Article Date: 2/1/2006

CONSEQUENCES OF HYPOXIA
Reducing the Consequences of Hypoxia: The Ocular Redness Response
Experts share evidence on the relevance of ocular surface vasculature to anterior eye health.
By Eric Papas, PhD, MCOptom, DCLP, and Mark Willcox, BSc (Hons), PhD

Contact lens wear can affect many aspects of the anterior surface of the eye, but perhaps the most noticeable changes are those that impact the bulbar and limbal vasculature, causing increased ocular redness (Figure 1). Over the years, several aspects of lens wear have been suggested as causes for these increases, including edge suction,1 central corneal edema,2 toxicity,3,4 mechanical abrasion,3 lens damage, surface deposition, poor fitting4 and hypoxia.3–5

While many of these factors are capable of producing hyperemia, we wouldn't expect to see them in the contemporary examination room where practitioners are using modern lens designs that are well-fitted and maintained. Based on evidence from more recent studies, it's increasingly clear that hypoxia is the factor most likely associated with increased redness during soft lens wear, and it's the hypoxic impact on the limbal region itself, rather than on the avascular cornea, that is the key driver for the response.6

In this article we'll review these studies and consider the relevance of the ocular surface vasculature to the health of the anterior eye.

Corneal Vascularization

Throughout life, the anterior surface of the eye experiences substantial changes in oxygen availability on a daily basis. Eye closure associated with sleep reduces oxygen tension at the ocular surface from about 155 mm Hg to about 55 mm Hg. Clearly, the anterior eye can withstand these changes and, typically, doesn't develop pathological consequences. Perhaps this is because we sleep for only about 8 hours a day, allowing substantial time for recovery. With lens wear, the prevalence of vascularization in the cornea increases, possibly due to the longer time the anterior eye is exposed to a relatively hypoxic environment.

The prevalence of corneal vascularization in patients wearing gas permeable contact lenses is generally very low, presumably because of the small size of the lenses and the consequent exposure of the limbus and peripheral cornea. Daily-wear hydrogel lenses of relatively low oxygen transmissibility are associated with a substantially higher prevalence. In one recent study,7 about 18% of subjects showed grade one or greater vessel growth during daily wear of hydrogel lenses. Extended wear
increases this value even further, to about 24%. Perhaps not surprisingly, the highest prevalence of corneal vascularization occurs with aphakic extended wear of low oxygen transmissible lenses.8

Limbal redness associated with low oxygen transmissibility lenses is also common, whether these lenses are worn on a daily or extended wear basis. About 31% to 35% of people in the Chalmers and colleagues study7 had grade one or greater limbal redness compared with only about 5% of non-lens wearing subjects.

Figure 1. Limbal redness during wear of low-transmissibility soft contact lenses.

Silicone Hydrogels and Limbal Redness

Over the past 6 years, we've seen the introduction
of silicone hydrogel lenses that provide higher levels of oxygen transmissibility to the cornea, limbus and perilimbal conjunctiva than conventional hydrogel lenses. Several studies6 have compared these various lenses for their potential to cause bulbar or limbal hyperemia, and some have compared lens wear with no lens wear.

The earliest of these investigations were relatively short-term, non-dispensing studies conducted over 8 hours to compare limbal redness responses produced by lenses of different oxygen transmissibility.6
Researchers found a strong relationship between
peripheral lens oxygen transmissibility and induced limbal redness as graded using a decimalized scale (Cornea and Contact Lens Research Unit [CCLRU] scale).

Low water content HEMA-based hydrogel lenses with peripheral oxygen transmissibility of 5 x 10-9 (cm s-1) (mLO2 mL-1 x mm Hg) produced the greatest
increase in redness over the 8 hours compared with the lowest levels, from an experimental silicone hydrogel of peripheral oxygen transmissibility
71 x 10-9 (cm s-1) (mLO2 mL-1 x mm Hg).

In a longer study from the same group,9 researchers monitored the change in limbal redness over a 16-hour period, including 8 hours of sleep. They compared no lens wear, a low water content HEMA-based hydrogel lens (peripheral oxygen transmissibility 6 x 10-9 [cm s-1] [mLO2 mL-1 x mm Hg]) and an experimental silicone hydrogel lens (20% water content (peripheral oxygen transmissibility 85 x 10-9 [cm s-1] [mLO2 mL-1 x mm Hg]). The two lenses were worn contralaterally.

Without lens wear, limbal redness increased during sleep but did not change during the day. During low oxygen transmissibility lens wear, limbal redness increased dramatically after only 4 hours and remained consistently high throughout the remaining 4 hours of open-eye wear and 8 hours of sleep. In contrast, eyes wearing the highly oxygen transmissible lens showed almost the same response as those wearing no lens — i.e., there was little change in redness during the day and a small but discernible change after 8 hours of sleep. 

To verify that these changes were most likely due to oxygen, researchers conducted subsequent experiments using nitrogen-filled goggles to reduce the oxygen available to the anterior eye.10 This procedure demonstrated that limbal vasculature does, indeed, respond directly to hypoxia rather than secondarily to other events, such as corneal swelling, as had been suggested previously.

Body of Evidence

The results of these short-term studies are supported by other researchers who have conducted examinations of limbal redness response during dispensing trials of various durations. Fonn and colleagues11 conducted a 4-month, contralateral study with subjects wearing balafilcon A (center oxygen transmissibility 110 x 10-9 [cm s-1] [mLO2 mL-1 x mm Hg]) lenses on one eye and Optima FW (24 x 10-9 [cm s-1] [mLO2 mL-1 x mm Hg]) on the other, both on a 6-night extended wear basis. Their results showed eyes wearing the higher transmissibility material had less frequent limbal redness and corneal vascularization than their fellows.

Figure 2. Percentage of eyes with change in limbal redness of > grade 1 from baseline through 3 months of lens wear.

In a 9-month study, Covey and colleagues12 compared wearers of an experimental, highly oxygen transmissible lens (center transmissibility 175 x 10-9 [cm s-1] [mLO2 mL-1 x mm Hg]) on a continuous 30-night wear schedule with a control group who wore no contact lenses. Researchers found no significant differences in either the limbal redness response or the vascular appearance of the peripheral cornea, measured as linear incursion of vessels from the
limbus.

Also making observations over a 9-month period, Dumbleton and colleagues13 found that subjects wearing lotrafilcon A lenses (center oxygen transmissibility 175 x 10-9 [cm s-1] [mLO2 mL-1 x mm Hg]) on a 30-night continuous wear schedule had significantly less limbal redness than subjects wearing etafilcon A lenses (center oxygen transmissibility 40 x 10-9 [cm s-1] [mLO2 mL-1 x mm Hg]) on a 6-night replacement schedule. The difference was caused by a significant increase in redness that manifested during the first month of wear and remained fairly constant thereafter for the group wearing etafilcon A. No change occurred with lotrafilcon A lenses, however. Researchers also monitored changes in corneal vascularization and, on average, found a differential behavior similar to limbal redness.

Brennan and colleagues14 conducted a 1-year study controlled with the same lenses as those used by Dumbleton and colleagues,13 but with balafilcon A as the test material. Again, no significant changes in corneal vascularization were found in the silicone hydrogel group, but there also was no alteration in the status of the control group relative to baseline.

Chalmers and colleagues7 used a multi-center approach over 12 months. They examined the effect of transferring patients from various low oxygen transmissibility lenses, worn on either an extended wear or daily wear schedule, to highly oxygen transmissible lotrafilcon A lenses worn on a 30-night continuous wear schedule. Regardless of the previous wearing schedule, patients refit into the highly oxygen transmissible lens experienced significant reductions in limbal redness and corneal vascularization, assessed using a slit lamp and the Efron grading scales. Subjective reports of redness also were significantly reduced after the first month.

Figure 3. Percentage of eyes with change in corneal vascularization of > grade 1 from baseline through 3 months of lens wear.

In an even longer study conducted by Stern and colleagues,15 researchers examined the effect of wearing schedule in groups of patients wearing lotrafilcon A lenses on either a 30-night continuous wear or a 6-night extended wear basis for 3 years. Study results showed no significant differences in limbal redness between the two groups over theobservation period.

One final effect that has been noted when people transfer from low to high oxygen transmissible lenses is the so-called "ghosting" of corneal blood vessels.16 The observation is the blood column within new vessels that may have penetrated the cornea during wear of low oxygen transmissible lenses withdraws when wear ceases, leaving an empty or "ghost" vessel as an essentially permanent marker of the tissue disturbance. Refitting the eye with highly oxygen permeable lenses does not generally cause refilling of these vessels, presumably indicating the hypoxic stress level has been effectively reduced.

The overall impression gained from these various reports in the literature is both limbal redness and peripheral corneal vascularization can be effectively controlled by substantially increasing the availability of oxygen in this region. These effects appear
repeatable, long-lasting and independent of wearing schedule.

Second Generation Silicone Hydrogels

Most of the studies we've considered so far have been concerned with lenses worn on a continuous or extended wear schedule. Recently, new silicone hydrogel lenses have become available with oxygen transmissibilities that fill the space between the very high levels of the first generation materials like lotrafilcon A and the low levels of conventional polymers such as etafilcon A. These second generation lenses are recommended for daily wear, and we'll be interested to learn how these lenses perform on a daily wear basis. 

Few published data currently exist, but these tend to support the view that redness reductions are also evident in the daily wear situation. Maldonado-
Codina and colleagues17 looked at the use of galyfilcon A, which has a central oxygen transmissibility of 86 x 10-9 (cm s-1) (mLO2 mL-1 x mm Hg), compared with lotrafilcon A and etafilcon A, all worn on a daily schedule, as well as a non lens-wearing control group. The study had a bilateral design, using different populations for each lens and lasted for 1 month, but the etafilcon A and galyfilcon A lenses were replaced after 2 weeks. Once again, researchers saw significantly increased limbal redness for etafilcon A compared with either of the other two lens types or no lens wear. This confirms the value of silicone hydrogel lenses in controlling limbal redness even during daily wear.

Figure 4. Percentage of eyes with change in bulbar redness of > grade 1 from baseline through 3 months of lens wear.

Our own studies conducted with groups of 30 daily wearers of various lens types on a bilateral basis tell a comparable story. Figure 2 shows data from subjects wearing etafilcon A, lotrafilcon A or balafilcon A. The percentage of subjects whose limbal redness increased by grade 1 or more is generally higher for the low transmissibility conventional hydrogel, but reduced with the silicone hydrogel materials. Corneal vascularization follows a similar trend, as seen in Figure 3.

Looking at Bulbar Redness

Despite its importance in corneal health maintenance, the limbus isn't the only region capable of displaying heightened redness during contact lens wear. The bulbar conjunctiva has a rich supply of vessels and can respond to appropriate stimuli as well. However, few studies have considered bulbar redness changes during lens wear.

Aakre and colleagues18 studied a group of 49 patients previously wearing a variety of low transmissibility hydrogel materials on a daily disposable basis. They refitted 30 of them with either lotrafilcon A or balafilcon A on a 30-night continuous wear schedule. The remaining 19 continued with their previous lens modality. After 3 months, bulbar redness had significantly increased in the low transmissibility group but remained unchanged in the refitted subjects. However, at 6 months, the differences were no longer significant.

These findings are difficult to interpret in terms of differential oxygen transmissibility between the lens types, as that would have been expected to produce a reduction in redness within the refit group, but no real change in the daily disposable group. Indeed, it's difficult to see how "through lens" oxygen availability could be a major influence on bulbar redness because most of the ocular surface remains uncovered throughout wear. It's reasonable to suppose that other factors constitute the major hyperemic stimuli in the bulbar region. 

The study by Maldonado-Codina and colleagues17 also supports this suggestion. In addition to observing increased limbal redness, these researchers also observed that etafilcon A lenses precipitated greater bulbar redness than either galyfilcon A or the no-lens control. The lack of any statistically significant difference between etafilcon A and lotrafilcon A lenses, despite their very different oxygen transmissibility, indicates that an alternative mechanism was involved.

Again, our own data are consistent with this suggestion. Figure 4 indicates the percentage of patients showing increased bulbar redness during daily wear of etafilcon A, lotrafilcon A or balafilcon A isn't correlated with lens transmissibility.

For hydrogel lenses, some evidence17 exists that the manufacturing process can affect redness responses during wear, and excessive protein deposits also may be detrimental.19 Other factors that might be influential include lens design, fit and mechanical properties, and edge shape. Figure 5 shows how this latter factor differs between the lenses used in our study. Tear-borne elements and osmotic changes within the conjunctival sac also are capable of precipitating hyperemia. And it shouldn't be forgotten that some care system components, as well as various eye preparations, can cause significant redness of both the limbal and the bulbar conjunctiva.

More Than Cosmesis

Figure 5. Lens edge shape of balafilcon A, etafilcon A and lotrafilcon A lenses.

To summarize all the studies examining the effect of oxygen transmissibility of the limbal and bulbar vasculature:

• Limbal redness and corneal vascularization are directly affected by the oxygen transmissibility of a contact lens, particularly at the lens periphery.

• Bulbar redness depends on multiple factors that may include the lens material, lens design, edge shape, manufacturing process, and amount, type and status of any surface deposition, as well as aspects of tear film and ocular surface physiology.

Redness of the eye is a frequent problem among contact lens wearers and, ultimately, may influence their decision to cease lens wear altogether. While cosmesis is clearly important to both wearers and practitioners, other aspects of vascular change may have more serious consequences. For example, limbal vessel dilation has been identified as the main, observable clinical sign preceding the development of corneal vascularization. While limbal hyperemia in itself isn't sufficient to cause corneal vascularization, it is a necessary factor.

Fortunately, actual vessel encroachment far into the cornea is rare and, consequently, so is any effect on vision. However, vascularization does appear to alter the immune privilege of the cornea and the anterior chamber,20 which, in turn, may influence the inflammatory response to trauma or injury. Furthermore, vascularized corneas are much more likely to either reject donor transplants or be rejected following transplantation. This is because the presence of blood vessels facilitates the movement of antigen presenting and other cells that play a key role in the graft rejection process.21 Thus, there's a clear advantage to wearing soft lenses that have a reduced capacity to incite (at least) limbal redness.

Maintaining White Eyes

The key question for most clinicians is: How do I eliminate redness in my contact lens wearers? In terms of limbal redness, the answer is straightforward: Take steps to maximize the availability of oxygen to the limbus and the peripheral cornea. With the advent of silicone hydrogel lenses, this is a much easier task.

To date, the only available estimate6 of how much transmissibility is required to eliminate limbal redness suggests an average figure of 125 x 10-9 (cm s-1) (mLO2 mL-1 x mm Hg). While the 95% confidence limits around this value are quite broad (56–274), they can be regarded as indicating the boundaries for clinical performance.

Thus, even the most responsive of wearers, in limbal hyperemia terms, might be expected to benefit from lenses that achieve peripheral oxygen transmissibilities of at least 60 x 10-9 (cm s-1) (mLO2 mL-1 x mm Hg), whatever the back vertex power or design of the lenses. Most other wearers will require even better transmissibility.

For bulbar redness, traditional contact lens skills continue to be important. Optimizing lens fit, minimizing lacrimation, removing potential chemicals, toxins and other contaminants from the ocular environment are all valuable pieces in the jigsaw puzzle of maintaining a white eye.

Dr. Papas (top) is executive director of research and development at the Vision Cooperative Research Centre, Sydney, Australia, and adjunct senior lecturer at the University of New South Wales.

 

Prof. Willcox (bottom) is aprofessor at the University of New South Wales and director of science at the Vision Cooperative Research Centre, Sydney, Australia.

 

REFERENCES

1. Mandell RB. The tight soft contact lens. Contact Lens Forum 1979;4:12-22.

2. Tomlinson A, Haas DD. Changes in corneal thickness and circumcorneal vascularization with contact lens wear. Int Contact Lens Clin. 1980;7:45-56.

3. Guillon M, Bilton S, Bleshoy H, et al. Limbal changes associated with hydrogel contact lens wear. J Br Contact Lens Assoc. 1985;8:15-19.

4. McMonnies CW, Chapman-Davies A. Assessment of conjunctival hyperemia in contact lens wearers. Part II. Am J Optom Physiol Opt. 1987;64:251-255.

5. Holden BA, Sweeney DF, Swarbrick HA, et al. The vascular response to long-term extended contact lens wear. Clin Exp Optom. 1986;69:112-196.

6. Papas EB. On the relationship between soft contact lens oxygen transmissibility and induced limbal hyperaemia. Exp Eye Res. 1998;67:125-131.

7. Chalmers RL, Dillehay S, Long B, et al. Impact of previous extended and daily wear schedules on signs and symptoms with high Dk lotrafilcon A lenses. Optom Vis Sci. 2005;82:549-554.

8. Liesegang TJ. Physiologic changes of the cornea with contact lens wear. CLAO J. 2002;28:12-27.

9. Papas EB, Vajdic CM, Austen R, Holden BA. High-oxygen-transmissibility soft contact lenses do not induce limbal hyperaemia. Curr Eye Res. 1997;16:942-948.

10. Papas EB. The role of hypoxia in the limbal vascular response to soft contact lens wear. Eye Contact Lens. 2003;29(1 Suppl):S72-4; discussion S83-4, S192-4.

11. Fonn D, MacDonald KE, Richter D, Pritchard N. The ocular response to extended wear of a high Dk silicone hydrogel contact lens. Clin Exp Optom. 2002;85:176-182.

12. Covey M, Sweeney DF, Terry R, et al. Hypoxic effects on the anterior eye of high-Dk soft contact lens wearers are negligible. Optom Vis Sci. 2001;78:95-99.

13. Dumbleton KA, Chalmers RL, Richter DB, Fonn D. Vascular response to extended wear of hydrogel lenses with high and low oxygen permeability. Optom Vis Sci. 2001;78:147-151.

14. Brennan NA, Coles ML, Comstock TL, Levy B. A 1-year prospective clinical trial of balafilcon a (PureVision) silicone-hydrogel contact lenses used on a 30-day continuous wear schedule. Ophthalmology. 2002;109:1172-1177.

15. Stern J, Wong R, Naduvilath TJ, et al. Comparison of the performance of 6- or 30-night extended wear schedules with silicone hydrogel lenses over 3 years. Optom Vis Sci. 2004;81:398-406.

16. Sweeney DF. Clinical signs of hypoxia with high-Dk soft lens extended wear: is the cornea convinced? Eye Contact Lens. 2003;29(1 Suppl):S22-5; discussion S6-9, S192-4.

17. Maldonado-Codina C, Morgan PB, Schnider CM, Efron N. Short-term physiologic response in neophyte subjects fitted with hydrogel and silicone hydrogel contact lenses. Optom Vis Sci. 2004;81:911-921.

18. Aakre BM, Ystenaes AE, Doughty MJ, et al. A 6-month follow-up of successful refits from daily disposable soft contact lenses to continuous wear of high-Dk silicone-hydrogel lenses. Ophthalmic Physiol Opt. 2004;24:130-141.

19. Michaud L, Giasson CJ. Overwear of contact lenses: increased severity of clinical signs as a function of protein adsorption. Optom Vis Sci. 2002;79:184-192.

20. Dana MR, Streilein JW. Loss and restoration of immune privilege in eyes with corneal neovascularization. Invest Ophthalmol Vis Sci. 1996;37:2485-2494.

21. Chen L, Hamrah P, Cursiefen C, et al. Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat Med. 2004;10:813-815.



Contact Lens Spectrum, Issue: February 2006