Assessing the utility of 2.5% phenylephrine for diagnostic pupillary dilation

Abstract

Objective:

To evaluate whether the addition of phenylephrine to tropicamide produces any clinically significant change in pupil size during diagnostic eye examination.

Methods:

Twenty healthy adults at the Washington University School of Medicine Eye Clinic were enrolled in this prospective, nonrandomized, crossover trial. Each had 3 dilating eye drop regimens administered to the left eye on separate days. Tropicamide (T) + proparacaine (PP) + phenylephrine (PE) (T+PP+PE) was considered the standard therapy, to which tropicamide alone (T alone) and tropicamide + proparacaine (T+PP) were compared against. Main outcome measures were postdilation pupil size and proportion of pupils able to achieve adequate clinical pupil dilation of >7 mm. Comparisons were made using Wilcoxon signed-ranked tests and McNemar’s test.

Results:

Mean postdilation pupil size was 7.94 ± 0.78 mm, 7.64 ± 0.78 mm, and 7.48 ± 0.77 mm for T+PP+PE, T+PP, and T alone, respectively. T+PP+PE was statistically superior to T+PP (p = 0.004) and T alone (p > 0.001) with respect to postdilation pupil size. The proportion of pupils able to achieve adequate pupil dilation of >7 mm was 90%, 80%, and 70% for T+PP+PE, T+PP, and T alone, respectively. No statistical difference was observed in each regimen’s ability to achieve adequate pupil dilation of >7 mm (T+PP+PE and T+PP: p = 0.47; T+PP+PE and T alone: p = 0.13).

Conclusion:

The addition of phenylephrine eye drops to tropicamide produced larger pupil dilation, but the magnitude of benefit was marginal and clinically insignificant in this young, healthy cohort. A single-dilating-agent regimen using tropicamide could be considered in routine clinical practice.

Diagnostic pupillary dilation is essential for comprehensive evaluation of the eye. The American Academy of Ophthalmology recommends comprehensive eye examinations to screen for vision-threatening conditions at least every 2–4 years in adults aged above 40 years, with even more frequent examinations in patients with systemic and ocular diseases such as diabetes mellitus, glaucoma, and macular degeneration.^1,2 To achieve the pupillary dilation necessary to effectively evaluate the structures in the back of the eye, it is common practice to use a dual-dilating-agent regimen with phenylephrine and tropicamide, as the 2 medications dilate the pupil by different mechanisms (i.e., tropicamide inhibits the iris sphincter via parasympathetic control, whereas phenylephrine activates the iris dilator via sympathetic control).³ Because of the unique mechanisms by which tropicamide and phenylephrine work, one would assume a pharmacologic synergism to their use in combination. Yet few studies have evaluated the degree to which this expected synergism translates into standard clinical practice.

The question of how much clinical benefit there is in a dual-dilating-agent regimen has become an increasingly salient one in light of the recent rise in phenylephrine prices. At Washington University Eye Clinic, the cost of tropicamide has remained relatively stable, with a current price of $6.50 per 15-mL bottle. In contrast, the cost of phenylephrine peaked at $140 per 15-mL bottle over the last 2 years. This represents more than a 50-fold increase from just a few years earlier, when the price per bottle was as low as $2.75. The price increase comes largely as a result of a single pharmaceutical manufacturer winning formal FDA approval for ophthalmic phenylephrine hydrochloride as a “new” drug, in effect ending the generic status of the medication and pushing other large manufacturers without FDA approval out of the market.⁴

This development comes at a time when the frequency of recommended ophthalmic screening examination already falls well short of adequate. For example, only about 50% of patients with diabetes in the United States are receiving comprehensive annual eye examinations for early detection and treatment of diabetic retinopathy.⁵ In this setting, where convincing patients to adhere to recommended screening guidelines is already an uphill battle, the sizable increase in the price of phenylephrine may further affect eye examination accessibility and quality. Additionally, the growing emphasis on efficient resource allocation and reduction of medical waste places a needed pressure to scrutinize any outdated medical practices that increases cost without adding clinical value.

Given these recent escalations in phenylephrine prices, there is growing consideration for alternative dilating regimens that preclude the use of phenylephrine altogether. Yet there is a paucity of published data regarding the viability of these alternatives. In particular, hardly any studies have compared combination therapy to single-dilating-agent regimen using tropicamide alone. One study compared the efficacy of 1% tropicamide alone, 2.5% phenylephrine alone, and a combination therapy of the 2 medications⁶. In that study, 50 patients were divided into 3 treatment groups based on the aforementioned dilating regimens and maximal pupil size was compared. The therapies were not repeated on the same patients, thereby introducing variability among individual responses to dilating drops. The study demonstrated that 2 drops of tropicamide produced a larger pupil size compared to 1 drop each of tropicamide and phenylephrine, though the results were not statistically significant and the difference in pupil sizes was not quantified. Interestingly, the authors suggested that combination therapy might still be more effective, despite their own evidence to the contrary.

A second study evaluated the efficacy of 10% phenylephrine alone against 10% phenylephrine plus 1% tropicamide.⁷ The authors’ conclusion also supported combination therapy, as it produced a mean pupil size of 8.0 mm compared to 6.9 mm with single-agent therapy. However, there was no statistical difference in either regimen’s ability to achieve >6-mm dilation, a generally accepted size of adequate pupil dilation for diagnostic examination.⁸ Additionally, tropicamide alone was not evaluated in this study despite evidence that it has a shorter latency period to dilation and produces a larger amount of dilation compared to phenylephrine alone.⁹

The current state of phenylephrine pricing has necessitated a critical eye in regard to its routine use. The present study evaluates the clinical benefit of including phenylephrine eye drops under typical dilated eye examination conditions and compares it to dilating regimens that preclude its use altogether.

Methods

This prospective, nonrandomized, crossover study was conducted at the Washington University School of Medicine with 20 healthy students and faculty affiliated with the institution. All study participants were free from any ocular disease other than refractive error. None were taking any medications known to affect pupil size. A minimum corrected vision of better than 20/40 for all participants was required and verified by an initial screening eye examination. The Institutional Review Board of the aforementioned medical centre approved the study before participants were recruited. The study was compliant with the Health Insurance Portability and Accountability Act, and informed consent was obtained from all participants.

Dilating Regimens

One of 3 eye drop regimens was instilled into the left eye only (intervention eye). T+PP+PE consisted of 1% tropicamide [Akorn Inc, Lake Forest, IL] + 0.5% proparacaine hydrochloride [Akorn Inc] + 2.5% phenylephrine hydrochloride [Akorn Inc]. This triple-drop therapy is considered the standard therapy at the Washington University Eye Center and was the “gold standard” to which statistical comparisons were made. T+PP consisted of 1% tropicamide + 0.5% proparacaine hydrochloride, and T alone consisted of 1% tropicamide.

A single drop of each agent was used in the prescribed regimen and delivered into the conjunctival sac of the left lower eyelid. Proparacaine was administered first if indicated by the prescribed dilating regimen (T+PP PE and T+PP). For these multidrop regimens, an interval of approximately 15 seconds was used between each eye drop. Although previous studies have recommended longer intervals for optimal pharmacologic effect of these medications,^10,11 we chose a time interval that closely resembles the clinical experience seen at Washington University Eye Clinic. Our priority was evaluation under typical clinical conditions, potentially at the expense of optimal pharmacology. Subjects were instructed to refrain from squinting and to tilt the head backward in order to avoid unintended loss of medications. The right eye (control eye) did not receive any drops and served as an internal control for possible environmental and systemic influences.

Measurements

Study participants were asked to sit in a darkened examination room for 5 minutes to allow pupils to dark-adapt. They were then asked to fixate their vision on an object 20 feet away to control for any accommodative effects on pupil size. After 5 minutes of dark adaptation, baseline pupil sizes were measured (predilation measurements). Automated measurements were taken with a NeurOptics PLR-200 pupillometer, which utilized a self-contained infrared illumination source and internal digital camera to record pupil size. Resting pupil diameter was first measured. Subsequently, a standardized light stimulus from the pupillometer with an intensity of 180 microwatts and duration of 30 milliseconds was presented to stimulate pupil constriction. Constricted pupil diameter was then measured at the point of maximal pupil constriction. A total of 3 repeated measurements were taken at approximately 15-second intervals in each eye and the results averaged. Resting and constricted pupil sizes were again measured at 30 minutes after eye drop administration (postdilation pupil size) using the pupillometer and the procedure described above.

Each participant returned to the examination room on 2 additional days, upon which a different eye drop regimen was administered utilizing the standardized measurement procedure previously outlined. A period of at least 24 hours in between each visit was required to help eliminate any lingering effects of previous dilation. The sequence of regimens and their administration is provided in Figure 1.

Fig. 1.

Sequence of dilating regimen administration. All 3 regimens were administered to each participant with at least 24 hours in between each intervention.

Statistical Analysis

Constricted pupil size served as the best surrogate for true examination conditions. Consequently, primary outcome measures included postdilation constricted pupil size and proportion of pupils able to achieve a postdilation constricted pupil size >7 mm. Paired t tests were used to compare these outcome measures between T+PP+PE against T+PP and T alone. McNemar’s test with a threshold of pupil size >7 mm was used to compare the clinical benefit of T+PP+PE against T+PP and T alone. Both 6 and 7 mm have been used in the literature as values considered to represent adequate pupillary dilation for diagnostic and surgical settings.^7,8,12–15 We chose to use the more rigorous 7-mm threshold in our analysis. Secondary measures included net change in pupil size (pre- to postdilation difference) in the intervention eye. Additionally, inferiority testing was conducted with threshold of 1 mm, with T+PP+PE serving as the standard therapy to which T+PP and T alone were compared.

Statistical analyses of measurements for the control eye were made to evaluate for any intertesting variability and systemic effects. Comparisons of predilation measurements (resting and constricted) were made using a repeated measures model taking into account that the 3 regimens were given to the same 20 participants. Paired t tests by regimen were used to evaluate for nonzero change between pre- and postdilation resting and constricted pupil size of the control eye. Correlation testing between changes in pupil size of the control eye to primary outcome measures of the intervention eye was also performed.

Data were analysed using SAS V9.3. All data were completely de-identified; participants were identified by a numerical assignment in accordance with the IRB protocol.

Results

A total of 20 participants were included in this study. There was 100% retention of participants across the 3 study regimens. The age range was 23 to 43 years, with a mean of 26.9 ± 4.1 years, including 2 participants of at least 30 years old (30, 43). Demographic information and predilation measurements are presented in Table 1.

Table 1.

Demographic information and predilation measurements

	T+PP+PE	T+PP	T alone
No. of participants	20	20	20
Age, years	23–43	23–43	23–43
Sex (M:F)	14:6	14:6	14:6
Race, n (%)
Asian	12 (60)	12 (60)	12 (60)
White	6 (30)	6 (30)	6 (30)
Black	1 (5)	1 (5)	1 (5)
Latino	1 (5)	1 (5)	1 (5)
Eye color, n (%)
Brown	18 (90)	18 (90)	18 (90)
Blue	1 (5)	1 (5)	1 (5)
Green	1 (5)	1 (5)	1 (5)
Predilation measurements, mm (mean ± SD)
Resting pupil size OS	6.14 ± 0.79	6.06 ± 0.95	5.99 ± 0.88
Resting pupil size OD	6.19 ± 0.86	6.08 ± 1.08	6.02 ± 0.93
Constricted pupil size OS	4.18 ± 0.73	4.10 ± 0.85	4.06 ± 0.77
Constricted pupil size OD	4.26 ± 0.74	4.16 ± 0.98	4.15 ± 0.84

T, tropicamide; PP, proparacaine; PE, phenylephrine

No statistically significant difference was seen in predilation measurements between the different testing regimens. Additionally, there was no statistically significant difference between any of the measurements (pre- and postdilation) in the control eye across the 3 regimens. An average change between pre- and postdilation pupil size of the control eye of less than 0.11 mm was found within all 3 groups. Furthermore, no correlation could be found between change in constricted pupil size in the control eye and primary or secondary measurements on the intervention eye. Consequently, all further statistical analysis will focus on the intervention eye alone.

Measurements of the intervention eye taken at 30 minutes after dilating drop administration are provided in Table 2. The mean constricted pupil size of T+PP+PE was statistically different compared to both T+PP (p=0.004) and T alone (p < 0.001). With T PP PE, 18 participants (90%) were able to achieve a pupil size >7 mm, whereas T+PP and T alone were able to produce that result in 16 (80%) and 14 (70%) participants, respectively. This distribution is shown in Tables 3 and 4. There was no statistically significant difference between T+PP+PE and T+PP (McNemar’s χ²= 0.5, p = 0.47) or between T+PP PE and T alone (McNemar’s χ²=2.25, p=0.13) in the proportion of pupils achieving a pupil size of >7 mm. When comparing the change in constricted pupil size (i.e., difference between pre- and postdilation constricted pupil size), T+PP+PE was statistically superior to T alone (p = 0.02), but no statistically significant difference was observed when compared to T+PP (p = 0.06). Finally, both T+PP (p < 0.001) and T alone (p = 0.02) demonstrated noninferiority to T+PP+PE, using a 1-mm threshold.

Table 2.

Postdilation measurements and net change in pupil size of the intervention eye (OS)

	T+PP+PE	T+PP	T alone
Postdilation measurements OS, mm (mean ± SD)
Resting pupil size	8.21 ± 0.71	7.94 ± 0.69	7.88 ± 0.67
Constricted pupil size	7.94 ± 0.78	7.64 ± 0.78	7.48 ± 0.77
pre- to postdilation change in pupil size OS, mm (mean ± SD)
Change in resting pupil size	2.07 ± 0.46	1.89 ± 0.49	1.89 ± 0.54
Change in constricted pupil size	3.76 ± 0.56	3.54 ± 0.58	3.42 ± 0.50

T, tropicamide; PP, proparacaine; PE, phenylephrine.

Constricted pupil size represents measurements after light stimulus.

Table 3.

Proportion of pupils that dilated >7 mm for T+PP+PE and T+PP

T+PP+PE	T+PP
	≤7 mm	>7 mm	Total
≤7 mm	2	0	2
>7 mm	2	16	18
Total	4	16

T, tropicamide; PP, proparacaine; PE, phenylephrine.

Table 4.

Proportion of pupils that dilated >7 mm for T+PP+PE and T alone

T+PP+PE	T alone
	≤7 mm	>7 mm	Total
≤7 mm	2	0	2
>7 mm	4	14	18
Total	6	14

T, tropicamide; PP, proparacaine; PE, phenylephrine

Of the 3 groups, T+PP+PE was able to produce the largest dilation in 17 of the 20 participants. T+PP produced the largest pupil size in 4 of 20 and T alone produced the largest pupil size in 1 of 20. There were 2 instances where the largest pupil size was equivalent between 2 regimens. Figures 2 and 3 illustrate postdilation sizes organized by individual response and dilating regimen, respectively.

Fig. 2.

Individual response in postdilation constricted pupil size to each of 3 dilating regimens.

Fig. 3.

Distribution of postdilation constricted pupil size for each dilating regimen. Lines connect measurements belonging to individual participants.

Discussion

The growing movement toward reducing medical excess and providing effective resource allocation has forced providers to reassess potentially outdated protocols and procedures common in daily practice. In the current study we examined the clinical benefit of phenylephrine eye drops for diagnostic dilated examination. Over the past 5 years, phenylephrine prices have increased as much as 50-fold at our institution, which reflects the national experience.⁴ These recent increases, when taken in aggregate, could be considerable. Although the use of phenylephrine for routine diagnostic examination is typical, the limited literature exploring its effects does not support its utility.^6,7,9 Thus, we questioned whether it provided enough clinical benefit to justify its routine use in the setting of escalating costs.

Although there appears to be a statistical difference in mean pupillary dilation when using phenlyephrine in addition to tropicamide and proparacaine, the real-world clinical benefit appears negligible. A mean difference of only 0.30 mm was found in the postdilation constricted pupil size between T+PP+PE (tropicamide + proparacaine + phenylephrine) versus T+PP (tropicamide + proparacaine). Additionally, with a conservative target pupil size of >7 mm, there was no statistically significant difference in the proportion of pupils able to achieve that target between any of the 3 regimens tested.

T alone (tropicamide alone) performed the worst out of the 3 groups, but still only trailed T+PP+PE by a mean difference of less than 0.5 mm in postdilation constricted pupil size. It was noted that, in the absence of proparacaine, study participants subjectively experienced sizable discomfort, potentially leading to increased tearing and propensity to squint. This may explain the relatively weaker performance of T alone. Additionally, proparacaine may potentiate dilating agents by disrupting the corneal epithelium, leading to greater absorption of eye drop medications and more effective dilation.^16–18 For these reasons, proparacaine is typically instilled before tropicamide and our results support this standard practice.

These observations could have clinical consequences on the standard dilated eye examination. In addition to the burden of the aforementioned cost of phenylephrine drops, eliminating exposure to unnecessary medication abrogates the potential for unwanted side effects. Although rare, allergic reactions to phenylephrine eye drops, systemic cardiovascular effects, and acute angle closure glaucoma have been reported and pose an unnecessary hazard upon at-risk patients,^19–22 particularly if there is no clear clinical benefit to adding phenylephrine for diagnostic dilation. These study results may offer a compelling reason to remove those risks, as sufficient conditions for examination can still be achieved without phenylephrine eye drops in certain patient populations.

It has been shown in previous studies that maximal pharmacologic effect of multiple eye drops requires a longer instillation time than the 15-second interval this study utilized in between drop administration.¹¹ The rationale for using this interval was to develop a procedure that best reflects standard clinical practices at our institution. In our experience, waiting for at least 5 minutes in between drops, as some studies have suggested, is not common in the clinical setting. Our focus was on the practical benefit of phenylephrine drops in the setting of typical examination, rather than evaluation under ideal pharmacologic conditions.

The relatively narrow demographics of the patient population do hinder the generalizability of these results. The majority of participants were younger than 30 years. These subjects may represent a subset of the general population with a more robust sympathetic tone when compared to the elderly or those with autonomic dysfunction, such as diabetic patients.¹² As a consequence of the small sample size and homogeneity of the subjects, the current study was unable to address how demographic factors may affect the pupillary response to dilating regimens with and without phenylephrine. Additionally, other measures such as patient discomfort, time to maximal dilation, and time to normalization of vision would be valuable measures to investigate in the future.

The shortcomings of this pilot study could be addressed by a larger randomized, controlled study with a cohort that not only is more diverse in demographics, but also expands beyond the healthy patient population. Because those with ocular disease are recommended to have more frequent dilated examinations than healthy individuals, it would be prudent to build upon the results from this pilot study to include the elderly and those with various types of ocular diseases. Additionally, this study was meant to explore pupillary dilation for diagnostic examination only. The results may not generalize to dilation in the setting of surgery, where concerns for venoconstriction, stability of pupillary dilation, and length of dilation are pertinent.

The results from this study and similar studies in the literature provide support for single-mydriatic-agent use with 1% tropicamide plus proparacaine during dilated diagnostic eye examination in select populations. Although there appeared to be a statistical benefit to the addition of 2.5% phenylephrine in achieving maximal pupil size, that benefit was minimal and clinically insignificant in this young, healthy cohort. Although we hope to expand on the size and demographics of the study population in the future, we believe that the results of this pilot study are important. We wanted to introduce the idea of a single-dilating-agent regimen early and at least encourage clinicians to have some pause when thinking about their standard practices. In the setting of rising costs for phenylephrine eye drops, it may be prudent to consider a protocol of using tropicamide and proparacaine for the dilated eye examination, reserving phenylephrine for more recalcitrant pupils and for surgical procedures.