CONSEQUENCES OF HYPOXIA
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
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.
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.
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
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
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
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
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
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
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
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
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.
published data currently exist, but these tend to support the view that redness
reductions are also evident in the daily wear situation. Maldonado-
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
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.
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Contact Lens Spectrum, Issue: February 2006