitivity and specificity of 80% and 92% respectively when using ISGEO gonioscopic classification of primary angle closure for reference and the equivalent of van Herick Grade II as the cut off for narrow angles. Furthermore, Dabasia et al.³⁴ find that combining a clinical opinion of occludable angles rather than the ISGEO classification, Smith’s method (cutoff of ≤2.50 mm for narrow angles) and a van Herick Grade II equivalent detected 100% of narrow angles. Lastly, when Park et al.³⁵ compared van Herick (angle closure defined cutoff of van Herick Grade I) to a gonioscopically defined angle closure (posterior pigmented trabecular meshwork not visible) the sensitivity (temporal: 92%; nasal 96%) and specificity (temporal: 0.90; nasal: 100%) was excellent.

Figure 4.

Methods of checking the angle. Top panels illustrate the van Herick method in two eyes with an open (A) and narrow (B) angle. Black line designates corneal thickness and red line depicts depth of anterior chamber. Open angle depicted by >1:1 ratio of anterior chamber depth to corneal thickness. Narrow angle depicted by approximate 1:4 ratio of anterior chamber depth to corneal thickness. Middle panels illustrate gonioscopy in the same eyes with an open (C) and narrow (D) angle. Purple arrows depict iris, green arrows depict ciliary body band, blue arrows depict trabecular meshwork, red arrows depict and Schwalbe’s line. Blue brackets depict the region of visible trabecular meshwork in panel D. An individual at risk of angle closure can be defined by the inability to visualize the trabecular meshwork in ≥180° of the anterior segment. Anterior segment OCT imaging in the same eyes with an open (E) and narrow (F) angle. Iridocorneal angle designated by θ. Angles greater than 20.7° can be considered open, while those less than this would be considered narrow.

Alternatively, optical coherence tomography (OCT) imaging of the anterior segment is an attractive non-invasive screening method in research settings as it would require less training and expertise. Dabasia et al.³⁴ found that an AS-OCT anterior chamber angle (narrow anterior chamber angle defined as ≤20.7°) referenced to gonioscopy with ISGEO definition of primary angle closure yielded a sensitivity and specificity of 87.2% and 86.8% respectively. Looking at temporal and nasal quadrants, Park et al.³⁵ also found that AS-OCT discriminated well for open and narrow quadrants defined by gonioscopy (“narrow angle quadrant” defined when posterior pigmented trabecular meshwork was not visible in ≥60° with or without peripheral anterior synechiae). They found that the area under the curve (AUC) at 500μm and 750μm in angle opening distance (AOD500/AOD750), angle recess area (ARA500/AOD750), and trabecular-iris space area (TISA500/TISA750) was >0.95 for both nasal and temporal quadrants. The AUC for temporal and nasal ACD was 0.93 and 0.96 respectively.³⁵ Narayanaswamy et al.³³ also compared nasal and temporal AS-OCT quadrants to gonioscopy defined narrow angles (narrow angle defined when posterior pigmented trabecular meshwork was not visible for 180°). Their highest noted AUCs in the quadrants were with AOD500 (Nasal/Temporal: 0.88/0.89), AOD750 (Nasal/Temporal: 0.90/0.91), and TISA750 (Nasal/Temporal: 0.87/0.88).

Steps for Reducing Risk Associated with the Dilation Procedure

Even once dilation has been determined to be safe or required based on study population, complications may still occur. Most of these can be minimized through relatively simple techniques. For example, simple hand hygiene or the use of gloves with dilation can lead to a decreased risk of person-to-person microbial transmission.¹⁰ In some countries, single-dose units may be available, which, when properly used, are associated with decreased rates of infection secondary to decreased cross-contamination.³⁶ Punctal occlusion, which consists of applying pressure to the lacrimal puncta of a closed eye for five minutes, can reduce systemic absorption of any topically applied eye drop¹² and is recommended for proper use on cyclopentolate and tropicamide package inserts.^3,4 Lastly, Costa et al.¹¹ recently found that microbial cross contamination can be reduced by instilling drops at a 90° angle and using bottles with a sharp, rather than round, nozzle geometry. When developing protocols for research-exclusive administration of eye drops, these steps are examples of information that can be mentioned to the IRB or funding agencies when asked to “identify features of the project intended to minimize safety risks to subjects”.

Reducing Risk with Repeated Dosing

When utilizing mydriatic agents, investigators may experience variability in the magnitude of dilatory and accommodative effects following administration. For instance, it is known that individuals with darkly pigmented irides can experience slower or incomplete pupil dilation.^37,38 Other concerns can include the time it takes to examine the eye post-dilation, as the intended effects may begin to wear off before the research procedures can commence.^39,40 In these situations, rather than using another drop of the same agent we recommend the use of another agent of preferably another class and at the lowest effective dose. This is a result of the dose-dependent nature of adverse effects that is found with discussed dilating agents.^13,15,41 For individuals with difficulty achieving dilation, a combination of phenylephrine 2.5% and tropicamide 1% can be used if appropriate.^13,14,42,43 Some investigation methods may involve imaging a dilated eye for extended periods of time. For instance, in their study on cone regeneration, Jonnal et al.³⁹ re-applied a dilating agent hourly over the course of 24 hours. In these circumstances, one can consider alternating between agents of a different class (i.e. tropicamide and phenylephrine) to limit systemic absorption of a single agent. This may potentially achieve more satisfactory dilation as well. Park et al.⁴² provide evidence that combined phenylephrine and tropicamide results in greater dilation than repeated drops of either tropicamide or phenylephrine alone. Furthermore, this combination also has evidence suggesting it is at least equivalent to the mydriatic effect of cyclopentolate and tropicamide combined.^14,43 Therefore, alternating between tropicamide and phenylephrine reduces risk by avoiding potential additive anticholinergic effects that can be experienced with repeated application of anticholinergic drops.^14,15 Phenylephrine and cyclopentolate are also shown to provide clinically effective dilation.^44–46 In their systematic review of mydriatics used for screening retinopathy in premature infants, Kremer et al.⁴⁵ note the lowest effective combination regimen consisted of phenylephrine 1% and cyclopentolate 0.2% for this population – lower doses being crucial in this population due to their immature blood brain barrier.

Atropine should not be used as a first line dilating agent in any research study that does not directly require its use. It has a greater systemic side effect profile,⁴⁷ and potential duration of action of up to fourteen days,⁶ thus its use should be reserved for specific situations. Paralysis of accommodation with atropine for 14 days has the potential to be inconvenient for adult research participants, but the effects of blur on children whose visual pathways are developing must also be considered – such blur could be considered amblyogenic, especially if unilateral, and indeed atropine treatment can be used as an alternative to deprivation therapy for amblyopia. The availability of alternative discussed mydriatics with shorter durations^3–5 should preclude the use of atropine, most especially in children except for very specific circumstances.

While the previous recommendations are made for the sole use of obtaining a dilated pupil, some studies may also aim to achieve concurrent cycloplegic effects through the mydriatic agents atropine, cyclopentolate, and/or tropicamide. This often requires multiple instillations of eyedrops, which can increase the potential for dose-dependent adverse effects.^13,15,41 Of the previously mentioned cycloplegic agents, tropicamide is the least likely to precipitate an adverse event.^15,41 Tropicamide is also noted to induce clinically significant cycloplegia as a sole agent in myopic and low to moderate hyperopic children.^48,49 Nevertheless, sole tropicamide use may complicate exams as a result of its shorter duration of action and weaker cycloplegic effects when compared to cyclopentolate,^50,51 which may become evident with children. Additionally, given that an accurate refractive status is unknown until full cycloplegia is obtained, the potential for overlooking significant hyperopia is present in children that are solely administered tropicamide. Currently, there is not a cycloplegic agent that has a rapid onset of action, rapid recovery of normal accommodation, and sufficient cycloplegia without local or systemic side effects.¹⁴ With this in mind, the American Academy of Ophthalmology (AAO) suggests that cyclopentolate 1% be used as the main agent when achieving cycloplegia in children older than 6 months with consideration for individual weight, iris color, and dilation history when determining dose.⁵² In those less than 6 months they suggest a combination of 0.2% cyclopentolate and phenylephrine 1%.⁵² Of note, AAO guidelines⁵² also mention that a combination of tropicamide 0.5% and phenylephrine 0.5% produces, “…adequate cycloplegia and dilation.”

Steps to Monitor for Possible Complications During and Following Dilation

Post-dilation protocols for researchers should include ocular examination to assess for potential angle closure in individuals deemed to be at high-risk prior to dilation. However, a previous study found that none of the questioned investigators examined the angle or intraocular pressure (IOP) after dilation.²

Angle closure complications from pupil dilation commonly occur while the pupil is in a semi-dilated state.^7,8 This state obstructs the outflow of aqueous humor and thus can result in an elevated IOP.⁸ However, even in higher risk individuals the risk of a post dilation angle closure event is low. One study, designed specifically to investigate this risk, did not note any associated angle closure events in their cohort of 78 individuals with narrow angles and visually significant cataracts.⁵³ Nonetheless, low risk does not equate to the absence of risk. Lavanya et al.⁵⁴ demonstrated a 0.64% (n=471) incidence of a dilation induced angle closure crisis in individuals with narrow angles. Furthermore, those events occurred despite administration of prophylactic acetazolamide. Therefore, some post dilation IOP monitoring is indicated in order to detect any sudden increases in IOP as increases ≥8 mmHg should raise concern for an underlying angle closure event. While the literature is limited in discussion surrounding timing and changes in IOP after dilation, and thus likely to vary, Mapstone et al.⁷ provided insight into this in eyes at risk for angle closure. They find that if an eye at risk for angle closure is dilated with tropicamide, any significant increases in pressure (>8 mmHg) will occur within the first hour. However, this short interval was not found to be the case with cyclopentolate, which found significant increases in pressure occurring 6 hours after administration. Phenylephrine on the other hand was not seen to induce angle closure in their study. However, several studies have shown phenylephrine associated angle closure events when used in combination with tropicamide.^16,55 IOP rises in Lavanya et al.⁵⁴ were recorded within 1 hour post dilation, although the 3 participants (0.64%) who developed post-dilation unilateral angle closure did so within a 12 hour window.

Perhaps the fastest preliminary screening method of an angle closure event would be to measure IOP through ocular tonometry. With handheld devices allowing for straightforward use outside of medical settings, an investigator armed with a tonometer can easily obtain post-dilation IOP. Individuals with an elevated IOP should also be questioned on any symptoms they are experiencing. An angle closure crisis will often present with dramatic symptoms including headache, eye pain, nausea, vomiting, redness, and blurred vision with halos around bright lights.⁸ Nevertheless, inducing a subacute angle closure event is also theoretically possible and the individual can often present with milder symptoms, such as an isolated headache.⁵⁶ These subacute events will resolve spontaneously and are not of emergent concern. However, individuals who report intermittent headaches several weeks after, especially associated with dimly lit rooms, should be clinically evaluated. In terms of an acute event, if a patient is found to experience any symptoms and elevated IOP over 21 mmHg, they should be referred to an eye care provider for further evaluation. For investigators without access to tonometry, screening can be accomplished by assessing the angle using the same method used pre-dilation and assessing for any concerning symptoms. While post-dilation assessment would be ideal, it is not infallible and may not be feasible for every researcher. It is therefore imperative that all study participants and investigators be properly educated on the signs/symptoms of angle closure events to allow for proper medical intervention should it arise.

Adverse effects that can occur post-dilation are not limited to angle closure. For instance, symptoms caused by an allergic reaction to a dilating agent can occur hours after use.^19–22 Given the delay associated with an allergic reaction presentation, there is not much that an investigator can screen for other than a history of atopy or allergies. However, an individual who has never had past allergic reactions to drops may also develop allergic reactions with repeat exposure after months or years of use.⁵⁷ Therefore, it is also imperative to educate all research participants on signs/symptoms of an allergic reaction to allow them to seek appropriate medical attention.

Almost all individuals will notice the more common effects of a dilating agents that last for several hours post dilation like photophobia and blurred vision at near.^3–6 These effects are secondary to the desired effects (dilation/cycloplegia) of a topical agent but crucially, can mimic the symptoms of angle closure such as blurring, halos and sensitivity, so should not be dismissed. Research participants should be informed that these effects may remain hours after administration of the drops. As the effects of the agent wear off, participants should be informed of these effects in advance and advised to bring shaded glasses to mitigate these effects, as appropriate.

Educating patients on symptoms that may persist or occur hours after administration should be a necessity. For effects that have significant consequences if left untreated (i.e angle closure) improved health literacy may lead to faster recognition and subsequent treatment and is already suggested as a preventative measure in the literature.^16,58 As mentioned, symptoms of angle closure that the research participant should be aware of include severe headache with severe eye pain, redness, blurry vision with halos around light, nausea and vomiting.⁸ Symptoms of allergic reactions may include itching, burning, periocular erythema, conjunctival hyperemia, eyelid edema^19,20 and/or chemosis.⁴⁷ Should any unanticipated reaction occur, individuals should also be encouraged to communicate them with their primary care physicians to allow for permanent reflection on patient records and allow for accurate assessment in future studies. Educating patients on commonly encountered transient effects is also beneficial as it can serve to reassure and appropriately prepare individuals (i.e., bringing sunglasses, arranging transport, etc.). Common side effects that the research participant should be aware of include blurred vision and sensitivity to light.^3–6

Consideration should be given to how this material is presented. Kessels et al.⁵⁹ have shown that providing simple written and verbal information to patients in a health care setting leads to improved retention. With this in mind, we propose examples of text for research participants (Figure 5). The sample text in Figure 5 discusses situations mentioned above but is not all encompassing. Their intent is to aid investigators and IRBs in creating their own materials.

Figure 5.

Text examples to aid in education of research participants being dilated in research studies.

Materials Informing Research Participants of Potential Risks Associated with Pupillary Dilation

In the absence of standardized guidance, risk information included on informed consent documents has been shown to vary among vision researchers.² This may be due to differences in the research environment – those conducting studies at medical centers or in collaboration with clinicians may be more comfortable summarizing the risks to prospective participants, whereas researchers conducting studies in a non-medical setting (i.e., university lab) may be less so. Remedying this can involve creating a table consolidating adverse reactions associated with mydriatic agents. This would allow members of the research team to quickly reference associated effects when creating an informed consent document. When choosing which risks to include in informed consent documents, it is important to remember that research regulations require that investigators disclose, “any reasonably foreseeable risks or discomforts to the subject.” ¹ This may vary based on the group being studied as well as the mydriatic agent being used. For instance, a study solely involving children that needs to use cyclopentolate may want to include adverse CNS effects that are more commonly seen in this population.^3,15,41 To assist in this process, we provide recommendations in Tables 1 & 2 that IRBs and investigators may find helpful when deciding on relative-risk language to include in an informed consent. Table 2 provides a list of adverse effects found with mydriatics as well as language discussing notable interactions in certain populations.

Table 2.

Potential adverse effects for commonly used mydriatic agents.

Mydriatic agent (drug class)	Adverse effects
Phenylephrine (adrenergic agonist)	Notable Interactions: Phenylephrine 10% is known to produce a higher propensity of adverse cardiovascular effects in individuals with cardiovascular disease, hyperthyroidism, and in infants. Ocular: blurred vision (a5; b13; c61), transient stinging (a5; b13; c61), conjunctival sensitization (a5; c61), photophobia (a5; c61), glare (b13), acute angle closure (c31,61). Non-ocular: allergic reaction (b21; d19,22), headache (a5), nausea (a5), vomiting (a5), anxiety (a5), flushing (b72), increased blood pressure (a5; c73; d63; b72), decreased blood pressure (d85), tachycardia (a5; c45), bradycardia (d85) arrythmia (a5; d63), myocardial infarction (a5; d63), syncope (a5), subarachnoid hemorrhage (a5).
Tropicamide (anticholinergic)	Notable interactions: Tropicamide has a weak affinity for its receptor and is generally seen as safe in all populations (b86–88; c89). Due to its anti-cholinergic class, there is a low potential for adverse anticholinergic effects, primarily in children. There are mixed accounts of increased sensitivity of anti-cholinergic drugs in individuals with Down syndrome. Ocular: blurred vision (a4; b13), transient stinging (a4; b13,40), superficial punctate keratitis (a4), photophobia (a4; b40), glare (b13), increased intraocular pressure (a4; b7), acute angle closure (b7; c31). Non-ocular: tachycardia (a4), nose bleeding (b15), fever (b15), flushing (b15,72), dryness of mouth (a4), nausea (a4), vomiting (a4), headache (a4), increased blood pressure (b72), pallor (a4), muscle rigidity (a4), excitation/behavioral disturbances (a4; b15), central nervous system disturbances (a4; d90), drowsiness (b15), allergic reaction (a4; d19), vasomotor or cardiorespiratory collapse (a4), psychotic reaction (a4; d90), delirium (d90), behavioral disturbances (a4), confusion (d90).
Cyclopentolate (anticholinergic)	Notable Interactions: Cyclopentolate is seen to have an increased propensity of adverse anticholinergic effects, primarily in pediatric populations. There are mixed accounts of increased sensitivity of anticholinergic drugs in individuals with Down syndrome. Ocular: pain with instillation (a3; b40), increased intraocular pressure (a3), blurred vision (a3), photophobia (a3; b40), hyperemia (a3), irritation (a3; b41), blepharoconjunctivitis (a3), conjunctivitis (a3; b41), synechiae (a3), punctate keratitis (a3), acute angle closure (c31). Non-ocular: abdominal distention in infants (a3), fever (a3; b41), flushing (b15,41,72; c74), increased blood pressure (a3; b72), tachycardia (a3; c74), nose bleeding (b15), drowsiness (a3; b 15,41; c74), dizziness (b15), fatigue (c74), nausea (c74), vasodilation (a3), diminished gastrointestinal motility (a3), urinary retention (a3), decreased secretion in salivary, sweat glands, nasal passages, bronchi, and pharynx(a3; c74), allergic reaction (d20), skin sore (b41), ataxia (a3; c74; d75), restlessness (a3; c74; d75), aggression (c74), behavioral problems (b15; c74), hyperactivity (a3; b15,41), seizures (a3; c74), disorientation to time and place (a3; c74), amnesia (c74), failure to recognize people (a3), incoherent speech (a3; c74), hallucinations (a3; c74; d75), medullary paralysis (a3), coma (a3), death (a3).
Atropine (anticholinergic)	Notable Interactions: There is a potential for significant cardiac effects in populations with pre-existing cardiac disease. There is a low potential of adverse cardiac effects in individuals with hyperthyroidism. There is significant potential of adverse anti-cholinergic effects in children. There are mixed accounts of increased sensitivity of anticholinergic drugs in individuals with Down syndrome. Ocular: photophobia (a6; c47), blurred vision (a6), eye pain/stinging with instillation (a6), superficial keratitis (a6; c47), decreased lacrimation (a6; c47), allergic reaction (a6; b57; c47), acute angle closure glaucoma (c47) Non-ocular: dry skin (a6; c47), dry mouth (a6; c47; b86), dry throat (a6; c47), restlessness (a6; c47), irritability (a6; c47), delirium (a6; c47; d91), hallucinations (c47; d91), confusion (c47), drowsiness (c47), ataxia (c47), coma (c47), tachycardia (a6; c47; e65; b84), bradycardia (b66,92,93), atrial fibrillation (e65), hypertension (a6), hypotension (c47; e65), flushed skin of face/neck (a6; c47; b41 86), fever (c47; b41,86), death (c47), vomiting (b86).

Effects are listed with their associated citation. Alphabetical letter designates type of literature as follows: a = drug label package inserts, b = original article, c = literature review or meta-analysis, d = case report, e = case series.

Conclusions

Pupil dilation is known to be a safe procedure when dilating the general population. However, extra care should be taken in the research setting when dealing with individuals who have factors placing them at elevated risk. This can be accomplished through simple screening measures that assess the relative risk for interaction between medications, personal health status and history, and anatomical features. Further risk mitigation can include thoughtful standardized practices during and after administration of the dilation drops. Lastly, careful post-dilation monitoring and proper education of research participants may lead to faster recognition of complications while concurrently dispelling concerns over expected effects.

Data Availability Statement:

The data that support the findings of this study are available from the corresponding author (JC) upon reasonable request.