Goodlaw surmised in 1948 that the cornea required an anterior supply of oxygen to maintain its physiology and transparency, but he did not quantify it.¹ It is now well known that the cornea, like all human tissues, requires oxygen for normal metabolic function. The cornea being avascular, oxygen reaches this tissue primarily from the atmosphere and secondarily from the anterior chamber (aqueous humor) under open-eye conditions. When the eye is closed (during sleep), oxygen is provided both from exposure to the tarsal palpebral conjunctiva as well as from the aqueous humor.^2,3

With a reduced oxygen supply, the cornea is susceptible to hypoxic complications: corneal swelling (and loss of transparency), corneal stromal acidosis, epithelial punctate staining, limbal hyperemia, and endothelial polymegathism. Therefore, the minimum oxygen tension that allows “normal” oxygen consumption as a direct index of corneal oxygen metabolism is a critical clinical parameter to ascertain.

To this end, Polse and Mandell published their research titled “Critical Oxygen Tension at the Corneal Surface” in 1970.⁴ This landmark study proposed that human corneas would swell if exposed to anterior oxygen tensions below 11 to 19 mmHg, while “normal” corneal thickness would be maintained as long as anterior corneal oxygen tension remained above this threshold. The implication was that there was a specific, well-defined, or “fixed” oxygen value in humans below which corneal metabolism would begin to suffer (leading to corneal swelling, among other complications) if only we could properly identify it.

Over the next several decades, many investigators spent much time, effort, thought, and money to try to definitively quantitate that “critical” oxygen value (in mmHg or tension, it was called the “COT”). Efron and Brennan published a meta-analysis documenting and discussing many potential values,⁵ ranging from the original Polse and Mandell 11 to 19 mmHg metric, to Brennan et al’s finding of 137 mmHg for swelling,⁶ to 100 mmHg to maintain epithelial mitosis.⁷ In their meta-analysis, Efron and Brennan speculated that the real figure might even be the sea-level room air oxygen tension of 21% or 155 mmHg.⁵

Quantification of the COT is important clinically as contact lens materials continue to evolve. Contact lens designers (material chemists, engineers, etc.) found it helpful over the years to have a precise and definitive oxygen goal. Once this goal is achieved in a lens design, they then typically focus on other lens characteristics such as lubricity of surfaces, anti-soiling, and anti-microbial properties as well as optics (including enhancing astigmatic and presbyopic corrections). Currently, the increasing use of modern-day scleral lenses and associated hypoxic complications has again highlighted the importance of understanding the COT.

WHY THE COT IS SO DIFFICULT TO QUANTITATE

Recent scientific work has led us to consider, however, that the COT cannot be a precise value, either in individual humans or in human beings in general. We therefore propose that the COT is more likely a range from around 80 to 100 mmHg for normal human corneas. There will undoubtedly be variability among individuals as well as differences at various times of day in the same individual—similar to the variability in “normal” corneal thickness⁸—with additional methodology variability and perhaps under different physiological conditions as well. Corneas that are not normal—such as those diagnosed with Fuchs’ corneal dystrophy or secondary to corneal transplants, etc.—may also behave differently.

This should come as no surprise. Polse and Mandell originally reported a range in COT.⁴ Efron and Brennan showed how varied were the results of previous research.⁵ Moreover, both Larke et al⁹ and Takatori et al¹⁰ showed that both human anterior corneal oxygen flux and consumption varied widely among individuals.

Moreover, consider that the measured COT is most likely a reflection of several physiological changes, primarily increased anaerobic metabolism^11,12,3 and the secondary increase in lactate production when the cornea’s cells (primarily basal epithelium) become more hypoxic.¹³

This is a very complex topic. Both Bonanno and Polse^14,15 and Giasson and Bonnano^16,17 observed that soft hydrogel lens hypoxia induces stromal acidosis. On the other hand, Harvitt and Bonanno state that acidosis increases the corneal oxygen consumption rate by up to 1.8 times the rate at normal pH.¹⁸ This increase is expressed relative to the consumption rate at pH 7.5, at which acidosis leads to activation of pH-regulatory mechanisms.¹⁹

Accordingly, the increase of oxygen consumption as a consequence of acidosis makes the corneal cells more hypoxic, producing more lactate and resulting in less oxygen for glucose oxidation. Aerobic breakdown of glucose requires consumption of one mole of glucose and six moles of oxygen to produce six moles each of carbon dioxide and water and, additionally, 36 moles of adenosine triphosphate (ATP). When the partial pressure of oxygen is low, the corneal cellular metabolism tends to be more hypoxic, and the oxygen consumption falls due to a decrease in glucose concentration. As a consequence of glucose breakdown, the aerobic glycolysis declines.²⁰ Frahm et al explained that only an excess of glucose is independent of glucose concentration in respiration.²¹

On the other hand, Compañ et al²² have observed using oxygen tension from in vivo estimations provided by Bonanno et al^23,24 that the Monod kinetics model for oxygen consumption reaction with glucose describes a maximum of around 105 mmHg with an apparent discontinuity showing a lambda-like behavior, similar to that which appears when matter exists as a phase transition. This behavior shows that the corneal oxygen consumption rate increases with acidosis and decreases with anaerobic transition. To include both effects in the metabolic model normally used for oxygen distribution into the cornea when a contact lens is worn, we should modify the metabolic model equation by adding at least an additional term to represent this behavior. That is, when lowering the pressure of oxygen, the maximum oxygen consumption rate parameter initially increases depending on the intensity of the change in pressure, which could be related with the variation of the pH. With regard to this, Compañ et al suggest the occurrence of a kinetic transition that can be understood not only as the result of the metabolic reactions that occur in the Krebs cycle, but also of the other observed corneal reactions that can exist between the transition from aerobic to anaerobic metabolism.²⁵

Furthermore, it is also noted that greater reductions in pressure are accompanied by a decrease in oxygen tension; therefore, a lower amount of glucose will react with the oxygen, and concomitantly declining levels of ATP will occur, possibly due to changes in the concentration of oxygen related to anaerobic respiration.

Weissman and Ye plotted several models of calculated contact lens-related tear layer oxygen tension versus contact lens oxygen transmissibility (Dk/t) (without considering tear exchange, such as would be the case for soft contact lenses) for both open and closed eye situations.²⁶ Several of the earlier proposed COT values were plotted on the same graph. Both sets of curves begin to asymptote at about 60 to 100 mmHg. There is no evidence of alignment, however, with any of the previously proposed fixed COT values.

Compañ et al²⁵ used Monod equations and the most current boundary conditions to calculate the corneal stroma location at which oxygen tension is minimal with different anterior corneal surface oxygen tensions using the assumptions that have previously been outlined in work by Harvitt and Bonanno,¹⁹ Brennan,²⁷ and Chhabra et al,²⁸ which assume a constant oxygen tension at the cornea/anterior chamber interface. Maximum corneal hypoxic stress deepens, advances from near the endothelium toward the epithelium, and broadens as corneal surface oxygen tension declines from 155 to 20 mmHg. Both calculated oxygen consumption and flux in the corneal epithelium and stroma are supported down to a corneal surface oxygen tension of about 60 to 100 mmHg, at which changes are seen in the graphs. But again, there is no clear boundary; rather, a slow shift in the curves occurs, consistent with the concept that the COT is a reflection of physiological changes such as described above.

Of interest, corneal neovascularization (probably in response to a hypoxia-induced change in cytokine-like vascular endothelial growth factor [VEGF] release rather than to lactate buildup) was also found recently to have a “critical” oxygen value of about 80 mmHg, also with a large variability.²⁹

Finally, we need to mention another source of variability. As noted previously, Polse and Mandell⁴ originally suggested a COT of around 2% oxygen or 11 to 19 mmHg. This brings up the question of whether these values should be reported in percent oxygen or mmHg oxygen tension.

Oxygen is responsible for 21% of atmospheric pressure on this planet: 21% of a normal barometric pressure of 760 mmHg. This suggests that each 1% of pressure is worth 7.6 mmHg, but this quantification is only true at sea level, so sea-level oxygen tension is about 160 mmHg. When considering elevations above sea-level, however, oxygen percentage remains at 21, but barometric pressure declines. At an elevation of 10,000 feet (3,000 meters), for example, barometric pressure declines to about 520 mmHg, and so oxygen partial pressure declines to about 110 mmHg. When authors report COT values in oxygen percentage, readers must assume, unless it is otherwise stated, that the evaluation is set at sea level and will be different at other elevations.

CONCLUSION

In summary, low-Dk/t contact lenses produce low oxygen tension in the post-lens tear film and then secondarily depress corneal oxygen consumption. We suggest that the COT in the anterior corneal surface tears (whether due to contact lens wear or otherwise) should no longer be considered a hard or fixed value, but rather be thought of as a range for normal human corneas—perhaps from about 80 to 100 mmHg. This is proposed both for clinicians considering care of their patients and for the contact lens industry as it develops new contact lens materials and designs. CLS

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