Article

EVOLUTION OF THE CRITICAL OXYGEN TENSION

While many have tried to pinpoint an exact value, it is now proposed that this value can’t be fixed.

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 metabolism11,12,3 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 Polse14,15 and Giasson and Bonnano16,17 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 al23,24 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

REFERENCES

  1. Goodlaw EI. Contact lens solutions and their wearing time. Optom Weekly. 1946 Nov 28;1675-1679.
  2. Fatt I. Steady-state distribution of oxygen and carbon dioxide in the in vivo cornea. II. The open eye in nitrogen and the covered eye. Exp. Eye Res. 1968 Jul;7:413-430.
  3. Freeman RD. Oxygen consumption by the component layers of the cornea. J. Physiol. 1972 Aug;225:15-32.
  4. Polse KA, Mandell RB. Critical oxygen tension at the corneal surface. Arch Ophthalmol. 1970 Oct;84:505-508.
  5. Efron N, Brennan NA. In search of the critical oxygen requirement of the cornea. Contax. 1987 Jul;2:5-8, 10, 18.
  6. Brennan NA, Efron N, Carney LG. The minimum equivalent oxygen percentage to avoid corneal edema. Invest Ophthalmol Vis Sci. 1987; (Suppl ARVO abstracts) 62:3P.
  7. Hamano H, Hori M, Hamano T, et al. Effects of contact lens wear on mitosis of corneal epithelium and lactate content in aqueous humor of rabbit. Jpn J Ophthalmol. 1983;27(3):451-458.
  8. Doughty MJ, Zaman ML. Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol. 2000 Mar-Apr;44:367-408.
  9. Larke JR, Parrish ST, Wigham CG. Apparent human corneal uptake rate. Am J Optom Physiol Opt. 1981 Oct;58:803-805.
  10. Takatori SC, de la Jara PL, Holden B, Ehrmann K, Ho A, Radke CJ. In vivo oxygen uptake into the human cornea. Invest Ophthalmol Vis Sci. 2012 Sep;53:6331-6337.
  11. Riley MV. Glucose and oxygen utilization by the rabbit cornea. Exp Eye Res. 1969 Apr;8:193-200.
  12. Maurice DM, Riley MV. The cornea. In Graymore CN (ed). Biochemistry of the Eye. London, Academic Press, 1970, pp. 35-44.
  13. Klyce SD. Stromal lactate accumulation can account for corneal edema osmotically following epithelial hypoxia in the rabbit. J Physiol. 1981 Dec;321:49-64.
  14. Bonanno JA, Polse KA. Measurement of in vivo human corneal stromal pH: open and closed eyes. Invest Opthalmol Vis Sci. 1987 Mar;28:522-530.
  15. Bonanno JA, Polse KA. Corneal acidosis during contact lens wear: effects of hypoxia and CO2. Invest Opthalmol Vis Sci. 1987 Sep;28:1514-1520.
  16. Giasson C, Bonanno JA. Corneal epithelial and aqueous humor acidification during in vivo contact lens wear in rabbits. Invest Ophthalmol Vis Sci. 1994 Mar;35:851-861.
  17. Giasson C, Bonanno JA. Acidification of rabbit corneal endothelium during contact lens wear in vitro. Curr Eye Res. 1995 Apr;14:311-318.
  18. Harvitt DM, Bonanno JA. Re-evaluation of the oxygen diffusion model for predicting minimum contact lens Dk/t values needed to avoid corneal anoxia. Optom Vis Sci. 1999 Oct;76:712-719.
  19. Harvitt DM, Bonanno JA. pH dependence of corneal oxygen consumption. Optom Vis Sci. 1998 Dec;39:2778-2781.
  20. Fatt I, Weissman BA. Physiology of the Eye: An Introduction to the Vegetative Functions, 2nd ed. Philadelphia: Butterworth-Heinemann;1992.
  21. Frahm B, Lane P, Markl H, Pörtner R. Improvement of a mammalian cell culture process by adaptive, model-based dialysis fed-batch cultivation and suppression of apoptosis. Bioprocess Biosyst Eng. 2003 Nov;26:1-10.
  22. Compañ V, Aguilella-Arzo M, Del Castillo LF, Hernández SI, Gonzalez-Meijome JM. Analysis of the application of the generalized Monod kinetics model to describe the human corneal oxygen-consumption rate during soft contact lens wear. J Biomed Mater Res B Appl Biomater. 2017 Nov;105:2269-2281.
  23. Bonanno JA, Stickel T, Nguyen T, et al. Estimation of human corneal oxygen consumption by noninvasive measurement of tear oxygen tension while wearing hydrogel lenses. Invest Opthalmol Vis Sci. 2002 Feb;43:371-376.
  24. Bonanno JA, Clark C, Pruitt J, Alvord L. Tear oxygen under hydrogel and silicone hydrogel contact lenses in humans. Optom Vis Sci. 2009 Aug;86:E936-E942.
  25. Compañ V, Aquilella-Arzo M, Weissman BA. Corneal equilibrium flux as a function of corneal surface oxygen tension. Optom Vis Sci. 2017 Jun;94:672-679.
  26. Weissman BA, Ye P. Calculated tear oxygen tension under contact lenses offering resistance in series: piggyback and scleral lenses. Cont Lens Anterior Eye. 2006 Dec;29;231-237.
  27. Brennan NA. Beyond flux: total corneal oxygen consumption as an index of corneal oxygenation during contact lens wear. Optom Vis Sci. 2005 Jun;82:467-472.
  28. Chhabra M, Prausnitz JM, Radke CJ. Modeling corneal metabolism and oxygen transport during contact lens wear. Optom Vis Sci. 2009 May;86:454-466.
  29. Yeung KK, Yang H, Nguyen AL, Weissman BA. Critical contact lens oxygen transmissibility and tear lens oxygen tension to preclude corneal neovascularization. Eye Contact Lens. 2017 Aug 9. [Epub ahead of print]