Hypoxia

George W. Mertz

INTRODUCTION

Hypoxia means oxygen deficiency. Etymologically, the word is derived from hypo, which means “under” or “less than” in Greek, and the combining form oxia, which means “oxygen containing”.

In the health care professions and related fields, hypoxia is a state of metabolic distress occurring in living tissue when its oxygen supply is reduced to such an extent that the normal aerobic respiration of its cells can no longer be sustained. If the tissue's oxygen supply is totally cut off, the condition is known as anoxia.

The amount of oxygen available for consumption by the cells of a given tissue is determined by the driving force or partial pressure of oxygen entering the tissue. The partial pressure of oxygen, known more commonly in biology as oxygen tension, is the proportion of the total pressure exerted by a gas mixture attributable to its oxygen component; it is a direct function of the number of oxygen molecules present. (Note: a similar definition applies to the oxygen portion of gas mixtures dissolved in liquids.) The oxygen tension of the atmosphere, for instance, is equal to the proportion of oxygen in the atmosphere (approximately 20.9 percent) multiplied by the total atmospheric pressure, which varies with altitude. At sea level, where the total atmospheric pressure is 760 mmHg, the atmospheric oxygen tension = 760 mmHg × 0.209 = 159 mmHg. A slight correction for the presence of a small amount of water vapor and carbon dioxide in the atmosphere reduces this to 155 mmHg, which is the value commonly encountered in the literature (Fatt, 1989). With increasing altitude, total atmospheric pressure drops (due to decreasing air density) and so, therefore, does atmospheric oxygen tension,



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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium Hypoxia George W. Mertz INTRODUCTION Hypoxia means oxygen deficiency. Etymologically, the word is derived from hypo, which means “under” or “less than” in Greek, and the combining form oxia, which means “oxygen containing”. In the health care professions and related fields, hypoxia is a state of metabolic distress occurring in living tissue when its oxygen supply is reduced to such an extent that the normal aerobic respiration of its cells can no longer be sustained. If the tissue's oxygen supply is totally cut off, the condition is known as anoxia. The amount of oxygen available for consumption by the cells of a given tissue is determined by the driving force or partial pressure of oxygen entering the tissue. The partial pressure of oxygen, known more commonly in biology as oxygen tension, is the proportion of the total pressure exerted by a gas mixture attributable to its oxygen component; it is a direct function of the number of oxygen molecules present. (Note: a similar definition applies to the oxygen portion of gas mixtures dissolved in liquids.) The oxygen tension of the atmosphere, for instance, is equal to the proportion of oxygen in the atmosphere (approximately 20.9 percent) multiplied by the total atmospheric pressure, which varies with altitude. At sea level, where the total atmospheric pressure is 760 mmHg, the atmospheric oxygen tension = 760 mmHg × 0.209 = 159 mmHg. A slight correction for the presence of a small amount of water vapor and carbon dioxide in the atmosphere reduces this to 155 mmHg, which is the value commonly encountered in the literature (Fatt, 1989). With increasing altitude, total atmospheric pressure drops (due to decreasing air density) and so, therefore, does atmospheric oxygen tension,

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium but the proportion of oxygen in the atmosphere always remains constant (20.9 percent) regardless of altitude. In order to supply enough oxygen for cells to carry out their intended biochemical functions, a tissue's ambient oxygen tension must exceed a certain critical threshold level. If the tissue oxygen tension falls below this critical level, a state of hypoxia is induced. At just what magnitude of oxygen tension the critical threshold of a tissue occurs depends on the tissue in question. Regardless of etiology, any drop in a tissue's ambient oxygen tension below its critical threshold immediately initiates the shutting down of any oxygen dependent biochemical processes (aerobic metabolism) resident within its cells. The clinical ramifications of this depend on how crucial a role aerobic metabolism plays in the sustentation of the tissue's cellular vital functions, and on the degree to which the tissue has been deprived of oxygen, anoxia being the worst case. In the human being, hypoxia can take various forms depending on the availability of oxygen both inside and outside the body. Table 1 lists some of the common forms of hypoxia. While most forms result from a reduction in the supply of oxygen of one manner or another, it is interesting to note that at least one form (histotoxic) occurs when oxygen is present in plentiful supply, yet cannot be properly utilized by the tissue's cells. In the field of contact lenses, there has long been prodigious interest in the effects of hypoxia on human corneal tissue. Such interest is certainly reasonable, given: (a) the cornea's fundamental role in the visual process as the eye's entry window for light en route to the retina, for which the maintenance of corneal transparency is essential: (b) the cornea's critical dependence on aerobic metabolism for the energy required to (among other functions) maintain its transparency: (c) the cornea's dominant role in contact lens wear as the principal biological substratum on which a contact lens resides in situ: and (d) the barrier a contact lens forms between the cornea and its anterior oxygen supply, which restricts oxygen flow into the cornea, thus reducing tissue oxygen tension, often enough to levels below the critical hypoxia threshold to make hypoxia probably the most common adverse ocular response associated with contact lens wear. HYPOXIA AND CORNEAL PHYSIOLOGY Transparency is the one feature that makes the cornea virtually unique among the other tissues of the body (the crystalline lens being the one notable exception). Although the physiological process responsible for this special property is still not fully understood, it has long been established, and demonstrated in various ways, that the transparency of the cornea is dependent upon its water content. The healthy cornea is about 78 percent

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium TABLE 1 Various Etiologies of Hypoxia/Anoxia in Human Body Tissue Condition Cause/Description Examples Anemic anoxia a Insufficient tissue O2 tension; Normal arterial O2 tension; EITHER reduced arterial hemoglobin with normal hemoglobin O2 capacity OR sufficient arterial hemoglobin with reduced hemoglobin O2 capacity Anemia Carbon monoxide poisoning Anoxic anoxia b Insufficient tissue O2 tension; Arterial anoxemia b ; Sufficient arterial hemoglobin with normal hemoglobin O2 capacity; Incomplete hemoglobin oxidation due to anoxemia resulting in less O2 being carried to tissues High altitude living environments Asphyxiation/drowning Pneumonia (reduces surface area for gas exchange from lungs to blood) Diffusion hypoxia Insufficient tissue O2 tension; Arterial hypoxemia due to nitrous oxide diffusion from plasma, reducing O2 in lung alveoli Recovery from surgery utilizing nitrous oxide anesthesia

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium Histotoxic hypoxia/anoxia c Sufficient tissue O2 tension; Cellular O2 utilization depressed by reduction of enzyme oxidase caused by poisoning of protoplasm Cyanide poisoning Stagnant (or hypokinetic) hypoxia/anoxia c Insufficient tissue O2 tension; Normal arterial O2 tension; failure Tissue O2 supply retarded by Shock decreased circulation of blood flow through capillaries Congestive heart failure Shock Cardiac thrombosis Arterial spasm a In medicine, anoxia, meaning absence of tissue oxygen, is frequently used erroneously to indicate inadequate tissue oxygen content, which is the definition of hypoxia. Therefore, in the medical literature, one can expect the word anoxia used to mean either anoxia or hypoxia. b Similarly to anoxia, anoxemia, meaning absence of oxygen in the blood, is also often misused in medicine to indicate insufficient blood oxygen content, which is more accurately defined by the word hypoxemia. c Indicates that nearly identical definitions for the condition were found for both words. SOURCES: Critchley (1978); Taber (1970).

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium FIGURE 1 Lactate theory of how hypoxia induced build up of stromal lactate leads to corneal edema (Klyce, 1981). SOURCE: Efron and Holden (1986a). Reprinted by permission. water by weight, which is substantially less than its surroundings. The tear film, which borders the anterior surface of the cornea, and the aqueous humor, which borders its posterior surface, both have a water content approaching 100 percent. This difference in water content between the cornea and its surroundings produces an osmotic gradient resulting in a net influx of water flowing into the cornea. The cornea maintains its relatively dehydrated, or deturgescent, state primarily through an active pumping mechanism located in the endothelium, the single layer of cells that forms the cornea's posterior surface. Endothelial cells pump bicarbonate ions from the cornea into the aqueous, causing water to follow through passive diffusion, and thus leads to an equilibrium whereby the corneal stroma is maintained in its relative state of dehydration (Hodson and Miller, 1976). The endothelium

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium is highly dependent on aerobic metabolism to satisfy the energy demands of its pumping mechanism. For this, it probably gets most of its oxygen supply from the aqueous (Kwan et al., 1972). The corneal epithelium, which is highly mitotic, is also very dependent on aerobic metabolism to meet its energy demands. Its primary supply of oxygen is from the atmosphere. If the cornea's atmospheric oxygen supply drops below approximately 74mmHg (Holden et al., 1984), as frequently occurs during contact lens wear, the cornea becomes hypoxic and its epithelial cells begin to respire anaerobically. When this occurs, the corneal stroma becomes edematous (swells). Corneal edema of a sufficient magnitude causes the cornea to become cloudy, and is ultimately, a threat to the tissue's transparency. It has been proposed (Klyce, 1981) that the edema associated with corneal hypoxia is caused by the excess amount of lactic acid produced by the epithelium under anaerobic conditions (see Figure 1). As lactate builds up in the stroma (along its pathway of elimination through the aqueous), an increase in osmotic pressure occurs causing more water to diffuse into the stroma than can be handled by the endothelial pump. CORNEAL EDEMA Corneal edema has received a great deal of attention in the literature because it is one of the few responses to the wearing of contact lenses that can actually be quantified. Hedbys and Mishima (1966) showed that the swelling of the cornea is linearly related to its thickness. Therefore, by measuring corneal thickness with a device known as a pachometer (or pachymeter) before and after the application of a potential stimulus to hypoxia (i.e, the wearing of a contact lens), the degree of corneal swelling (edema) can be established, usually expressed in terms of the percentage change in corneal thickness from a baseline value. Mandell and Polse (1969) were the first to apply electronics to the Haag-Streit pachometer to enable the instrument to measure corneal thickness with the necessary precision and accuracy for this purpose. For the last 20 years, a wide variety of pachometry studies have been conducted to characterize corneal swelling response to various stimuli under various conditions. For instance, it has been shown that the normal cornea swells approximately 4 percent during overnight sleep (Mandell and Fatt, 1965; Mertz, 1980). This is probably due, at least in part, to the reduced oxygen environment available to the cornea behind the closed lid (Table 2), where oxygen is supplied almost exclusively from the capillary plexus of the palpebral conjunctiva.

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium TABLE 2 Comparison of Ambient Conditions at the Anterior Surface of the Human Cornea: Opened Versus Closed Eye Condition Units Opened Eye Closed Eye Source O2 Tension mmHg (EOP) 155 (20.9) 55 (7.5) 61.4 (8.2) Fatt et al.(1974) Holden and Sweeney (1985) O2 Uptake µl/cm2/hr 4.8 1.5 Hill and Fatt (1963a) Hill and Fatt (1963b) pH log [H+]−1 7.45 7.25 Carney and Hill (1976) Osmolality mOsm/kg (%NaCl) 310 (0.97) 285 (0.89) Terry and Hill (1978) Temperature °C (°F) 31.4 (88.5) 33.9 (93.0) 36.2 (97.2) Hill and Leighton (1965) Holden and Sweeney (1985) CO2 Tension mmHg 0 45 Holden et al. (1987)

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium THE CLOSED EYE ENVIRONMENT With the introduction of extended-wear contact lenses in the 1980s, there has been a great deal of interest in the closed eye environment. It is certainly appropriate to know what sort of environment the closed eye presents to contact lenses that are worn during sleep (Table 2). Knowledge of the level of sleep-induced corneal edema (4 percent), which generally dissipates completely during the first few hours following awakening, has been a useful guide for contact lens designers in establishing the level of corneal edema that might be deemed tolerable during contact lens wear. Studies of the corneal swelling response to the wearing of extended-wear lenses (Holden et al., 1983; Holden and Mertz, 1984) have shown that significant levels of corneal edema occur during the overnight wear of these lenses, but suggest that this might be a minimally tolerable situation so long as the lenses transmit enough oxygen during daytime open-eye wear to allow overnight swelling to subside to baseline levels. HYPOXIA AND ITS CLINICAL SEQUELAE Figure 2 shows how corneal edema associated with contact lens wear can progress from relatively safe levels to levels that actually threaten the transparency of corneal tissue. The clinical observation (using a slit lamp biomicroscope) FIGURE 2 Stages of stromal edema of the cornea in terms of percentage increases in corneal thickness. SOURCE: Efron and Holden (1986a). Reprinted by permission.

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium of vertical striae in the posterior portion of the cornea is generally regarded as evidence of excessive corneal swelling associated with contact lens wear (Polse and Mandell, 1976). Other adverse conditions can occur in the cornea associated with contact lens related hypoxia. These conditions, which include punctate keratitis, epithelial microcysts, stromal infiltrates, endothelial polymegethism, corneal vascularization, etc., are conveniently summarized in a pair of outstanding articles published by Efron and Holden (1986a, 1985b). REFERENCES Carney, L.G., and R.M. Hill 1976 Human tear pH. Archives of Ophthalmology 94(5):821–824. Critchley, M. ed. 1978 Butterworths Medical Dictionary. London: Butterworths Efron, N., and B.A. Holden 1986a A review of some common contact lens complications-part 1: the corneal epithelium and stroma. Optician 192(5057):21–26. 1986b A review of some common contact lens complications-part 2: the corneal endothelium and conjunctiva. Optician 192(5062):17–33. Fatt, I. 1989 Oxygen transmission. Pp. 10.1–10.45 in O.H. Dabezies ed., Contact Lenses: The CLAO Guide to Basic Science and Clinical Practice . Orlando, Florida: Grune and Stratton, Inc. Fatt, I., R.D. Freeman, and D. Lin 1974 Oxygen tension in the cornea: a re-examination. Experimental Eye Research 18:357–365. Hedbys, B.O., and S. Mishima 1966 The thickness-hydration relationship of the cornea. Experimental Eye Research 5(3):221–228. Hill, R.M., and I. Fatt 1963a Oxygen depletion of a limited reservoir by human conjunctiva. Nature 200(4910):1011–1012. 1963b Oxygen uptake from a limited volume reservoir by in vivo human cornea. Science 142(3597):1295–1297. Hill, R.M., and A.J. Leighton 1965 Temperature changes of human cornea and tears under a contact lens: part I. American Journal of Optometry and Physiological Optics 42(1):9– 16. Hodson, S., and F. Miller 1976 The bicarbonate ion pump in the endothelium which regulates the hydration of the rabbit cornea. Journal of Physiology 263:563–577. Holden, B.A., and G.W. Mertz 1984 Critical oxygen levels to avoid corneal edema for daily and extended

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Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium wear contact lenses. Investigative Ophthalmology and Visual Science 25(10):1161–1167. Holden, B.A., G.W. Mertz, and J.J. McNally 1983 Corneal swelling response to contact lenses worn under extended wear conditions. Investigative Ophthalmology and Visual Science 24(2):218– 226 Holden, B.A., R. Ross, and J. Jenkins 1987 Hydrogel contact lenses impede carbon dioxide efflux from the human cornea. Current Eye Research 6(11):1283–1290. Holden, B.A., and D.F. Sweeney 1985 The oxygen tension and temperature of the superior palpebral conjunctiva. Acta Ophthalmologica 63:100–103. Holden, B.A., D.F. Sweeney, and G. Sanderson 1984 The minimum precorneal oxygen tension to avoid corneal edema. Investigative Ophthalmology and Visual Science 25(4):476–480. Klyce, S.D. 1981 Stromal lactate accumulation can account for corneal oedema osmotically following epithelial hypoxia in the rabbit. Journal of Physiology 321:49–64. Kwan, M., J. Niinikoski, and T.K. Hunt 1972 In vivo measurements of oxygen tension in the cornea, aqueous humor, and anterior lens of the open eye. Investigative Ophthalmology and Visual Science 11(2):108–114. Mandell, R.B., and I. Fatt 1965 Thinning of the human cornea on awakening. Nature 208(5007):292–293. Mandell, R.B., and K.A. Polse 1969 Keratoconus: spatial variation of corneal thickness as a diagnostic test. Archives of Ophthalmology 82(2):182–188. Mertz, G.W. 1980 Overnight swelling of the living human cornea. Journal of the American Optometric Association 51(3):211–214. Polse, K.A., and R.B. Mandell 1976 Etiology of corneal striae accompanying hydrogel contact lenses. Investigative Ophthalmology and Visual Science 15(7):553–556. Taber, C.W. 1970 Taber's Cyclopedic Medical Dictionary. Philadelphia : Terry, J.E., and R.M. Hill 1977 The osmotic variable. Journal of the American Optometric Association 48(3):311–313.